bluuebunny/crossref_metadata_2025 huggingface dataset:
Construct a molecular associations network to systematically understand intermolecular associations inHumancells
Authors: Yi Hai-Cheng , You Zhu-Hong , Guo Zhen-Hao
Published: July 2019

A key aim of post-genomic biomedical research is to systematically integrate and model all molecules and their interactions in living cells. Existing research usually only focusing on the associations between individual or very limited type of molecules. But the interactions between molecules shouldn’t be isolated but interconnected and influenced. In this study, we revealed, constructed and analyzed a large-scale molecular association network of multiple biomolecules inhumancells by modeling all associations among lncRNA, miRNA, protein, circRNA, microbe, drug, and disease, in which various associations are interconnected and any type of associations can be predicted. More specifically, we defined the molecular associations network and constructed a molecular associations dataset containing 105546 associations. Then, each node is represented by its attribute feature and network embedding learned by Structural Deep Network Embedding. Moreover, Random Forest is trained to predict any kind of associations. And we compared the features and classifiers under five-fold cross-validation. Our method achieves a remarkable performance on entire molecular associations network with an AUC of 0.9552 and an AUPR of 0.9338. To further evaluate the performance of our method, a case study for predicting lncRNA-protein interactions was executed. The experimental results demonstrate that the systematic insight for understanding the synergistic interactions between various molecules and complex diseases. It is anticipated that this work can bring beneficial inspiration and advance related systems biology and biomedical research.

Author Summary

The interactions between the various biomolecules in the cells should not be isolated, but interconnected and influenced. There have been many valuable studies on the interactions between two individual molecules. Based on a systematic and holistic perspective, we revealed and constructed a large-scale molecular associations network by combining various associations in human living cells, including miRNA-lncRNA association, miRNA-disease association, miRNA-protein interaction, lncRNA-disease association, protein-protein interaction, protein-disease association, drug-protein interaction, drug-disease interaction, and lncRNA-protein interaction. To model and analyze this molecular associations network, we employed the network representation learning model to learn how to represent the node. Each node in the network can be represented by network embedding and its own attribute information. Any node can be classified. And any type of the associations in this network can be predicted, which can be considered as link prediction task. Our work provides a new systematic view and conceptual framework to understand complex diseases and life activities. It is anticipated that our study can advance related biological macromolecules, systems biology and biomedical research, and bring some meaningful inspiration.
Genome wide identification of NAC transcription factors and their role in abiotic stress tolerance in Chenopodium quinoa
Authors: Alshareef Nouf Owdah , Rey Elodie , Khoury Holly , Tester Mark , Schmöckel Sandra M.
Published: July 2019

Chenopodium quinoa Willd. (quinoa) is a pseudocereal with high nutritional value and relatively high tolerance to several abiotic stresses, including water deficiency and salt stress, making it a suitable plant for the study of mechanisms of abiotic stress tolerance. NAC (NAM, ATAF and CUC) transcription factors are involved in a range of plant developmental processes and in the response of plants to biotic and abiotic stresses. In the present study, we perform a genome-wide comprehensive analysis of the NAC transcription factor gene family in quinoa. In total, we identified 107 quinoa NAC transcription factor genes, distributed equally between sub-genomes A and B. They are phylogenetically clustered into two major groups and 18 subgroups. Almost 75% of the identified CqNAC genes were duplicated two to seven times and the remaining 25% of the CqNAC genes were found as a single copy. We analysed the transcriptional responses of the identified quinoa NAC TF genes in response to various abiotic stresses. The transcriptomic data revealed 28 stress responsive CqNAC genes, where their expression significantly changed in response to one or more abiotic stresses, including salt, water deficiency, heat and phosphate starvation. Among these stress responsive NACs, some were previously known to be stress responsive in other species, indicating their potentially conserved function in response to abiotic stress across plant species. Six genes were differentially expressed specifically in response to phosphate starvation but not to other stresses, and these genes may play a role in controlling plant responses to phosphate deficiency. These results provide insights into quinoa NACs that could be used in the future for genetic engineering or molecular breeding.
Additional analytical support for a new method to compute the likelihood of diversification models
Authors: Laudanno Giovanni , Haegeman Bart , Etienne Rampal S.
Published: July 2019

Molecular phylogenies have been increasingly recognized as an important source of information on species diversification. For many models of macro-evolution, analytical likelihood formulas have been derived to infer macro-evolutionary parameters from phylogenies. A few years ago, a general framework to numerically compute such likelihood formulas was proposed, which accommodates models that allow speciation and/or extinction rates to depend on diversity. This framework calculates the likelihood as the probability of the diversification process being consistent with the phylogeny from the root to the tips. However, while some readers found the framework presented in Etienne et al. (2012) convincing, others still questioned it (personal communication), despitenumericalevidence that for special cases the framework yields the same (i.e. within double precision) numerical value for the likelihood as analytical formulas do that were independently derived for these special cases. Here we proveanalyticallythat the likelihoods calculated in the new framework are correct for all special cases with known analytical likelihood formula. Our results thus add substantial mathematical support for the overall coherence of the general framework.
Pupil responses to pitch deviants reflect predictability of melodic sequences
Authors: Roberta Bianco , Esther Ptasczynski Lena , Diana Omigie
Published: July 2019

