bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer Mutational Processes Vary in Their Association with Replication Timing and Chromatin Accessibility
Authors: Yaacov Adar , Vardi Oriya , Blumenfeld Britny , Greenberg Avraham , Massey Dashiell J. , Koren Amnon , Adar Sheera , Simon Itamar , Rosenberg Shai 
Published: October 2021

Abstract

Cancer somatic mutations are the product of multiple mutational and repair processes, both of which are tightly associated with DNA replication. Distinctive patterns of somatic mutation accumulation, termed mutational signatures, are indicative of processes sustained within tumors. However, the association of various mutational processes with replication timing (RT) remains an open question. In this study, we systematically analyzed the mutational landscape of 2,787 tumors from 32 tumor types separately for early and late replicating regions using sequence context normalization and chromatin data to account for sequence and chromatin accessibility differences. To account for sequence differences between various genomic regions, an artificial genome–based approach was developed to expand the signature analyses to doublet base substitutions and small insertions and deletions. The association of mutational processes and RT was signature specific: Some signatures were associated with early or late replication (such as SBS7b and SBS7a, respectively), and others had no association. Most associations existed even after normalizing for genome accessibility. A focused mutational signature identification approach was also developed that uses RT information to improve signature identification; this approach found that SBS16, which is biased toward early replication, is strongly associated with better survival rates in liver cancer. Overall, this novel and comprehensive approach provides a better understanding of the etiology of mutational signatures, which may lead to improved cancer prevention, diagnosis, and treatment.

Significance:
Many mutational processes associate with early or late replication timing regions independently of chromatin accessibility, enabling development of a focused identification approach to improve mutational signature detection.
Early HPV ctDNA Kinetics and Imaging Biomarkers Predict Therapeutic Response in p16+ Oropharyngeal Squamous Cell Carcinoma
Authors: Cao Yue , Haring Catherine T. , Brummel Collin , Bhambhani Chandan , Aryal Madhava , Lee Choonik , Heft Neal Molly , Bhangale Apurva , Gu Wenjin , Casper Keith , Malloy Kelly , Sun Yilun , Shuman Andrew , Prince Mark E. , Spector Matthew E. , Chinn Steven , Shah Jennifer , Schonewolf Caitlin , McHugh Jonathan B. , Mills Ryan E. , Tewari Muneesh , Worden Francis P. , Swiecicki Paul L. , Mierzwa Michelle , Brenner J. Chad 
Published: October 2021

AbstractPurpose:In locally advanced p16+ oropharyngeal squamous cell carcinoma (OPSCC), (i) to investigate kinetics of human papillomavirus (HPV) circulating tumor DNA (ctDNA) and association with tumor progression after chemoradiation, and (ii) to compare the predictive value of ctDNA to imaging biomarkers of MRI and FDG-PET.Experimental Design:Serial blood samples were collected from patients with AJCC8 stage III OPSCC (n = 34) enrolled on a randomized trial: pretreatment; during chemoradiation at weeks 2, 4, and 7; and posttreatment. All patients also had dynamic-contrast-enhanced and diffusion-weighted MRI, as well as FDG-PET scans pre-chemoradiation and week 2 during chemoradiation. ctDNA values were analyzed for prediction of freedom from progression (FFP), and correlations with aggressive tumor subvolumes with low blood volume (TVLBV) and low apparent diffusion coefficient (TVLADC), and metabolic tumor volume (MTV) using Cox proportional hazards model and Spearman rank correlation.Results:Low pretreatment ctDNA and an early increase in ctDNA at week 2 compared with baseline were significantly associated with superior FFP (P &lt; 0.02 and P &lt; 0.05, respectively). At week 4 or 7, neither ctDNA counts nor clearance were significantly predictive of progression (P = 0.8). Pretreatment ctDNA values were significantly correlated with nodal TVLBV, TVLADC, and MTV pre-chemoradiation (P &lt; 0.03), while the ctDNA values at week 2 were correlated with these imaging metrics in primary tumor. Multivariate analysis showed that ctDNA and the imaging metrics performed comparably to predict FFP.Conclusions:Early ctDNA kinetics during definitive chemoradiation may predict therapy response in stage III OPSCC.
Strategizing for grand challenges: economic development and governance traditions in Malaysian local government
Authors: Hughes Jeffrey , Orr Kevin , Yusoff Mazlan 
Published: October 2021

