bluuebunny/crossref_metadata_2025 huggingface dataset:
The RhoGAP RRC-1 is required for the assembly or stability of integrin adhesion complexes and is a member of the PIX pathway in muscle
Authors: Moody Jasmine C. , Qadota Hiroshi , Benian Guy M.
Published: March 2024

GTPases cycle between active GTP bound and inactive GDP bound forms. Exchange of GDP for GTP is catalyzed by guanine nucleotide exchange factors (GEFs). GTPase activating proteins (GAPs) accelerate GTP hydrolysis, to promote the GDP bound form. We reported that the RacGEF, PIX-1, is required for assembly of integrin adhesion complexes (IAC) in striated muscle of Caenorhabditis elegans. In C. elegans, IACs are found at the muscle cell boundaries (MCBs), and bases of sarcomeric M-lines and dense bodies (Z-disks). Screening C. elegans mutants in proteins containing RhoGAP domains revealed that loss of function of rrc-1 results in loss of IAC components at MCBs, disorganization of M-lines and dense bodies, and reduced whole animal locomotion. RRC-1 localizes to MCBs, like PIX-1. The localization of RRC-1 at MCBs requires PIX-1, and the localization of PIX-1 requires RRC-1. Loss of function of CED-10 (Rac) shows lack of PIX-1 and RRC-1 at MCBs. RRC-1 exists in a complex with PIX-1. Transgenic rescue of rrc-1 was achieved with wild type RRC-1 but not RRC-1 with a missense mutation in a highly conserved residue of the RhoGAP domain. Our results are consistent with RRC-1 being a RhoGAP for the PIX pathway in muscle.
Reversible assembly and disassembly of V-ATPase during the lysosome regeneration cycle
Authors: Sava Ioana , Davis Luther J. , Gray Sally R. , Bright Nicholas A. , Luzio J. Paul
Published: March 2024

Regulation of the luminal pH of late endocytic compartments in continuously fed mammalian cells is poorly understood. Using normal rat kidney fibroblasts, we investigated the reversible assembly/disassembly of the proton pumping V-ATPase when endolysosomes are formed by kissing and fusion of late endosomes with lysosomes and during the subsequent reformation of lysosomes. We took advantage of previous work showing that sucrosomes formed by the uptake of sucrose are swollen endolysosomes from which lysosomes are reformed after uptake of invertase. Using confocal microscopy and subcellular fractionation of NRK cells stably expressing fluorescently tagged proteins, we found net recruitment of the V1 subcomplex during sucrosome formation and loss during lysosome reformation, with a similar time course to RAB7a loss. Addition of invertase did not alter mTORC1 signalling, suggesting that the regulation of reversible V-ATPase assembly/disassembly in continuously fed cells differs from that in cells subject to amino acid depletion/refeeding. Using live cell microscopy, we demonstrated recruitment of a fluorescently tagged V1 subunit during endolysosome formation and a dynamic equilibrium and rapid exchange between the cytosolic and membrane bound pools of this subunit. We conclude that reversible V-ATPase assembly/disassembly plays a key role in regulating endolysosomal/lysosomal pH in continuously fed cells.
Histone methyltransferase SETD2 is required for proper hippocampal lamination and neuronal maturation
Authors: Hu Guangda , Zheng Yue , Zhang Bo , Zhao Chen , Xu Lichao , Wei Jiayi , Jing Jing , Liu Ying , Zeng Tao , Zhou Yan
Published: March 2024

Proper formation of the hippocampus is crucial for the brain to execute memory and learning functions. However, many questions remain regarding how pyramidal neurons (PNs) of the hippocampus mature and precisely position. Here we revealed that Setd2, the methyltransferase for histone 3 lysine 36 trimethylation (H3K36me3), is essential for the precise localization and maturation of PNs in the hippocampal CA1. The ablation of Setd2 in neural progenitors leads to irregular lamination of the CA1 and increased numbers of PNs in the stratum oriens. Setd2 deletion in postmitotic neurons causes mislocalization and immaturity of CA1 PNs. Transcriptome analyses revealed that SETD2 maintains the expressions of clustered protocadherin ( cPcdh) genes. Together, Setd2 is required for proper hippocampal lamination and maturation of CA1 PNs.
Romantic Poets and the Laughter of Feeling
Authors: Ward Matthew
Published: March 2024

Romantic Poets and the Laughter of Feeling is a new and original reading of British Romanticism. While the Romantic period witnessed decisive interest in how feeling might align with forms of artistic expression, most critical studies have focused on the serious side and melancholic moods of Romantic poets. This book takes a markedly different approach, by embracing the sublime and the ridiculous, and revealing the decisive role laughter and the laughable play in Romantic emotions, aesthetics, and ethics. As this study uncovers, laughter was one of the principal means by which Romantics embraced and expanded upon, but also frequently aped and lampooned, sympathetic feeling. The laughter of feeling is both the expression of sympathy and an articulation of its implications, prejudices, and constraints. Voicing faith in sympathy, it also speaks to the complicated and ambivalent responses of Romantics to it: at once utterance, ideology, and irony. For Romantic poets like Wordsworth, Shelley, and Keats, the sound of laughter carries the hope that greater knowledge of others derives from feeling for and with them through poetry, and might lead to better understanding of oneself. Yet laughter also makes them all the more aware that our emotional lives are utterly unfamiliar and perhaps ultimately unknowable. Their prosody of laughter enlivens and exposes: embodies their sense of and ambitions for poetry, and calls those matters into the most comical and gravest doubt. Laughter helps define what it is to be human. This book shows that it also defines what it is to be a ‘Romantic’ poet.
Feeling Singular
Authors: Bascom Ben
Published: March 2024

