bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oligodendrocyte precursor cells prune axons in the mouse neocortex
Authors: Buchanan JoAnn , Elabbady Leila , Collman Forrest , Jorstad Nikolas L. , Bakken Trygve E. , Ott Carolyn , Glatzer Jenna , Bleckert Adam A. , Bodor Agnes L. , Brittan Derrick , Bumbarger Daniel J. , Mahalingam Gayathri , Seshamani Sharmishtaa , Schneider-Mizell Casey , Takeno Marc M. , Torres Russel , Yin Wenjing , Hodge Rebecca D. , Castro Manuel , Dorkenwald Sven , Ih Dodam , Jordan Chris S. , Kemnitz Nico , Lee Kisuk , Lu Ran , Macrina Thomas , Mu Shang , Popovych Sergiy , Silversmith William M. , Tartavull Ignacio , Turner Nicholas L. , Wilson Alyssa M. , Wong William , Wu Jingpeng , Zlateski Aleksandar , Zung Jonathan , Lippincott-Schwartz Jennifer , Lein Ed S. , Seung H. Sebastian , Bergles Dwight E. , Reid R. Clay , da Costa Nuno Maçarico 
Published: May 2021

ABSTRACTNeurons in the developing brain undergo extensive structural refinement as nascent circuits adopt their mature form1. This transformation is facilitated by the engulfment and degradation of excess axonal branches and inappropriate synapses by surrounding glial cells, including microglia and astrocytes2,3. However, the small size of phagocytic organelles and the complex, highly ramified morphology of glia has made it difficult to determine the contribution of these and other glial cell types to this process. Here, we used large scale, serial electron microscopy (ssEM) with computational volume segmentation to reconstruct the complete 3D morphologies of distinct glial types in the mouse visual cortex. Unexpectedly, we discovered that the fine processes of oligodendrocyte precursor cells (OPCs), a population of abundant, highly dynamic glial progenitors4, frequently surrounded terminal axon branches and included numerous phagolysosomes (PLs) containing fragments of axons and presynaptic terminals. Single- nucleus RNA sequencing indicated that cortical OPCs express key phagocytic genes, as well as neuronal transcripts, consistent with active axonal engulfment. PLs were ten times more abundant in OPCs than in microglia in P36 mice, and declined with age and lineage progression, suggesting that OPCs contribute very substantially to refinement of neuronal circuits during later phases of cortical development.
Tumor growth of neurofibromin-deficient cells is driven by decreased respiration and hampered by NAD+ and SIRT3
Authors: Masgras Ionica , Cannino Giuseppe , Ciscato Francesco , Sanchez-Martin Carlos , Pizzi Marco , Menga Alessio , Castegna Alessandra , Rasola Andrea 
Published: May 2021

SUMMARYNeurofibromin loss drives neoplastic growth and a rewiring of mitochondrial metabolism. Here, we report that neurofibromin ablation dampens expression and activity of NADH dehydrogenase, the respiratory chain complex I, in an ERK-dependent fashion. This provides cells with resistance to pro-oxidants targeting complex I and decreases both respiration and intracellular NAD+. Expression of the alternative NADH dehydrogenase NDI1 raises NAD+/NADH ratio, enhances the activity of the mitochondrial NAD+-dependent deacetylase SIRT3 and interferes with tumorigenicity in neurofibromin-deficient cells. This anti-neoplastic effect is mimicked both in vitro and in vivo by administration of NAD+ precursors or by rising expression of the NAD+ deacetylase SIRT3, and is synergistic with ablation of the mitochondrial chaperone TRAP1, which augments succinate dehydrogenase activity further contributing to block pro-neoplastic metabolic changes of these cells. These findings shed light on chemotherapeutic resistance and on bioenergetic adaptations of tumors lacking neurofibromin, linking complex I inhibition to mitochondrial NAD+/NADH unbalance and SIRT3 inhibition, as well as to down-regulation of succinate dehydrogenase. This metabolic rewiring could unveil attractive therapeutic targets for neoplasms related to neurofibromin loss.
Trikafta therapy alters the CF lung mucus metabolome reshaping microbiome niche space
Authors: Sosinski Lauren M. , Martin H Christian , Neugebauer Kerri A. , Ghuneim Lydia-Ann J. , Guzior Douglas V. , Castillo-Bahena Alicia , Mielke Jenna , Thomas Ryan , McClelland Marc , Conrad Doug , Quinn Robert A. 
Published: June 2021