This qualitative study provides empirical knowledge and develops theory about the role of strategic management in Malaysian local government. As the country addresses the grand challenge of economic growth amid enduring national aspirations of moving from developing to fully developed status, the analysis identifies six approaches to strategic management across nine Malaysian local authorities. Rather than presenting a linear story of progression, the six models of strategizing in Malaysia illuminate the governance traditions that co-exist in this setting. The study examines the assumptions about public management that underpin the different approaches and relates these to the country's inheritance of classical public administration and centralized government, the introduction of New Public Management, and the subsequent emergence of features of New Public Governance. It contributes to theory by providing an analysis of the role of strategy in each of the three governance traditions and connects debates about local governance with scholarship on strategic management. It also contributes to the emerging literature on strategizing for grand challenges and the limited repository of such studies located in a public sector context. The article ends by identifying the implications for policy and practice and suggesting areas for further research. Points for practitioners This study highlights the need for collaboration to address strategic meta problems, manage economic pressures and deliver public services. The six approaches to strategy development presented provide a set of models and frames through which practitioners may assess their local environment. Our typology offers a basis for cross-sectoral learning and reflection, including ways of diagnosing contextual variables and developing strategic knowledge. The Malaysian case shows how the context of strategy formation has been affected by the shift from local government to governance, as well as by interacting colonial legacies.
Reducing Children’s Preoperative Fear with an Educational Pop‐up Book: A Randomized Controlled Trial
Authors: Cordray Holly , Patel Chhaya , Prickett Kara K. 
Published: October 2021

ObjectivePreoperative education empowers children to approach surgery with positive expectations, and providers need efficient, child‐focused resources. This study aimed to evaluate an interactive pop‐up book as a tool for explaining surgery, managing preoperative anxiety, and strengthening coping strategies.Study DesignProspective randomized controlled trial.SettingPediatric outpatient surgery center.MethodsPatients ages 5 to 12 undergoing outpatient surgery read a pop‐up book about anesthesia (intervention) or received standard care (control). Patients self‐reported their preoperative fear, pain expectations, views of the procedure and preoperative explanations, and coping strategies. Outcomes also included observer‐rated behavioral anxiety and caregiver satisfaction.ResultsIn total, 148 patients completed the study. The pop‐up book had a significant, large effect in reducing patients’ fear of anesthesia induction (Cohen’s d effect size = 0.94; P <. 001). Intervention patients also expected less pain than control patients from the anesthesia mask and during surgery (d = 0.60‐0.80; P <. 001). The book encouraged more positive views of the procedure and preoperative explanations (P <. 005). Furthermore, the book prepared patients to cope adaptively: intervention patients were significantly more likely to generate positive active coping strategies, distraction strategies, and support‐seeking strategies (P <. 001). Observer‐rated behavioral anxiety at anesthesia induction did not differ between groups (P =. 75). Caregivers in the intervention group were significantly more satisfied with each aspect of the surgical experience (P≤. 02).ConclusionThe educational pop‐up book offers a child‐focused resource that helps alleviate children’s preoperative fears, encourages positive coping, and improves caregivers’ perceptions of the experience. This study was registered at ClinicalTrials.gov (NCT04796077).
Long survival of a young patient with Xp11.2 translocation metastatic clear cell renal carcinoma: case report
Authors: Pipitone Stefania , Vitale Maria Giuseppa , Baldessari Cinzia , Dominici Massimo , Sabbatini Roberto 
Published: October 2021

Introduction: Xp11.2 translocation is a rare subtype of renal cell carcinoma (RCC), identified as a single entity only from 2004 by World Health Organization (WHO). These tumors involve pediatric age group and rarely patients over 40 years old. Children show indolent disease; adult population has invasive tumor at diagnosis with rapid progression. Case report: We describe a case report of a young woman affected by metastatic clear cell renal carcinoma with Xp11.2 translocation. She achieved a longer stable disease (SD) to first line treatment with atezolizumab plus bevacizumab, obtaining a progression free survival (PFS) of 21 months. After she received cabozantinib, sunitinib and then sorafenib. Conclusions: The patient had an overall survival (OS) of 51 months, which is much higher than that reported in literature data. Unfortunately, the biology of Xp11.2 translocation RCC and its therapeutic management are still unclear.
The Effects of Neurofeedback on Executive Functioning in Children With ADHD: A Meta-Analysis
Authors: Louthrenoo Orawan , Boonchooduang Nonglak , Likhitweerawong Narueporn , Charoenkwan Kittipat , Srisurapanont Manit 
Published: October 2021

