bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Training and Development Process for a Multiple-Grand-Slam Finalist in Tennis
Authors: Haugen Thomas A. , Ruud Caroline , Bucher Sandbakk Silvana , Sandbakk Øyvind , Tønnessen Espen 
Published: August 2024

Purpose: To investigate the training and development process of a multiple-Grand-Slam finalist. Methods: A mixed-methods case-study design was used to capture the quantitative and qualitative aspects related to the training and successful development process. We used a 3-step data-collection process and pragmatic analyses of (1) training history based on logs, plans, and questionnaires; (2) in-depth semistructured interviews with the player’s head coach/father, physical coach, and team administrator/mother; and (3) systematic quality assurance through negotiation among researchers and all key informants, including the player. Results: The player’s exceptional performance level was achieved by a progressive, nonlinear increase in annual training load during childhood and early youth, stabilizing at 800 sessions and 1250 to 1300 hours per year at the age of 19. The annual tennis-specific training plateaued at ∼750 hours from the age of 15, and 60 to 80 matches were played in most of the analyzed years. Point-play accounted for approximately 50% of the total amount of specific tennis training, clearly ahead of ground strokes (∼30%), serve/return (∼15%), and smash/volley (∼5%). Physical-conditioning hours increased 5-fold from 12 to 19 years, before stabilizing at ∼500 hours at senior age. Key success factors included the athlete’s multidimensional sports talent, discipline, and inner drive; a highly dedicated father and tennis-enthusiastic family; and strong support from a complementary and interdisciplinary performance team. Conclusion: This study provides novel information regarding the training and development process for a world-leading tennis player, providing a point of departure for the development of future talents.
Habituation Does Not Change Running Economy in Advanced Footwear Technology
Authors: Schwalm Lars C. , Fohrmann Dominik , Schaffarczyk Marcelle , Gronwald Thomas , Willwacher Steffen , Hollander Karsten 
Published: August 2024

Purpose: This study aimed to compare running economy across habituated and nonhabituated advanced footwear technology (AFT) in trained long-distance runners. Methods: A total of 16 participants completed up to six 5-minute trials in 1 to 3 pairs of their own habituated shoes and 3 different and standardized AFTs at individual marathon pace. We measured oxygen uptake and carbon dioxide production and expressed running economy as oxygen uptake (in milliliters oxygen per kilogram per minute), oxygen cost of transport (oxygen per kilogram per minute), energetic cost (in watts per kilogram), and energetic cost of transport (in joules per kilogram per kilometer). We used linear mixed-effect models to evaluate differences. Relative shoe weight and shoe mileage (distance worn during running) were covariates. Results: Forty-eight standardized and 29 individual AFT conditions were measured (mileage 117.0 [128.8] km, range 0–522 km; 25 habituated 135.7 [129.2] km, range 20–522 km; 4 nonhabituated 0 [0] km, range 0–0 km). Rating of perceived exertion, blood [La], and respiratory exchange ratio ranged from 9 to 15, 1.11 to 4.54 mmol/L, and 0.76 to 1.01. There was no effect for habituation on energetic cost of transport (thabituation = −.232, P = .409, b = −0.006; 95% CI, −0.058 to 0.046) or other running economy metrics. Neither shoe weight nor shoe mileage had an effect. Conclusions: Our results suggest that habituation to AFTs does not result in greater benefits in the use of AFTs. This means that implementation in training may not be needed, even if we cannot rule out any other possible benefits of habituation at this stage, such as adaptation of the musculoskeletal system.
The Role of Grandparents in Facilitating Children’s Physical Activity
Authors: Jongenelis Michelle I. , Budden Timothy , Christian Hayley , Coall David A. , Jackson Ben , Nathan Andrea , Glassenbury Emma 
Published: August 2024