AbstractBackgroundNovel small molecule therapies for cystic fibrosis (CF) are showing promising efficacy and becoming more widely available since recent FDA approval. The newest of these is a triple therapy of Elexacaftor-Tezacaftor-Ivacaftor (ETI, Trikafta®). Little is known about how these drugs will affect polymicrobial lung infections, which are the leading cause of morbidity and mortality among people with CF (pwCF).Methodswe analyzed the sputum microbiome and metabolome from pwCF (n=24) before and after ETI therapy using 16S rRNA gene amplicon sequencing and untargeted metabolomics.ResultsThe lung microbiome diversity, particularly its evenness, was increased (p = 0.044) and the microbiome profiles were different between individuals before and after therapy (PERMANOVA F=1.92, p=0.044). Despite these changes, the microbiomes were more similar within an individual than across the sampled population. There were no specific microbial taxa that were different in abundance before and after therapy, but collectively, the log-ratio of anaerobes to classic CF pathogens significantly decreased. The sputum metabolome also showed changes due to ETI. Beta-diversity increased after therapy (PERMANOVA F=4.22, p=0.022) and was characterized by greater variation across subjects while on treatment. This significant difference in the metabolome was driven by a decrease in peptides, amino acids, and metabolites from the kynurenine pathway. Metabolism of the three small molecules that make up ETI was extensive, including previously uncharacterized structural modifications.ConclusionsThis study shows that ETI therapy affects both the microbiome and metabolome of airway mucus. This effect was stronger on sputum biochemistry, which may reflect changing niche spaces for microbial residency in lung mucus as the drug’s effects take hold, which then leads to changing microbiology.FundingThis project was funded by a National Institute of Allergy and Infectious Disease Grant R01AI145925
AR-V7 exhibits non-canonical mechanisms of nuclear import and chromatin engagement in Castrate-Resistant Prostate Cancer
Authors: Kim Seaho , Bin Jamalruddin Mohd Azrin , Au CheukMan Cherie , Mukhtar Eiman , Portella Luigi , Berger Adeline , Worroll Daniel , Rickman David S. , Nanus David M. , Giannakakou Paraskevi 
Published: June 2021

SummaryExpression of the AR splice variant, AR-V7, in prostate cancer is correlated with poor patient survival and resistance to AR targeted therapies and taxanes. Currently, there is no specific inhibitor of AR-V7, while the molecular mechanisms regulating its biological function are not well elucidated. Here we report that AR-V7 has unique biological features that functionally differentiate it from canonical AR-fl or from the second most prevalent variant, AR-v567. First, AR-V7 exhibits fast nuclear import kinetics via a pathway distinct from the nuclear localization signal dependent importin-α /β pathway used by AR-fl and AR-v567. We also show that the dimerization box domain, known to mediate AR dimerization and transactivation, is required for AR-V7 nuclear import but not for AR-fl. Once in the nucleus, AR-V7 is transcriptionally active, yet exhibits unusually high intranuclear mobility and transient chromatin interactions, unlike the stable chromatin association of liganded AR-fl. The high intranuclear mobility of AR-V7 together with its high transcriptional output, suggest a Hit-and-Run mode of transcription. Our findings reveal unique mechanisms regulating AR-V7 activity, offering the opportunity to develop selective therapeutic interventions.
KIF18B is a cell-type specific regulator of spindle orientation in the epidermis
Authors: Moreci Rebecca S. , Lechler Terry 
Published: June 2021

