bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age-related pathological impairments in induced neurons derived from patients with idiopathic Parkinson’s disease
Authors: Drouin-Ouellet Janelle , Pircs Karolina , Legault Emilie M. , Birtele Marcella , Nilsson Fredrik , Shrigley Shelby , Pereira Maria , Storm Petter , Sharma Yogita , Vuono Romina , Stoker Thomas B. , Jakobsson Johan , Barker Roger A. , Parmar Malin 
Published: April 2021

AbstractUnderstanding the pathophysiology of Parkinson’s disease has been hampered by the lack of models that recapitulate all the critical factors underlying its development. Here, we generated functional induced dopaminergic neurons (iDANs) that were directly reprogrammed from adult human dermal fibroblasts of patients with idiopathic Parkinson’s disease to investigate diseaserelevant pathology. We show that iDANs derived from Parkinson’s disease patients exhibit lower basal chaperone-mediated autophagy as compared to iDANs of healthy donors. Furthermore, stress-induced autophagy resulted in an accumulation of macroautophagic structures in induced neurons (iNs) derived from Parkinson’s disease patients, independently of the specific neuronal subtype but dependent on the age of the donor. Finally, we found that these impairments in patient-derived iNs lead to an accumulation of phosphorylated alpha-synuclein, a hallmark of Parkinson’s disease pathology. Taken together, our results demonstrate that direct neural reprogramming provides a patient-specific model to study aged neuronal features relevant to idiopathic Parkinson’s disease.
In vivoKRAS G12D/V degradation mediated by CANDDY using a modified proteasome inhibitor
Authors: Imanishi Satoshi , Huang Lijuan , Itakura Shoko , Ishizaka Masamichi , Iwasaki Yoichi , Yamaguchi Tomohiro , Miyamoto-Sato Etsuko 
Published: April 2021

Abstract“Undruggable” proteins, such as RAS proteins, remain problematic despite efforts to discover inhibitors against them. KRAS mutants are prevalent in human cancers. Recently, the KRAS G12C inhibitor have been clinically approved, but inhibitors for KRAS G12D/V are still under development. Here, we described the development of a novel chemical knockdown strategy, termed CANDDY (Chemical knockdown with Affinity aNd Degradation DYnamics). This strategy involves a CANDDY tag modified from a proteasome inhibitor inducing direct proteasomal degradation. We constructed TUS-007 as a multispecific small molecule tethered from a KRAS interactor and CANDDY tag to target KRAS G12D/V. We confirmed that the degradation by TUS-007 was independent of target ubiquitination. This allows to solve a laborious design of matchmaker in the current ubiquitination-dependent proteolysis technology. And TUS-007 successfully suppressed tumors due to in vivo degradation of KRAS G12D/V. The CANDDY technology could represent a simple and rational strategy to degrade currently “undruggable” proteins.
Assembly-free rapid differential gene expression analysis in non-model organisms using DNA-protein alignment
Authors: Shrestha Anish M.S. , Guiao Joyce Emlyn B. , Santiago Kyle Christian R. 
Published: April 2021

AbstractBackgroundRNA-seq is being increasingly adopted for gene expression studies in a panoply of non-model organisms, with applications spanning the fields of agriculture, aquaculture, ecology, and environment. For organisms that lack a well-annotated reference genome or transcriptome, a conventional RNA-seq data analysis workflow requires constructing a de-novo transcriptome assembly and annotating it against a high-confidence protein database. The assembly serves as a reference for read mapping, and the annotation is necessary for functional analysis of genes found to be differentially expressed. However, assembly is computationally expensive. It is also prone to errors that impact expression analysis, especially since sequencing depth is typically much lower for expression studies than for transcript discovery.ResultsWe propose a shortcut, in which we obtain counts for differential expression analysis by directly aligning RNA-seq reads to the high-confidence proteome that would have been otherwise used for annotation. By avoiding assembly, we drastically cut down computational costs – the running time on a typical dataset improves from the order of tens of hours to under half an hour, and the memory requirement is reduced from the order of tens of Gbytes to tens of Mbytes. We show through experiments on simulated and real data that our pipeline not only reduces computational costs, but has higher sensitivity and precision than a typical assembly-based pipeline. A Snakemake implementation of our workflow is available at:https://bitbucket.org/project_samar/samarConclusionsThe flip side of RNA-seq becoming accessible to even modestly resourced labs has been that the time, labor, and infrastructure cost of bioinformatics analysis has become a bottleneck. Assembly is one such resource-hungry process, and we show here that it can be avoided for quick and easy, yet more sensitive and precise, differential gene expression analysis in non-model organisms.
Amino acid residues involved in inhibition of host gene expression by influenza A/Brevig Mission/1/1918 PA-X
Authors: Chiem Kevin , Martinez-Sobrido Luis , Nogales Aitor , DeDiego Marta L. 
Published: April 2021