Humans automatically detect events that, in deviating from their expectations, may signal prediction failure and a need to reorient behaviour. The pupil dilation response (PDR) to violations has been associated with subcortical signals of arousal and prediction resetting. However, it is unclear how the context in which a deviant occurs affects the size of the PDR. Using ecological musical stimuli that we characterised using a computational model, we showed that the PDR to pitch deviants is sensitive to contextual uncertainty (quantified as entropy), whereby the PDR was greater in low than high entropy contexts. The PDR was also positively correlated with unexpectedness of notes. No effects of music expertise were found, suggesting a ceiling effect due to enculturation. These results show that the same sudden environmental change can lead to differing arousal levels depending on contextual factors, providing evidence for a sensitivity of the PDR to long-term context.
Safety of intralesional injection of lauromacrogol combined with triamcinolone for infantile hemangiomas
Authors: Chai Yimeng , Zhou Zifu , Song Jiayin , Lv Renrong , Xu Guangqi , Bi Jianhai , Li Xueqing , Li Zhiyu , Huo Ran
Published: July 2019

The efficacy of lauromacrogol injection therapy and intralesional triamcinolone for infantile hemangiomas (IH) has been well documented recently, but with an increase in serious or rare adverse reactions. The aim of this study is to investigate the safety concerns regarding intralesional injection of lauromacrogol combined with triamcinolone for IH and to study its effect on infant growth and development. A total of 1039 IH patients who were subjected to intralesional injection of lauromacrogol combined with triamcinolone in the Plastic Surgery Department of Shandong Provincial Hospital between 1 January 2015 and 31 May 2018 were enrolled in this study. When the dose of lauromacrogol and triamcinolone was less than 3.5 and 2.0 mg/kg respectively, no serious side‐effects were observed. The adverse event rate reported was 7.7%. Among the 405 patients not subjected to propranolol before the last injection, the study included three modes of treatment response: regression (82.7%), stabilization (13.8%) and failure (3.5%). By comparing height and weight to the reference standards and also by comparisons between the same‐sex groups, our results confirmed that there was no significant effect on children's height and weight, regardless of whether the injection therapy was combined with oral propranolol at the appropriate dose and with more than 4‐week intervals. Intralesional injection of lauromacrogol combined with triamcinolone in the treatment of IH was highly safe and effective.
High expression of DLG3 is associated with decreased survival from breast cancer
Authors: Liu Jie , Li Pingping , Wang Ruiqi , Li Juan , Zhang Miao , Song Zhangjun , Liu Peijun
Published: July 2019

Abnormal expression or activity of proteins that regulate cell polarity can contribute to tumour progression. Discs large homolog (DLG) proteins play crucial roles in the maintenance of cell polarity and tissue morphogenesis. Previous studies of breast cancer patients showed that DLG3 had greater expression in the cancerous tissues than non‐cancerous tissues, but the relationship between DLG3 expression and breast cancer progression and prognosis is not clear. Here, we investigated the association of DLG3 expression with breast cancer progression and prognosis using data on clinicopathological parameters from The Cancer Genome Atlas (TCGA) database, with different clinicopathological parameters using ualcan and LinkedOmics, and with different stages and subtypes using immunohistochemical staining. The results indicated greater DLG3 expression in cancerous breast tissues than normal breast tissues and in luminal and Her2+ subtypes than in the triple‐negative subtype. DLG3 expression also had a positive correlation with pathologic stage and decreased survival rate. Our data suggest that DLG3 should be considered as a new diagnostic and prognostic biomarker for breast cancer.
Synthesis and characterisation of a selective adsorbent based on the molecularly imprinted polymer for the removal of cloxacillin antibiotic residue from milk
Authors: Jafari Saeid , Dehghani Mohammad , Nasirizadeh Navid , Baghersad Mohammad Hadi
Published: July 2019

In recent decades, environmental pollution has been a subject of growing concern. This is partly due to the overuse of antibiotics, the consequent drug resistance and the discharge of drugs into the environment. The aim of this study was to synthesise molecularly imprinted polymer (MIP) particles via a noncovalent procedure for the removal of cloxacillin from milk. Accordingly, the effects of operational parameters such as pH, contact time and MIP dosage were studied. The performance of MIP particles in removing cloxacillin from livestock milk samples proved that these adsorbents can effectively help to reduce drug contamination from dairy sources.
Identification and expression profiles analysis of odorant‐binding proteins in soybean aphid, Aphis glycines (Hemiptera: Aphididae)
Authors: Wang Ling , Bi Ying‐Dong , Liu Ming , Li Wei , Liu Miao , Di Shu‐Feng , Yang Shuai , Fan Chao , Bai Lei , Lai Yong‐Cai
Published: July 2019

