bluuebunny/crossref_metadata_2025_split huggingface dataset:
How competition for funding impacts scientific practice
Authors: Meirmans Stephanie 
Published: August 2022

AbstractIn the research integrity literature, funding enters in two different ways: as elevating questionable research practices due to perverse incentives, and as being a potential player to incentivize researchers to behave well. Other recent studies have emphasized the importance of the latter, asking funding experts. Here, I explored how the impact of competitive research funding on science is being perceived by active researchers. More specifically, I have conducted a series of group sessions with researchers in two different countries with a different degree of competition for funding, in three disciplinary fields (medical sciences, natural sciences and the humanities), and with researchers in two different career stages (permanent versus temporary employment). Researchers across all groups experienced that competition for funding shapes science, with many unintended questionable side effects. Intriguingly, these questionable effects had little to do with the type of questionable research practices (QRP’s) typically being presented in the research integrity literature. While the notion of QRP’s focuses on publications and assumes that there would essentially be a correct way to do the science, researchers worried about the shaping of science via funding. According to my session participants, rather than ending up as really being wrong, this shaping could result in predictable, fashionable, short-sighted, and overpromising science. And still, this was seen as highly problematic: scientists experienced that the ‘projectification’ of science makes it more and more difficult to do any science of real importance: plunging into the unknown or addressing big issues that would need a long-term horizon to mature.
Activity in developing prefrontal cortex is shaped by sleep and sensory experience
Authors: Gómez Lex J. , Dooley James C. , Blumberg Mark S. 
Published: August 2022

ABSTRACTIn developing rats, behavioral state exerts a profound modulatory influence on neural activity throughout the sensorimotor system, including primary motor cortex (M1). We hypothesized that similar state-dependent modulation occurs in higher-order cortical areas with which M1 forms functional connections. Here, using 8- and 12-day-old rats cycling freely between sleep and wake, we record neural activity in M1, secondary motor cortex (M2), and medial prefrontal cortex (mPFC). At both ages in all three areas, neural activity increased during active sleep (AS) compared with wake. Regardless of behavioral state, neural activity in M2 and mPFC increased during periods when limbs were moving. This movement-related activity in M2 and mPFC, like that in M1, is driven by sensory feedback. Our results, which diverge from those of previous studies using anesthetized pups, demonstrate that AS-dependent modulation and sensory responsivity extend to prefrontal cortex. These findings expand the range of factors shaping the activity-dependent development of higher-order cortical areas.
Activating mutations in FGFR3 are associated with clonal expansion events and high de novo rates in the male germline
Authors: Moura Sofia , Hartl Ingrid , Yasari Atena , Brumovska Veronika , Striedner Yasmin , Bishara Marina , Mair Theresa , Ebner Thomas , Schütz Gerhard J. , Sevcsik Eva , Tiemann-Boege Irene 
Published: August 2022

AbstractDelayed fatherhood results in a higher risk to inherit a new germline mutation that might result in a congenital disorder in the offspring. In particular, some FGFR3 mutations increase in frequency with age, but there are still a large number of uncharacterized FGFR3 mutations that could be expanding in the male germline with potentially early or late-onset effects in the offspring. Here, we investigated the mutation frequency in the DNA of human testis and sperm and the activation state of the expressed mutant protein of eight different FGFR3 variants categorized by ClinVar as deleterious, benign, or not reported. Overall, the ligand-independent activation of the mutant protein resulted in a increased number of mutant sperm; although, strong activating mutations did not necessarily result in the highest frequencies. Moreover, only two mutants c.952G>A and c.1620C>A showed an increase with the donor’s age; the latter also forming larger clonal expansions in the testis. We also showed that the prediction of deleteriousness of a mutation is not always accurate, and similar in silico scores can reflect either a gain-of-function or loss-of-function. Our approach led to the discovery of two novel variants c.1261G>A and c.952G>A to have promiscuous FGFR3 activation and increased mutation frequencies in the male germline. The large fraction of donors with mutations suggests a high de novo rate potentially explained by a selective advantage before the maturation of the male germline. This sequence-function study provides important data for the evaluation and interpretation of variants with relevant clinical implications.
Analysis of multiple causes of death: a review of methods and practices
Authors: Bishop Karen , Balogun Saliu , Eynstone-Hinkins James , Moran Lauren , Martin Melonie , Banks Emily , Rao Chalapati , Joshy Grace 
Published: August 2022

