bluuebunny/crossref_metadata_2025 huggingface dataset:
CALLR: a semi-supervised cell-type annotation method for single-cell RNA sequencing data
Authors: Wei Ziyang , Zhang Shuqin
Published: April 2021

Motivation

Single-cell RNA sequencing (scRNA-seq) technology has been widely applied to capture the heterogeneity of different cell types within complex tissues. An essential step in scRNA-seq data analysis is the annotation of cell types. Traditional cell-type annotation is mainly clustering the cells first, and then using the aggregated cluster-level expression profiles and the marker genes to label each cluster. Such methods are greatly dependent on the clustering results, which are insufficient for accurate annotation.

Results

In this article, we propose a semi-supervised learning method for cell-type annotation called CALLR. It combines unsupervised learning represented by the graph Laplacian matrix constructed from all the cells and supervised learning using sparse logistic regression. By alternately updating the cell clusters and annotation labels, high annotation accuracy can be achieved. The model is formulated as an optimization problem, and a computationally efficient algorithm is developed to solve it. Experiments on 10 real datasets show that CALLR outperforms the compared (semi-)supervised learning methods, and the popular clustering methods.

Availability and implementation

The implementation of CALLR is available at https://github.com/MathSZhang/CALLR.

Supplementary information

Supplementary data are available at Bioinformatics online.
A novel constrained genetic algorithm-based Boolean network inference method from steady-state gene expression data
Authors: Trinh Hung-Cuong , Kwon Yung-Keun
Published: April 2021

Motivation

It is a challenging problem in systems biology to infer both the network structure and dynamics of a gene regulatory network from steady-state gene expression data. Some methods based on Boolean or differential equation models have been proposed but they were not efficient in inference of large-scale networks. Therefore, it is necessary to develop a method to infer the network structure and dynamics accurately on large-scale networks using steady-state expression.

Results

In this study, we propose a novel constrained genetic algorithm-based Boolean network inference (CGA-BNI) method where a Boolean canalyzing update rule scheme was employed to capture coarse-grained dynamics. Given steady-state gene expression data as an input, CGA-BNI identifies a set of path consistency-based constraints by comparing the gene expression level between the wild-type and the mutant experiments. It then searches Boolean networks which satisfy the constraints and induce attractors most similar to steady-state expressions. We devised a heuristic mutation operation for faster convergence and implemented a parallel evaluation routine for execution time reduction. Through extensive simulations on the artificial and the real gene expression datasets, CGA-BNI showed better performance than four other existing methods in terms of both structural and dynamics prediction accuracies. Taken together, CGA-BNI is a promising tool to predict both the structure and the dynamics of a gene regulatory network when a highest accuracy is needed at the cost of sacrificing the execution time.

Availability and implementation

Source code and data are freely available at https://github.com/csclab/CGA-BNI.

Supplementary information

Supplementary data are available at Bioinformatics online.
Data-driven speciation tree prior for better species divergence times in calibration-poor molecular phylogenies
Authors: Tao Qiqing , Barba-Montoya Jose , Kumar Sudhir
Published: April 2021

Motivation

Precise time calibrations needed to estimate ages of species divergence are not always available due to fossil records' incompleteness. Consequently, clock calibrations available for Bayesian dating analyses can be few and diffused, i.e. phylogenies are calibration-poor, impeding reliable inference of the timetree of life. We examined the role of speciation birth–death (BD) tree prior on Bayesian node age estimates in calibration-poor phylogenies and tested the usefulness of an informative, data-driven tree prior to enhancing the accuracy and precision of estimated times.

Results

We present a simple method to estimate parameters of the BD tree prior from the molecular phylogeny for use in Bayesian dating analyses. The use of a data-driven birth–death (ddBD) tree prior leads to improvement in Bayesian node age estimates for calibration-poor phylogenies. We show that the ddBD tree prior, along with only a few well-constrained calibrations, can produce excellent node ages and credibility intervals, whereas the use of an uninformative, uniform (flat) tree prior may require more calibrations. Relaxed clock dating with ddBD tree prior also produced better results than a flat tree prior when using diffused node calibrations. We also suggest using ddBD tree priors to improve the detection of outliers and influential calibrations in cross-validation analyses.

These results have practical applications because the ddBD tree prior reduces the number of well-constrained calibrations necessary to obtain reliable node age estimates. This would help address key impediments in building the grand timetree of life, revealing the process of speciation and elucidating the dynamics of biological diversification.

Availability and implementation

An R module for computing the ddBD tree prior, simulated datasets and empirical datasets are available at https://github.com/cathyqqtao/ddBD-tree-prior.
Disease gene prediction with privileged information and heteroscedastic dropout
Authors: Shu Juan , Li Yu , Wang Sheng , Xi Bowei , Ma Jianzhu
Published: April 2021

Motivation

Recently, machine learning models have achieved tremendous success in prioritizing candidate genes for genetic diseases. These models are able to accurately quantify the similarity among disease and genes based on the intuition that similar genes are more likely to be associated with similar diseases. However, the genetic features these methods rely on are often hard to collect due to high experimental cost and various other technical limitations. Existing solutions of this problem significantly increase the risk of overfitting and decrease the generalizability of the models.