Feeling Singular presents the early United States as a queer and messy world of social outcasts and eccentric personalities all vying—and in spectacular ways failing—for public attention. What image of the early United States emerges through the perspective of a cantankerous and workaday mechanic who botched his attempts to get people interested in his steamboat contraption? Through closely reading a range of texts—from manuscripts to hastily printed books, and from phonetically spelled pamphlets to sexually explicit broadsides—this book uses the language of queer studies to understand what makes someone singular in the early United States and how that singularity points at the ruptures in social codes that often get normalized through historical analysis. These figures include a struggling working-class mechanic named John Fitch; a formerly enslaved Black Revolutionary War veteran and Vermont farmer named Jeffrey Brace; a self-declared “Lord” named Timothy Dexter; Dexter’s strange “poet laureate” Jonathan Plummer; and lastly a hermit named William “Amos” Wilson. These singular life narratives provide noncanonical counters to what tends to be the staid studies of early U.S. literary cultures. By telling the stories of a motley set of characters, this book emphasizes the singular elements that constitute the lives that live under the shadow of cultural canons and norms. Departing from the likes of Benjamin Franklin, whom tradition positions as a paragon of self-production, this book offers the everyday queer failures that permeate the past.
Memorializing the Republic of Failure
Authors: Bascom Ben
Published: March 2024

This chapter examines the writings of a struggling working-class mechanic named John Fitch (1743–1798), who believed his was the genius to have discovered the ability to use steam power for mechanized automation. Fitch wrote an uncirculated multivolume manuscript about his life, and he used public forms of newsprint and pamphlet to work out his frustrations and animosity against a series of individuals he felt had balked his rise to prominence. Fitch is the ultimate anti-Franklinian figure, and his writings complicate accounts of republicanism, individualism, and the gendering of the public sphere.
Introduction to the EMBARK Approach
Authors: Brennan Bill , Belser Alex
Published: March 2024

Chapter 2 provides a rationale for the EMBARK approach, a therapeutic framework for administering psychedelic medicines. The authors assess previous PAT models, highlighting their strengths and shortcomings. They identify gaps in areas such as attentiveness to the body, attending to the therapeutic relationship, counseling for spiritual experiences, and ethical considerations. The chapter also discusses the challenges associated with prior PAT models, including (a) underdeveloped therapeutic frames and (b) single EBT-based PAT approaches. The EMBARK approach is presented as a solution to these challenges, offering a flexible and adaptable model for psychedelic therapy. EMBARK is an acronym, and its six clinical domains are outlined: Existential–Spiritual, Mindfulness, Body-Aware, Affective–Cognitive, Relational, and Keeping Momentum. EMBARK is also built upon a foundational belief that efficacious treatment is ethical treatment. It is built upon four cornerstones of care: Trauma-Informed Care, Culturally Competent Care, Ethically Rigorous Care, and Collective care.
EMBARK Mechanisms of Change in the Treatment of Depression
Authors: Brennan Bill , Belser Alex
Published: March 2024

Chapter 3 describes proposed psychological mechanisms of change within the EMBARK psychedelic therapy model for the treatment of depression. Twelve mechanisms of therapeutic change are described across the six EMBARK clinical domains: Existential–Spiritual: (a) spiritual self-development, (b) mystical experiences; Mindfulness: (c) freedom from rumination, (d) a more flexible identity, (e) greater compassion for oneself; Body-Aware: (f) embodiment and enlivenment, (g) somatic trauma processing; Affective–Cognitive: (h) transforming emotions and updating core beliefs, (i) increased acceptance of emotions; Relational: (j) relational repatterning, (k) increased interpersonal openness; Keeping Momentum: (l) building motivation for beneficial new habits and other life changes. Other potential mechanisms supported by the EMBARK approach are enumerated. A critique of the field’s overreliance on neurobiological mechanisms is offered. This chapter includes descriptions of the EBTs that inform the EMBARK approach to depression, including CBT approaches, emotion-focused therapy (EFT), motivational interviewing (MI), and acceptance and commitment therapy (ACT). The influence of other modalities on EMBARK is also discussed: the hakomi method, compassion-focused therapy, and spiritual evocation.
A 5-step root cause analysis model for test overutilization: A study on its application to plasma transferrin testing
Authors: Jittapranerat Jiracha , Chinswangwatanakul Wimol
Published: March 2024

Objectives

This study aimed to develop a root cause analysis (RCA) model for test overutilization, applying it to transferrin overordering at our institution.