AbstractBackgroundResearch and reporting of mortality indicators typically focus on a single underlying cause of death selected from multiple causes recorded on a death certificate. The need to incorporate the multiple causes in mortality statistics - reflecting increasing multimorbidity and complex causation patterns - is recognised internationally. This review aims to identify and appraise relevant multiple cause analytical methods and practices.MethodsWe searched Medline, PubMed, Scopus and Web of Science from inception to December 2020 without language restrictions, supplemented by consultation with international experts. Eligible articles included those analysing multiple causes of death from death certificates. The process identified 4,080 articles; after screening, 434 full texts were reviewed.ResultsMost reviewed articles (77%, n=332) were published since 2001. The majority examined mortality by “any-mention” of a cause of death (87%, n=377) and assessed pairwise combinations of causes (56%, n=245). Recently emerging (since 2001) were applications of methods to group deaths based on common cause patterns using, for example, cluster analysis (2%, n=9), and the application of multiple cause weights to re-evaluate mortality burden (1%, n=5). Multiple cause methods applied to specific research objectives are described for recently emerging approaches.ConclusionThis review confirms rapidly increasing international interest in the analysis of multiple causes of death and provides the most comprehensive overview of methods and practices to date. Available multiple cause methods are diverse but suit a range of research objectives, that with greater data availability and technology could be further developed and applied across a range of settings.
The transcriptomic landscape of normal and ineffective erythropoiesis at single cell resolution
Authors: Doty Raymond T. , Lausted Christopher G. , Munday Adam D. , Yang Zhantao , Yan Xiaowei , Meng Changting , Tian Qiang , Abkowitz Janis L. 
Published: August 2022

AbstractIneffective erythropoiesis, the death of maturing erythroid cells, is a common cause of anemia. To better understand why this occurs, we studied the fates and adaptations of single erythroid marrow cells from individuals with Diamond Blackfan anemia (DBA), del(5q) myelodysplastic syndrome (del(5q) MDS), and normal controls, and defined an unhealthy (vs. healthy) differentiation trajectory, using velocity pseudotime and cell surface protein assessment. The pseudotime trajectories diverge immediately after the cells upregulate transferrin receptor (CD71), import iron, and initiate heme synthesis, although cell death occurs much later. Cells destined to die highly express heme responsive genes, including ribosomal protein and globin genes. In contrast, surviving cells downregulate heme synthesis, while upregulating DNA damage response, hypoxia and HIF1 pathways. Surprisingly, 24±12% of cells from controls follow the unhealthy trajectory, implying that heme also regulates cell fate decisions during normal red cell production. Del(5q) MDS (unlike DBA) results from somatic mutations, so many normal (unmutated) erythroid cells persist. By independently tracking their trajectory, we gained insight into why they cannot expand to prevent anemia. In addition, we show that intron retention is especially prominent during red cell differentiation. The additional information provided by messages with retained introns also allowed us to align data from multiple independent experiments and thus accurately query the transcriptomic changes that occur as single erythroid cells mature.
The potential health impact of prospective Strep A vaccines: a modeling study
Authors: Giannini Fiona , Cannon Jeffrey W. , Cadarette Daniel , Bloom David E. , Moore Hannah C , Carapetis Jonathan , Abbas Kaja 
Published: August 2022

AbstractThe World Health Organization published the preferred product characteristics for a Group AStreptococcus(Strep A) vaccine in 2018. Based on these parameters for the age of vaccination, vaccine efficacy, duration of protection from vaccine-derived immunity, and vaccination coverage, we developed a static cohort model to estimate the projected health impact of Strep A vaccination at the global, regional, and national levels and by country-income category. We used the model to analyse six strategic scenarios. Based on Strep A vaccine introduction between 2022 and 2034 for the primary scenario, we estimated vaccination at birth for 30 vaccinated cohorts could avert 2.5 billion episodes of pharyngitis, 345 million episodes of impetigo, 1.3 million episodes of invasive disease, 24 million episodes of cellulitis, and 6 million cases of rheumatic heart disease globally. Vaccination impact in terms of burden averted per fully vaccinated individual is highest in North America for cellulitis and in Sub-Saharan Africa for rheumatic heart disease.
Psychological frailty in older adults: a systematic scoping review
Authors: Zhao Jinlong , Liu Justina , Tyrovolas Stefanos , Mutz Julian 
Published: August 2022