SUMMARYProper spindle orientation is required for asymmetric cell division and the establishment of complex tissue architecture. In the developing epidermis, spindle orientation requires a conserved cortical protein complex of LGN/NuMA/dynein-dynactin. However, how microtubule dynamics are regulated to interact with this machinery and properly position the mitotic spindle is not fully understood. Furthermore, our understanding of the processes that link spindle orientation during asymmetric cell division to cell fate specification in distinct tissue contexts remains incomplete. We report a role for the microtubule catastrophe factor KIF18B in regulating microtubule dynamics to promote spindle orientation in keratinocytes. During mitosis, KIF18B accumulates at the cell cortex, colocalizing with the conserved spindle orientation machinery. In vivo we find that KIF18B is required for oriented cell divisions within the hair placode, the first stage of hair follicle morphogenesis, but is not essential in the interfollicular epidermis. Disrupting spindle orientation in the placode, using mutations in either KIF18B or NuMA, results in aberrant cell fate marker expression of hair follicle progenitor cells. These data functionally link spindle orientation to cell fate decisions during hair follicle morphogenesis. Taken together, our data demonstrate a role for regulated microtubule dynamics in spindle orientation in epidermal cells. This work also highlights the importance of spindle orientation during asymmetric cell division to dictate cell fate specification.
Accelerating RepeatClassifier Based on Spark and Greedy Algorithm with Dynamic Upper Boundary
Authors: Hu Kang , Liao Xingyu , Zou You , Wang Jianxin 
Published: June 2021

1AbstractTransposable elements (TEs) represent quantitatively important components of genome sequences (e.g. 90% of the wheat genome), and play important roles in genome organization and evolution. The promotion of unsupervised annotation of transposable elements is of great significance. Classification is an important step in TE annotation, which summarize the information about the type or mechanism for the raw repetitive sequences. RepeatClassifier is a basic homology-based classification tool which compares the TE families to both the Repeat Protein Database (DB) and libraries of RepeatMasker. Unfortunately, RepeatClassifier is inefficient and takes a few days to classify the repetitive sequences of large genomes. Hence, we proposed Spark-based RepeatClassifier (SRC) which uses Greedy Algorithm with Dynamic Upper Boundary (GDUB) for data division and load balancing, and Spark to improve the parallelism of RepeatClassifier. Experimental results show that SRC can not only ensure the same level of accuracy as that of RepeatClassifier, but also achieve 42-88 times of acceleration compared to RepeatClassifier. At the same time, SRC shows excellent parallel performance when dealing with input datasets with unbalanced length distribution. SRC is publicly available at https://github.com/BioinformaticsCSU/SRC.
What do participants value in a diversity mentorship program? Perspectives from a Canadian medical school
Authors: Zhou Stephanie Yifan , Balakrishna Anita , Nyhof-Young Joyce , Javeed Imaan , Robinson Lisa Annette 
Published: May 2021

PurposeAs medical schools become increasingly diverse, there is a growing demand for schools to support their equity-seeking students. At the University of Toronto, the diversity mentorship program (DMP) is a new program created to support equity-seeking and diverse medical students in first- and second-year through didactic lectures, networking opportunities and mentorship from senior clinicians. This article aims to share participant perspectives on how diversity-focused mentorship benefits them, perceived barriers and insights for other institutions developing a similar program.Design/methodology/approachUsing a mixed methods design, students and mentors completed semi-structured surveys to assess broad perceptions of their mentorship experiences. Focus groups were conducted with both groups to gain deeper understandings of participants' experiences. The authors performed thematic analysis to identify qualities of successful experiences and barriers to participation.FindingsMost mentors and mentees found the DMP helpful and identified five themes contributing to a positive mentorship experience: (1) accessibility, (2) program diversity focus with clear expectations, (3) career guidance, (4) exposure to different perspectives and (5) community and shared identity. Uncertainty on how to help less assertive mentees, mentorship pair discordance where mentees paired by race did not share racial identities and logistical challenges was identified as barriers to maintaining mentoring relationships.Originality/valueTo the authors’ knowledge, this is the first qualitative study exploring the feelings and impressions of participants in a mentorship program at a medical school addressing the needs of equity-seeking groups. By understanding the characteristics and value of diversity-focused mentorship, this will inform the creation of similar supportive programs across various professional fields at other schools.
Co-creating dementia care: manoeuvring fractured reflexivity in service design
Authors: Bast Ane , Røhnebæk Maria Taivalsaari , Engen Marit 
Published: June 2021