The soybean aphid, Aphis glycines, is an extreme specialist and an important invasive pest that relies on olfaction for behaviors such as feeding, mating, and foraging. Odorant‐binding proteins (OBPs) play a vital role in olfaction by binding to volatile compounds and by regulating insect sensing of the environment. In this work we used rapid amplification of complementary DNA ends technology to identify and characterize 10 genes encoding A. glycines OBPs (AglyOBPs) belonging to 3 subfamilies, including 4 classic OBPs, 5 Plus‐C OBPs, and one Minus‐C OBP. Quantitative real‐time polymerase chain reaction demonstrated variable specific expression patterns for the 10 genes based on developmental stage and aphid tissue sampled. Expression levels of 7 AglyOBPs (2, 3, 4, 5, 7, 9, and 10) were highest in the 4th instar, indicating that the 4th nymphal instar is an important developmental period during which soybean aphids regulate feeding and search for host plants. Tissue‐specific expression results demonstrated that AglyOBP2, 7, and 9 exhibited significantly higher expression levels in antennae. Meanwhile, ligand‐binding analysis of 5 OBPs demonstrated binding of AglyOBP2 and AglyOBP3 to a broad spectrum of volatiles released by green leaf plants, with bias toward 6‐ to 8‐carbon chain volatiles and strong binding of AglyOBP7 to trans‐β‐farnesene. Taken together, our findings build a foundation of knowledge for use in the study of molecular olfaction mechanisms and provide insights to guide future soybean aphid research.
A molecular framework for the embryo growth in germinating seeds of Solanum lycocarpum A. St.‐Hil., a nurse plant species
Authors: Silveira Lilian E. D. , Ribeiro‐Oliveira João Paulo , Ajala‐Luccas Daiani , Bravo Juliana P. , da Silva Edvaldo A. A.
Published: July 2019

We are clarifying how the functional embryo growth occurs in germinating seeds of Solanum lycocarpum A. St.‐Hil., a nurse plant with a central role in forest dynamics in the Cerrado (a biodiversity hotspot). For that, we used classical seed germination measurements (germinability, mean germination time, mean germination rate, coefficient of variation of the germination time, synchronisation index and germination time range) and gene expression of mRNA codifying key proteins/enzymes for the success in the seed–seedling transition (Cyclin, Actin, Small Heat Shock Protein, Glutathione S‐transferase, Malate Dehydrogenase, Alcohol Dehydrogenase). Our findings demonstrate: (a) Although germination kinetics in S. lycocarpum seeds is slower than that in tomato seeds, the fold change of genes codifying key enzymes for the embryo development is similar in germinating seeds of both species. (b) The genes used here are useful, from a technical point of view, for classifying commercial seed samples of the species in relation to physiological quality. More notably, cyclin and malate dehydrogenase genes have a greater expression, both in germination sensu stricto and in immediate post‐germination. (c) A molecular framework for the embryo growth in germinating seeds of S. lycocarpum can be a functional explication for the species to be a nurse plant. Thus, the overlapping of classical and contemporary measurements is especially interesting to those species playing a central role in the environment, such as nurse plants, and may represent a new conservationist paradigm.
Inhaled prostacyclin for the prevention of increased pulmonary vascular resistance in cemented hip hemiarthroplasty—A randomised trial
Authors: Hård af Segerstad Mathias , Olsen Fredrik , Houltz Erik , Nellgård Bengt , Ricksten Sven‐Erik
Published: July 2019

Background

Bone cementation may cause pulmonary vasoconstriction and ventilation/perfusion abnormalities in patients undergoing cemented hip hemiarthroplasty. In this randomised trial, we tested the hypothesis that intra‐operative inhalation of prostacyclin could attenuate the increase in pulmonary vascular resistance index (PVRI, primary endpoint) when compared to inhaled saline in this group of patients.

Methods

Twenty‐two patients with displaced femoral neck fractures were allocated to receive inhaled aerosolised prostacyclin (20 ng/kg/min) (n = 11) or inhaled saline (NaCl, 9 mg/mL) (n = 11). All patients received total intravenous anaesthesia and were catheterised with radial and pulmonary artery fast response thermodilution catheters, for measurements of arterial and pulmonary arterial pressures, cardiac output, right ventricular ejection fraction and effective pulmonary arterial elastance. Haemodynamic measurements were performed after induction of anaesthesia, during surgery before and immediately after bone cementation and prosthesis insertion, 10 and 20 min after insertion and during skin closure.

Results

During the surgical procedure, PVRI increased both in the saline (44%, P < 0.001) and the prostacyclin (36%, P = 0.019) groups, with a less pronounced increase in the prostacyclin group (P = 0.031). Effective pulmonary arterial elastance increased both in the saline (44%, P < 0.001) and the prostacyclin groups (29%, P = 0.032), with a trend for a less pronounced increase in the prostacyclin group (P = 0.084). Right ventricular ejection fraction decreased significantly in both groups with no difference between the groups.