Methods

A comprehensive review was undertaken to establish a systematic RCA model. Upon implementation, the questionnaire identifying the root causes of transferrin overordering with infographic intervention was distributed to clinicians and nurses.

Results

The RCA model comprises 5 steps: (1) problem identification, (2) causal factor determination, (3) data collection, (4) significant factor identification, and (5) corrective action development and outcome measurement. The major causes of transferrin overutilization were confusion between transferrin and transferrin saturation, as well as unfamiliarity with the laboratory handbook. An infographic reduced postintervention transferrin ordering among clinicians (84.9%, P < .001) and nurses (46.8%, P < .001).

Conclusions

This study presents a 5-step RCA model that offers a customized method to identify the causes of test overutilization. Applying this model to transferrin at our institution revealed 22 leading root causes. Laboratories are encouraged to adopt this RCA model as it can contribute to optimized patient care and more efficient resource allocation.
A novel approach to study multi-domain motions in JAK1’s activation mechanism based on energy landscape
Authors: Sun Shengjie , Rodriguez Georgialina , Zhao Gaoshu , Sanchez Jason E , Guo Wenhan , Du Dan , Rodriguez Moncivais Omar J , Hu Dehua , Liu Jing , Kirken Robert Arthur , Li Lin
Published: March 2024

The family of Janus Kinases (JAKs) associated with the JAK–signal transducers and activators of transcription signaling pathway plays a vital role in the regulation of various cellular processes. The conformational change of JAKs is the fundamental steps for activation, affecting multiple intracellular signaling pathways. However, the transitional process from inactive to active kinase is still a mystery. This study is aimed at investigating the electrostatic properties and transitional states of JAK1 to a fully activation to a catalytically active enzyme. To achieve this goal, structures of the inhibited/activated full-length JAK1 were modelled and the energies of JAK1 with Tyrosine Kinase (TK) domain at different positions were calculated, and Dijkstra’s method was applied to find the energetically smoothest path. Through a comparison of the energetically smoothest paths of kinase inactivating P733L and S703I mutations, an evaluation of the reasons why these mutations lead to negative or positive regulation of JAK1 are provided. Our energy analysis suggests that activation of JAK1 is thermodynamically spontaneous, with the inhibition resulting from an energy barrier at the initial steps of activation, specifically the release of the TK domain from the inhibited Four-point-one, Ezrin, Radixin, Moesin-PK cavity. Overall, this work provides insights into the potential pathway for TK translocation and the activation mechanism of JAK1.
Incorporating temporal information during feature engineering bolsters emulation of spatio-temporal emergence
Authors: Cain Jason Y , Evarts Jacob I , Yu Jessica S , Bagheri Neda
Published: March 2024

Motivation

Emergent biological dynamics derive from the evolution of lower-level spatial and temporal processes. A long-standing challenge for scientists and engineers is identifying simple low-level rules that give rise to complex higher-level dynamics. High-resolution biological data acquisition enables this identification and has evolved at a rapid pace for both experimental and computational approaches. Simultaneously harnessing the resolution and managing the expense of emerging technologies—e.g. live cell imaging, scRNAseq, agent-based models—requires a deeper understanding of how spatial and temporal axes impact biological systems. Effective emulation is a promising solution to manage the expense of increasingly complex high-resolution computational models. In this research, we focus on the emulation of a tumor microenvironment agent-based model to examine the relationship between spatial and temporal environment features, and emergent tumor properties.

Results

Despite significant feature engineering, we find limited predictive capacity of tumor properties from initial system representations. However, incorporating temporal information derived from intermediate simulation states dramatically improves the predictive performance of machine learning models. We train a deep-learning emulator on intermediate simulation states and observe promising enhancements over emulators trained solely on initial conditions. Our results underscore the importance of incorporating temporal information in the evaluation of spatio-temporal emergent behavior. Nevertheless, the emulators exhibit inconsistent performance, suggesting that the underlying model characterizes unique cell populations dynamics that are not easily replaced.

Availability and implementation

All source codes for the agent-based model, emulation, and analyses are publicly available at the corresponding DOIs: 10.5281/zenodo.10622155, 10.5281/zenodo.10611675, 10.5281/zenodo.10621244, respectively.
pyM2aia: Python interface for mass spectrometry imaging with focus on deep learning
Authors: Cordes Jonas , Enzlein Thomas , Hopf Carsten , Wolf Ivo
Published: March 2024

Python is the most commonly used language for deep learning (DL). Existing Python packages for mass spectrometry imaging (MSI) data are not optimized for DL tasks. We, therefore, introduce pyM2aia, a Python package for MSI data analysis with a focus on memory-efficient handling, processing and convenient data-access for DL applications. pyM2aia provides interfaces to its parent application M2aia, which offers interactive capabilities for exploring and annotating MSI data in imzML format. pyM2aia utilizes the image input and output routines, data formats, and processing functions of M2aia, ensures data interchangeability, and enables the writing of readable and easy-to-maintain DL pipelines by providing batch generators for typical MSI data access strategies. We showcase the package in several examples, including imzML metadata parsing, signal processing, ion-image generation, and, in particular, DL model training and inference for spectrum-wise approaches, ion-image-based approaches, and approaches that use spectral and spatial information simultaneously.