Objective: Possible beneficial effects of neurofeedback in improving ADHD functional outcomes have been increasingly reported. This meta-analysis aimed to evaluate the relationship between neurofeedback and executive functioning in children with ADHD. Methods: PubMed, EMBASE, EBSCO, Web of Science, and Cochrane databases were searched to identify studies reporting the effects of neurofeedback on executive functioning, including response inhibition, sustained attention, and working memory, assessed by neuropsychological tests. Only randomized controlled studies of children aged 5 to 18 years were included using a random-effects model. Results: Ten studies were included. The effects of neurofeedback were not found on three domains of executive functions. A meta-regression analysis revealed a trend of numbers of neurofeedback sessions positively associated with response inhibition ( p = .06). Conclusion: Results did not show the benefits of neurofeedback on executive functions assessed by neuropsychological tests. Future studies should focus on standard neurofeedback protocols, the intensity of intervention, and neuropsychological outcomes.
Elevated sCD40L in Secondary Progressive Multiple Sclerosis in Comparison to Non-progressive Benign and Relapsing Remitting Multiple Sclerosis
Authors: Wu Qi , Wang Qin , Yang Jennifer , Martens Jacob WS , Mills Elizabeth A , Saad Aiya , Chilukuri Pavani , Dowling Catherine A , Mao-Draayer Yang 
Published: October 2021

Background: The long-term prognosis of relapsing-remitting multiple sclerosis (RRMS) is usually unfavorable as most patients transition to secondary progressive multiple sclerosis (SPMS) with accumulative disability. A rare form of non-progressive multiple sclerosis (MS) also exists, known as benign MS (BMS or NPMS), which lacks disease progression defined as Expanded Disability Status Scale (EDSS) ≤3 after 15 years of disease onset without treatment. Purpose: Our study aims to identify soluble plasma factors predicting disease progression in multiple sclerosis (MS). Research Design and Study Sample: We utilized Luminex multiplex to analyze plasma levels of 33 soluble factors, comparing 32 SPMS patients to age-, sex-, and disease duration-matched non-progressive BMS patients, as well as to RRMS patients and healthy controls. Results: Plasma levels of EGF, sCD40L, MCP1/CCL2, fractalkine/CX3CL1, IL-13, Eotaxin, TNFβ/LTα, and IL-12p40 were significantly different between the various types of MS. Plasma sCD40L was significantly elevated in SPMS compared to BMS and RRMS. The combination of MCP1/CCL2 and sCD40L discriminated between RRMS and SPMS. MCP1/CCL2 was found to be the most effective classifier between BMS and RRMS, while BMS was most effectively distinguished from SPMS by the combination of sCD40L and IFNγ levels. Conclusions: These differences may facilitate personalized precision medicine and aid in the discovery of new therapeutic targets for disease progression through the improvement of patient stratification.
Posttraumatic Osteoarthritis Damage in Mice: From Histological and Micro–Computed Tomodensitometric Changes to Gait Disturbance
Authors: Fouasson-Chailloux Alban , Dauty Marc , Bodic Benoit , Masson Martial , Maugars Yves , Metayer Benoit , Veziers Joëlle , Lesoeur Julie , Rannou François , Guicheux Jérôme , Vinatier Claire 
Published: October 2021