Conclusion

Inhalation of prostacyclin attenuates the increase in pulmonary vascular resistance in patients undergoing cemented hip hemiarthroplasty and could potentially attenuate/prevent haemodynamic instability induced by an increase in right ventricular afterload seen in this procedure.
Influence of anti‐inflammatory irrigant on substance P expression for single‐visit root canal treatment of teeth with irreversible pulpitis
Authors: Bamini Lavanya , Anand Sherwood I , Abbott Paul V. , Uthandakalaipandian Ramesh , Velu Vijay
Published: July 2019

One of the main objectives of root canal treatment is to alleviate the pain associated with irreversibly inflamed pulps. However, some patients may have moderate to severe pain following treatment. The aim of this study was to compare and assess the effect of ketorolac tromethamine on substance P expression in the pulp and periapical tissues when used as a root canal irrigant for single‐visit root canal treatment in teeth with irreversible pulpitis. Thirty‐six patients were randomly allotted to three irrigant groups – saline (n = 14), 3% sodium hypochlorite (n = 11) and ketorolac tromethamine (n = 11). Pulp blood samples (S1) were collected on gaining access to the pulp, and periapical blood samples (S2) were collected after root canal preparation. Quantification of substance P was done by ELISA test. The ketorolac tromethamine group had greater reduction in substance P expression (S2). Post‐operative pain levels were not significantly influenced by the different root canal irrigants.
Logistic early warning scores to predict death, cardiac arrest or unplanned intensive care unit re‐admission after cardiac surgery
Authors: Chiu Y.‐D. , Villar S. S. , Brand J. W. , Patteril M. V. , Morrice D. J. , Clayton J. , Mackay J. H.
Published: July 2019

NHS England recently mandated that the National Early Warning Score of vital signs be used in all acute hospital trusts in the UK despite limited validation in the postoperative setting. We undertook a multicentre UK study of 13,631 patients discharged from intensive care after risk‐stratified cardiac surgery in four centres, all of which used VitalPACTM to electronically collect postoperative National Early Warning Score vital signs. We analysed 540,127 sets of vital signs to generate a logistic score, the discrimination of which we compared with the national additive score for the composite outcome of: in‐hospital death; cardiac arrest; or unplanned intensive care admission. There were 578 patients (4.2%) with an outcome that followed 4300 sets of observations (0.8%) in the preceding 24 h: 499 out of 578 (86%) patients had unplanned re‐admissions to intensive care. Discrimination by the logistic score was significantly better than the additive score. Respective areas (95%CI) under the receiver‐operating characteristic curve with 24‐h and 6‐h vital signs were: 0.779 (0.771–0.786) vs. 0.754 (0.746–0.761), p < 0.001; and 0.841 (0.829–0.853) vs. 0.813 (0.800–0.825), p < 0.001, respectively. Our proposed logistic Early Warning Score was better than the current National Early Warning Score at discriminating patients who had an event after cardiac surgery from those who did not.
Impact of oral immunoglobulins on animal health—A review
Authors: Balan Prabhu , Sik‐Han Kyoung , Moughan Paul J
Published: July 2019

Immunoglobulin (Ig) is the one of the main anti‐infective components of blood, colostrum and breast milk. It is the unique glycoprotein that defends the body from harmful bacteria, viruses and other environmental pathogens by either binding to them or by forming an encapsulating barrier. The expansion of antimicrobial and immunomodulatory products from natural sources for dietary supplementation in both animals and humans is an ever growing and thriving area of research. Purified Ig from sheep serum (ovine serum Ig) is one such candidate product. Recent work has shown the various biological effects of oral Ig in different animal models including its effect on growth, immunity, intestinal growth and gut barrier function. The objective of this paper is to review the results of recent studies demonstrating the effects of oral Ig in both pathogenic and non‐pathogenic animal models and to suggest a possible mechanism of its action. Overall, purified oral Ig improves growth of healthy (and challenged) rats and defends against enteric infection by immunomodulation, mucin protein and/or modification of commensal microbial composition. The findings contribute to knowledge of how orally administered ovine Ig can influence and enhance key indicators of gut function and overall growth performance in an animal model.
Testing independence between two random sets for the analysis of colocalization in bioimaging
Authors: Lavancier Frédéric , Pécot Thierry , Zengzhen Liu , Kervrann Charles
Published: July 2019

Colocalization aims at characterizing spatial associations between two fluorescently tagged biomolecules by quantifying the co‐occurrence and correlation between the two channels acquired in fluorescence microscopy. Colocalization is presented either as the degree of overlap between the two channels or the overlays of the red and green images, with areas of yellow indicating colocalization of the molecules. This problem remains an open issue in diffraction‐limited microscopy and raises new challenges with the emergence of superresolution imaging, a microscopic technique awarded by the 2014 Nobel prize in chemistry. We propose GcoPS, for Geo‐coPositioning System, an original method that exploits the random sets structure of the tagged molecules to provide an explicit testing procedure. Our simulation study shows that GcoPS unequivocally outperforms the best competitive methods in adverse situations (noise, irregularly shaped fluorescent patterns, and different optical resolutions). GcoPS is also much faster, a decisive advantage to face the huge amount of data in superresolution imaging. We demonstrate the performances of GcoPS on two biological real data sets, obtained by conventional diffraction‐limited microscopy technique and by superresolution technique, respectively.
Longer treatment duration and history of osteoarticular symptoms predispose to tyrosine kinase inhibitor withdrawal syndrome
Authors: Berger Marc G. , Pereira Bruno , Rousselot Philippe , Cony‐Makhoul Pascale , Gardembas Martine , Legros Laurence , Escoffre‐Barbe Martine , Nicolini Franck‐Emmanuel , Saugues Sandrine , Lambert Céline , Réa Delphine , Guerci‐Bresler Agnès , Giraudier Stéphane , Guilhot Joëlle , Saussele Susanne , Mahon François‐Xavier ,   the (France Intergroupe des Leucémies Myéloïdes Chroniques)
Published: July 2019