Availability and implementation

Python package, code and examples are available at (https://m2aia.github.io/m2aia)
Adaptive selection of the optimal strategy to improve precision and power in randomized trials
Authors: Balzer Laura B , Cai Erica , Godoy Garraza Lucas , Amaranath Pracheta
Published: March 2024

Benkeser et al. demonstrate how adjustment for baseline covariates in randomized trials can meaningfully improve precision for a variety of outcome types. Their findings build on a long history, starting in 1932 with R.A. Fisher and including more recent endorsements by the U.S. Food and Drug Administration and the European Medicines Agency. Here, we address an important practical consideration: how to select the adjustment approach—which variables and in which form—to maximize precision, while maintaining Type-I error control. Balzer et al. previously proposed Adaptive Pre-specification within TMLE to flexibly and automatically select, from a prespecified set, the approach that maximizes empirical efficiency in small trials (N < 40). To avoid overfitting with few randomized units, selection was previously limited to working generalized linear models, adjusting for a single covariate. Now, we tailor Adaptive Pre-specification to trials with many randomized units. Using V-fold cross-validation and the estimated influence curve-squared as the loss function, we select from an expanded set of candidates, including modern machine learning methods adjusting for multiple covariates. As assessed in simulations exploring a variety of data-generating processes, our approach maintains Type-I error control (under the null) and offers substantial gains in precision—equivalent to 20%-43% reductions in sample size for the same statistical power. When applied to real data from ACTG Study 175, we also see meaningful efficiency improvements overall and within subgroups.
Surface guided radiotherapy practice in paediatric oncology: a survey on behalf of the SIOPE Radiation Oncology Working Group
Authors: Seravalli Enrica , Kroon Petra S , Bolle Stephanie , Dunlea Cathy , Harrabi Semi B , Laprie Anne , Lassen-Ramshad Yasmin , Whitfield Gillian , Janssens Geert O
Published: March 2024

Introduction

Surface guided radiotherapy (SGRT) is increasingly being implemented to track patient’s surface movement and position during radiation therapy. However, limited information is available on the SGRT use in paediatrics. The aim of this double survey was to map SIOPE (European Society for Paediatric Oncology)-affiliated centres using SGRT and to gain information on potential indications, observed, or expected benefits.

Methods

A double online survey was distributed to 246 SIOPE-affiliated radiotherapy (RT) centres. Multiple choices, yes/no, and open answers were included. The first survey (41 questions) was active from February to March 2021. A shortened version (13 questions) was repeated in March 2023 to detect trends in SGRT use within the same community.

Results

Respectively, 76/142 (54%) and 28/142 (20%) responding centres used and planned to use SGRT clinically, including 4/34 (12%) new centres since 2021. Among the SGRT users, 33/76 (43%) already applied this technology to paediatric treatments. The main benefits of improved patient comfort, better monitoring of intrafraction motion, and more accurate initial patient set-up expected by future users did not differ from current SGRT-users (P = .893). Among non-SGRT users, the main hurdles to implement SGRT were costs and time for installation. In paediatrics, SGRT is applied to all anatomical sites.

Conclusion

This work provides information on the practice of SGRT in paediatrics across SIOPE-affiliated RT centres which can serve as a basis for departments when considering the purchase of SGRT systems.

Advances in knowledge

Since little information is available in the literature on the use of SGRT in paediatrics, the results of this double survey can serve as a basis for departments treating children when considering the purchase of an SGRT system.
Prophylaxis in hereditary angioedema: a United Kingdom Delphi consensus
Authors: Yong Patrick F K , Annals Rachel , Diwakar Lavanya , Elkhalifa Shuayb , Gompels Mark , Jain Rashmi , Karim Mohammed Yousuf , Khan Sujoy , Metcalfe Angela , Noorani Sadia , Steele Cathal , Kiani-Alikhan Sorena , Garcez Tomaz
Published: March 2024

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development.
Quantifying microglial morphology: an insight into function
Authors: Green Tabitha R F , Rowe Rachel K
Published: March 2024

Microglia are specialized immune cells unique to the central nervous system (CNS). Microglia have a highly plastic morphology that changes rapidly in response to injury or infection. Qualitative and quantitative measurements of ever-changing microglial morphology are considered a cornerstone of many microglia-centric research studies. The distinctive morphological variations seen in microglia are a useful marker of inflammation and severity of tissue damage. Although a wide array of damage-associated microglial morphologies has been documented, the exact functions of these distinct morphologies are not fully understood. In this review, we discuss how microglia morphology is not synonymous with microglia function, however, morphological outcomes can be used to make inferences about microglial function. For a comprehensive examination of the reactive status of a microglial cell, both histological and genetic approaches should be combined. However, the importance of quality immunohistochemistry-based analyses should not be overlooked as they can succinctly answer many research questions.
Clinical and Virological Outcome of Monoclonal Antibody Therapies Across SARS-CoV-2 Variants in 245 Immunocompromised Patients: A Multicenter Prospective Cohort Study
Authors: Huygens Sammy , GeurtsvanKessel Corine , Gharbharan Arvind , Bogers Susanne , Worp Nathalie , Boter Marjan , Bax Hannelore I , Kampschreur Linda M , Hassing Robert-Jan , Fiets Roel B , Levenga Henriette , Afonso Pedro Miranda , Koopmans Marion , Rijnders Bart J A , Oude Munnink Bas B
Published: March 2024

Background

Immunocompromised patients (ICPs) have an increased risk for a severe and prolonged COVID-19. SARS-CoV-2 monoclonal antibodies (mAbs) were extensively used in these patients, but data from randomized trials that focus on ICPs are lacking. We evaluated the clinical and virological outcome of COVID-19 in ICPs treated with mAbs across SARS-CoV-2 variants.

