bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bimodal regulation of the PRC2 complex by USP7 underlies tumorigenesis
Authors: Su Dongxue , Wang Wenjuan , Hou Yongqiang , Wang Liyong , Yi Xianfu , Cao Cheng , Wang Yuejiao , Gao Huan , Wang Yue , Yang Chao , Liu Beibei , Chen Xing , Wu Xiaodi , Wu Jiajing , Yan Dong , Wei Shuqi , Han Lulu , Liu Shumeng , Wang Qian , Shi Lei , Shan Lin 
Published: April 2021

Abstract
Although overexpression of EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is an eminent feature of various cancers, the regulation of its abundance and function remains insufficiently understood. We report here that the PRC2 complex is physically associated with ubiquitin-specific protease USP7 in cancer cells where USP7 acts to deubiquitinate and stabilize EZH2. Interestingly, we found that USP7-catalyzed H2BK120ub1 deubiquitination is a prerequisite for chromatin loading of PRC2 thus H3K27 trimethylation, and this process is not affected by H2AK119 ubiquitination catalyzed by PRC1. Genome-wide analysis of the transcriptional targets of the USP7/PRC2 complex identified a cohort of genes including FOXO1 that are involved in cell growth and proliferation. We demonstrated that the USP7/PRC2 complex drives cancer cell proliferation and tumorigenesis in vitro and in vivo. We showed that the expression of both USP7 and EZH2 elevates during tumor progression, corresponding to a diminished FOXO1 expression, and the level of the expression of USP7 and EZH2 strongly correlates with histological grades and prognosis of tumor patients. These results reveal a dual role for USP7 in the regulation of the abundance and function of EZH2, supporting the pursuit of USP7 as a therapeutic target for cancer intervention.
HPF1-dependent PARP activation promotes LIG3-XRCC1-mediated backup pathway of Okazaki fragment ligation
Authors: Kumamoto Soichiro , Nishiyama Atsuya , Chiba Yoshie , Miyashita Ryota , Konishi Chieko , Azuma Yoshiaki , Nakanishi Makoto 
Published: April 2021

Abstract
DNA ligase 1 (LIG1) is known as the major DNA ligase responsible for Okazaki fragment joining. Recent studies have implicated LIG3 complexed with XRCC1 as an alternative player in Okazaki fragment joining in cases where LIG1 is not functional, although the underlying mechanisms are largely unknown. Here, using a cell-free system derived from Xenopus egg extracts, we demonstrated the essential role of PARP1-HPF1 in LIG3-dependent Okazaki fragment joining. We found that Okazaki fragments were eventually ligated even in the absence of LIG1, employing in its place LIG3-XRCC1, which was recruited onto chromatin. Concomitantly, LIG1 deficiency induces ADP-ribosylation of histone H3 in a PARP1-HPF1-dependent manner. The depletion of PARP1 or HPF1 resulted in a failure to recruit LIG3 onto chromatin and a subsequent failure in Okazaki fragment joining in LIG1-depleted extracts. Importantly, Okazaki fragments were not ligated at all when LIG1 and XRCC1 were co-depleted. Our results suggest that a unique form of ADP-ribosylation signaling promotes the recruitment of LIG3 on chromatin and its mediation of Okazaki fragment joining as a backup system for LIG1 perturbation.
What makes a type IIA topoisomerase a gyrase or a Topo IV?
Authors: Hirsch Jana , Klostermeier Dagmar 
Published: April 2021