Results

In this work, we propose a graph neural network (GNN) version of the Learning under Privileged Information paradigm to predict new disease gene associations. Unlike previous gene prioritization approaches, our model does not require the genetic features to be the same at training and test stages. If a genetic feature is hard to measure and therefore missing at the test stage, our model could still efficiently incorporate its information during the training process. To implement this, we develop a Heteroscedastic Gaussian Dropout algorithm, where the dropout probability of the GNN model is determined by another GNN model with a mirrored GNN architecture. To evaluate our method, we compared our method with four state-of-the-art methods on the Online Mendelian Inheritance in Man dataset to prioritize candidate disease genes. Extensive evaluations show that our model could improve the prediction accuracy when all the features are available compared to other methods. More importantly, our model could make very accurate predictions when >90% of the features are missing at the test stage.

Availability and implementation

Our method is realized with Python 3.7 and Pytorch 1.5.0 and method and data are freely available at: https://github.com/juanshu30/Disease-Gene-Prioritization-with-Privileged-Information-and-Heteroscedastic-Dropout.
Neighborhoods, Criminal Incidents, Race, and Sentencing: Exploring the Racial and Social Context of Disparities in Incarceration Sentences
Authors: Donnelly Ellen A
Published: April 2021

As an extra-legal factor, social context is a key contributor to racial/ethnic disparities in incarceration sentences. Neighborhoods may have important, yet underexplored influences on sentencing. This study evaluates whether the social conditions and racial characteristics of communities where defendants allegedly offend affect Black-White sentencing disparities. Three-level multilevel model results suggest larger Black populations in neighborhoods of criminal incident increase the odds of incarceration and, to a lesser extent, lengthen sentences for all defendants. Offending outside one’s residential community increases the probability and length of a prison sentence. Neighbourhood effects differ by race, however. Unlike Whites, Blacks receive more punitive sentences for committing offences in disadvantaged areas and less proportionally Black communities. Neighbourhoods thus contribute to racial differences in sentencing outcomes.
Exploring Koch’s postulate for SARS-CoV-2-induced acute pancreatitis: is it all about the ACE?
Authors: Pandanaboyana S
Published: April 2021

The pathogenesis of SARS-CoV-2 infection depends on the ability of the virus to bind to the angiotensin-converting enzyme 2 (ACE2) receptor-primed cellular transmembrane serine protease 2 (TMPRSS2) receptor to facilitate entry into cells.
A Policy Decoupled from Practice: Children’s Participation in Swedish Social Assistance
Authors: Pålsson David , Wiklund Stefan
Published: April 2021

In many countries, there are calls for children to be allowed to participate in social work decision-making. This article analyses child participation vis-à-vis social assistance (SA), which is a municipal cash benefit representing the last safety net. In Sweden, SA is part of the professional field of social work and national policy recommends that children are consulted. The aim is to analyse local policies and practices regarding child participation, and the data are based on case studies in six social service offices. Unlike most participation studies, children’s participation is conceived as an institutional pressure and the concept of decoupling is used to examine how local authorities relate to participation. The findings show that in local policies there is a general openness towards participation, but in practice no efforts are being made to promote participation. The absence of participation is analysed as deriving from organisational barriers (practices are adult-centred and child welfare units are seen as responsible for participation) and the scepticism of social workers (participation is an infringement on parental obligations and children should be protected from involvement in financial issues). The article ends with a discussion on the decoupling and adequacy of children’s participation in settings comparable with Swedish SA.
Rapid Neural Representations of Personally Relevant Faces
Authors: Bayer Mareike , Berhe Oksana , Dziobek Isabel , Johnstone Tom
Published: April 2021

The faces of those most personally relevant to us are our primary source of social information, making their timely perception a priority. Recent research indicates that gender, age and identity of faces can be decoded from EEG/MEG data within 100 ms. Yet, the time course and neural circuitry involved in representing the personal relevance of faces remain unknown. We applied simultaneous EEG-fMRI to examine neural responses to emotional faces of female participants’ romantic partners, friends, and a stranger. Combining EEG and fMRI in cross-modal representational similarity analyses, we provide evidence that representations of personal relevance start prior to structural encoding at 100 ms, with correlated representations in visual cortex, but also in prefrontal and midline regions involved in value representation, and monitoring and recall of self-relevant information. Our results add to an emerging body of research that suggests that models of face perception need to be updated to account for rapid detection of personal relevance in cortical circuitry beyond the core face processing network.
Modernized uniform representation of carbohydrate molecules in the Protein Data Bank
Authors: Shao Chenghua , Feng Zukang , Westbrook John D , Peisach Ezra , Berrisford John , Ikegawa Yasuyo , Kurisu Genji , Velankar Sameer , Burley Stephen K , Young Jasmine Y
Published: April 2021

