bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping yeast mitotic 5′ resection at base resolution reveals the sequence and positional dependence of nucleases in vivo
Authors: Bazzano Dominic , Lomonaco Stephanie , Wilson Thomas E 
Published: June 2021

Abstract
Resection of the 5′-terminated strand at DNA double-strand breaks (DSBs) is the critical regulated step in the transition to homologous recombination. Recent studies have described a multi-step model of DSB resection where endonucleolytic cleavage mediated by Mre11 and Sae2 leads to further degradation mediated by redundant pathways catalyzed by Exo1 and Sgs1/Dna2. These models have not been well tested at mitotic DSBs in vivo because most methods used to monitor resection cannot precisely map early cleavage events. Here we report resection monitoring with high-throughput sequencing using molecular identifiers, allowing exact counting of cleaved 5′ ends at base resolution. Mutant strains, including exo1Δ, mre11-H125N and exo1Δ sgs1Δ, revealed a major Mre11-dependent cleavage position 60–70 bp from the DSB end whose exact position depended on local sequence. They further revealed an Exo1-dependent pause point approximately 200 bp from the DSB. Suppressing resection extension in exo1Δ sgs1Δ yeast exposed a footprint of regions where cleavage was restricted within 119 bp of the DSB. These results provide detailed in vivo views of prevailing models of DSB resection and extend them to show the combined influence of sequence specificity and access restrictions on Mre11 and Exo1 nucleases.
Golgi-58K can re-localize to late endosomes upon cellular uptake of PS-ASOs and facilitates endosomal release of ASOs
Authors: Liang Xue-Hai , Nichols Joshua G , De Hoyos Cheryl Li , Sun Hong , Zhang Lingdi , Crooke Stanley T 
Published: June 2021

Abstract
Phosphorothioate (PS) modified antisense oligonucleotide (ASO) drugs can trigger RNase H1 cleavage of cellular target RNAs to modulate gene expression. Internalized PS-ASOs must be released from membraned endosomal organelles, a rate limiting step that is not well understood. Recently we found that M6PR transport between Golgi and late endosomes facilitates productive release of PS-ASOs, raising the possibility that Golgi-mediated transport may play important roles in PS-ASO activity. Here we further evaluated the involvement of Golgi in PS-ASO activity by examining additional Golgi proteins. Reduction of certain Golgi proteins, including Golgi-58K, GCC1 and TGN46, decreased PS-ASO activity, without substantial effects on Golgi integrity. Upon PS-ASO cellular uptake, Golgi-58K was recruited to late endosomes where it colocalized with PS-ASOs. Reduction of Golgi-58K caused slower PS-ASO release from late endosomes, decreased GCC2 late endosome relocalization, and led to slower retrograde transport of M6PR from late endosomes to trans-Golgi. Late endosome relocalization of Golgi-58K requires Hsc70, and is most likely mediated by PS-ASO–protein interactions. Together, these results suggest a novel function of Golgi-58K in mediating Golgi-endosome transport and indicate that the Golgi apparatus plays an important role in endosomal release of PS-ASO, ensuring antisense activity.
Characterization of systemic immunosuppression by IDH mutant glioma small extracellular vesicles
Authors: Ludwig Nils , Rao Aparna , Sandlesh Poorva , Yerneni Saigopalakrishna S , Swain Alexander D , Bullock Kristin M , Hansen Kim M , Zhang Xiaoran , Jaman Emade , Allen Jordan , Krueger Katharine , Hong Chang-Sook , Banks William A , Whiteside Theresa L , Amankulor Nduka M 
Published: June 2021

Abstract

Background
Gliomas are the most common primary brain tumors and are universally fatal. Mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) define a distinct glioma subtype associated with an immunosuppressive tumor microenvironment. Mechanisms underlying systemic immunosuppression in IDH mutant (mutIDH) gliomas are largely unknown. Here, we define genotype-specific local and systemic tumor immunomodulatory functions of tumor-derived glioma small extracellular vesicles (TEX).

Methods
TEX produced by human and murine wildtype and mutant IDH glioma cells (wtIDH and mutIDH, respectively) were isolated by size exclusion chromatography (SEC). TEX morphology, size, quantity, molecular profiles and biodistribution were characterized. TEX were injected into naive and tumor-bearing mice, and the local and systemic immune microenvironment composition was characterized.