AbstractBackgroundPsychological frailty, along with physical and cognitive frailty, is linked to an increased risk of negative health outcomes among older adults. However, the definition of psychological frailty has received limited attention. A thorough comprehension of the concept of psychological frailty is therefore required.ObjectivesTo review existing definitions of psychological frailty and to provide a comprehensive overview of the concept of psychological frailty and associated measurements.MethodsThis review followed the PRISMA guidelines for scoping reviews and the JBI Manual for Evidence Synthesis. Eligibility criteria were developed based on the Participants-Concept-Context (PCC) framework. We searched CINAHL, Scopus, PubMed, Web of Science, and PsycINFO databases and other sources for relevant studies published between January 2003 to March 2022.ResultsThe final scoping review included 58 studies. 40 (69%) of these studies provided a definition of psychological frailty and 7 studies provided a novel definition. The other 11 studies focused on components of defining psychological frailty. To better characterize psychological frailty, we propose four groups of components, including mood, cognitive, mental health, and fatigue-associated problems. We identified 28 measuring tools across studies and the Tilburg frailty indicator was the most frequently used (46.6% of studies).ConclusionsPsychological frailty is a complex concept that lacks a consensus definition. It should include both psychological features and physical frailty. Depression and other psychological problems are commonly used to define psychological frailty. This scoping review outlines future research directions to refine the concept of psychological frailty.
The Effects of CdSe/ZnS Quantum Dots on the Photosynthesis Rate of the Chlorella Vulgaris Beads
Authors: Dissanayake Wimeth , Hailstone Richard , Bao Mengdi , Wang Ruo-Qian , Yong Xin , Du Ke 
Published: August 2022

AbstractPhotosynthesizing microalgae produce more than 50% of oxygen in the atmosphere and are crucial for the survival of many living systems such as coral reefs. To address the declining of coral reefs, artificial reefs have been introduced to encapsulate the aglae cells in a polymer matrix but the effects of nanoscale pollutants on these engineered systems have not been fully understood. In this work, quantum dots with a size smaller than 10 nm are being used to elucidate the photosynthesis performance of the sodium alginate beads encapsulated with Chlorella vulgaris (C. vulgaris). The fluorescent quantum dots can move into the alginate matrix and the fluorescence intensity in the algae beads is correlated with the quantum dot concentration. We further show that the photosynthesis of the algae beads are sensitive to the quantum dot concentration and are also time sensitive. In the first 48 min of quantum dot exposure, both carbon dioxide absorption and oxygen production are low, suggesting limited photosynthesis. After the initial incubation, the photosynthesis rate quickly increases even though more inhibition is still observed with higher concentration of the quantum dots.
Neuronal dynamics of the default mode network and anterior insular cortex: Intrinsic properties and modulation by salient stimuli
Authors: Chao Tzu-Hao Harry , Lee Byeongwook , Hsu Li-Ming , Cerri Domenic Hayden , Zhang Wei-Ting , Wang Tzu-Wen Winnie , Ryali Srikanth , Menon Vinod , Shih Yen-Yu Ian 
Published: August 2022

