bluuebunny/crossref_metadata_2025_split huggingface dataset:
INCIDENCE, RISK FACTORS, AND OUTCOME OF SUSPECTED CENTRAL VENOUS CATHETER-RELATED INFECTIONS IN CRITICALLY ILL COVID-19 PATIENTS: A MULTICENTER RETROSPECTIVE COHORT STUDY
Authors: Smit Jasper M. , Exterkate Lotte , van Tienhoven Arne J. , Haaksma Mark E. , Heldeweg Micah L.A. , Fleuren Lucas , Thoral Patrick , Dam Tariq A. , Heunks Leo M.A. , Gommers Diederik , Cremer Olaf L. , Bosman Rob J. , Rigter Sander , Wils Evert-Jan , Frenzel Tim , Vlaar Alexander P. , Dongelmans Dave A. , de Jong Remko , Peters Marco , Kamps Marlijn J.A , Ramnarain Dharmanand , Nowitzky Ralph , Nooteboom Fleur G.C.A. , de Ruijter Wouter , Urlings-Strop Louise C. , Smit Ellen G.M. , Mehagnoul-Schipper D. Jannet , Dormans Tom , de Jager Cornelis P.C. , Hendriks Stefaan H.A. , Achterberg Sefanja , Oostdijk Evelien , Reidinga Auke C. , Festen-Spanjer Barbara , Brunnekreef Gert B. , Cornet Alexander D. , van den Tempel Walter , Boelens Age D. , Koetsier Peter , Lens Judith , Faber Harald J. , Karakus A. , Entjes Robert , de Jong Paul , Rettig Thijs C.D. , Arbous Sesmu , Vonk Bas , Machado Tomas , Girbes Armand R.J. , Sieswerda Elske , Elbers Paul W.G. , Tuinman Pieter R. 
Published: September 2022

ABSTRACT

Background: Aims of this study were to investigate the prevalence and incidence of catheter-related infection, identify risk factors, and determine the relation of catheter-related infection with mortality in critically ill COVID-19 patients. Methods: This was a retrospective cohort study of central venous catheters (CVCs) in critically ill COVID-19 patients. Eligible CVC insertions required an indwelling time of at least 48 hours and were identified using a full-admission electronic health record database. Risk factors were identified using logistic regression. Differences in survival rates at day 28 of follow-up were assessed using a log-rank test and proportional hazard model. Results: In 538 patients, a total of 914 CVCs were included. Prevalence and incidence of suspected catheter-related infection were 7.9% and 9.4 infections per 1,000 catheter indwelling days, respectively. Prone ventilation for more than 5 days was associated with increased risk of suspected catheter-related infection; odds ratio, 5.05 (95% confidence interval 2.12–11.0). Risk of death was significantly higher in patients with suspected catheter-related infection (hazard ratio, 1.78; 95% confidence interval, 1.25–2.53). Conclusions: This study shows that in critically ill patients with COVID-19, prevalence and incidence of suspected catheter-related infection are high, prone ventilation is a risk factor, and mortality is higher in case of catheter-related infection.
Microglia are involved in regulating histamine dependent and non-dependent itch transmissions with distinguished signal pathways
Authors: Yang Yuxiu , Mou Bin , Zhang Qi-Ruo , Zhao Hong-Xue , Zhang Jian-Yun , Yun Xiao , Xiong Ming-Tao , Liu Ying , Liu Yong U. , Pan Haili , Ma Chao-Lin , Li Bao-Ming , Peng Jiyun 
Published: September 2022