Background: Research suggests there is considerable opportunity to improve children’s movement behaviors while they are being cared for by their grandparents. An understanding of the extent to which grandparent practices facilitate children’s engagement in physical activity is critical to the development of health interventions targeting grandparent caregivers. This study examined the activity-related beliefs and practices of grandparents and their association with grandchildren’s engagement in various movement behaviors while in grandparental care. Methods: Australian grandparents (N = 1190; 60% women) who provided regular care to a grandchild aged 3–14 years were recruited via a web panel provider to complete an online survey. The survey assessed grandparents’ physical activity-related beliefs (eg, perceived importance) and practices (eg, support and social control) and their grandchildren’s engagement in physical activity (unstructured, structured, and outdoor play) and screen-based activities while in grandparental care. Results: The importance of grandchildren’s physical activity was rated highly by grandparents. Grandparents’ support for their grandchildren’s physical activity was positively associated with their grandchildren’s engagement in structured physical activity, unstructured physical activity, and outdoor play. Negative social control was associated with greater engagement in screen-based activities. Other correlates of grandchildren’s physical activity and screen-based activities included grandparents’ own engagement in these activities. Conclusions: Findings highlight the importance of reinforcing the beliefs and practices that positively influence children’s movement behaviors and addressing those that have unintended consequences. Encouraging grandparents to support their grandchildren’s physical activity and discouraging forms of negative social control are likely to be important in efforts to promote physical activity in children.
High heart rates during paroxysmal atrial fibrillation: continuous rhythm monitoring data of the RACE V study
Authors: Koldenhof Tim , Van Gelder Isabelle C , van de Lande Martijn E , Al-Jazairi Meelad I H , Tieleman Robert G , Rienstra Michiel 
Published: August 2024

BackgroundPreventing high heart rates in patients with atrial fibrillation (AF) is a key objective of AF management. Data regarding heart rates in patients with paroxysmal AF (PAF) is lacking. This analysis aimed to provide insight into heart rates during PAF episodes measured with continuous implantable loop monitoring.MethodsIn present analysis of the Interaction between hyperCoagulability, Electrical remodeling, and Vascular Destabilization in the Progression of AF study, we included 349 patients with at least one year of continuous rhythm monitoring and an episode of AF. Mean heart rates and duration of AF episodes were used to calculate total AF duration and AF duration above different heart rate cut-offs.ResultsThe median age was 64.0 (58.4 to 70.5) years, 152 (44%) were women and CHA2DS2-VASc score ≥2 or higher in 255 (73%) patients. During 28.3 (21.3 to 35.0) months of follow-up, the median number of AF episodes was 62 (12 to 293) with a median total AF duration of 4.6 (0.8 to 26.8) days. At baseline, 172 (49%) patients used beta-blockers, 64 (18%) used diltiazem or verapamil and 5 (1%) used digoxin. A total of 133 patients (38%) experienced a heart rate >110 bpm for more than 50% of the time during AF. Fifty-six (16%) patients had a heart rate >130 bpm for more than 50% of the time while in AF. During follow-up, 39 patients (11%) received an increase of rate-controlling medication.ConclusionContinuous rhythm monitoring revealed that more than a third of PAF patients had heart rates above 110 bpm for more than half of their time in AF.Trial registration numberClinicaltrials.gov identifierNCT02726698.
PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis
Authors: Wu Jinghao , Mei Yunyun , Li XinYu , Yu Wen-Kai , Zhou Zi Han , Yang Yinghao , Niu Pengpeng , Wang Yunchao , Shi Chang-He , Zhu Hanghang , He Wenjun , Gao Yuan , Xu Yuming , Li Yusheng 
Published: August 2024

Background
Cerebral aneurysms are life-threatening cerebrovascular disorders. Currently, there are no effective treatments for preventing disease progression. Mendelian randomisation (MR) is widely used to repurify licensed drugs and identify new therapeutic targets. Therefore, this study aims to investigate effective drug targets for preventing the formation and rupture of cerebral aneurysms and analyse their potential mechanisms.

Methods

We performed a comprehensive study integrating two-sample MR analysis, colocalisation analysis and summary data-based Mendelian randomisation (SMR) to assess the causal effects of blood and brain druggable cis-expression quantitative trait loci (cis-eQTLs) on intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA) and subarachnoid haemorrhage of IA rupture (SAH). Druggable genes were obtained from the study by Chris Finan
et al
, cis-eQTLs from the eQTLGen and PsychENCODE consortia. Results were validated using proteomic and transcriptomic data. Single-gene functional analyses probed potential mechanisms, culminating in the construction of a drug-gene regulation network.