Results
Using in vitro and in vivo glioma models, we show that mutIDH TEX are more numerous, possess distinct morphological features and are more immunosuppressive than wtIDH TEX. mutIDH TEX cargo mimics their parental cells, and induces systemic immune suppression in naive and tumor-bearing mice. TEX derived from mutIDH gliomas and injected into wtIDH tumor-bearing mice reduce tumor-infiltrating effector lymphocytes, dendritic cells and macrophages, and increase circulating monocytes. Astonishingly, mutIDH TEX injected into brain tumor-bearing syngeneic mice accelerate tumor growth and increase mortality compared with wtIDH TEX.

Conclusions
Targeting of mutIDH TEX represents a novel therapeutic approach in gliomas.
Significant loss of soil inorganic carbon at the continental scale
Authors: Song Xiao-Dong , Yang Fei , Wu Hua-Yong , Zhang Jing , Li De-Cheng , Liu Feng , Zhao Yu-Guo , Yang Jin-Ling , Ju Bing , Cai Chong-Fa , Huang Biao , Long Huai-Yu , Lu Ying , Sui Yue-Yu , Wang Qiu-Bing , Wu Ke-Ning , Zhang Feng-Rong , Zhang Ming-Kui , Shi Zhou , Ma Wan-Zhu , Xin Gang , Qi Zhi-Ping , Chang Qing-Rui , Ci En , Yuan Da-Gang , Zhang Yang-Zhu , Bai Jun-Ping , Chen Jia-Ying , Chen Jie , Chen Yin-Jun , Dong Yun-Zhong , Han Chun-Lan , Li Ling , Liu Li-Ming , Pan Jian-Jun , Song Fu-Peng , Sun Fu-Jun , Wang Deng-Feng , Wang Tian-Wei , Wei Xiang-Hua , Wu Hong-Qi , Zhao Xia , Zhou Qing , Zhang Gan-Lin 
Published: June 2021

Abstract
Widespread soil acidification due to atmospheric acid deposition and agricultural fertilization may greatly accelerate soil carbonate dissolution and CO2 release. However, to date, few studies have addressed these processes. Here, we use meta-analysis and nationwide-survey datasets to investigate changes in soil inorganic carbon (SIC) stocks in China. We observe an overall decrease in SIC stocks in topsoil (0–30 cm) (11.33 g C m–2 yr–1) from the 1980s to the 2010s. Total SIC stocks have decreased by ∼8.99 ± 2.24% (1.37 ± 0.37 Pg C). The average SIC losses across China (0.046 Pg C yr–1) and in cropland (0.016 Pg C yr–1) account for ∼17.6%–24.0% of the terrestrial C sink and 57.1% of the soil organic carbon sink in cropland, respectively. Nitrogen deposition and climate change have profound influences on SIC cycling. We estimate that ∼19.12%–19.47% of SIC stocks will be further lost by 2100. The consumption of SIC may offset a large portion of global efforts aimed at ecosystem carbon sequestration, which emphasizes the importance of achieving a better understanding of the indirect coupling mechanisms of nitrogen and carbon cycling and of effective countermeasures to minimize SIC loss.
INVESTIGATIONS OF OCCUPATIONAL RADIATION DOSE INCIDENTS RELATED TO MEDICAL PRACTICES IN SAUDI ARABIA
Authors: Shubayr N , Alashban Y 
Published: June 2021

Abstract
This study aimed to investigate national incidents related to medical radiation practices in Saudi Arabia from 2015 to 2019, and the actions taken to deal with these cases. The radiation protection program of the Saudi Ministry of Health monitors occupational doses for medical staff. When the radiation doses exceed the assigned investigation levels, an investigation protocol should be followed to identify the reasons and present recommendations. A total of 96 cases of radiation doses were above the investigation levels; 70% above level I, and 30% above level II. These cases were found to be 44% overload exposure, 32% intentional exposure, 8% accidental/unintentional exposure and 16% dosimeter misadventure. The majority of cases (80%) were in 2015 and 2016 with a significant drop in cases following these 2 years mainly due to continuing education and training. Investigations of incidents and the actions taken contributed to improving the radiation protection program.
“Could We Just Breathe for 30 Seconds?”: Social Worker Experiences of Holistic Engagement Practice Training
Authors: Pyles Loretta , Cosgrove Darren T , Gardner Erin , Raheim Salome , Adam Gwendolyn J , Chakravarty Sreyashi , Cooke Collina 
Published: June 2021