Methods

In this multicenter prospective cohort study, we enrolled B-cell– and/or T-cell–deficient patients treated with casirivimab/imdevimab, sotrovimab, or tixagevimab/cilgavimab. SARS-CoV-2 RNA was quantified and sequenced weekly, and time to viral clearance, viral genome mutations, hospitalization, and death rates were registered.

Results

Two hundred and forty five patients infected with the Delta (50%) or Omicron BA.1, 2, or 5 (50%) variant were enrolled. Sixty-seven percent were vaccinated; 78 treated as outpatients, of whom 2 required hospital admission, but both survived. Of the 159 patients hospitalized at time of treatment, 43 (27%) required mechanical ventilation or died. The median time to viral clearance was 14 days (interquartile range, 7–22); however, it took >30 days in 15%. Resistance-associated spike mutations emerged in 9 patients in whom the median time to viral clearance was 63 days (95% confidence interval, 57–69; P < .001). Spike mutations were observed in 1 of 42 (2.4%) patients after treatment with 2 active mAbs, in 5 of 34 (14.7%) treated with actual monotherapy (sotrovimab), and 3 of 20 (12%) treated with functional monotherapy (ie, tixagevimab/cilgavimab against tixagevimab-resistant variant).

Conclusions

Despite treatment with mAbs, morbidity and mortality of COVID-19 in ICPs remained substantial. Combination antiviral therapy should be further explored and may be preferred in severely ICPs.
Potential role of cardiopulmonary exercise testing in evaluating functional improvement after transcatheter edge-to-edge tricuspid valve repair: a case report
Authors: Cumitini Luca , Giubertoni Ailia , Mennuni Marco Giovanni , Degiovanni Anna , Patti Giuseppe
Published: March 2024

Background

Tricuspid regurgitation (TR) is common and severe or greater TR is linked to poor prognosis. Treatment of TR with transcatheter edge-to-edge repair has emerged as a safe and potentially effective therapy in these patients. However, the impact of transcatheter tricuspid repair on functional capacity remains to be elucidated.

Case summary

We describe the case of a 77-year-old woman complaining of heart failure symptoms, undergoing transcatheter edge-to-edge valve repair for severe TR with the PASCAL Ace® device. One month later, cardiopulmonary exercise testing (CPET) showed significant improvement in peak O2 uptake and O2 pulse compared with the test performed before the procedure.

Discussion

A positive impact of novel transcatheter edge-to-edge valve repair on symptoms and quality of life in patients with severe or greater TR at prohibitive surgical risk has recently emerged. The presence of severe TR has prognostic relevance, and novel percutaneous tricuspid valve repair systems have emerged in the last few years. Cardiopulmonary exercise testing is an established tool to assess functional capacity and prognosis in heart failure patient. Detecting functional capacity improvement after transcatheter edge-to-edge repair for severe TR can be challenging, and CPET may arise as a promising tool to help these purposes.
Prediction of symptom development and aortic valve replacement in patients with low-gradient severe aortic stenosis
Authors: Miyahara Daisuke , Izumo Masaki , Sato Yukio , Shoji Tatsuro , Murata Risako , Oda Ryutaro , Okuno Taishi , Kuwata Shingo , Akashi Yoshihiro J
Published: March 2024

Aims

Current evidence on the prognostic value of exercise stress echocardiography (ESE) in asymptomatic patients with low-gradient severe aortic stenosis (AS) is limited. Therefore, this study aimed to elucidate its prognostic implications for patients with low-gradient severe AS and determine the added value of ESE in risk stratification for this population.

Methods and results

This retrospective observational study included 122 consecutive asymptomatic patients with either moderate [mean pressure gradient (MPG) < 40 mmHg and aortic valve area (AVA) 1.0–1.5 cm2] or low-gradient severe (MPG < 40 mmHg and AVA < 1.0 cm2) AS and preserved left ventricular ejection fraction (≥50%) who underwent ESE. All patients were followed up for AS-related events. Of 143 patients, 21 who met any exclusion criteria, including early interventions, were excluded, and 122 conservatively managed patients [76.5 (71.0–80.3) years; 48.3% male] were included in this study. During a median follow-up period of 989 (578–1571) days, 64 patients experienced AS-related events. Patients with low-gradient severe AS had significantly lower event-free survival rates than those with moderate AS (log-rank test, P < 0.001). Multivariable Cox regression analysis showed that the mitral E/e′ ratio during exercise was independently associated with AS-related events (hazard ratio = 1.075, P < 0.001) in patients with low-gradient severe AS.