Since 1971, the Protein Data Bank (PDB) has served as the single global archive for experimentally determined 3D structures of biological macromolecules made freely available to the global community according to the FAIR principles of Findability–Accessibility–Interoperability–Reusability. During the first 50 years of continuous PDB operations, standards for data representation have evolved to better represent rich and complex biological phenomena. Carbohydrate molecules present in more than 14,000 PDB structures have recently been reviewed and remediated to conform to a new standardized format. This machine-readable data representation for carbohydrates occurring in the PDB structures and the corresponding reference data improves the findability, accessibility, interoperability and reusability of structural information pertaining to these molecules. The PDB Exchange MacroMolecular Crystallographic Information File data dictionary now supports (i) standardized atom nomenclature that conforms to International Union of Pure and Applied Chemistry-International Union of Biochemistry and Molecular Biology (IUPAC-IUBMB) recommendations for carbohydrates, (ii) uniform representation of branched entities for oligosaccharides, (iii) commonly used linear descriptors of carbohydrates developed by the glycoscience community and (iv) annotation of glycosylation sites in proteins. For the first time, carbohydrates in PDB structures are consistently represented as collections of standardized monosaccharides, which precisely describe oligosaccharide structures and enable improved carbohydrate visualization, structure validation, robust quantitative and qualitative analyses, search for dendritic structures and classification. The uniform representation of carbohydrate molecules in the PDB described herein will facilitate broader usage of the resource by the glycoscience community and researchers studying glycoproteins.
Integrative genomics analysis reveals a 21q22.11 locus contributing risk to COVID-19
Authors: Ma Yunlong , Huang Yukuan , Zhao Sen , Yao Yinghao , Zhang Yaru , Qu Jia , Wu Nan , Su Jianzhong
Published: April 2021

The systematic identification of host genetic risk factors is essential for the understanding and treatment of coronavirus disease 2019 (COVID-19). By performing a meta-analysis of two independent genome-wide association summary datasets (N = 680 128), a novel locus at 21q22.11 was identified to be associated with COVID-19 infection (rs9976829 in IFNAR2-IL10RB, odds ratio = 1.16, 95% confidence interval = 1.09–1.23, P = 2.57 × 10−6). The rs9976829 represents a strong splicing quantitative trait locus for both IFNAR2 and IL10RB genes, especially in lung tissue (P = 1.8 × 10−24). Integrative genomics analysis of combining genome-wide association study with expression quantitative trait locus data showed the expression variations of IFNAR2 and IL10RB have prominent effects on COVID-19 in various types of tissues, especially in lung tissue. The majority of IFNAR2-expressing cells were dendritic cells (40%) and plasmacytoid dendritic cells (38.5%), and IL10RB-expressing cells were mainly nonclassical monocytes (29.6%). IFNAR2 and IL10RB are targeted by several interferons-related drugs. Together, our results uncover 21q22.11 as a novel susceptibility locus for COVID-19, in which individuals with G alleles of rs9976829 have a higher probability of COVID-19 susceptibility than those with non-G alleles.
Hate Speech and the European Court of Human Rights: Whatever Happened to the Right to Offend, Shock or Disturb?
Authors: Mchangama Jacob , Alkiviadou Natalie
Published: April 2021

In Handyside v. The United Kingdom, the European Court of Human Rights (ECHR) held that the right to freedom of expression, as provided for in Article 10 of the European Convention on Human Rights protects not only expressions that are favorably received but also those that ‘offend, shock or disturb’. 1 Yet, the Court has since developed a substantial body of inconsistent case-law allowing restrictions on ‘hate speech’ that severely questions the degree to which offensive, shocking and disturbing speech is truly protected by the ECHR. Against a qualitative and quantitative backdrop, the authors argue that the Court and previously the Commission, have adopted an overly restrictive approach to hate speech, which fails to provide adequate protection to political speech on controversial issues, including criticism of public officials and government institutions and has created an inconsistent and even arbitrary body of case law. Instead, jurisdictions that recognize a need to balance the freedom of expression with limits on hate speech have adopted more convincing approaches of hate speech, providing a robust protection of free speech while leaving room for the State to curtail the most extreme forms of non-violent hate speech.
Tracheobronchial stents in patients with malignant airway disease: Finnish tertiary care experience
Authors: Routila Johannes , Herhi Eino , Korpi Jarkko , Pulkkinen Jaakko , Koivunen Petri , Rekola Jami
Published: April 2021

OBJECTIVES

Tracheobronchial stenting has an established role in the palliation of malignant central airway obstruction (CAO). The purpose of this study is to describe the experience with self-expanding metal airway stents in 2 tertiary referral centres, covering a third of the population of Finland.

METHODS

Patients referred to and treated with airway stenting for malignant CAO using self-expanding metal-stents were identified from electronic patient records, and data were collected using a structured Endoscopic Lower Airway Management instrument. Statistical analysis to reveal factors affecting patient benefit and survival was carried out.

RESULTS

A total of 101 patients (mean age 65.8) and 116 procedures were identified. Procedure-related mortality was rare (3/101 patients) and complications infrequent. The median survival was 2.3 months [95% confidence interval (CI): 1.4–3.1). Stent benefit was not significantly affected by clinical characteristics. Survival was impacted by the use of adjunct procedures [hazard ratio (HR) 0.36, 95% CI: 0.23–0.58, P < 0.001), procedural urgency (HR 0.40; 95% CI: 0.23–0.71, P = 0.002) and post-treatment chemoradiotherapy (HR 0.29, 95% CI: 0.15–0.56, P < 0.001).