AbstractInfluenza A virus (IAV) PA-X protein is a virulence factor that selectively degrades host mRNAs leading to protein shutoff. This function modulates host inflammation, antiviral responses, cell apoptosis, and pathogenesis. In this work we describe a novel approach based on the use of bacteria and a plasmid encoding the PA-X gene under the control of the bacteriophage T7 promoter to identify amino acid residues important for A/Brevig Mission/1/1918 H1N1 PA-X’s shutoff activity. Using this system, we have identified PA-X mutants encoding single or double amino acid changes, which diminish its host shutoff activity, as well as its ability to counteract interferon responses upon viral infection. This novel bacteria-based approach could be used for the identification of viral proteins that inhibit host gene expression as well as the amino acid residues responsible for inhibition of host gene expression.
The effect of stress on memory for temporal context
Authors: Montijn Nicole D. , Gerritsen Lotte , Engelhard Iris. M. 
Published: April 2021

AbstractStress and emotional arousal interfere with encoding of temporal context memory for episodic events. However, it remains unclear how stress affects more fine-grained temporal memory, such as episodic events sequences and event times. Here, 86 healthy participants (M age = 22.5; 46% women, 54% men) were subjected to either a stress condition (socially evaluated cold pressor test) or a control condition, directly after or at a delay of 30 minutes they were presented the temporal structure of four virtual days. In these virtual days, time was scaled and participants could use clock cues to construe the passage of time within a day. We examined whether acute stress would interfere with encoding of episodic event sequences and temporal memory. Our results show that when learning took place directly after a stressor, virtual time estimates were more strongly biased towards a generalized timeline but temporal memory overall was not differentially affected between the stress and control groups. Exploratory analyses suggest that memory accuracy improved in men and deteriorated in women as a function of subjective stress levels following acute stress. In conclusion, acute stress amplified memory generalization but we found no stress related differences in memory accuracy across levels of temporal granularity,.
Hair regrowth in cicatricial alopecia: A literature review
Authors: Poliner Anna D. , Tosti Antonella 
Published: April 2021

AbstractCicatricial alopecias (CA) describes multiple subtypes of hair loss in which the hair follicle is destroyed by an unknown inflammatory mechanism. The main goal of treatment is to stop this inflammatory process and prevent further hair loss; however, there have been occasional reports of hair regrowth following treatment in some subtypes of CA. This review aims to highlight these reports. A total of 71 cases of hair regrowth were found documented in the literature. The treatments used varied widely both between and within each subtype of alopecia. This review highlights that regrowth is possible in at least a subset of patients with cicatricial alopecia; however, the mechanism by which this occurs has yet to be elucidated.
Empirical attrition modelling and discrimination: Balancing validity and group differences
Authors: Speer Andrew B. 
Published: April 2021

AbstractAttrition models combine variables into statistical algorithms to understand and predict employee turnover. People analytics teams and external vendors use attrition models to offer insights and to develop organisational interventions. However, if attrition models or other data‐driven models inform employment decisions, model scores may then be subjected to civil rights laws and diversity concerns resulting from group differences in scores. This paper discusses adverse impact when building attrition models, outlining how researchers test for adverse impact in this context, strategies to reduce group differences and how attrition modelling and other human resources ‘big data’ predictions fit within larger validity frameworks. Procedures were applied to field data in an applied demonstration of an attrition model with disparate impact. Model revisions resulted in adverse impact reductions while simultaneously maintaining model validity. Collectively, this paper provides timely attention to important aspects of the people analytics, turnover and legal domains.
Hazardous and harmful alcohol use in the Northern Territory, Australia: the impact of alcohol policy on critical care admissions using an extended sampling period
Authors: Secombe Paul , Campbell Lewis , Brown Alex , Bailey Michael , Pilcher David 
Published: April 2021