The effectiveness of tyrosine kinase inhibitors (TKIs) has made it possible to consider treatment discontinuation in chronic myeloid leukaemia (CML) patients that achieve an excellent response. However, a few of the patients included in the Europe Stop Tyrosine Kinase Inhibitors (EURO‐SKI) trial reported musculoskeletal pain shortly after stopping TKIs, considered as a withdrawal syndrome (WS). To identify factors that may predispose to TKI WS, we analysed the pharmacovigilance declarations for the 6 months after stopping TKIs in a large cohort of CML (n = 427) that combined the French patients included in the STop IMatinib 2 (STIM2; n = 224) and EURO‐SKI (n = 203) trials. Among these patients, 23% (99/427) developed TKI WS after stopping imatinib (77/373; 20·4%), nilotinib (12/29; 41·4%) or dasatinib (10/25; 40%). WS concerned mainly the upper body joints, and required multiple symptomatic treatments in 30% of patients. Univariate and multivariate analyses identified two risk factors: duration of TKI treatment [risk ratio (RR) = 1·68 (1·02–2·74)] with a 93‐month cut‐off time, and history of osteoarticular symptoms [RR = 1·84 (1·04–3·28)]. These findings confirm that WS is a TKI class effect. CML patients should be carefully screened before treatment initiation to identify pre‐existent osteoarticular symptoms. Moreover, before TKI discontinuation, patients should be informed of the possibility of WS, particularly after a long treatment period.
An overview of the pharmacology of olive oil and its active ingredients
Authors: Visioli Francesco , Davalos Alberto , López de las Hazas María‐Carmen , Crespo María Carmen , Tomé‐Carneiro Joao
Published: July 2019

In addition to providing sensory stimuli, usually taste, smell and sight, olive oil contains a range of minor components, mostly phenolic in nature. These components are endowed with pharmacological or pharma‐nutritional properties that are the subject of active research worldwide. Based on our more than 25 years of experience in this field, we critically focus on what we believe are the most pharmacologically prominent actions of the constituents of olive oil. Most of the effects are due to the phenolic compounds in extra virgin olive oil, such as hydroxytyrosol and oleocanthal (which are often mis‐categorized as in vivo antioxidants) and concern the cardiovascular system. Other potentially beneficial activities are still to be investigated in depth. We conclude that—in the context of a proper diet that includes high‐quality products—the use of high‐quality olive oil contributes to achieving and sustaining overall health.

Linked Articles

This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc
Tipping the scales: Are females more at risk for obesity‐ and high‐fat diet‐induced hypertension and vascular dysfunction?
Authors: Taylor Lia E. , Ramirez Lindsey A. , Musall Jacqueline B. , Sullivan Jennifer C.
Published: July 2019

Obesity is a common metabolic disorder that has become a widespread epidemic in several countries. Sex and gender disparities in the prevalence of cardiovascular disease (CVD) have been well documented with premenopausal women having a lower incidence of CVD than age‐matched men. However, women are more likely than men to suffer from obesity, which can predispose them to a greater risk of CVD. The mechanisms underlying high‐fat diet (HFD)‐ or obesity‐induced hypertension are not well defined, although immune system activation and inflammation have been implicated in several studies. Further, the sex of the subject can have a profound influence on the immune response to hypertensive stimuli. Therefore, the purpose of this review is to examine the effects of sex and gender on the role of the immune system in HFD‐induced hypertension and vascular dysfunction.

LINKED ARTICLES

This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc
Evaluation and use of an anti‐cynomolgus monkey CD79b surrogate antibody–drug conjugate to enable clinical development of polatuzumab vedotin
Authors: Li Dongwei , Lee Donna , Dere Randall C. , Zheng Bing , Yu Shang‐Fan , Fuh Franklin K. , Kozak Katherine R. , Chung Shan , Bumbaca Yadav Daniela , Nazzal Denise , Danilenko Dimitry , Go Mary Ann T. , Williams Marna , Polson Andrew G. , Poon Kirsten Achilles , Prabhu Saileta
Published: July 2019

Background and Purpose

Polatuzumab vedotin is an antibody–drug conjugate (ADC) being developed for non‐Hodgkin's lymphoma. It contains a humanized anti‐CD79b IgG1 monoclonal antibody linked to monomethyl auristatin E (MMAE), an anti‐mitotic agent. Polatuzumab vedotin binds to human CD79b only. Therefore, a surrogate ADC that binds to cynomolgus monkey CD79b was used to determine CD79b‐mediated pharmacological effects in the monkey and to enable first‐in‐human clinical trials.

Experimental Approach

Polatuzumab vedotin, the surrogate ADC, and the corresponding antibodies were evaluated in different assays in vitro and in animals. In vitro assessments included binding to peripheral blood mononuclear cells from different species, binding to a human and monkey CD79b‐expressing cell line, binding to human Fcγ receptors, and stability in plasma across species. In vivo, ADCs were assessed for anti‐tumour activity in mice, pharmacokinetics/pharmacodynamics in monkeys, and toxicity in rats and monkeys.