SummaryThe default mode network (DMN) is closely associated with self-referential mental functions and its dysfunction is implicated in many neuropsychiatric disorders. However, the neurophysiological properties and task-based functional organization of the rodent DMN are poorly understood, limiting its translational utility. Here, we combine fiber-photometry with fMRI and computational modeling to characterize dynamics of putative rodent DMN nodes and their interactions with the anterior insular cortex (AI) of the salience network. We reveal neuronal activity changes in AI and DMN nodes prior to fMRI-derived DMN activations and uncover cyclical transition patterns between spatiotemporal neuronal activity states. Finally, we demonstrate that salient oddball stimuli suppress the DMN and enhance AI neuronal activity, and that the AI causally inhibits the retrosplenial cortex, a prominent DMN node. These findings elucidate previously unknown properties regarding the neurobiological foundations of the rodent DMN and its modulation by salient stimuli, paving the way for future translational studies.HighlightsConcurrent measurement of neuronal (GCaMP) and fMRI signals in retrosplenial, cingulate, prelimbic, and anterior insula corticesGCaMP signals reveal neuronal antagonism between AI and fMRI-derived DMN activation and deactivationGCaMP signals reveal salient oddball stimuli-induced suppression of prelimbic, cingulate and retrosplenial cortices, and activation of anterior insular cortexAnterior insular cortex causally inhibits retrosplenial cortex during processing of salient oddball stimuliFindings delineate neurofunctional organization of the rodent DMN and provide a more informed model for translational studies
A comprehensive single-cell breast tumor atlas defines cancer epithelial and immune cell heterogeneity and interactions predicting anti-PD-1 therapy response
Authors: Xu Lily , Saunders Kaitlyn , Knutsdottir Hildur , Chen Kenian , Maués Julia , Hodgdon Christine , Roussos Torres Evanthia T. , Reddy Sangeetha M. , Xu Lin , Chan Isaac S. 
Published: August 2022

ABSTRACTWe present an integrated single-cell RNA-seq resource of the breast tumor microenvironment consisting of 236,363 cells from 119 biopsy samples across 8 publicly available datasets. In this computational study, we first leverage this novel resource to define cancer epithelial cell heterogeneity based on two clinically relevant markers and identify six new and distinct subsets of natural killer cells. We then illustrate how cancer epithelial cell heterogeneity impacts immune cell interactions. We develop T cell InteractPrint, which considers how cancer epithelial cell heterogeneity shifts the predicted strength of T cell interactions. We use InteractPrint to predict response to immune checkpoint inhibition (ICI) in two clinical trials testing immunotherapy in patients with breast cancer. T cell InteractPrint was predictive in both trials (AUC = 0.81 and 0.84), versus PD-L1 expression (AUC = 0.54 and 0.72). This result provides an alternative predictive biomarker to PD-L1 to select patients who should receive ICI.STATEMENT OF SIGNIFICANCEWe developed a novel integrated single-cell atlas of the breast tumor microenvironment to interrogate breast tumor cell heterogeneity and define how heterogenous cancer epithelial cell and immune cell interactions predict response to anti-PD-1 therapy.
3D-Beacons: Decreasing the gap between protein sequences and structures through a federated network of protein structure data resources
Authors: Varadi Mihaly , Nair Sreenath , Sillitoe Ian , Tauriello Gerardo , Anyango Stephen , Bienert Stefan , Borges Clemente , Deshpande Mandar , Green Tim , Hassabis Demis , Hatos Andras , Hegedus Tamas , Hekkelman Maarten L , Joosten Robbie , Jumper John , Laydon Agata , Molodenskiy Dmitry , Piovesan Damiano , Salladini Edoardo , Salzberg Steven L. , Sommer Markus J , Steinegger Martin , Suhajda Erzsebet , Svergun Dmitri , Tenorio-Ku Luiggi , Tosatto Silvio , Tunyasuvunakool Kathryn , Waterhouse Andrew Mark , Žídek Augustin , Schwede Torsten , Orengo Christine , Velankar Sameer 
Published: August 2022