CONCLUSIONS

The beneficial impact observed supports the further use of tracheobronchial stenting in malignant CAO. The use of self-expanding metal stents is encouraged.
Early Initiation of Antiretroviral Therapy Following In Utero HIV Infection Is Associated With Low Viral Reservoirs but Other Factors Determine Viral Rebound
Authors: Millar Jane R , Bengu Nomonde , Vieira Vinicius A , Adland Emily , Roider Julia , Muenchhoff Maximilian , Fillis Rowena , Sprenger Kenneth , Ntlantsana Vuyokazi , Fatti Isabella , Archary Moherndran , Groll Andreas , Ismail Nasreen , García-Guerrero Maria C , Matthews Philippa C , Ndung’u Thumbi , Puertas Maria C , Martinez-Picado Javier , Goulder Philip
Published: April 2021

Background

Early HIV diagnosis allows combination antiretroviral therapy (cART) initiation in the first days of life following in utero (IU) infection. The impact of early cART initiation on infant viral reservoir size in the setting of high-frequency cART nonadherence is unknown.

Methods

Peripheral blood total HIV DNA from 164 early treated (day 0–21 of life) IU HIV-infected South African infants was measured using droplet digital PCR at birth and following suppressive cART. We evaluated the impact of cART initiation timing on HIV reservoir size and decay, and on the risk of subsequent plasma viremia in cART-suppressed infants.

Results

Baseline HIV DNA (median 2.8 log10 copies/million peripheral blood mononuclear cells, range 0.7–4.8) did not correlate with age at cART initiation (0–21 days) but instead with maternal antenatal cART use. In 98 infants with plasma viral suppression on cART, HIV DNA half-life was 28 days. However, the probability of maintenance of plasma aviremia was low (0.46 at 12 months) and not influenced by HIV DNA load. Unexpectedly, longer time to viral suppression was associated with protection against subsequent viral rebound.

Conclusions

With effective prophylaxis against mother-to-child transmission, cART initiation timing in the first 3 weeks of life is not critical to reservoir size.
Smartwatch User Authentication Based on the Arm-Raising Gesture
Authors: Zhao Yanchao , Gao Ran , Tu Huawei
Published: April 2021

Smartwatches have arguably become a popular wearable device nowadays. It is important to protect privacy data stored in smartwatches from being stolen. This study proposes a novel smartwatch user authentication technique based on the arm-raising gesture, which is the process of moving the arm from one side of the body to the chest height. We conducted two experiments to verify the effectiveness of the proposed technique. In Experiment 1, we investigated the performance of identifying users with the arm-raising gesture. We selected a set of features and applied them to five basic machine learning algorithms (i.e. random forest, simple logistic, naive Bayes, multilayer perceptron and linear classifier). Results with 32 participants show that with combined features, these classifiers generally achieved high authentication accuracy with high true accept rate (TAR) ($\geq $92.1% for random forest, simple logistic and multilayer perceptron), low false accept rate (FAR) ($\leq $0.6%) and large area under the curve (AUC) of receiver operating characteristics) ($\geq $92.4%). In Experiment 2, we examined the performance of identifying the arm-raising gesture across different day-to-day gestures. Results show that the arm-raising gesture can be identified from other eight common gestures with high TAR ($\geq $99.5%), low FAR ($\leq $3.6%) and large AUC ($\geq $99%). Overall, the results indicate that our technique could be a viable alternative for smartwatch user authentication.
Research Handbook on Feminist Engagement with International Law
Authors: Coray Erica
Published: April 2021

This review analyzes the efficacy of the collection in engaging with international law through the lens of feminist jurisprudence. The editors have compiled a diverse collection that applies feminist thought to varying topics of international law, including economic topics that do not obviously lend themselves to feminist engagement, that demonstrates the benefits of such analysis. The handbook effectively illustrates the potential for feminist thought to apply broadly to international law topics and provides a path forward for continued engagement with feminist theories in international law.
The potential protective effect of the Polygonum hydropiper L against the development of fructose-induced oxidative stress and metabolic disorders in male Sprague-Dawely rats
Authors: Batool Amna , Saleem Muhammad , Alamgeer  , Mushtaq Muhammad Naveed , Alotaibi Nasser Hadal , Alharbi Khalid Saad , Bukhari Syed Nasir Abbas
Published: April 2021

Objectives

Polygnum hydropiper L (Polygonaceae) is commonly known as smart weed. This study was designed to assess the effect of aqueous methanolic extract of P. hydropiper on oxidative stress and metabolic changes in fructose-induced hypertensive rats.

Methods

Male Sprague-Dawely rats were divided into six groups of five animals each (n = 5) and designated as normotensive group with distilled water, fructose-fed group with 10% fructose, standard control group with 10% fructose plus amlodipine (10 mg/kg) and treated groups with different doses of the aqueous methanolic extract of P. hydropiper (100, 200 and 400 mg/kg) plus 10% fructose daily for 6 weeks. Body weight gain was checked every week. Blood pressure parameters [systolic (SBP), diastolic (DBP), mean arterial pressure (MAP) and heart rate (HR)] and reactivity of extract with phenylephrine and adrenaline were measured by invasive method. Metabolic changes and oxidative stress parameters were measured from blood samples. Phytochemical analysis was also performed.

Key findings

Aqueous methanolic extract of P. hydropiper at 400 mg/kg decreased the blood pressure, heart rate, body weight and produced significant effect on metabolic and oxidative stress changes as compared to fructose-fed group. Phytochemical analysis revealed the presence of polyphenols and flavonoids in it.