Key Results

Polatuzumab vedotin and surrogate ADC bind with similar affinity to human and cynomolgus monkey B cells, respectively. Comparable in vitro plasma stability, in vivo anti‐tumour activity, and mouse pharmacokinetics were also observed between the surrogate ADC and polatuzumab vedotin. In monkeys, only the surrogate ADC showed B‐cell depletion and B‐cell‐mediated drug disposition, but both ADCs showed similar MMAE‐driven myelotoxicity, as expected.

Conclusions and Implications

The suitability of the surrogate ADC for evaluation of CD79b‐dependent pharmacology was demonstrated, and anti‐tumour activity, pharmacokinetics/pharmacodynamics, and toxicity data with both ADCs supported the entry of polatuzumab vedotin into clinical trials.
Drug‐induced shortening of the electromechanical window is an effective biomarker for in silico prediction of clinical risk of arrhythmias
Authors: Passini Elisa , Trovato Cristian , Morissette Pierre , Sannajust Frederick , Bueno‐Orovio Alfonso , Rodriguez Blanca
Published: July 2019

Background and Purpose

Early identification of drug‐induced cardiac adverse events is key in drug development. Human‐based computer models are emerging as an effective approach, complementary to in vitro and animal models. Drug‐induced shortening of the electromechanical window has been associated with increased risk of arrhythmias. This study investigates the potential of a cellular surrogate for the electromechanical window (EMw) for prediction of pro‐arrhythmic cardiotoxicity, and its underlying ionic mechanisms, using human‐based computer models.

Experimental Approach

In silico drug trials for 40 reference compounds were performed, testing up to 100‐fold the therapeutic concentrations (EFTPCmax) and using a control population of human ventricular action potential (AP) models, optimised to capture pro‐arrhythmic ionic profiles. EMw was calculated for each model in the population as the difference between AP and Ca2+ transient durations at 90%. Drug‐induced changes in the EMw and occurrence of repolarisation abnormalities (RA) were quantified.

Key Results

Drugs with clinical risk of Torsade de Pointes arrhythmias induced a concentration‐dependent EMw shortening, while safe drugs lead to increase or small change in EMw. Risk predictions based on EMw shortening achieved 90% accuracy at 10× EFTPCmax, whereas RA‐based predictions required 100× EFTPCmax to reach the same accuracy. As it is dependent on Ca2+ transient, the EMw was also more sensitive than AP prolongation in distinguishing between pure hERG blockers and multichannel compounds also blocking the calcium current.

Conclusion and Implications

The EMw is an effective biomarker for in silico predictions of drug‐induced clinical pro‐arrhythmic risk, particularly for compounds with multichannel blocking action.
Mibefradil, a T‐type Ca2+ channel blocker also blocks Orai channels by action at the extracellular surface
Authors: Li Pengyun , Rubaiy Hussein N. , Chen Gui‐Lan , Hallett Thomas , Zaibi Nawel , Zeng Bo , Saurabh Rahul , Xu Shang‐Zhong
Published: July 2019

Background and Purpose

Mibefradil, a T‐type Ca2+ channel blocker, has been investigated for treating solid tumours. However, its underlying mechanisms are still unclear. Here, we have investigated the pharmacological actions of mibefradil on Orai store‐operated Ca2+ channels.

Experimental Approach

Human Orai1‐3 cDNAs in tetracycline‐regulated pcDNA4/TO vectors were transfected into HEK293 T‐REx cells with stromal interaction molecule 1 (STIM1) stable expression. The Orai currents were recorded by whole‐cell and excised‐membrane patch clamp. Ca2+ influx or release was measured by Fura‐PE3/AM. Cell growth and death were monitored by WST‐1, LDH assays and flow cytometry.

Key Results

Mibefradil inhibited Orai1, Orai2, and Orai3 currents dose‐dependently. The IC50 for Orai1, Orai2, and Orai3 channels was 52.6, 14.1, and 3.8 μM respectively. Outside‐out patch demonstrated that perfusion of 10‐μM mibefradil to the extracellular surface completely blocked Orai3 currents and single channel activity evoked by 2‐APB. Intracellular application of mibefradil did not alter Orai3 channel activity. Mibefradil at higher concentrations (>50 μM) inhibited Ca2+ release but had no effect on cytosolic STIM1 translocation evoked by thapsigargin. Inhibition on Orai channels by mibefradil was structure‐related, as other T‐type Ca2+ channel blockers with different structures, such as ethosuximide and ML218, had no or minimal effects on Orai channels. Moreover, mibefradil inhibited cell proliferation, induced apoptosis, and arrested cell cycle progression.

Conclusions and Implications

Mibefradil is a potent cell surface blocker of Orai channels, demonstrating a new pharmacological action of this compound in regulating cell growth and death, which could be relevant to its anti‐cancer activity.
Changes in whole metabolites after exenatide treatment in overweight/obese polycystic ovary syndrome patients
Authors: Tang Liang , Yuan Lei , Yang Gangyi , Wang Feng , Fu Mao , Chen Min , Liu Dongfang
Published: July 2019

Objective

Exenatide is a new agent for diabetes therapy, and its use in polycystic ovary syndrome (PCOS) has gradually increased; however, the clinical benefit and metabolic improvement need further evidence. This research aimed to study the changes in whole metabolites before and after exenatide treatment in overweight/obese PCOS patients to gain a better understanding of exenatide for the treatment of PCOS.