Objectives Osteoarthritis is a painful joint disease responsible for walking impairment. Its quantitative assessment by gait analysis in mice may be a relevant and noninvasive strategy to assess the disease severity. In this study, we aimed to determine the severity of osteoarthritis at the tissular and gait levels in unilateral and bilateral posttraumatic murine osteoarthritis. Methods Twenty-four C57BL/6 male mice were randomly assigned to 3 groups ( n = 8/group): controls, unilateral surgery, and bilateral surgery. Posttraumatic osteoarthritis was induced unilaterally or bilaterally by destabilization of the medial meniscus. Gait analysis was performed weekly with the CatWalkTM XT system until the 16th week after surgery. After animal sacrifices, histological and micro–computed tomographic assessment was performed. Results Operated knees showed a significant increase in the histological score compared with controls ( P < 0.001). Calcified anterior medial meniscal bone volume was higher on the ipsilateral side after unilateral destabilization of the medial meniscus ( P < 0.001) and on both sides after bilateral intervention ( P < 0.01). One week after surgery, the mice mean speed decreased significantly in both operated groups ( P < 0.001 and P < 0.05). In the unilateral group, a significant increase in the contralateral hind print area appeared from week 4 to week 16. Conclusions While bilateral destabilization of the medial meniscus induced no detectable gait modification except 1 week after surgery, unilateral model was responsible for a gait disturbance on the contralateral side. Further studies are needed to better define the place of the CatWalkTM in the evaluation of mouse models of osteoarthritis.
Association Between Blunted Glomerular Hyperfiltration in Pregnancy and Severe Maternal Morbidity—A Research Letter
Authors: Harel Ziv , Park Alison L. , Ray Joel G. 
Published: October 2021

Background: Glomerular hyperfiltration is one physiological adaptation to pregnancy, marked by a decline in serum creatinine (SCr) concentration by 16 weeks’ gestation. It is not known whether blunted glomerular hyperfiltration leads to adverse maternal outcomes, including severe maternal morbidity (SMM). Objective: To evaluate the association between blunted glomerular hyperfiltration and subsequent SMM or death. Design: Population-based cohort study Setting: Ontario, Canada, from 2008 to 2019. Participants: Included were births among women who had ≥ 1 SCr measured as an outpatient within 10 weeks before conception (“preconception”), and again, at 110/7 to 206/7 weeks’ gestation (“in-pregnancy”). Excluded were women who died before birth, who had end-stage renal disease or kidney transplantation before conception, or whose pre-pregnancy SCr was 125 μmol/L. Exposure: Net glomerular hyperfiltration defined as the preconception minus the in-pregnancy SCr. Measures: The primary study outcome was SMM or death arising from 23 weeks’ gestation up to 42 days after the index birth. Methods: Adjusted relative risks (aRRs) were calculated using Modified Poisson regression per 1-SD net blunting of glomerular hyperfiltration adjusting for important covariates. Results: A total of 10,323 births met all inclusion criteria. The mean (SD) SCr was 61.7 (11.0) μmol/L preconception, 48.0 (9.2) μmol/L in-pregnancy, and the mean net difference 13.6 (8.2) μmol/L. Among these births, the adjusted RR of SMM or death from 23 weeks’ gestation up to 42 days post-partum was 1.16 (95% confidence interval 1.14-1.30) per 1-SD (8.2 μmol/L) net blunting of glomerular hyperfiltration. Limitations: As SCr assessment is not a routine part of pregnancy care, its measurement could have been for a specific health condition thereby imparting selection bias. Conclusions: Blunted glomerular hyperfiltration in pregnancy may identify some women at higher risk of SMM. Further prospective research is needed about the implications of glomerular hyperfiltration in early pregnancy.
A novel mechanism of thrombocytopenia by PS exposure through TMEM16F in sphingomyelin synthase 1 deficiency
Authors: Fujii Yoritaka , Taniguchi Makoto , Nagaya Shingo , Ueda Yoshibumi , Hashizume Chieko , Watanabe Ken , Takeya Hiroyuki , Kosaka Takeo , Okazaki Toshiro 
Published: October 2021