Abstract
Type IIA topoisomerases catalyze a variety of different reactions: eukaryotic topoisomerase II relaxes DNA in an ATP-dependent reaction, whereas the bacterial representatives gyrase and topoisomerase IV (Topo IV) preferentially introduce negative supercoils into DNA (gyrase) or decatenate DNA (Topo IV). Gyrase and Topo IV perform separate, dedicated tasks during replication: gyrase removes positive supercoils in front, Topo IV removes pre-catenanes behind the replication fork. Despite their well-separated cellular functions, gyrase and Topo IV have an overlapping activity spectrum: gyrase is also able to catalyze DNA decatenation, although less efficiently than Topo IV. The balance between supercoiling and decatenation activities is different for gyrases from different organisms. Both enzymes consist of a conserved topoisomerase core and structurally divergent C-terminal domains (CTDs). Deletion of the entire CTD, mutation of a conserved motif and even by just a single point mutation within the CTD converts gyrase into a Topo IV-like enzyme, implicating the CTDs as the major determinant for function. Here, we summarize the structural and mechanistic features that make a type IIA topoisomerase a gyrase or a Topo IV, and discuss the implications for type IIA topoisomerase evolution.
High-Speed Excitation-Spectral Microscopy Uncovers In Situ Rearrangement of Light-Harvesting Apparatus in Chlamydomonas during State Transitions at Submicron Precision
Authors: Zhang Xian Jun , Fujita Yuki , Tokutsu Ryutaro , Minagawa Jun , Ye Shen , Shibata Yutaka 
Published: April 2021

Abstract
Photosynthetic organisms adjust to fluctuating natural light under physiological ambient conditions through flexible light-harvesting ability of light-harvesting complex II (LHCII). A process called state transition is an efficient regulation mechanism to balance the excitations between photosystem II (PSII) and photosystem I (PSI) by shuttling mobile LHCII between them. However, in situ observation of the migration of LHCII in vivo remains limited. In this study, we investigated the in vivo reversible changes in the intracellular distribution of the chlorophyll (Chl) fluorescence during the light-induced state transitions in Chlamydomonas reinhardtii. The newly developed noninvasive excitation-spectral microscope provided powerful spectral information about excitation-energy transfer between Chl-a and Chl-b. The excitation spectra were detected through the fluorescence emission in the 700–750-nm spectral range, where PSII makes the main contribution, though PSI still makes a non-negligible contribution at room temperature. The technique is sensitive to the Chl-b spectral component specifically bound to LHCII. Using a PSI-specific 685-nm component also provided visualization of the local relative concentration of PSI within a chloroplast at room temperature. The decrease in the relative intensity of the Chl-b band in state 2 was more conspicuous in the PSII-rich region than in the PSI-rich region, reflecting the dissociation of LHCII from PSII. We observed intracellular redistributions of the Chl-b-related light-harvesting abilities within a chloroplast during the state transitions. This observation implies the association of the state transitions with the morphological changes in the thylakoid membrane.
A single-cell view of the transcriptome during lateral root initiation inArabidopsis thaliana
Authors: Gala Hardik P. , Lanctot Amy , Jean-Baptiste Ken , Guiziou Sarah , Chu Jonah C. , Zemke Joseph E. , George Wesley , Queitsch Christine , Cuperus Josh T. , Nemhauser Jennifer L. 
Published: April 2021

AbstractRoot architecture is a major determinant of plant fitness and is under constant modification in response to favorable and unfavorable environmental stimuli. Beyond impacts on the primary root, the environment can alter the position, spacing, density, and length of secondary or lateral roots. Lateral root development is among the best-studied examples of plant organogenesis, yet there are still many unanswered questions about its earliest steps. Among the challenges faced in capturing these first molecular events is the fact that this process occurs in a small number of cells with unpredictable timing. Single-cell sequencing methods afford the opportunity to isolate the specific transcriptional changes occurring in cells undergoing this fate transition. Using this approach, we successfully captured the transcriptomes of initiating lateral root primordia in Arabidopsis thaliana and discovered many upregulated genes associated with this process. We developed a method to selectively repress target gene transcription in the xylem pole pericycle cells where lateral roots originate and demonstrated that the expression of several of these targets is required for normal root development. We also discovered subpopulations of cells in the pericycle and endodermal cell files that respond to lateral root initiation, highlighting the coordination across cell files required for this fate transition.
Profile of Mood States Factor Structure Does Not Accurately Account for Patients with Chronic Pain
Authors: López-Jiménez Celia María , Cano-García Francisco Javier , Sanduvete-Chaves Susana , Chacón-Moscoso Salvador 
Published: April 2021

Abstract

Objective
The need for measuring emotional functioning in patients with chronic pain was recognized decades ago. The Initiative on Methods, Measures, and Pain Assessment in Clinical Trials (IMMPACT) proposed the Profile of Mood States for this purpose. However, to date, its factor structure has not been confirmed in these patients.