PurposeThis study aims to theorise and empirically investigate how vulnerable users suffering from cognitive impairments can be involved in service design.Design/methodology/approachThe data were collected through an ongoing field study following the processes of designing new forms of dementia care. The data consist of document studies, observations and interviews with actors involved in the service design process.FindingsThe findings demonstrate how the involvement of vulnerable users with cognitive impairment in service design requires the ability to manoeuvre users' “fractured reflexivity”. The design process was found to be constrained and enabled by three interrelated features: cognitive aspects, social aspects and representativeness.Practical implicationsThis paper provides insight into concrete ways of involving vulnerable user groups in service design. The introduced concept – fractured reflexivity – may create awareness of how the involvement of users with cognitive impairment can be difficult but is also valuable, providing a means to rethink what may enable involvement and how to manage the constraints.Originality/valueAlthough design processes rely on reflexivity, there is limited research addressing how reflexivity capacity differs among actors. The authors contribute by exploring how fractured reflexivity may aid the analysis and understandings of intertwined issues related to the involvement of users with cognitive impairment. Therefore, this study initiates research on how service design entails enactments of different modes of reflexivity. The paper concludes with directions for future research avenues on service design and reflexivity modes.
Organizational resilience process: integrated model of safety culture
Authors: Hafeez Hira , Abdullah Muhammad Ibrahim , Zaheer Muhammad Asif , Ahsan Qurratulain 
Published: June 2021

Purpose
The purpose of the study is to create substantial awareness for safety precautions and safety parameters to lessen occupational injuries and accidents. Utilization of safety culture phenomenon with its fundamental understanding has imperative consideration for safety compliance and participation behaviors. Thoughtful aim of this study is the extension of knowledge related to safety orientation particularly in primary health-care workforce.

Design/methodology/approach
Only slips and trips accounted for 40% of workplace injuries in nursing professionals. To identity, the data were collected through structured surveys from nursing professionals of public and private hospitals in Pakistan. To evaluate that data for current study, standardized regression coefficients (parameter estimation) with 95% confidence interval and 5,000 bootstrap samples were subjected. Confirmatory factor analysis was also used to measure the validity of study constructs.

Findings
The potential findings of present study have assured the presence of safety culture at workplace has potential to influences negative safety outcomes. In addition, safety compliance and safety participation as mediation paths would be the strengthening addition to safety model. These findings have extended the existing understanding of compliance and participation behaviors from single factor to two different constructs of safety orientation. This safety culture model offers an evidence-based approach to nursing practitioners and nursing managers with implications for nurse’s safety, education and training.

Originality/value
Occupational injuries and accidental happenings have adversely affecting the quality of care, patient’s recovery spam, satisfaction level and psychological health in care agents. This study has proposed a comprehensive model for understanding the mechanism of possible and reliable safety implications at health-care units. Prior knowledge has limitation to the inevitable effects of occupational injuries only rather than focusing on corrective actions against this phenomenon.
Thermal tolerance of early development predicts the realized thermal niche in marine ectotherms
Authors: Collin Rachel , Rebolledo Adriana P. , Smith Emily , Chan Kit Yu Karen 
Published: June 2021

Abstract

Predictions of ectotherms' responses to global warming depend on the relationship between environmental temperature and organismal performance. To date, most predictions of thermal responses are generated from experimentally derived measures of thermal tolerances of adults or estimates of thermal niches derived from geographic distributions of adults. It is unknown how measures derived from these different approaches compare, or, as thermal performance of ectotherms varies through ontogeny, how they compare across life stages.

To understand the efficacy of the temperature–performance relationship of early developmental stages as predictors of geographic range, we empirically documented the upper and lower thermal tolerance limits of embryos of eight species of ectotherms with complex life cycles.

We compared the embryonic thermal tolerances of each species to that of the adults (documented in a previous study), as well as to an estimate of the thermal niche derived from adult distributions.

Our results show that in all eight species the upper thermal limit estimated from embryos is significantly lower than the upper thermal limit estimated from adults. The lower thermal limit for embryos and for adult performance are similar, but the lower thermal limit for adult survival is significantly lower.