Abstract
Given the still emerging evidence base about the effectiveness of practices, such as mindfulness, somatics, and integrative body-mind-spirit social work, there is a need to know more about the impacts that training in such areas can have on social workers and their professional work. This mixed-methods article reports on a pilot study that explored practitioners’ perceptions regarding the impact of learning holistic engagement practice (HEP) skills on their service delivery and well-being. The research inquires into the perceptions of social workers who received the training, particularly in relation to their quality of presence and the therapeutic relationship; HEP as a form of self-care and a facilitator of compassion satisfaction; the impact it has on social work practice and settings; and the facilitators and barriers to using holistic engagement. Implications from the findings focus on the need for additional research, training, organizational change, and communities of practice to facilitate changes that could promote more effective social work practice, greater levels of empathy, and compassion satisfaction.
Variation in resistance to oxidative stress in Oregon-(R)R-flare and Canton-S strains of Drosophila melanogaster
Authors: Sigrist-Flores Santiago Cristobal , Castañeda-Partida Laura , Campos-Aguilar Myriam , Santos-Cruz Luis Felipe , Miranda-Gutierrez Aranza , Gallardo-Ortíz I A , Villalobos-Molina R , Dueñas-García Irma Elena , Heres-Pulido María Eugenia , Piedra-Ibarra Elías , Rosales-García Víctor Hugo , Jimenez-Flores Rafael , Ponciano-Gómez Alberto 
Published: June 2021

Abstract
All aerobic organisms are susceptible to damage by reactive oxygen species (ROS). ROS-induced damage has been associated with aging and diseases such as metabolic syndrome and cancer. However, not all organisms develop these diseases, nor do they age at the same rate; this is partially due to resistance to oxidative stress, a quantitative trait attributable to the interaction of factors including genetics and environmental. Drosophila melanogaster represents an ideal system to study how genetic variation can affect resistance to oxidative stress. In this work, oxidative stress (total and mitochondrial ROS), antioxidant response, and Cap 'n' collar isoform C and Spineless gene expression, one pesticide resistant (Oregon R(R)-flare) and wild-type (Canton-S) strains of D. melanogaster, were analyzed to test resistance to basal oxidative stress. ROS, catalase, and superoxide dismutase were determined by flow cytometry, and Cap 'n' collar isoform C and Spineless expression by qRT-PCR. The intensity of oxidative stress due to the pro-oxidant zearalenone in both was evaluated by flow cytometry. Data confirm expected differences in oxidative stress between strains that differ in Cyp450s levels. The Oregon (R)R-flare showed greater ROS, total and mitochondrial, compared to Canton-S. Regarding oxidative stress genes expression Cap 'n' collar isoform C and Spineless (Ss), Oregon R(R)-flare strain showed higher expression. In terms of response to zearalenone mycotoxin, Canton-S showed higher ROS concentration. Our data show variation in the resistance to oxidative stress among these strains of D. melanogaster.
Continued Supervision for the Common Pediatric Subspecialty Entrustable Professional Activities May Be Needed Following Fellowship Graduation
Authors: Turner David A. , Schwartz Alan , Carraccio Carol , Herman Bruce , Weiss Pnina , Baffa Jeanne M. , Chess Patricia , Curran Megan , Dammann Christiane , High Pamela , Hsu Deborah , Pitts Sarah , Sauer Cary , Aye Tandy , Fussell Jill , Kesselheim Jennifer , Mahan John , McGann Kathleen , Myers Angie , Mink Richard 
Published: June 2021

Purpose
Entrustable professional activities (EPAs) are one approach to competency-based medical education (CBME), and 7 EPAs have been developed that address content relevant for all pediatric subspecialties. However, it is not known what level of supervision fellowship program directors (FPDs) deem necessary for graduation. The Subspecialty Pediatrics Investigator Network (SPIN) investigated FPD perceptions of the minimum level of supervision required for a trainee to successfully graduate.

Method
In 2017, SPIN surveyed all FPDs of accredited fellowships for 14 subspecialties. For each EPA, the minimum supervision level for graduation (ranging from observation only to unsupervised practice) was set such that no more than 20% of FPDs would accept a lower level.