Results
Through the MR analysis, we identified four potential drug targets in the blood, including prolylcarboxypeptidase (PRCP), proteasome 20S subunit alpha 4 (PSMA4), LTBP4 and GPR160 for SAH. Furthermore, two potential drug targets (PSMA4 and SLC22A4) were identified for IA and one potential drug target (KL) for UIA after accounting for multiple testing (P(inverse-variance weighted)<8.28e-6). Strong evidence of colocalisation and SMR analysis confirmed the relevance of PSMA4 and PRCP in outcomes. Elevated PRCP circulating proteins correlated with a lower SAH risk. PRCP gene expression was significantly downregulated in the disease cohort.

Conclusions
This study supports that elevated PRCP gene expression in blood is causally associated with the decreased risk of IA rupture. Conversely, increased PSMA4 expression in the blood is causally related to an increased risk of IA rupture and formation.
Z boson emission by an electron and the decays of Z boson into fermions in a de Sitter universe
Authors: Crucean Cosmin , Dumitrele Diana 
Published: August 2024

AbstractIn this paper we develop a method to obtain the rates for the decay of a Z boson into fermions in de Sitter geometry. Our general results obtained in de Sitter space-time allow us to obtain the Minkowski limits for the transition rates when the expansion parameter vanishes. Another important result reported in the present study is related to the emission of Z bosons by electrons and positrons. All the processes were studied by implementing perturbative methods that allow us to define the transition amplitudes in the first order of perturbation theory. The variation of probabilities and rates in terms of expansion parameter and particles masses is also given, pointing out that the processes that generate particle production are possible only in the early universe. For computing the transition rates and probabilities we use the dimensional regularization method and the minimal substraction method.
Periodic Orbit-Dividing Surfaces in Rotating Hamiltonian Systems with Three Degrees of Freedom – I
Authors: Katsanikas Matthaios , Wiggins Stephen 
Published: August 2024

In this paper, we extend the notion of periodic orbit-dividing surfaces (PODSs) to rotating Hamiltonian systems with three degrees of freedom. First, we present how to apply our first method for the construction of PODSs [ Katsanikas & Wiggins , 2021a , 2023a ] to rotating Hamiltonian systems with three degrees of freedom. Then, we study the structure of these surfaces in a rotating quadratic normal-form Hamiltonian system with three degrees of freedom.
PTEN Loss Shapes Macrophage Dynamics in High-Grade Serous Ovarian Carcinoma
Authors: Spear Sarah , Le Saux Olivia , Mirza Hasan B. , Iyer Nayana , Tyson Katie , Grundland Freile Fabio , Walton Josephine B. , Woodman Chloé , Jarvis Sheba , Ennis Darren P. , Aguirre Hernandez Carmen , Xu Yuewei , Spiliopoulou Pavlina , Brenton James D. , Costa-Pereira Ana P. , Cook David P. , Vanderhyden Barbara C. , Keun Hector C. , Triantafyllou Evangelos , Arnold James N. , McNeish Iain A. 
Published: August 2024

Abstract
High-grade serous ovarian carcinoma (HGSC) remains a disease with poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity. Single-cell RNA sequencing identified populations of resident macrophages specific to Pten-null omental tumors in murine models, which were confirmed by flow cytometry. These macrophages were derived from peritoneal fluid macrophages and exhibited a unique gene expression program, marked by high expression of the enzyme heme oxygenase-1 (HMOX1). Targeting resident peritoneal macrophages prevented the appearance of HMOX1hi macrophages and reduced tumor growth. In addition, direct inhibition of HMOX1 extended survival in vivo. RNA sequencing identified IL33 in Pten-null tumor cells as a likely candidate driver, leading to the appearance of HMOX1hi macrophages. Human HGSC tumors also contained HMOX1hi macrophages with a corresponding gene expression program. Moreover, the presence of these macrophages was correlated with activated tumoral PI3K/mTOR signaling and poor overall survival in patients with HGSC. In contrast, tumors with low numbers of HMOX1hi macrophages were marked by increased adaptive immune response gene expression. These data suggest targeting HMOX1hi macrophages as a potential therapeutic strategy for treating poor prognosis HGSC.
Significance: Macrophages with elevated HMOX1 expression are enriched in PTEN-deficient high-grade serous ovarian carcinoma, promote tumor growth, and represent a potential therapeutic target.
CRISPR Screening of Transcribed Super-Enhancers Identifies Drivers of Triple-Negative Breast Cancer Progression
Authors: Lewis Michael W. , King Caitlin M. , Wisniewska Kamila , Regner Matthew J. , Coffey Alisha , Kelly Michael R. , Mendez-Giraldez Raul , Davis Eric S. , Phanstiel Douglas H. , Franco Hector L. 
Published: August 2024