Methods
We set out to use confirmatory factor analysis to test the theoretical structure of seven factors: Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, Confusion-Bewilderment, and Friendliness.

Participants
The sample consisted of 588 Spanish adult patients with chronic pain.

Results
The original structure could not be verified according to the obtained fit indices (e.g., root-mean-square error of approximation = 0.11). For this reason, we carried out a second study that relied on exploratory factor analysis to evaluate the structure in half of the cases and confirmatory factor analysis to validate it in the other half. The factor structure detected in the exploratory factor analysis was not satisfactory, nor could it be validated with confirmatory factor analysis (e.g., normed fit index between 0.54 and 0.56).

Conclusions
The factor structure of the Profile of Mood States could not be satisfactorily confirmed. Consequently, other mood measures and shorter, optimized versions of the POMS are discussed as possible alternatives.
Molecular flexibility in computational protein design: an algorithmic perspective
Authors: Bouchiba Younes , Cortés Juan , Schiex Thomas , Barbe Sophie 
Published: April 2021

AbstractComputational protein design (CPD) is a powerful technique for engineering new proteins, with both great fundamental implications and diverse practical interests. However, the approximations usually made for computational efficiency, using a single fixed backbone and a discrete set of side chain rotamers, tend to produce rigid and hyper-stable folds that may lack functionality. These approximations contrast with the demonstrated importance of molecular flexibility and motions in a wide range of protein functions. The integration of backbone flexibility and multiple conformational states in CPD, in order to relieve the inaccuracies resulting from these simplifications and to improve design reliability, are attracting increased attention. However, the greatly increased search space that needs to be explored in these extensions defines extremely challenging computational problems. In this review, we outline the principles of CPD and discuss recent effort in algorithmic developments for incorporating molecular flexibility in the design process.
Using Treatment Fidelity Measures to Understand Walking Recovery: A Secondary Analysis From the Community Ambulation Project
Authors: Mangione Kathleen K , Posner Michael A , Craik Rebecca L , Wolff Edward F , Fortinsky Richard H , Beamer Brock A , Binder Ellen F , Orwig Denise L , Magaziner Jay , Resnick Barbara 
Published: April 2021

Abstract

Objectives
Physical therapist intervention studies can be deemed ineffective when, in fact, they may not have been delivered as intended. Measurement of treatment fidelity (TF) can address this issue. The purpose of this study was to describe TF of a home-based intervention, identify factors associated with TF, and examine whether components of TF were associated with the outcome of change in 6-minute walk distance (∆6MWD).

Methods
This is a secondary analysis of community-dwelling hip fracture participants who completed standard therapy and were randomly assigned to the active intervention (Push). Push was 16 weeks of lower extremity strengthening, function, and endurance training. TF was defined as delivery (attendance rate, exercise duration) and receipt (progression in training load, heart rate reserve [HRR] during endurance training, and exercise position [exercise on floor]). The outcome was ∆6MWD. Independent variables included baseline (demographic and clinical) measures. Descriptive statistics were calculated; linear and logistic regressions were performed.

Results
Eighty-nine participants were included in this analysis; 59 (66%) had attendance of 75% or greater. Participants walked for 20 minutes or more for 78% of sessions. The average training load increased by 22%; the mean HRR was 35%; and 61 (69%) participants exercised on the floor for at least 75% of sessions. Regression analyses showed that a higher body mass index and greater baseline 6MWD were related to components of TF; 4 out of 5 components of TF were significantly related to ∆6MWD. The strongest TF relationship showed that those who exercised on the floor improved by 62 m (95% CI = 31–93 m) more than those who did not get on the floor.

Conclusions
Measures of TF should extend beyond attendance rate. This analysis demonstrates how measures of TF, including program attendance, progression in training load, endurance duration, and exercising on the floor were significantly related to improvement in 6MWD in participants post hip fracture.