Results
The survey response rate was 82% (660/802). The minimum supervision level for graduation varied across the 7 EPAs from 2 (direct) to 4 (indirect for complex cases), with significant differences between EPAs. The percentage of FPDs desiring a lower minimum supervision level ranged from 3% to 17%. Compared with the 4 nonclinical EPAs (quality improvement, management, lead within the profession, scholarship), the 3 clinical EPAs (consultation, handover, lead a team) had higher minimum supervision graduation levels (P < .001), with less likelihood that an FPD would graduate a learner below their minimum level (P < .001)

Conclusions
Consensus among FPDs across all pediatric subspecialties demonstrates the potential need for ongoing supervision for graduates in all 7 common pediatric subspecialty EPAs after fellowship. As CBME programs are implemented, processes and infrastructure to support new graduates are important considerations for leaders.
Learner Levels of Supervision Across the Continuum of Pediatrics Training
Authors: Schwartz Alan , Borman-Shoap Emily , Carraccio Carol , Herman Bruce , Hobday Patricia M. , Kaul Paritosh , Long Michele , O’Connor Meghan , Mink Richard , Schumacher Daniel J. , Turner David A. , West Daniel C. 
Published: June 2021

Purpose
To describe trajectories in level of supervision ratings for linked entrustable professional activities (EPAs) among pediatric learners in medical school, residency, fellowship.

Method
The authors performed secondary analyses of 3 linked datasets of level of supervision ratings for the Core EPAs for Entering Residency, the General Pediatrics EPAs, and the Subspecialty Pediatrics EPAs. After identifying 9 activities in common across training stages and aligning the level of entrustment-supervision scales across the datasets, piecewise ordinal and linear mixed effects models were fitted to characterize trajectories of supervision ratings.

Results
Within each training period, learners were rated as needing less supervision over time in each activity. When transitioning from medical school to residency or during the first year of residency, learners were rated as needing greater supervision in activities related to patient management, teamwork, emergent care, and public health/QI than in earlier periods. When transitioning from residency to fellowship, learners were always rated as needing greater supervision than they had been accorded at the end of residency and sometimes even more than they had been accorded at the start of residency.

Conclusions
Although development over training is often imagined as continuous and monotonically increasing competence, this study provides empirical evidence supporting the idea that entrustment is a set of discrete decisions. The relaxation of supervision in training is not a linear process. Even with a seamless curriculum, supervision is tightly bound to the training setting. Several explanations for these findings are discussed.
Entrustable Professional Activities and Entrustment Decision Making: A Development and Research Agenda for the Next Decade
Authors: ten Cate Olle , Balmer Dorene F. , Caretta-Weyer Holly , Hatala Rose , Hennus Marije P. , West Daniel C. 
Published: June 2021

To establish a research and development agenda for Entrustable Professional Activities (EPAs) for the coming decade, the authors, all active in this area of investigation, reviewed recent research papers, seeking recommendations for future research. They pooled their knowledge and experience to identify 3 levels of potential research and development: the micro level of learning and teaching; the meso level of institutions, programs, and specialty domains; and the macro level of regional, national, and international dynamics. Within these levels, the authors categorized their recommendations for research and development.
The authors identified 14 discrete themes, each including multiple questions or issues for potential exploration, that range from foundational and conceptual to practical.
Much research to date has focused on a variety of issues regarding development and early implementation of EPAs. Future research should focus on large-scale implementation of EPAs to support competency-based medical education (CBME) and on its consequences at the 3 levels. In addition, emerging from the implementation phase, the authors call for rigorous studies focusing on conceptual issues. These issues include the nature of entrustment decisions and their relationship with education and learner progress and the use of EPAs across boundaries of training phases, disciplines and professions, including continuing professional development. International studies evaluating the value of EPAs across countries are another important consideration. Future studies should also remain alert for unintended consequences of the use of EPAs.
EPAs were conceptualized to support CBME in its endeavor to improve outcomes of education and patient care, prompting creation of this agenda.
The Implementation of Entrustable Professional Activities in Postgraduate Medical Education in the Netherlands: Rationale, Process, and Current Status
Authors: de Graaf Jacqueline , Bolk Marieke , Dijkstra Auk , van der Horst Marieke , Hoff Reinier G. , ten Cate Olle 
Published: June 2021