Conclusion

This study suggests that asymptomatic patients with low-gradient severe AS have worse prognoses than those with moderate AS. Additionally, the mitral E/e′ ratio during exercise is a useful parameter for risk stratification in patients with low-gradient severe AS.
Exploring moral education in the Chinese EFL classroom
Authors: Lin Lin
Published: March 2024

Traditional EFL classes for English majors in mainland China have focused on promoting students’ language skills while, at the same time, cultivating their communication and critical thinking. In this article, I discuss a recent nationwide educational reform, i.e., moral education. I will highlight the challenges facing Chinese English language teachers in incorporating this reform and specify how I identified the moral components within the English course I taught. Some strategies for integrating these components into the English instruction are provided accordingly to enhance students’ moral development in addition to language skills.
Comparative assessment of Nanotrap and polyethylene glycol-based virus concentration in wastewater samples
Authors: Farkas Kata , Kevill Jessica L , Williams Rachel C , Pântea Igor , Ridding Nicola , Lambert-Slosarska Kathryn , Woodhall Nick , Grimsley Jasmine M S , Wade Matthew J , Singer Andrew C , Weightman Andrew J , Cross Gareth , Jones Davey L
Published: March 2024

Wastewater-based epidemiology is now widely used in many countries for the routine monitoring of SARS-CoV-2 and other viruses at a community level. However, efficient sample processing technologies are still under investigation. In this study, we compared the performance of the novel Nanotrap® Microbiome Particles (NMP) concentration method to the commonly used polyethylene glycol (PEG) precipitation method for concentrating viruses from wastewater and their subsequent quantification and sequencing. For this, we first spiked wastewater with SARS-CoV-2, influenza and measles viruses and norovirus and found that the NMP method recovered 0.4%–21% of them depending on virus type, providing consistent and reproducible results. Using the NMP and PEG methods, we monitored SARS-CoV-2, influenza A and B viruses, RSV, enteroviruses and norovirus GI and GII and crAssphage in wastewater using quantitative PCR (qPCR)-based methods and next-generation sequencing. Good viral recoveries were observed for highly abundant viruses using both methods; however, PEG precipitation was more successful in the recovery of low-abundance viruses present in wastewater. Furthermore, samples processed with PEG precipitation were more successfully sequenced for SARS-CoV-2 than those processed with the NMP method. Virus recoveries were enhanced by high sample volumes when PEG precipitation was applied. Overall, our results suggest that the NMP concentration method is a rapid and easy virus concentration method for viral targets that are abundant in wastewater, whereas PEG precipitation may be more suited to the recovery and analysis of low-abundance viruses and for next generation sequencing.
Disability history in France: past, present and future
Authors: Scales Rebecca P , Bas Jérôme , Brégain Gildas , Briggs Jonathyne , Hewitt Jessie , Kudlick Catherine J , Park Sun-Young
Published: March 2024

What is disability? How might a focus on disability as a category of human experience change the way we think and write about the French past? In this roundtable seven historians discuss the emergence of disability studies in France, assessing the continued relevance of classics in the field as well as new directions in research. Scholarly attention to disability, the contributors argue, has the potential to transform modern French historiography, not only by challenging our understanding of major ‘turning points’ such as the French Revolution or the world wars, but offering fresh insights into race, class and gender identities, as well as citizenship, inclusion and belonging in French society.
Physical properties variations in a shaly formation across a fault core
Authors: Bonnelye Audrey , David Christian , Wassermann Jérôme , Schubnel Alexandre , Henry Pierre , Guglielmi Yves , Gout Claude , Dick Pierre
Published: March 2024

Faults in general, and in clay materials in particular, have complex structures that can be linked to both a polyphased tectonic history and to the anisotropic nature of the intact rock. Drilling through faults in shaly materials allows measuring properties such as the structure, mineralogical composition, stress orientation and physical properties. We combine different petrophysical measurements on core samples retrieved from a borehole drilled perpendicularly to a fault zone affecting Toarcian shales from the Tournemire underground research laboratory (France). The borehole is cross-cutting the entire fault thickness which is of the order of 10 m. We perform several types of measurements: density, porosity, saturation directly in the field and P-wave velocities together with P-waves anisotropy on core samples taken at regular intervals. Special protocols were developed to preserve as much as possible the saturation state of the samples. From our measurements, we were able to track the increase of damage, characterized by a smooth decrease in elastic moduli from the intact zone to the fault core. We then calculated Thomsen's parameters to quantify the elastic anisotropy evolution across the fault. Our results show strong variations of the elastic anisotropy with the distance to the fault core as well as the occurrence of anisotropy reversal.
Geomechanical modelling of injection-induced seismicity: the case study of the Muara Laboh geothermal plant
Authors: Gerardi G , Dublanchet P , Jeannin L , Kazantsev A , Duboeuf L , Ramadhan I , Azis H , Ganefianto N , Nugroho I A
Published: March 2024