Conclusion

The present results showed that aqueous methanolic extract of P. hydropiper possesses effect on oxidative stress and metabolic changes due to polyphenols and flavonoids.
Behcet’s disease and multiple arterial aneurysms: 4 case reports
Authors: Salimi Javad , Omrani Zahra , Cheraghali Roozbeh
Published: April 2021

Behcet’s disease (BD) is a vasculitis of unknown origin. BD is rare in Western countries and the southern hemisphere and is mainly seen in countries along the Silk Road such as the Middle East and Mediterranean regions including Iran. We report four interesting cases of BD with multiple aneurysms three of which had subclavian aneurysms. We chose different surgical approaches for each of these patients due to the different presentations and unique circumstances of each case. Endovascular stent graft used for patients and we discussed open vs. endovascular treatment for BD aneurysms in the discussion.
Conserved and unique transcriptional features of pharyngeal arches in the skate (Leucoraja erinacea) and evolution of the jaw
Authors: Hirschberger Christine , Sleight Victoria A , Criswell Katharine E , Clark Stephen J , Gillis J Andrew
Published: April 2021

The origin of the jaw is a long-standing problem in vertebrate evolutionary biology. Classical hypotheses of serial homology propose that the upper and lower jaw evolved through modifications of dorsal and ventral gill arch skeletal elements, respectively. If the jaw and gill arches are derived members of a primitive branchial series, we predict that they would share common developmental patterning mechanisms. Using candidate and RNAseq/differential gene expression analyses, we find broad conservation of dorsoventral (DV) patterning mechanisms within the developing mandibular, hyoid, and gill arches of a cartilaginous fish, the skate (Leucoraja erinacea). Shared features include expression of genes encoding members of the ventralizing BMP and endothelin signaling pathways and their effectors, the joint markers nkx3.2 and gdf5 and prochondrogenic transcription factor barx1, and the dorsal territory marker pou3f3. Additionally, we find that mesenchymal expression of eya1/six1 is an ancestral feature of the mandibular arch of jawed vertebrates, whereas differences in notch signaling distinguish the mandibular and gill arches in skate. Comparative transcriptomic analyses of mandibular and gill arch tissues reveal additional genes differentially expressed along the DV axis of the pharyngeal arches, including scamp5 as a novel marker of the dorsal mandibular arch, as well as distinct transcriptional features of mandibular and gill arch muscle progenitors and developing gill buds. Taken together, our findings reveal conserved patterning mechanisms in the pharyngeal arches of jawed vertebrates, consistent with serial homology of their skeletal derivatives, as well as unique transcriptional features that may underpin distinct jaw and gill arch morphologies.
Reconstructing the Human Genetic History of Mainland Southeast Asia: Insights from Genome-Wide Data from Thailand and Laos
Authors: Kutanan Wibhu , Liu Dang , Kampuansai Jatupol , Srikummool Metawee , Srithawong Suparat , Shoocongdej Rasmi , Sangkhano Sukrit , Ruangchai Sukhum , Pittayaporn Pittayawat , Arias Leonardo , Stoneking Mark
Published: April 2021

Thailand and Laos, located in the center of Mainland Southeast Asia (MSEA), harbor diverse ethnolinguistic groups encompassing all five language families of MSEA: Tai-Kadai (TK), Austroasiatic (AA), Sino-Tibetan (ST), Hmong-Mien (HM), and Austronesian (AN). Previous genetic studies of Thai/Lao populations have focused almost exclusively on uniparental markers and there is a paucity of genome-wide studies. We therefore generated genome-wide SNP data for 33 ethnolinguistic groups, belonging to the five MSEA language families from Thailand and Laos, and analyzed these together with data from modern Asian populations and SEA ancient samples. Overall, we find genetic structure according to language family, albeit with heterogeneity in the AA-, HM-, and ST-speaking groups, and in the hill tribes, that reflects both population interactions and genetic drift. For the TK speaking groups, we find localized genetic structure that is driven by different levels of interaction with other groups in the same geographic region. Several Thai groups exhibit admixture from South Asia, which we date to ∼600–1000 years ago, corresponding to a time of intensive international trade networks that had a major cultural impact on Thailand. An AN group from Southern Thailand shows both South Asian admixture as well as overall affinities with AA-speaking groups in the region, suggesting an impact of cultural diffusion. Overall, we provide the first detailed insights into the genetic profiles of Thai/Lao ethnolinguistic groups, which should be helpful for reconstructing human genetic history in MSEA and selecting populations for participation in ongoing whole genome sequence and biomedical studies.
Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress
Authors: Misra Jagannath , Holmes Michael J , T. Mirek Emily , Langevin Michael , Kim Hyeong-Geug , Carlson Kenneth R , Watford Malcolm , Dong X Charlie , Anthony Tracy G , Wek Ronald C
Published: April 2021