Abstract
Triple-negative breast cancer (TNBC) is the most therapeutically recalcitrant form of breast cancer, which is due in part to the paucity of targeted therapies. A systematic analysis of regulatory elements that extend beyond protein-coding genes could uncover avenues for therapeutic intervention. To this end, we analyzed the regulatory mechanisms of TNBC-specific transcriptional enhancers together with their noncoding enhancer RNA (eRNA) transcripts. The functions of the top 30 eRNA-producing super-enhancers were systematically probed using high-throughput CRISPR-interference assays coupled to RNA sequencing that enabled unbiased detection of target genes genome-wide. Generation of high-resolution Hi-C chromatin interaction maps enabled annotation of the direct target genes for each super-enhancer, which highlighted their proclivity for genes that portend worse clinical outcomes in patients with TNBC. Illustrating the utility of this dataset, deletion of an identified super-enhancer controlling the nearby PODXL gene or specific degradation of its eRNAs led to profound inhibitory effects on target gene expression, cell proliferation, and migration. Furthermore, loss of this super-enhancer suppressed tumor growth and metastasis in TNBC mouse xenograft models. Single-cell RNA sequencing and assay for transposase-accessible chromatin with high-throughput sequencing analyses demonstrated the enhanced activity of this super-enhancer within the malignant cells of TNBC tumor specimens compared with nonmalignant cell types. Collectively, this work examines several fundamental questions about how regulatory information encoded into eRNA-producing super-enhancers drives gene expression networks that underlie the biology of TNBC.
Significance: Integrative analysis of eRNA-producing super-enhancers defines molecular mechanisms controlling global patterns of gene expression that regulate clinical outcomes in breast cancer, highlighting the potential of enhancers as biomarkers and therapeutic targets.
Fitness Screens Map State-Specific Glioblastoma Stem Cell Vulnerabilities
Authors: MacLeod Graham , Molaei Fatemeh , Haider Shahan , Almeida Maira P. , Lin Sichun , Kushida Michelle , Sureshkumar Haresh , Bhatti Jasmine K. , Lu Jack Q. , Schramek Daniel , Dirks Peter B. , Angers Stephane 
Published: August 2024

Abstract
Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults and is driven by self-renewing glioblastoma stem cells (GSC) that persist after therapy and seed treatment-refractory recurrent tumors. GBM tumors display a high degree of intra- and intertumoral heterogeneity that is a prominent barrier to targeted treatment strategies. This heterogeneity extends to GSCs that exist on a gradient between two transcriptional states or subtypes termed developmental and injury response. Drug targets for each subtype are needed to effectively target GBM. To identify conserved and subtype-specific genetic dependencies across a large and heterogeneous panel of GSCs, we designed the GBM5K-targeted guide RNA library and performed fitness screens in a total of 30 patient-derived GSC cultures. The focused CRISPR screens identified the most conserved subtype-specific vulnerabilities in GSCs and elucidated the functional dependency gradient existing between the developmental and injury response states. Developmental-specific fitness genes were enriched for transcriptional regulators of neurodevelopment, whereas injury response–specific fitness genes were highlighted by several genes implicated in integrin and focal adhesion signaling. These context-specific vulnerabilities conferred differential sensitivity to inhibitors of β1 integrin, focal adhesion kinase, MEK, and OLIG2. Interestingly, the screens revealed that the subtype-specific signaling pathways drive differential cyclin D (CCND1 vs. CCND2) dependencies between subtypes. These data provide a biological insight and mechanistic understanding of GBM heterogeneity and point to opportunities for precision targeting of defined GBM and GSC subtypes to tackle heterogeneity.
Significance: CRISPR-Cas9 screens in a panel of patient-derived glioblastoma stem cells reveal heterogeneity in genetic vulnerabilities across subtypes that have important implications for targeted and combination treatment strategies for glioblastoma.
SC134-TCB Targeting Fucosyl-GM1, a T Cell–Engaging Antibody with Potent Antitumor Activity in Preclinical Small Cell Lung Cancer Models
Authors: Dave Foram , Vaghela Poonam , Heath Bryony , Dunster Zuzana , Dubinina Elena , Thakker Dhruma , Mann Katie , Chadwick Joe , Cane Gaëlle , Kaira Bubacarr G. , Mohammed Omar J. , Choudhury Ruhul , Paston Samantha , Parsons Tina , Vankemmelbeke Mireille , Durrant Lindy 
Published: August 2024