Impact
This careful analysis of treatment fidelity assured that the intervention was delivered and received as intended. Analysis of data from a large trial with participants after hip fracture showed that regular attendance, frequent endurance training for 20 minutes, increases in lower extremity training loads, and exercising on the floor were associated with improvements in the outcome of 6-minute-walk distance. The strongest association with improvement was exercising on the floor.
Unravelling resilience mechanisms in forests: role of non-structural carbohydrates in responding to extreme weather events
Authors: D’Andrea Ettore , Scartazza Andrea , Battistelli Alberto , Collalti Alessio , Proietti Simona , Rezaie Negar , Matteucci Giorgio , Moscatello Stefano 
Published: April 2021

Abstract
Extreme weather events are increasing in frequency and intensity due to global climate change. We hypothesized that tree carbon reserves are crucial for resilience of beech, buffering the source–sink imbalance due to late frosts and summer droughts, and that different components of non-structural carbohydrates (NSCs) play specific roles in coping with stressful situations. To assess the compound effects on mature trees of two extreme weather events, first a late frost in spring 2016 and then a drought in summer 2017, we monitored the phenology, radial growth and the dynamics of starch and soluble sugars in a Mediterranean beech forest. A growth reduction of 85% was observed after the spring late frost, yet not after the drought event. We observed a strong impact of late frost on starch, which also affected its dynamic at the beginning of the subsequent vegetative season. In 2017, the increase of soluble sugars, associated with starch hydrolysis, played a crucial role in coping with the severe summer drought. Non-structural carbohydrates helped to counteract the negative effects of both events, supporting plant survival and buffering source–sink imbalances under stressful conditions. Our findings indicate a strong trade-off between growth and NSC storage in trees. Overall, our results highlight the key role of NSCs on beech trees, response to extreme weather events, confirming the resilience of this species to highly stressful events. These insights are useful for assessing how forests may respond to the potential impacts of climate change on ecosystem processes in the Mediterranean area.
Clinical and Epidemiological Characteristics of Paediatric Patients Diagnosed with COVID-19 in a Tertiary Hospital in Mexico City
Authors: Macias-Parra Mercedes , Fortes-Gutierrez Sofia , Aguilar-Gomez Nancy , Diaz-Garcia Luisa , Otero-Mendoza Francisco , Arias de la Garza Eduardo , Ordoñez-Ortega Javier , Palacios-Reyes Debora , Diaz-Jimenez Irma Virginia , Serrano-Sierra Alejandro , Xochihua-Díaz Luis , Saltigeral-Simental Patricia 
Published: April 2021

Abstract
COVID-19 affects the paediatric population less frequently than adults. A retrospective study was performed in a tertiary paediatric hospital in Mexico City in children &lt;18 years of age who were hospitalized with a positive reverse transcription-polymerase chain reaction for SARS-CoV-2. Included in the study were 86 patients with a median age of 10 years old (IQR 2.6–14.3 years), who were classified in three groups: previously healthy, with chronic disease and immunosuppressed patients. The principal signs and symptoms were fever (81%), cough (51%) and headache (35%). A total of 20 patients (23%) required management in the paediatric intensive care unit (PICU) and 17% needed mechanical ventilation for an average of 12.7 days (IQR 2–29 days). There was no statistically significant difference between the three clinical classification groups in those patients admitted to the PICU, most of which were previously healthy patients. The mortality rate was 5% (four patients). Given that the paediatric population is susceptible to infection, potential transmitters and to clinical presentations with variable degrees of severity, it is important to continue reinforcing social distancing measures.
Special, Personal and Broad Expression: Exploring Freedom of Expression Norms under the General Data Protection Regulation
Authors: Erdos David 
Published: April 2021