AbstractSphingomyelin synthase 1 (SMS1) contributes to the generation of membrane sphingomyelin (SM) and affects SM-mediated physiological functions. Here, we describe the hematologic phenotypes, such as reduced circulating platelets and dysfunctional hemostasis, in SMS1-deficient (SMS1-KO) mice. SMS1-KO mice display pathologic manifestations related to idiopathic thrombocytopenia (ITP), including relatively high amounts of peripheral blood reticulated platelets, enhanced megakaryopoiesis in the bone marrow and spleen, and splenomegaly. Deficiency of SMS1, but not SMS2, prevented SM production and enhanced phosphatidylserine (PS) externalization on the plasma membranes of platelets and megakaryocytes. Consequently, SMS1-KO platelets were excessively cleared by macrophages in the spleen. Multimer formation in the plasma membrane of TMEM16F, a known calcium (Ca2+)-activated nonselective ion channel and Ca2+-dependent PS scramblase, was enhanced; the result was PS externalization to outer leaflets through increased Ca2+ influx in immortalized mouse embryonic fibroblasts established from SMS1-KO mice (SMS1-KO tMEFs), as seen with SMS1-KO platelets. Thus, SMS1 deficiency changed the TMEM16F distribution on the membrane microdomain, regulating Ca2+ influx-dependent PS exposure. SMS1-KO tMEFs in which TMEM16F was knocked out by using the CRISPR/Cas9 system lacked both the Ca2+ influx and excess PS exposure seen in SMS1-KO tMEFs. Therefore, SM depletion on platelet membrane microdomains due to SMS1 deficiency enhanced PS externalization via a Ca2+ influx through TMEM16F activation, leading to elevated platelet clearance and causing hemostasis dysfunction through thrombocytopenia. Our current findings show that the SM-rich microdomain generated by SMS1 is a potent regulator of thrombocytopenia through TMEM16F, suggesting that its dysfunction may be a novel additional mechanism of ITP.
A Markov random field model for network-based differential expression analysis of single-cell RNA-seq data
Authors: Li Hongyu , Zhu Biqing , Xu Zhichao , Adams Taylor , Kaminski Naftali , Zhao Hongyu 
Published: October 2021

Abstract
Background
Recent development of single cell sequencing technologies has made it possible to identify genes with different expression (DE) levels at the cell type level between different groups of samples. In this article, we propose to borrow information through known biological networks to increase statistical power to identify differentially expressed genes (DEGs).

Results
We develop MRFscRNAseq, which is based on a Markov random field (MRF) model to appropriately accommodate gene network information as well as dependencies among cell types to identify cell-type specific DEGs. We implement an Expectation-Maximization (EM) algorithm with mean field-like approximation to estimate model parameters and a Gibbs sampler to infer DE status. Simulation study shows that our method has better power to detect cell-type specific DEGs than conventional methods while appropriately controlling type I error rate. The usefulness of our method is demonstrated through its application to study the pathogenesis and biological processes of idiopathic pulmonary fibrosis (IPF) using a single-cell RNA-sequencing (scRNA-seq) data set, which contains 18,150 protein-coding genes across 38 cell types on lung tissues from 32 IPF patients and 28 normal controls.

Conclusions
The proposed MRF model is implemented in the R package MRFscRNAseq available on GitHub. By utilizing gene-gene and cell-cell networks, our method increases statistical power to detect differentially expressed genes from scRNA-seq data.
Alternative splicing during fruit development among fleshy fruits
Authors: Yan Xiaomin , Bai Dan , Song Hongtao , Lin Kui , Pang Erli 
Published: October 2021

Abstract
Background
Alternative splicing (AS) is an important mechanism of posttranscriptional modification and dynamically regulates multiple physiological processes in plants, including fruit ripening. However, little is known about alternative splicing during fruit development in fleshy fruits.

Results
We studied the alternative splicing at the immature and ripe stages during fruit development in cucumber, melon, papaya and peach. We found that 14.96–17.48% of multiexon genes exhibited alternative splicing. Intron retention was not always the most frequent event, indicating that the alternative splicing pattern during different developmental process differs. Alternative splicing was significantly more prevalent at the ripe stage than at the immature stage in cucumber and melon, while the opposite trend was shown in papaya and peach, implying that developmental stages adopt different alternative splicing strategies for their specific functions. Some genes involved in fruit ripening underwent stage-specific alternative splicing, indicating that alternative splicing regulates fruits ripening. Conserved alternative splicing events did not appear to be stage-specific. Clustering fruit developmental stages across the four species based on alternative splicing profiles resulted in species-specific clustering, suggesting that diversification of alternative splicing contributes to lineage-specific evolution in fleshy fruits.

Conclusions
We obtained high quality transcriptomes and alternative splicing events during fruit development across the four species. Dynamics and nonconserved alternative splicing were discovered. The candidate stage-specific AS genes involved in fruit ripening will provide valuable insight into the roles of alternative splicing during the developmental processes of fleshy fruits.