Methods

Sixty‐seven women, including 32 with PCOS and 35 age‐matched controls, were recruited. The metabolite changes were detected with nontargeted gas chromatography‐tandem mass spectrometry (NTGC‐MS) before and after exenatide treatment, and changes in clinical biochemical characteristics were also observed.

Results

A total of 62 metabolites were differentially expressed between the healthy and PCOS groups, and 31 differentially expressed metabolites were detected before and after exenatide treatment. Abnormal lipid metabolism and amino acid metabolism were the main metabolic disorders. Exenatide improved lipid and amino acid metabolism, especially amino acid metabolites. Three types of branched‐chain amino acids (valine, leucine and isoleucine), two types of aromatic amino acids (phenylalanine and tyrosine) and lysine are important potential metabolites for the therapeutic efficacy of exenatide. Many abnormal metabolic disorders are related to insulin resistance, oxidative stress and even ovulatory dysfunction. Moreover, in this small sample clinical study, we also found that exenatide improved insulin sensitivity, reduced body weight and improved glycolipid metabolism in PCOS.

Conclusions

NTGC‐MS‐based metabolic pathway analysis revealed that exenatide has a beneficial effect on overweight/obese PCOS patients by regulating metabolic disorders, especially amino acid disorders.
The Embodied Penman: Effector‐Specific Motor–Language Integration During Handwriting
Authors: Afonso Olivia , Suárez‐Coalla Paz , Cuetos Fernando , Ibáñez Agustín , Sedeño Lucas , García Adolfo M.
Published: July 2019

Several studies have illuminated how processing manual action verbs (MaVs) affects the programming or execution of concurrent hand movements. Here, to circumvent key confounds in extant designs, we conducted the first assessment of motor–language integration during handwriting—a task in which linguistic and motoric processes are co‐substantiated. Participants copied MaVs, non‐manual action verbs, and non‐action verbs as we collected measures of motor programming and motor execution. Programming latencies were similar across conditions, but execution was faster for MaVs than for the other categories, regardless of whether word meanings were accessed implicitly or explicitly. In line with the Hand‐Action‐Network Dynamic Language Embodiment (HANDLE) model, such findings suggest that effector‐congruent verbs can prime manual movements even during highly automatized tasks in which motoric and verbal processes are naturally intertwined. Our paradigm opens new avenues for fine‐grained explorations of embodied language processes.
Myth debunked: Keratinous pangolin scales do not contain the analgesic tramadol
Authors: Jacobs Rachel L. , McClure Pamela J. , Baker Barry W. , Espinoza Edgard O.
Published: July 2019

Conservation plans aiming to reduce the threat of illegal wildlife trade increasingly recognize the need for multifaceted approaches that include both enhanced enforcement and demand reduction initiatives. Both are complex issues that involve understanding consumer motives. Pangolins represent some of the most heavily trafficked species, largely due to high consumer demand for their scales for use in traditional medicines. Recent media reports also suggest that demand is related to the purported presence of the analgesic tramadol in scales. We examined chemotypes of scales from 104 individual pangolins representing all extant species. None of the specimens demonstrated the presence of tramadol. Given that demand for pangolins and their parts is decimating wild populations, it is imperative that such false claims be rectified. These results could be incorporated into demand reduction campaigns in areas where this misinformation is perpetuated.
The relation between subitizable symbolic and non‐symbolic number processing over the kindergarten school year
Authors: Hutchison Jane E. , Ansari Daniel , Zheng Samuel , De Jesus Stefanie , Lyons Ian M.
Published: July 2019

A long‐standing debate in the field of numerical cognition concerns the degree to which symbolic and non‐symbolic processing are related over the course of development. Of particular interest is the possibility that this link depends on the range of quantities in question. Behavioral and neuroimaging research with adults suggests that symbolic and non‐symbolic quantities may be processed more similarly within, relative to outside of, the subitizing range. However, it remains unclear whether this unique link exists in young children at the outset of formal education. Further, no study has yet taken numerical size into account when investigating the longitudinal influence of these skills. To address these questions, we investigated the relation between symbolic and non‐symbolic processing inside versus outside the subitizing range, both cross‐sectionally and longitudinally, in 540 kindergarteners. Cross‐sectionally, we found a consistently stronger relation between symbolic and non‐symbolic number processing within versus outside the subitizing range at both the beginning and end of kindergarten. We also show evidence for a bidirectional relation over the course of kindergarten between formats within the subitizing range, and a unidirectional relation (symbolic → non‐symbolic) for quantities outside of the subitizing range. These findings extend current theories on symbolic and non‐symbolic magnitude development by suggesting that non‐symbolic processing may in fact play a role in the development of symbolic number abilities, but that this influence may be limited to quantities within the subitizing range.
Returning to normalcy in the short term: a preliminary examination of recovery from Hurricane Harvey among individuals with home damage
Authors: Rivera Jason D.
Published: July 2019