Appropriate regulation of the Integrated stress response (ISR) and mTORC1 signaling are central for cell adaptation to starvation for amino acids. Halofuginone (HF) is a potent inhibitor of aminoacylation of tRNAPro with broad biomedical applications. Here, we show that in addition to translational control directed by activation of the ISR by general control nonderepressible 2 (GCN2), HF increased free amino acids and directed translation of genes involved in protein biogenesis via sustained mTORC1 signaling. Deletion of GCN2 reduced cell survival to HF whereas pharmacological inhibition of mTORC1 afforded protection. HF treatment of mice synchronously activated the GCN2-mediated ISR and mTORC1 in liver whereas Gcn2-null mice allowed greater mTORC1 activation to HF, resulting in liver steatosis and cell death. We conclude that HF causes an amino acid imbalance that uniquely activates both GCN2 and mTORC1. Loss of GCN2 during HF creates a disconnect between metabolic state and need, triggering proteostasis collapse.
LIMS1 risk genotype and T cell–mediated rejection in kidney transplant recipients
Authors: Caliskan Yasar , Karahan Gonca , Akgul Sebahat Usta , Mirioglu Safak , Ozluk Yasemin , Yazici Halil , Demir Erol , Dirim Ahmet B , Turkmen Aydin , Edwards John , Savran Fatma Oguz , Sever Mehmet S , Kiryluk Krzysztof , Gharavi Ali , Lentine Krista L
Published: April 2021

Background

This study aims to examine the association of LIM zinc finger domain containing 1 (LIMS1) genotype with allograft rejection in an independent kidney transplant cohort.

Methods

We genotyped 841 kidney transplant recipients for the LIMS1 rs893403 variant by Sanger sequencing followed by polymerase chain reaction confirmation of the deletion. Recipients who were homozygous for the LIMS1 rs893403 genotype GG were compared with the AA/AG genotypes. The primary outcome was T cell–mediated or antibody-mediated rejection (TCMR or ABMR, respectively) and secondary outcome was allograft loss.

Results

After a median follow-up of 11.4 years, the rate of TCMR was higher in recipients with the GG genotype (n = 200) compared with the AA/AG genotypes (n = 641) [25 (12.5%) versus 35 (5.5%); P = 0.001] while ABMR did not differ by genotype [18 (9.0%) versus 62 (9.7%)]. Recipients with the GG genotype had 2.4 times higher risk of TCMR than those who did not have this genotype [adjusted hazard ratio2.43 (95% confidence interval 1.44–4.12); P = 0.001]. A total of 189 (22.5%) recipients lost their allografts during follow-up. Kaplan–Meier estimates of 5-year (94.3% versus 94.4%; P = 0.99) and 10-year graft survival rates (86.9% versus 83.4%; P = 0.31) did not differ significantly in the GG versus AA/AG groups.

Conclusions

Our study demonstrates that recipient LIMS1 risk genotype is associated with an increased risk of TCMR after kidney transplantation, confirming the role of the LIMS1 locus in allograft rejection. These findings may have clinical implications for the prediction and clinical management of kidney transplant rejection by pretransplant genetic testing of recipients and donors for LIMS1 risk genotype.
The Effect of Maternal Smoking on Offspring Smoking Is Unrelated to Heritable Personality Traits or Initial Subjective Experiences
Authors: Weber Tess L , Selya Arielle , Wakschlag Lauren S , Dierker Lisa , Rose Jennifer S , Hedeker Don , Mermelstein Robin J
Published: April 2021

Introduction

Maternal smoking is a risk factor for offspring smoking. Lifetime maternal smoking vs. prenatal tobacco exposure (PTE) appears to act through different mechanisms. This study tested the hypothesis that maternal smoking measures’ effects on offspring smoking could be attributable to hereditary mechanisms: personality traits (novelty-seeking, impulsivity, neuroticism, and self-esteem) and initial subjective smoking experiences (pleasurable, unpleasurable, and dizziness).

Methods

Data were drawn from the Social and Emotional Contexts of Adolescent Smoking Patterns study, an 8-year longitudinal study of 9th or 10th graders at baseline (≈age 15) who experiment with smoking (<100 lifetime cigarettes; N = 594) at baseline. The young adult smoking frequency at the 8-year follow-up (≈age 23) was examined as a function of baseline characteristics (heritable trait, maternal smoking, PTE, and sex) and baseline smoking frequency and nicotine dependence. Structural equation models determined whether the inclusion of each heritable trait among offspring confounded the effects of maternal smoking (PTE or maternal smoking) on offspring smoking and nicotine dependence.

Results

Impulsiveness was associated with intermediate adolescent smoking frequency (B = 0.135, SD = 0.043, p = .002) and nicotine dependence (B = 0.012, SD = 0.003, p < .001). Unpleasurable first experience (B = 0.886, SD = 0.374, p = .018) and dizziness (B = 0.629, SD = 0.293, p = .032) showed a trend with intermediate smoking frequency that was nonsignificant after correcting for multiple comparisons. These traits did not confound maternal smoking’s effects.

Conclusions

None of the heritable traits examined in this model explained the effect of maternal smoking measures on adolescence or young adulthood offspring smoking. Further research is needed to elucidate the mechanism by which PTE and maternal smoking are linked to offspring smoking.