AbstractAimsTo describe the effect of alcohol policy on the incidence of intensive care unit (ICU) admissions associated with hazardous and harmful alcohol use in the Northern Territory (NT) of AustraliaDesign, setting and participantsBefore and after analysis of admissions to NT ICUs between April 2018 and September 2019, extending on both a descriptive study describing hazardous and harmful alcohol use and single‐centre analyses of harm minimization policies. After exclusions, 2281 (83%) admissions were analysed, 20.3% of which were associated with hazardous and harmful alcohol use.MeasurementsPrimary outcome was the incidence of admissions associated with hazardous and harmful alcohol use in the 5 months preceding (baseline period) the introduction of new alcohol policies [full‐time stationing of Police Auxiliary Liquor Inspectors (PALIs) and minimum unit price (MUP)] compared with 12 months (post‐intervention) following. Secondary outcomes included measures of resource use [length of stay (LoS), need for mechanical ventilation] and mortality, stratified by site.FindingsOverall, there was a 4.5% [95% confidence interval (CI) = 0.8–8.2%] absolute risk reduction between the time‐periods (95% CI = 23.4 versus 18.9% for baseline and post‐intervention, respectively, P = 0.01), predominantly due to a reduction in admissions associated with acute misuse (2.3%, 95% CI = −0.2 to 4.9% risk reduction, P = 0.06). There were regional differences, with a more marked relative risk reduction observed in Central Australia compared with the city of Darwin (27.0 versus 16.7% relative risk reduction, respectively).ConclusionsIntroduction of new alcohol harm minimization policies in the Northern Territory of Australia appears to have reduced the number of intensive care unit admissions associated with hazardous and harmful alcohol use. Strength of effect varies by geographical region and chronicity of hazardous and harmful alcohol use.
Who, me? Optimism bias about US teenagers’ ability to quit vaping
Authors: Strombotne Kiersten , Sindelar Jody , Buckell John 
Published: April 2021

AbstractBackground and aimsThe vaping rate among US teenagers has doubled in the last 2 years, which may be explained in part by teenagers’ optimism that they would have relatively little trouble in quitting. The aim of this study was to estimate the extent to which teenagers exhibited optimism bias, what characteristics are associated with optimism bias and which factors are related to respondents’ perceptions of how hard it would be for them to quit.DesignA national, on‐line, cross‐sectional survey in 2018 using quota sampling.SettingUnited States.ParticipantsRespondents were 1610 teenagers aged 14–18 years who had ever tried or heard of JUULs or e‐cigarettes generally.MeasurementsOptimism bias was defined as respondents’ perceptions of their own difficulty quitting vaping compared with that of an average US person of their own age. Linear regression was used to examine associations between respondents’ characteristics with both optimism bias and their own perceived difficulty quitting vaping.FindingsMore than 60% of teenagers were optimistically biased about their ability to quit vaping. Smoking (b = −0.69, P < 0.01) and JUULing (b = −0.62, P < 0.01) were negatively associated with optimism bias but reduced‐price school lunch eligibility (0.27, P = 0.02) and school satisfaction were positively associated (b = 0.05, P = 0.02). Smoking (b = 0.85, P < 0.01) was associated with an increased perception of the difficulty of quitting. That association was negative for black respondents (b = −0.81, P = 0.01) and those eligible for reduced‐priced lunches (b = −0.48, P = 0.01), and positive for Hispanic respondents (b = 0.47, P = 0.04).ConclusionsOn average, US teenagers appear to show optimism bias about their ability to quit vaping, which decreases with smoking and vaping and increases with eligibility for reduced‐price school lunches.
Gynaecological and IVF procedures billed through the Medicare Benefits Schedule (MBS) during the COVID‐19 pandemic
Authors: Alonso Anais , Deans Rebecca , Nesbitt‐Hawes Erin , Yazdani Anusch , McCormack Lalla , Koh Yi Ying , Abbott Jason 
Published: April 2021