In this work, we study the induced seismicity recorded during an injection operation at the Muara Laboh geothermal plant (Indonesia). The swarm, consisting of three bursts activating a normal fault zone, is characterized by rapid earthquake (km d−1) migration. We use a 2-D rate-and-state asperity model to better understand the physical mechanisms controlling the evolution of this induced swarm. The model suggests that the observed rapid seismic migration can be explained by the interaction among asperities through the expansion of slow post-seismic slip fronts. Also, it shows that the amount of seismicity generated by the fluid injection is strongly controlled by the background seismicity of the system, that is by the seismicity determined by the tectonic load charging the fault. This close correlation between natural and induced seismicity suggests that the injection in Muara Laboh principally stimulates critically stressed faults, which release the seismicity determined by their natural seismic cycle.
SdrR, a LysR-type regulator, responds to the mycobacterial antioxidant defense
Authors: Zhu Chen , Wei Wen-ping , An Jing-ning , Hu Jia-ling , Gao Chun-hui , Yang Min
Published: March 2024

Protection against oxidative stress is a vital defense mechanism for Mycobacterium tuberculosis within the host. However, few transcription factors that control bacterial antioxidant defense are known. Here, we present evidence that SdrR, encoded by the MSMEG_5712 (Ms5712) gene, functions as an oxidative stress response regulator in Mycobacterium smegmatis. SdrR recognizes an 11-bp motif sequence in the operon's upstream regulatory region and negatively regulates the expression of short-chain dehydrogenases/reductases (SDR). Overexpressing sdrR inhibited SDR expression, which rendered the strain oxidative more stress-sensitive. Conversely, sdrR knockout alleviates SDR repression, which increases its oxidative stress tolerance. Thus, SdrR responds to oxidative stress by negatively regulating sdr expression. Therefore, this study elucidated an underlying regulatory mechanism behind mycobacterial oxidative stress adaptation.
Coming out in America: thirty years of cultural change
Authors: Fernández Raquel , Parsa Sahar , Viarengo Martina
Published: March 2024

The last few decades witnessed a dramatic change in public opinion toward gay people. We show that this process was initiated by a sharp increase in the approval of same-sex relationships in 1992–93, following the debate on whether gay people could serve openly in the military. We study the hypothesis that the greater salience of gay-related issues during this period initiated a process of cultural change. Using a difference-in-difference empirical strategy, we show that greater exposure to the gay population, measured in a variety of ways, led to a greater increase in approval. Furthermore, media attention and campaign contributions increased by more in high exposure locations. Our results, we show, cannot be explained simply by a process of expanding liberal views of civil liberties.
Synergistic regulation of fusion pore opening and dilation by SNARE and synaptotagmin-1
Authors: Li Kaiju , Li Kaiyu , Fan Jiaqi , Zhang Xing , Tao Chengyan , Xiang Yijuan , Cui Lele , Li Hao , Li Minghan , Zhang Yanjing , Geng Jia , Lai Ying
Published: March 2024

Fusion pore opening is a transient intermediate state of synaptic vesicle exocytosis, which is highly dynamic and precisely regulated by the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex and synaptotagmin-1 (Syt1). Yet, the regulatory mechanism is not fully understood. In this work, using single-channel membrane fusion electrophysiology, we determined that SNAREpins are important for driving fusion pore opening and dilation but incapable of regulating the dynamics. When Syt1 was added, the closing frequency of fusion pores significantly increased, while the radius of fusion pores mildly decreased. In response to Ca2+, SNARE/Syt1 greatly increased the radius of fusion pores and reduced their closing frequency. Moreover, the residue F349 in the C2B domain of Syt1, which mediates Syt1 oligomerization, was required for clamping fusion pore opening in the absence of Ca2+, probably by extending the distance between the two membranes. Finally, in Ca2+-triggered fusion, the primary interface between SNARE and Syt1 plays a critical role in stabilizing and dilating the fusion pore, while the polybasic region of Syt1 C2B domain has a mild effect on increasing the radius of the fusion pore. In summary, our results suggest that Syt1, SNARE, and the anionic membrane synergically orchestrate the dynamics of fusion pore opening in synaptic vesicle exocytosis.
Effects of a change in recall period on reporting severe symptoms: an analysis of a pragmatic multisite trial
Authors: Paudel Roshan , Enzinger Andrea C , Uno Hajime , Cronin Christine , Wong Sandra L , Dizon Don S , Hazard Jenkins Hannah , Bian Jessica , Osarogiagbon Raymond U , Jensen Roxanne E , Mitchell Sandra A , Schrag Deborah , Hassett Michael J
Published: March 2024

Background

Optimal methods for deploying electronic patient-reported outcomes to manage symptoms in routine oncologic practice remain uncertain. The electronic symptom management (eSyM) program asks chemotherapy and surgery patients to self-report 12 common symptoms regularly. Feedback from nurses and patients led to changing the recall period from the past 7 days to the past 24 hours.

Methods

Using questionnaires submitted during the 16 weeks surrounding the recall period change, we assessed the likelihood of reporting severe or moderate and severe symptoms across 12 common symptoms and separately for the 5 most prevalent symptoms. Interrupted time-series analyses modeled the effects of the change using generalized linear mixed-effects models. Surgery and chemotherapy cohorts were analyzed separately. Study-wide effects were estimated using a meta-analysis method.