Implications

Prenatal tobacco exposure (PTE) and mother’s lifetime smoking present separate and independent risks for offspring smoking; however, their mechanisms seem unrelated to heritable personality traits and initial subjective smoking experiences. These findings have implications for separate screening strategies tailored to different age groups, especially related to PTE’s risk of smoking in young adulthood. Additionally, these findings add to the known risks of maternal smoking. Further research is needed to understand the mechanism underlying the risk posed by maternal lifetime smoking and PTE on offspring smoking behavior.
The Illegal Experimental Tobacco Marketplace I: Effects of Vaping Product Bans
Authors: Freitas-Lemos Roberta , Stein Jeffrey S , Tegge Allison N , Kaplan Brent A , Heckman Bryan W , Cummings K Michael , Bickel Warren K
Published: April 2021

Objectives

Banning vaping products may have unintended outcomes, such as increased demand for illegal products. This study experimentally examined the effects of a vaping ban and a flavored vaping ban on the probability of purchasing illicit vaping products, and factors affecting purchasing from a hypothetical illegal marketplace.

Methods

A crowdsourced sample of exclusive cigarette smokers, exclusive e-cigarette users, and frequent dual users (n = 150) completed hypothetical purchasing trials in an Experimental Tobacco Marketplace under three conditions (no ban, vaping ban, and flavored vaping ban). Participants chose to purchase in a hypothetical legal experimental tobacco marketplace (LETM) or illegal experimental tobacco marketplace (IETM). Vaping products were available in each marketplace depending on the condition. Other tobacco products were always available in the LETM. A hypothetical illicit purchase task with five fine amounts assessed the effect of monetary penalties.

Results

Participants from all groups were more likely to purchase from the IETM when product availability in the LETM was more restricted, with e-cigarette users being most affected. The likelihood of purchasing illegal products was systematically decreased as monetary penalties associated with the IETM increased, with e-cigarette users showing greater persistence in defending their illicit purchases.

Conclusions

Restricting vaping products from the marketplace may shift preference towards purchasing vaping products in the illegal marketplace. Nevertheless, penalties imposed on consumer’s behavior might be effective in preventing illicit trade. The IETM is a methodological extension that supports the utility and flexibility of the ETM as a framework for understanding the impact of different tobacco regulatory policies.

Implications

This study suggests that limiting or banning vaping products as a possible strategy to reduce the adverse effects of vaping products could result in some tobacco-users seeking banned products from illegal sources. Monetary fines were shown to reduce illegal purchases. Therefore, policymakers should consider implementing strategies that may mitigate illegal purchases.
Season, anthocyanin supplementation, and flight training have mixed effects on the antioxidant system of migratory European Starlings
Authors: Frawley Abigail E , DeMoranville Kristen J , Carbeck Katherine M , Trost Lisa , Bryła Amadeusz , Dzialo Maciej , Sadowska Edyta T , Bauchinger Ulf , Pierce Barbara J , McWilliams Scott R
Published: April 2021

Migratory birds engage in 2 periods of endurance flight annually as they travel between summer breeding and overwintering grounds, and such endurance flights likely incur oxidative costs. These costs may differ between fall and spring migration, especially for females who must prepare for breeding and egg laying in spring. The objective of this study of a migratory bird was to test proposed hypotheses about how key components of the female’s antioxidant system differ in response to flight training in the fall and spring and to dietary antioxidant supplementation. We hand raised female European Starlings (Sturnus vulgaris) and fed them either a diet supplemented with dietary anthocyanins or a diet without added anthocyanins. We flew females in a wind tunnel for 15 days during fall and spring migration seasons and measured over time oxidative lipid damage (d-ROMs) and 3 components of the antioxidant system: nonenzymatic antioxidant capacity (OXY), uric acid, and glutathione peroxidase (GPx) activity. Prior to flight training, OXY and oxidative damage were lower in females during spring compared with fall, and females fed a low-antioxidant diet had consistently higher circulating uric acid. GPx activity decreased more in spring immediately after a long-duration flight. Females fed a high-antioxidant diet had a greater decrease in OXY after the 15-day flight training. Flight-trained females had higher circulating uric acid than untrained females immediately after the longest-duration flight and decreased GPx activity after the 15-day flight training. In sum, females upregulated enzymatic and nonenzymatic endogenous antioxidants in spring, and females fed a diet with less antioxidants appear to compensate by increasing circulating uric acid. Our findings emphasize the important role of dietary antioxidants for birds during migration, and similar flights in fall and spring likely represent distinct oxidative challenges in the life history of female birds.
Super determinant1A, a RAWULdomain-containing protein, modulates axillary meristem formation and compound leaf development in tomato
Authors: López Hernán , Schmitz Gregor , Thoma Rahere , Theres Klaus
Published: April 2021

Shoot branching and complex leaf development relies on the establishment of boundaries that precedes the formation of axillary meristems (AMs) and leaflets. The tomato (Solanum lycopersicum) super determinant mutant is compromised in both processes, due to a mutation in Sde1A. Sde1A encodes a protein with a RAWUL domain, which is also present in Polycomb Group Repressive Complex 1 (PRC1) RING finger proteins and WD Repeat Domain 48 proteins. Genetic analysis revealed that Sde1A and Bmi1A cooperate, whereas Bmi1C antagonizes both activities, indicating the existence of functionally opposing PRC1 complexes that interact with Sde1A. Sde1A is expressed at early stages of boundary development in a small group of cells in the center of the leaf-axil boundary, but its activity is required for meristem formation at later stages. This suggests that Sde1A and Bmi1A promote AM formation and complex leaf development by safeguarding a pool of cells in the developing boundary zones. Genetic and protein interaction analyses showed that Sde1A and Lateral suppressor (Ls) are components of the same genetic pathway. In contrast to ls, sde1a mutants are not compromised in inflorescence branching, suggesting that Sde1A is a potential target for breeding tomato cultivars with reduced side-shoot formation during vegetative development.
Combined action of guard cell plasma membrane rapid- and slow-type anion channels in stomatal regulation
Authors: Jalakas Pirko , Nuhkat Maris , Vahisalu Triin , Merilo Ebe , Brosché Mikael , Kollist Hannes
Published: April 2021