This study focuses on coastal counties in Texas, United States, affected by Hurricane Harvey in 2017 to gauge the influence of individual and contextual characteristics on people's ability to return to normalcy in the short term. Data from a survey conducted by the Kaiser Family Foundation and the Episcopal Health Foundation between October and November 2017 were utilised in the analysis. The paper observes, based on the results of an ordered logistic regression, and contrary to previous work, that age, gender, levels of poverty, and social capital are not significant predictors of a return to normalcy. However, indicators such as whether a person evacuated, if he/she identified as Hispanic/Latino, the extent of damage sustained to one's home, and if one's automobile was damaged or destroyed are shown to affect recovery. A discussion of the potential reasons for these findings is provided as a means of informing future research on disaster recovery.
Marcos do desenvolvimento da Academia Latino‐Americana de Desenvolvimento Infantil e Deficiência
Authors: Schiariti Verónica
Published: July 2019

Video Podcast: https://www.youtube.com/watch?v=ynDjHGJq_Rg
Testing the link between species interactions and species co‐occurrence in a trophic network
Authors: Thurman Lindsey L. , Barner Allison K. , Garcia Tiffany S. , Chestnut Tara
Published: July 2019

Species interactions are dynamic processes that vary across environmental and ecological contexts, and operate across scale boundaries, making them difficult to quantify. Nevertheless, ecologists are increasingly interested in inferring species interactions from observational data using statistical analyses of their spatial co‐occurrence patterns. Trophic interactions present a particular challenge, as predators and prey may frequently or rarely co‐occur, depending on the spatial or temporal scale of observation. In this study, we investigate the accuracy of inferred interactions among species that both compete and trophically interact. We utilized a long‐term dataset of pond‐breeding amphibian co‐occurrences from Mt Rainier National Park (Washington, USA) and compiled a new dataset of their empirical interactions from the literature. We compared the accuracy of four statistical methods in inferring these known species interactions from spatial associations. We then used the best performing statistical method, the Markov network, to further investigate the sensitivity of interaction inference to spatial scale‐dependence and the presence of predators. We show that co‐occurrence methods are generally inaccurate when estimating trophic interactions. Further the strength and sign of inferred interactions were dependent upon the spatial scale of observation and predator presence influenced the detectability of competitive interactions among prey species. However, co‐occurrence analysis revealed new patterns of spatial association among pairs of species with known interactions. Overall, our study highlights a limiting frontier in co‐occurrence theory and the disconnect between widely implemented methodologies and their ability to accurately infer interactions in trophically‐structured communities.
Modes of timing and spacing professional decisions: On the relationship between costing and caring in child protection work
Authors: Schrøder Ida
Published: July 2019

Within public sector accounting research, the question of how “costing” is implemented and how it transforms professional “caring” work has been widely studied and debated. Studies have, for instance, pointed to contextual variables that make cost information more or less useful in professional decision making. However, in doing so, scholars also assume that decision making follows a linear path that can be informed and transformed by cost information. In this paper, I take it as my starting point that both costing and caring vary as they are combined in professional decision‐making processes. I use the broad and processual definition of calculation from the work of Callon and Muniesa to analyze how distinctions about vulnerable children's situations are made relevant for the choice and delimitation of social services. This allows me to investigate how, when, and where distinctions between costing and caring are drawn rather than assuming that costing and caring are preexisting and stable practices that can be put to use or not.
Observation of irrigation‐induced climate change in the Midwest United States
Authors: Nocco Mallika A. , Smail Robert A. , Kucharik Christopher J.
Published: July 2019

Irrigated agriculture alters near‐surface temperature and humidity, which may mask global climate change at the regional scale. However, observational studies of irrigation‐induced climate change are lacking in temperate, humid regions throughout North America and Europe. Despite unknown climate impacts, irrigated agriculture is expanding in the Midwest United States, where unconfined aquifers provide groundwater to support crop production on coarse soils. This is the first study in the Midwest United States to observe and quantify differences in regional climate associated with irrigated agricultural conversion from forests and rainfed agriculture. To this end, we established a 60 km transect consisting of 28 stations across varying land uses and monitored surface air temperature and relative humidity for 31 months in the Wisconsin Central Sands region. We used a novel approach to quantify irrigated land use in both space and time with a database containing monthly groundwater withdrawal estimates by parcel for the state of Wisconsin. Irrigated agriculture decreased maximum temperatures and increased minimum temperatures, thus shrinking the diurnal temperature range (DTR) by an average of 3°C. Irrigated agriculture also decreased the vapor pressure deficit (VPD) by an average of 0.10 kPa. Irrigated agriculture significantly decreased evaporative demand for 25% and 66% of study days compared to rainfed agriculture and forest, respectively. Differences in VPD across the land‐use gradient were highest (0.21 kPa) during the peak of the growing season, while differences in DTR were comparable year‐round. Interannual variability in temperature had greater impacts on differences in DTR and VPD across the land‐use gradient than interannual variability in precipitation. These regional climate changes must be considered together with increased greenhouse gas emissions, changes to groundwater quality, and surface water degradation when evaluating the costs and benefits of groundwater‐sourced irrigation expansion in the Midwest United States and similar regions around the world.