AbstractWhile scientists can often infer the biological function of proteins from their 3-dimensional quaternary structures, the gap between the number of known protein sequences and their experimentally determined structures keeps increasing. A potential solution to this problem is presented by ever more sophisticated computational protein modelling approaches. While often powerful on their own, most methods have strengths and weaknesses. Therefore, it benefits researchers to examine models from various model providers and perform comparative analysis to identify what models can best address their specific use cases. To make data from a large array of model providers more easily accessible to the broader scientific community, we established 3D-Beacons, a collaborative initiative to create a federated network with unified data access mechanisms. The 3D-Beacons Network allows researchers to collate coordinate files and metadata for experimentally determined and theoretical protein models from state-of-the-art and specialist model providers and also from the Protein Data Bank.
A tumour-promoting senescent secretome triggered by platinum chemotherapy exploits a targetable TGFβR1/Akt-mTOR axis in lung cancer
Authors: González-Gualda Estela , Macias David , Morsli Samir , Martín José Ezequiel , Ou Hui-Ling , Denholm Mary , Olan Ioana , Hoffmann Reuben , Dane Mark , Veroutis Dimitris , Medrano Guillermo , Mulero Francisca , Martins Carla P. , Barbacid Mariano , Gorgoulis Vassilis , Korkola James E. , Rassl Doris M. , Doherty Gary J. , Rintoul Robert C. , Narita Masashi , Muñoz-Espín Daniel 
Published: August 2022

AbstractPlatinum-based chemotherapy is commonly used for non-small cell lung cancer (NSCLC) treatment, yet clinical outcomes remain poor. Cellular senescence and its associated secretory phenotype (SASP) can have multiple tumour-promoting activities, although these are largely unexplored in lung cancer. Here we show that cisplatin-derived SASP enhances the malignant phenotype of lung cancer cells. Using xenograft, orthotopic and KrasG12V-driven murine NSCLC models, we demonstrate that cisplatin-induced senescent cells strongly promote tumour progression. Mechanistically, we find that a TGF-β-enriched SASP drives pro-proliferative effects through TGFβR1 and Akt/mTOR pathway activation. We validate the translational relevance of chemotherapy-induced SASP using clinical NSCLC samples from patients who received neoadjuvant platinum-based chemotherapy. Importantly, TGFβR1 inhibition with galunisertib or senolytic treatment significantly reduces tumour promotion driven by cisplatin-induced senescence. Finally, we demonstrate, using distinct murine NSCLC models, that addition of TGFBR1 inhibitors to platinum-based chemotherapy reduces tumour burden and improves survival, providing pre-clinical proof-of-concept for future trial designs.
Hepatic inactivation of murine Surf4 results in marked reduction in plasma cholesterol
Authors: Tang Vi T. , McCormick Joseph , Xu Bolin , Wang Yawei , Fang Huan , Wang Xiao , Siemieniak David , Khoriaty Rami , Emmer Brian T. , Chen Xiao-Wei , Ginsburg David 
Published: August 2022

AbstractPCSK9 negatively regulates low-density lipoprotein receptor (LDLR) abundance on the cell surface, leading to decreased hepatic clearance of LDL particles and increased levels of plasma cholesterol. We previously identified SURF4 as a cargo receptor that facilitates PCSK9 secretion in HEK293T cells (Emmer et al., 2018). Here, we generated hepatic SURF4-deficient mice (Surf4fl/flAlb-Cre+) to investigate the physiologic role of SURF4 in vivo. Surf4fl/flAlb-Cre+ mice exhibited normal viability, gross development, and fertility. Plasma PCSK9 levels were reduced by ∽60% in Surf4fl/flAlb-Cre+ mice, with a corresponding ∽50% increase in steady state LDLR protein abundance in the liver, consistent with SURF4 functioning as a cargo receptor for PCSK9. Surprisingly, these mice exhibited a marked reduction in plasma cholesterol and triglyceride levels out of proportion to the partial increase in hepatic LDLR abundance. Detailed characterization of lipoprotein metabolism in these mice instead revealed a severe defect in hepatic lipoprotein secretion, consistent with prior reports of SURF4 also promoting the secretion of apolipoprotein B. Despite a small increase in liver mass and lipid content, histologic evaluation revealed no evidence of steatohepatitis or fibrosis in Surf4fl/flAlb-Cre+ mice. Acute depletion of hepatic SURF4 by CRISPR/Cas9 or liver-targeted siRNA in adult mice confirms these findings. Together, these data support the physiologic significance of SURF4 in the hepatic secretion of PCSK9 and APOB-containing lipoproteins and its potential as a therapeutic target in atherosclerotic cardiovascular diseases.