Abstract
The interface between data protection and freedom of expression is increasingly crucial and the General Data Protection Regulation (GDPR) solidifies a bipartite or potentially even tripartite conceptualization of this relationship. Whilst the GDPR’s personal exemption can play some role in governing individual expression, it must be construed narrowly so as to only exclude innocuous publication that is not liable to infringe other’s fundamental rights. The special expression derogation remains central and encompasses not just journalism but also other forms of special expression (academic, artistic, literary) which, when published, are objectively orientated towards a collective public. Whilst Member States do retain considerable discretion given the wide diversity of national constitutional norms in this area, a strict balancing between fundamental rights should still be ensured. Freedom of expression is also distinctly furthered by, inter alia, self-expression on social networking sites and the facilitation of a range of expressive purposes by search engines. As shown in GC and Others v CNIL, the stricter reconciliation of rights here must retain a direct role for data protection’s core substance including its legal grounds and principles and is thereby substantially (albeit not completely) harmonized across the EU.
The Single Accreditation System: Risks to the Osteopathic Profession
Authors: Cummings Mark 
Published: April 2021

In August 2014, the American Osteopathic Association (AOA) and the American Association of Colleges of Osteopathic Medicine (AACOM) signed a memorandum of understanding with the Accreditation Council for Graduate Medical Education (ACGME) to create the Single Accreditation System (SAS) for graduate medical education (GME) in the United States. The AOA made the decision that it would close its GME accreditation system in response to dramatic growth in colleges of osteopathic medicine, a shortfall in osteopathic GME positions with increasing dependence on the ACGME system, ACGME policy decisions that adversely impacted osteopathic students, and declining osteopathic student interest in primary care.
Osteopathic teaching institutions bore responsibility for meeting ACGME accreditation standards between 2015 and 2020, including determining institutional sponsorship, which program applications to submit, program size, educational leadership, and whether to pursue Osteopathic Recognition. Approximately 692 of 954 (72.5%) eligible osteopathic GME programs in 2014–2015 obtained ACGME accreditation by June 1, 2020. There were sharp reductions in surgical and subspecialty programs and a significant drop of DOs in educational leadership positions. A low percentage of ACGME-accredited programs applied for Osteopathic Recognition.
In closing its GME accreditation system and joining the ACGME, the AOA gave up control of its direct relationship with osteopathic residents, fellows, and teaching institutions to gain critical GME opportunities. In this article, the author considers whether this gain will offset the risks taken by the AOA, including decreased DO leadership opportunities and role models, lower than expected interest in Osteopathic Recognition, and possible decreased DO interest in osteopathic organizations and osteopathic specialty board certification. Time and the choices of current and future DO trainees in ACGME programs will determine the future of the osteopathic profession—and whether these risks were worth taking.
Visceral fat is associated with high-grade complications in patients undergoing minimally invasive partial nephrectomy for small renal masses
Authors: Nesbitt Kelan , Sharma Pranav 
Published: April 2021

Abstract

Introduction:
Minimally invasive partial nephrectomy is standard of care treatment for small renal masses.

Objective:
We evaluated the relationship between subcutaneous and visceral obesity with high-grade postoperative 30-day complications in patients undergoing minimally invasive partial nephrectomy.

Methods:
We retrospectively identified 98 patients at our institution from 2014 to 2017 who underwent laparoscopic or robotic-assisted partial nephrectomy due to suspected renal cell carcinoma. Patients were stratified based on presence or absence of high-grade (Clavien ≥ IIIa) 30-day postoperative complications. Means were compared with the independent t test and proportions with chi-square analysis. Multivariate logistic regression was performed to determine independent predictors of high-grade 30-day complications.

Results:
Mean nephrometry score was 6.7 with 21 (21.4%) patients having hilar tumors. Mean estimation of blood loss was 207 mL, mean operating time was 223 min, and mean warm ischemia time was 23 min. The majority of patients had clear renal cell carcinoma (n = 83, 84.7%) and pT1a disease (n = 76, 77.6%) with negative margins (n = 89, 90.8%) on pathology. There were 5 (5.1%) patients who experienced a high-grade postoperative 30-day complication. Mean visceral fat index was an independent predictor of high-grade 30-day complications (odds ratio: 1.02; 95% confidence interval: 1.002–1.03; p = 0.027).

Conclusions:
Visceral obesity should be considered as a prognostic indicator of outcomes in patients undergoing surgical treatment for a small renal mass.