Abstract
Small cell lung cancer (SCLC) is an aggressive disease with limited treatment options. Fucosyl-GM1 (FucGM1) is a glycolipid overexpressed in the majority of SCLC tumors but virtually absent from normal healthy tissues. In this study, we validate a FucGM1-targeting T cell–redirecting bispecific (TCB) antibody for the treatment of SCLC. More than 80% of patient-derived xenograft tissues of SCLC expressed FucGM1, whereas only three normal human tissues: pituitary, thymus, and skin expressed low and focal FucGM1. A FucGM1-targeting TCB (SC134-TCB), based on the Fc-silenced humanized SC134 antibody, exhibited nanomolar efficiency in FucGM1 glycolipid and SCLC cell surface binding. SC134-TCB showed potent ex vivo killing of SCLC cell lines with donor-dependent EC50 ranging from 7.2 pmol/L up to 211.0 pmol/L, effectively activating T cells, with picomolar efficiency, coinciding with target-dependent cytokine production such as IFNγ, IL2, and TNFα and robust proliferation of both CD4 and CD8 T cells. The ex vivo SC134-TCB tumor controlling activity translated into an effective in vivo anti-DMS79 tumor therapy, resulting in 100% tumor-free survival in a human peripheral blood mononuclear cell admixed setting and 40% overall survival (55% tumor growth inhibition) with systemically administered human peripheral blood mononuclear cells. Combination treatment with atezolizumab further enhanced survival and tumor growth inhibition (up to 73%). A 10-fold SC134-TCB dose reduction maintained the strong in vivo antitumor impact, translating into 70% overall survival (P &lt; 0.0001). Whole-blood incubation with SC134-TCB, as well as healthy human primary cells analysis, revealed no target-independent cytokine production. SC134-TCB presents an attractive candidate to deliver an effective immunotherapy treatment option for patients with SCLC.
Chromothripsis-Mediated Small Cell Lung Carcinoma
Authors: Rekhtman Natasha , Tischfield Sam E. , Febres-Aldana Christopher A. , Lee Jake June-Koo , Chang Jason C. , Herzberg Benjamin O. , Selenica Pier , Woo Hyung Jun , Vanderbilt Chad M. , Yang Soo-Ryum , Xu Fei , Bowman Anita S. , da Silva Edaise M. , Noronha Anne Marie , Mandelker Diana L. , Mehine Miika , Mukherjee Semanti , Blanco-Heredia Juan , Orgera John J. , Nanjangud Gouri J. , Baine Marina K. , Aly Rania G. , Sauter Jennifer L. , Travis William D. , Savari Omid , Moreira Andre L. , Falcon Christina J. , Bodd Francis M. , Wilson Christina E. , Sienty Jacklynn V. , Manoj Parvathy , Sridhar Harsha , Wang Lu , Choudhury Noura J. , Offin Michael , Yu Helena A. , Quintanal-Villalonga Alvaro , Berger Michael F. , Ladanyi Marc , Donoghue Mark T.A. , Reis-Filho Jorge S. , Rudin Charles M. 
Published: August 2024

Abstract
Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here, we performed detailed clinicopathologic, genomic, and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis—massive, localized chromosome shattering—recurrently involving chromosome 11 or 12 and resulting in extrachromosomal amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors. Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers.
Significance: Here, we provide the first detailed description of a unique SCLC subset lacking RB1/TP53 alterations and identify extensive chromothripsis and pathogenetic links to pulmonary carcinoids as its hallmark features. This work defines atypical SCLC as a novel entity among lung cancers, highlighting its exceptional histogenesis, clinicopathologic characteristics, and therapeutic vulnerabilities.
See related commentary by Nadeem and Drapkin, p. 8