BackgroundIn response to the COVID‐19 pandemic in Australia, restrictions to elective surgeries were implemented nationwide.AimsTo investigate the response to these restrictions in elective gynaecological and In vitro fertilisation (IVF) procedures during the first wave of the COVID‐19 pandemic.Materials and MethodsWe analysed the Medicare Item Reports for the number of elective gynaecological (labioplasty, vulvoplasty; prolapse and continence; operative hysteroscopy; hysterectomy; fertility) and IVF procedures claimed in Australia between January–June 2020 and compared these to January–June 2019.ResultsThe number of included gynaecological and IVF procedures performed in January–June 2020 decreased by −13.71% and −12.56%, respectively, compared to January–June 2019. The greatest reductions were in May 2020 (gynaecology −43.71%; IVF −51.63% compared to May 2019), while April 2020 reported decreases of −37.69% and −31.42% in gynaecological and IVF procedures, respectively. In April 2020, 1963 IVF cycle initiations (−45.20% compared to April 2019), 2453 oocyte retrievals (−26.99%) and 3136 embryo transfers (−22.95%) were billed. The procedures with greatest paired monthly decrease were prolapse and continence surgeries in April (676 procedures; −51.85%) and May 2020 (704 procedures; −60.05%), and oocyte retrievals in May 2020 (1637 procedures; −56.70%).ConclusionsWhile we observed a decrease in procedural volumes, elective gynaecological and IVF procedures continued in considerable numbers during the restricted timeframes. In the event of future overwhelming biological threat, careful consideration must be given to more effective measures of limiting access for non‐emergency procedures to conserve essential resources and reduce risk to both the public and healthcare staff.
Effect of deglucuronidation on the results of the Basel phenotyping cocktail
Authors: Bachmann Fabio , Duthaler Urs , Krähenbühl Stephan 
Published: April 2021

We investigated the effect of deglucuronidation on the plasma concentration of the constituents of the Basel phenotyping cocktail and on the interpretation of the phenotyping results under basal conditions and after cytochrome P450 (CYP) induction with metamizole. The cocktail containing caffeine (CYP1A2), efavirenz (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6) and midazolam (CYP3A4) was administered to 12 healthy subjects before (basal) and after treatment with metamizole for 1 week. In the basal state, deglucuronidation caused an increase in the plasma concentrations and area under the curve (AUC) of metoprolol, 8′‐hydroxyefavirenz, 4′‐hydroxyflurbiprofen and 1′‐hydroxymidazolam. This effect could be visualized in Bland–Altman plots, where the values for 8′‐hydroxyefavirenz, 4′‐hydroxyflurbiprofen and 1′‐hydroxymidazolam were mostly above the +20% threshold. As a result, the metabolic ratio (MR), calculated as AUCparent drug/AUCmetabolite, decreased with deglucuronidation for CYP2B6, CYP2C9 and CYP3A4 and increased for CYP2D6. Treatment with metamizole, a constitutive androstane receptor‐dependent inducer of CYP2B6, CYP2C9, CYP2C19 and CYP3A4, accentuated the effect of deglucuronidation on AUC and MR. The correlation of MRs calculated as the plasma concentration ratio parent drug/metabolite with the MR calculated as the AUC ratio showed that 1 sample obtained between 2 and 6 hours after cocktail ingestion and analysed with and without deglucuronidation is sufficient to obtain reliable phenotyping results. Importantly, CYP2C9 and 3A4 induction would have been missed without deglucuronidation of the plasma samples. In conclusion, deglucuronidation of the plasma samples improves the stability of the phenotyping results of the Basel phenotyping cocktail and is necessary to reliably detect CYP induction.
Periodontal (formerly type VIII) Ehlers–Danlos syndrome: Description of 13 novel cases and expansion of the clinical phenotype
Authors: El Chehadeh Salima , Legrand Anne , Stoetzel Corinne , Geoffroy Véronique , Billon Clarisse , Adham Salma , Jeunemaître Xavier , Jaussaud Roland , Muller Jean , Schaefer Elise , Benistan Karelle , Gaertner Sébastien , Bloch‐Zupan Agnès , Courval Aymeric , Manière Marie‐Cécile , Petit Catherine , Bursztejn Anne‐Claire , Bal Laurence , Reyre Anthony , Chammas Agathe , Busa Tiffany , Dollfus Hélène , Lipsker Dan 
Published: April 2021