Results

In total, 1692 patients from 6 institutions submitted 7823 eSyM assessments during the 16 weeks surrounding the recall period change. Shortening the recall period was associated with lower odds of severe symptom reporting in the surgery cohort (odds ratio = 0.65, 95% confidence interval = 0.46 to 0.93; P = .02) and lower odds of moderate and severe symptom reporting in the chemotherapy cohort (odds ratio = 0.83, 95% confidence interval = 0.71 to 0.97; P = .02). Among the most prevalent symptoms, 24-hour recall was associated with a lower rate of reporting postoperative constipation but no differences in reporting rates for other symptoms.

Conclusion

A shorter recall period was associated with a reduction in the proportion of patients reporting moderate-severe symptoms. The optimal recall period may vary depending on whether electronic patient-reported outcomes are collected for active symptom management, as a clinical trial endpoint, or another purpose.

ClinicalTrials.gov ID NCT03850912.
Reimagining academic freedom: a companion piece
Authors: Pirrie Anne , Manum Kari
Published: March 2024

We consider academic freedom in the context of broader developments in higher education. We suggest that the tenor of contemporary debates on the subject is a manifestation of pervasive forms of authoritarianism that undermine the university as a home of adventure, a place and space that is conducive to the conduct of free inquiry.

It is evident that some champions of academic freedom engage in dangerously polarized forms of spectacle, engendered by a management culture that embraces showmanship and routinely favours talking over listening. As such, they represent a force for conformity rather than dissent; division rather than collective action. These forms of spectacle jeopardize rather than promote the principles of academic freedom by polarizing the terms of the debate for maximum ‘impact’. We explore the implications of conceptualizations of academic freedom that focus on the rights of everyone in the university. We also suggest that the notion might usefully be extended to those on precarious contracts, and to students facing normative expectations about what constitutes ‘progress’ in academic practice. Drawing upon Timothy Snyder’s On Tyranny: Twenty Lessons from the Twentieth Century and an essay by Vaclav Havel, we reassess the notion of the ‘pursuit of truth’ that underlies conventional definitions of academic freedom.

We conclude with a brief vignette, a rousing endorsement of the ineffable and irreducible qualities of friendship. This entails slaying a fictitious, three-headed dragon and embracing a form of spectacle that transcends attempts to capture why it moves us. We leave the reader with warm-blooded traces of energy, curiosity, liveliness, and quiet determination.
Application of the thermal death time model in predicting thermal damage accumulation in plants
Authors: Faber Andreas H , Ørsted Michael , Ehlers Bodil Kirstine
Published: March 2024

The thermal death time (TDT) model suggests that the duration for which an organism can tolerate thermal stress decreases exponentially as the intensity of the temperature becomes more extreme. This model has been used to predict damage accumulation in ectothermic animals and plants under fluctuating thermal conditions. However, the critical assumption of the TDT model, which is additive damage accumulation, remains unverified for plants. We assessed thermal damage in Thymus vulgaris under different heat and cold treatments, and used TDT models to predict time to thermal failure of PSII. Additionally, thermal tolerance estimates from previous studies were used to create TDT models to assess the applicability of this framework in plants. We show that thermal damage is additive between 44 °C and 47 °C and between –6.5 °C and –8 °C, and that the TDT model can predict damage accumulation at both temperature extremes. Data from previous studies indicate a broad applicability of this approach across plant species and traits. The TDT framework reveals a thermal tolerance landscape describing the relationship between exposure duration, stress intensity, and percentage damage accumulation. The extreme thermal sensitivity of plants emphasizes that even a 1 °C increase in future extreme temperatures could impact their mortality and distribution.
Influence of the Emitter Shape on the Field-of-View in Atom Probe Tomography
Authors: Dialameh Masoud , Ling Yu-Ting , Bogdanowicz Janusz , Zharinov Vyacheslav S , Richard Olivier , Vandervorst Wilfried , Fleischmann Claudia
Published: March 2024

Atom probe tomography (APT) is a unique analytical technique that offers three-dimensional elemental mapping with a spatial resolution down to the sub-nanometer. When APT is applied on complex heterogenous systems and/or under certain experimental conditions, that is, laser illumination, the specimen shape can deviate from an ideal hemisphere. Insufficient consideration of this aspect can introduce artifacts in the reconstructed dataset, ultimately degrading its spatial accuracy. So far, there has been limited investigation into the detailed evolution of emitter shape and its impact on the field-of-view (FOV). In this study, we numerically and experimentally investigated the FOV for asymmetric emitters and its evolution throughout the analysis depth. Our analysis revealed that, for asymmetric emitters, the ions evaporated from the topmost region of the specimen (summit) project approximately to the detector center. Furthermore, we demonstrated the implications of this finding on the FOV location for asymmetric emitters. Based on our findings, the location of the center of the FOV can deviate from the specimen central axis with an evolution depending on the evolution of the emitter shape. This study highlights the importance of accounting for the specimen shape when developing advanced data reconstruction schemes to enhance spatial resolution and accuracy.