Postgraduate medical education in the Netherlands has adopted competency-based education since the turn of the century. In 2006, the CanMEDS competency framework was introduced.
A 2013 government plan to reduce the length and budgets of training programs led the Dutch Association of Medical Specialists (DAMS) to respond with a proposal to create more flexibility and individualization rather than a blunt cut in the length across all training programs. DAMS launched a government-funded, nation-wide, 4-year project (2014–2018) to blueprint the reform of postgraduate medical education in this direction.
To achieve competency-based individualization, the fixed duration of postgraduate programs was abandoned, and entrustable professional activities (EPAs) were introduced in all specialty programs. Implementation of this new generation of programs took place in 2017–2019 in all disciplines.
The project focused on EPA-based individualization of all programs, while addressing issues of the continuity of patient care in time-variable programs and the legal and regulatory consequences of individualization. About 30 specialty programs were revised at national, regional, local, and individual levels to incorporate EPAs; portfolio systems were adapted, clinical competency committees were installed for all programs, and procedures for summative entrustment decision making were elaborated.
This paper reports on the rationale and the process that led to a more time-variable postgraduate education landscape, and, on average, a shortening of training length by 3 months.
Constructing a Validity Map for a Workplace-Based Assessment System: Cross-Walking Messick and Kane
Authors: Kinnear Benjamin , Kelleher Matthew , May Brian , Sall Dana , Schauer Daniel P. , Schumacher Daniel J. , Warm Eric J. 
Published: June 2021

Problem
Health professions education has shifted to a competency-based paradigm in which many programs rely heavily on workplace-based assessment (WBA) to produce data for summative decisions about learners. However, WBAs are complex and require validity evidence beyond psychometric analysis. Here, the authors describe their use of a rhetorical argumentation process to develop a map of validity evidence for summative decisions in an entrustment-based WBA system.

Approach
To organize evidence, the authors cross-walked 2 contemporary validity frameworks, one that emphasizes sources of evidence (Messick) and another that stresses inferences in an argument (Kane). They constructed a validity map using 4 steps: (1) Asking critical questions about the stated interpretation and use, (2) Seeking validity evidence as a response, (3) Categorizing evidence using both Messick’s and Kane’s frameworks, and (4) Building a visual representation of the collected and organized evidence. The authors used an iterative approach, adding new critical questions and evidence over time.

Outcomes
The first map draft produced 25 boxes of evidence that included all 5 sources of evidence detailed by Messick and spread across all 4 inferences described by Kane. The rhetorical question–response process allowed for structured critical appraisal of the WBA system, leading to the identification of evidentiary gaps.

Next Steps
Future map iterations will integrate evidence quality indicators and allow for deeper dives into the evidence. The authors intend to share their map with graduate medical education stakeholders (e.g., accreditors, institutional leaders, learners, patients) to understand if it adds value for evaluating their WBA programs’ validity arguments.
The role of CD8+ T-cell systemic lupus erythematosus pathogenesis: an update
Authors: Chen Ping-Min , Tsokos George C. 
Published: June 2021

Purpose of review
Systemic lupus erythematosus (SLE) is a serious autoimmune disease with a wide range of organ involvement. In addition to aberrant B-cell responses leading to autoantibody production, T-cell abnormalities are important in the induction of autoimmunity and the ensuing downstream organ damage. In this article, we present an update on how subsets of CD8+ T cells contribute to SLE pathogenesis.

Recent findings
Reduced cytolytic function of CD8+ T cells not only promotes systemic autoimmunity but also accounts for the increased risk of infections. Additional information suggests that effector functions of tissue CD8+ T cells contribute to organ damage. The phenotypic changes in tissue CD8+ T cells likely arise from exposure to tissue microenvironment and crosstalk with tissue resident cells. Research on pathogenic IL-17-producing double negative T cells also suggests their origin from autoreactive CD8+ T cells, which also contribute to the induction and maintenance of systemic autoimmunity.

Summary
Reduced CD8+ T-cell effector function illustrates their role in peripheral tolerance in the control of autoimmunity and to the increased risk of infections. Inflammatory cytokine producing double negative T cells and functional defects of regulatory CD8+ T cell both contribute to SLE pathogenesis. Further in depth research on these phenotypic changes are warranted for the development of new therapeutics for people with SLE.