AbstractPeriodontal Ehlers–Danlos syndrome (pEDS) is a rare condition caused by pathogenic variants in the C1R and C1S genes, encoding subunits C1r and C1s of the first component of the classical complement pathway. It is characterized by early‐onset periodontitis with premature tooth loss, pretibial hyperpigmentation and skin fragility. Rare arterial complications have been reported, but venous insufficiency is rarely described. Here we report 13 novel patients carrying heterozygous pathogenic variants in C1R and C1S including three novel C1S variants (c.962G > C, c.961 T > G and c.961 T > A). In addition to the pEDS phenotype, three patients and one relative displayed widespread venous insufficiency leading to persistent varicose leg ulcers. One patient suffered an intracranial aneurysm with familial vascular complications including thoracic and abdominal aortic aneurysm and dissection and intracranial aneurysm rupture. This work confirms that vascular complications can occur, although they are not frequent, which leads us to propose to carry out a first complete non‐invasive vascular evaluation at the time of the diagnosis in pEDS patients. However, larger case series are needed to improve our understanding of the link between complement pathway activation and connective tissue alterations observed in these patients, and to better assess the frequency, type and consequences of the vascular complications.
Growth in Criticism?
Authors: De Mey Peter 
Published: April 2021

AbstractReports of global ecumenical conversations are regularly published by the World Council of Churches in a collection of volumes titled Growth in Agreement. The assumption is that the dialogues are not just repeating the same arguments they made half a century ago, but that relations between member churches have grown qualitatively as a result of this process. This paper asks whether Orthodox critique of Roman Catholic ecclesiology reflects signs of growth or continues “traditional” stereotypical thinking about other churches and religions. The paper first examines Orthodox reactions to Lumen Gentium during and immediately after the Second Vatican Council, then compares them with Orthodox reactions to the council’s 50th anniversary. The paper concludes by asking whether Pope Francis’ endeavour to reform the Catholic Church in the direction of greater synodality is partly the result of the expectations of our sister churches’ representatives over the past 50 years.
What Have Lutherans Learned from Orthodox?
Authors: Kärkkäinen Veli‐Matti 
Published: April 2021

AbstractThe purpose of this article is to consider the influence of Eastern Orthodox theology and spirituality, particularly soteriology, upon the Lutheran doctrine of salvation. It focuses on the emergence of a new interpretation of Martin Luther’s view of justification as union and Christ’s “real” presence in the believer through the Holy Spirit. This account materially reflects key intuitions of the Eastern Orthodox vision of deification (divinization, theosis) and was developed in Helsinki, Finland, under the tutelage of Tuomo Mannermaa and his school. Even though this new interpretation continues to be contested and debated, particularly in German Luther scholarship, it has also exercised wide influence on international theological discussion. The latter part of the article, more constructive in nature, seeks to link the Helsinki School insights to some other current Lutheran contributions as well as relevant viewpoints from the wider Christian West.
EQUILIBRIUM COUNTERFACTUALS
Authors: Chemla Gilles , Hennessy Christopher 
Published: April 2021

AbstractWe incorporate structural modelers into the economy they model. Using traditional moment matching, they treat policy changes as zero probability (or exogenous) “counterfactuals.” Bias occurs since real‐world agents understand policy changes are positive probability events guided by modelers. Downward, upward, or sign bias occurs. Bias is illustrated by calibrating the Leland model to the 2017 tax cut. The traditional identifying assumption, constant moment partial derivative sign, is incorrect with policy optimization. The correct assumption is constant moment total derivative sign accounting for estimation‐policy feedback. Model agent expectations can be updated iteratively until policy advice converges to agent expectations, with bias vanishing.
Surgical treatment of non‐small‐cell lung cancer in octogenarians: a single‐centre retrospective study
Authors: Chen Charlotte , Kolbe John , Christmas Tim 
Published: April 2021

AbstractLung resection in patients aged ≥80 years is considered high risk and contributes to the low rates of resection in this population. This review of 79 octogenarians who underwent curative surgery for non‐small‐cell lung cancer demonstrated no intraoperative mortality, 30‐day mortality of 1.3% and 12‐month mortality of 10%. In this selected cohort of octogenarians, surgery resulted in acceptable short‐ to medium‐term outcomes.