Initiation of stomatal closure by various stimuli requires activation of guard cell plasma membrane anion channels, which are defined as rapid (R)- and slow (S)-type. The single-gene loss-of-function mutants of these proteins are well characterized. However, the impact of suppressing both the S- and R-type channels has not been studied. Here, by generating and studying double and triple Arabidopsis thaliana mutants of SLOW ANION CHANNEL1 (SLAC1), SLAC1 HOMOLOG3 (SLAH3), and ALUMINUM-ACTIVATED MALATE TRANSPORTER 12/QUICK-ACTIVATING ANION CHANNEL 1 (QUAC1), we show that impairment of R- and S-type channels gradually increased whole-plant steady-state stomatal conductance. Ozone-induced cell death also increased gradually in higher-order mutants with the highest levels observed in the quac1 slac1 slah3 triple mutant. Strikingly, while single mutants retained stomatal responsiveness to abscisic acid, darkness, reduced air humidity, and elevated CO2, the double mutant lacking SLAC1 and QUAC1 was nearly insensitive to these stimuli, indicating the need for coordinated activation of both R- and S-type anion channels in stomatal closure.
Histopathologic PD-L1 Tumor Expression and Prognostic Significance in Nonmelanoma Skin Cancers: A Systematic Review
Authors: Lehmer Larisa , Choi Franchesca , Kraus Christina , Shiu Jessica , de Feraudy Sebastien , Elsensohn Ashley
Published: April 2021

PD-L1 and PD-1 inhibitors are being increasingly used to treat a variety of nonmelanoma skin cancers (NMSCs). This systematic review summarizes PD-L1 expression in NMSCs and determines its use for prognosis using targeted immunotherapy. A primary search of peer-reviewed English-language medical literature was conducted for studies on PD-L1 tumor expression in biopsied or excised NMSCs. Fifty-nine articles met criteria for inclusion. PD-L1 expression in advanced NMSCs ranged from 22%–89% for basal cell carcinomas, 42%–50% for Merkel cell carcinomas, and 26%–100% for squamous cell carcinomas. Study limitations included clone heterogeneity across studies, complicating comparison of PD-L1 expression. Differences were also noted in the selection of tumor reactivity threshold. We conclude that there is insufficient evidence to determine the prognostic significance of PD-L1 expression in NMSCs as a whole, but this remains a promising area. More investigation into the role of tumor PD-L1 as a biomarker for predicting clinical response to PD-L1 and PD-1 inhibitors in NMSCs is needed.
Understanding the Complexity, Underlying Processes, and Influencing Factors for Optimal Multidisciplinary Teamwork in Hospital-Based Cancer Teams
Authors: Horlait Melissa , Baes Saskia , De Regge Melissa , Leys Mark
Published: April 2021

Background

Multidisciplinary teamwork has become the standard in care for oncological patients and their treatment trajectory when comprehensive, holistic, and high-quality cancer care is needed. Working together from a variety of perspectives is difficult to achieve and has well-known pitfalls, such as miscommunication and poor coordination.

Objective

To describe and synthesize the factors influencing and the processes underlying optimal multidisciplinary teamwork.

Methods

An integrative review was conducted, guided by the framework of Whittemore and Knafl. The systematic search for literature published since 2010 in 3 databases (PubMed, Web of Science, and Scopus) yielded 49 articles.

Results

Eighty-eight percent of the included studies focus on multidisciplinary team meetings, rather than on the wider notion of multidisciplinary teamwork. We identified influencing factors on the basis of structural features of the team, hospital, and health system, as well as process features of multidisciplinary teamwork in multidisciplinary team meetings.

Conclusion

To improve multidisciplinary teamwork, the focus needs to be on the process of collaboration throughout the cancer care trajectory of the patient. A more integrated, interdisciplinary approach should be aimed for to recognize the role and contribution of all disciplines involved.

Implications

A cultural change is needed toward interdisciplinary practice in hospitals to reach partnership between all involved professionals as part of a participatory, collaborative, and coordinated approach.
A Case of Multisystem Inflammatory Syndrome in Children Following SARS-CoV-2 Infection in a Rural Emergency Department
Authors: Glover Hilary Ashton , Davis Amy B.
Published: April 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), also known as COVID-19, has rapidly spread across the globe resulting in a worldwide pandemic. This disease has such varying presentation within the population. Although rare, multisystem inflammatory syndrome in children (MIS-C) is a potentially fatal complication of SARS-CoV2 infection and can be easily missed in the early stages. Because emergency department (ED) providers are often the initial treating providers, knowledge of the clinical manifestations and treatment of MIS-C is essential. The purpose of this article is to present a case of MIS-C in a rural ED, describe the subtle signs of disease, and educate clinicians on this rare and potentially deadly disease.