Warming tolerances, calculated as the difference between upper tolerance limit and the average ambient temperature during the warmest month, for each species are also smaller for embryos (~1°C) than for adults (~5°C).

These results show that thermal tolerances of early developmental stages, which are often easier to obtain for large sample sizes over an array of temperatures than are tolerances of adults, are a powerful, and potentially more accurate tool for predicting future responses to climate change.

A free Plain Language Summary can be found within the Supporting Information of this article.
The vaginal microbiota composition of women undergoing assisted reproduction: a prospective cohort study
Authors: Karaer A , Doğan B , Günal S , Tuncay G , Arda Düz S , Ünver T , Tecellioğlu N 
Published: May 2021

ObjectiveTo evaluate the impact of vaginal microbiota on pregnancy outcomes in women undergoing assisted reproduction.DesignA prospective cohort study.SettingA university‐based assisted reproductive technology (ART) centre.Population223 women undergoing ART treatment.MethodsPrior to embryo transfer, vaginal samples were collected from the posterior fornix. Vaginal microbiota identification was carried out using next‐generation sequencing and categorised according to the V3–V4 hypervariable region in the 16S rRNA gene region.Main outcome measuresART clinical outcomes (implantation, clinical pregnancy rates and live birth rates).ResultsThe live birth rate in women with community state type (CST)‐I (39%) was higher than that in women with CST‐III (21.5%) but the difference was not statistically significant (P = 0.052). The relative abundance of Lactobacillus was lower in women who failed to become pregnant (NP group) (67.71%) than in women who became pregnant (PR group) (79.72%). However, this difference was not statistically significant (P = 0.06). In the NP group, the relative abundance of Streptococcus (7.81%) and Gardnerella (9.40%) was higher than that in the PR group (relative abundance of Streptococcus and Gardnerella was 2.28% and 5.56%, respectively). The abundance of Streptococcus was found to be statistically significantly different between the two study groups (P = 0.014). Linear discriminant analysis (LDA) further validated that Streptococcus had the highest contribution (LDA score >4.0) to the difference between these two groups.ConclusionsStreptococcus has the highest contribution to the distinction between the PR and NP groups.Tweetable abstractA relatively high abundance of Streptococcus in the vaginal microbiota may be associated with a lower ART success rate.
Immunotherapy in advanced Merkel cell carcinoma: Sydney west cancer network experience
Authors: Hasmat Shaheen , Howle Julie R , Karikios Deme J , Carlino Matteo S , Veness Michael J 
Published: May 2021

AbstractIntroductionMerkel cell carcinoma (MCC) is a highly aggressive skin cancer with no survival benefit demonstrated using palliative cytotoxic chemotherapy in the setting of metastatic MCC. Recently, immune checkpoint inhibitors (anti‐PD‐L1/PD1) have been approved in this setting after durable clinical response was demonstrated in several clinical trials. In this series, we present a multicentre real‐world experience in using anti‐PD‐L1/PD1 in advanced MCC.MethodsA retrospective review was performed of all patients with metastatic MCC who were treated with at least one dose of anti‐PD‐L1/PD1 presenting to Sydney West Cancer Network (Westmead, Nepean and Blacktown hospitals) was performed between 2016 and 2020. Treatment response was assessed based on morphologic and/or metabolic changes of the disease on FDG‐PET/CT scans. Primary end point investigated was objective response rate. Secondary outcomes included therapy toxicity, disease control and overall survival.ResultsThirteen patients received anti‐PD‐L1/PD1 with a median age of 82 (range 62–89). Two patients had undergone prior palliative chemotherapy. The median follow‐up time was 17 months (range 2–34). The overall, complete and partial response rates were 77% (10), 54% (7) and 23% (3), respectively. Treatment‐related grade 1 or 2 toxicity was experienced by 69% with only 2 cases of greater severity. The median progression‐free survival and overall survival were 18 months (95% CI 10–26 months) and 33 months (95% CI range 7.6–58.4 months), respectively.ConclusionsConsistent with clinical trial results, anti‐PD‐L1/PD1 therapy in this small series demonstrated efficacy and safety in patients with metastatic MCC.