AbstractAlthough itch and pain have many similarities, they are completely different in perceptual experience and behavioral response. In recent years, we have a deep understanding of the neural pathways of itch sensation transmission. However, there are few reports on the role of non-neuronal cells in itch. Microglia are known to play a key role in chronic neuropathic pain and acute inflammatory pain. It is still unknown whether microglia are also involved in regulating the transmission of itch sensation. In the present study, we used several kinds of transgenic mice to specifically deplete CX3CR1+ central microglia and peripheral macrophages together (whole depletion), or selectively deplete central microglia alone (central depletion). We observed that the acute itch responses to histamine, compound 48/80 and chloroquine were all significantly reduced in mice with either whole or central depletion. Spinal c-fos mRNA assay and further studies revealed that histamine and compound 48/80, but not chloroquine elicited primary itch signal transmission from DRG to spinal Npr1- and somatostatin-positive neurons relied on microglial CX3CL1-CX3CR1 pathway. Our results suggested that central microglia were involved in multiple types of acute chemical itch transmission, while the underlying mechanisms for histamine dependent and non-dependent itch transmission were different that the former required the CX3CL1-CX3CR1 signal pathway.
PKB/AKT attenuates Lewy Body-like pathology in primary neurons via Cathepsins B and D
Authors: Konovalova Julia , Er Safak , Barut Justyna , Rafa-Zabłocka Katarzyna , Luk Kelvin C. , Figiel Małgorzata , Airavaara Mikko , Domanskyi Andrii , Chmielarz Piotr 
Published: September 2022

AbstractMotor symptoms of Parkinson’s disease (PD) are caused by the loss of dopamine neurons in the substantia nigra pars compacta. Current PD therapies offer only symptomatic relief, and the research on novel ways to stop or slow down the degeneration of dopamine neurons in PD attracts considerable efforts.A characteristic feature of PD is the abnormal accumulation and spread of misfolded α-synuclein (α-syn) protein leading to the formation of Lewy neurites and bodies in different neuronal populations, including dopamine neurons. The process of Lewy body formation compromises neuronal functions and contributes to the progression of the disease and neurodegeneration in PD patients. Treatments preventing α-syn misfolding, aggregation and/or spread may therefore provide much-needed disease-modifying therapies for PD. We and others have demonstrated that α-syn aggregation and Lewy body formation can be modelled in primary neuronal cultures treated with α-syn pre-formed fibrils (PFFs). Using this approach, we have identified several factors preventing the accumulation of phosphorylated α-syn in dopamine neurons in vitro and in vivo. In particular, we and others have demonstrated a prominent role of PKB/AKT pathway activation in promoting the survival of dopamine neurons.Here, we utilize lentiviral vectors (LVs) to express constitutively active myristoylated serine-threonine protein kinase AKT1 (mAKT1) in primary dopamine neurons. We show that lentivirally-delivered mAKT1 promoted survival of dopamine neurons after thapsigargin-induced endoplasmic reticulum (ER) stress and prevented fibril-induced accumulation of phosphorylated α-syn. Furthermore, using pharmacological tools, we demonstrate that this activity of mAKT1 is dependent on the functional Cathepsins B and D. These proof-of-principle results demonstrate the critical importance of lysosomal enzymes for processing misfolded α-syn and establish a basis for the use of LVs to develop neuroprotective gene therapy strategies for dopamine neurons in PD.
Predicting treatment outcome using kinome activity profiling in HER2+ breast cancer biopsies
Authors: Debets Donna O. , de Graaf Erik L. , Liefaard Marte C. , Sonke Gabe S. , Lips Esther H. , Ressa Anna , Altelaar Maarten 
Published: September 2022

AbstractIn this study, we measured the kinase activity profiles of 32 pre-treatment tumour biopsies of HER2-positive breast cancer patients. The aim of this study was to assess the prognostic potential of kinase activity levels to identify potential mechanisms of resistance and to predict treatment success of HER2-targeted therapy combined with chemotherapy. Indeed, our system-wide kinase activity analysis, based on targeted mass spectrometry measurement of kinase activation loops, allowed us to link kinase activity to treatment response. Overall, high kinase activity in the HER2-pathway was associated with good treatment outcome. Furthermore, we found eleven kinases differentially regulated between treatment outcome groups. Amongst those, well-known players in therapy resistance were found, such as p38a, ERK and FAK, as well as a potential new player in drug resistance, namely MARK. Lastly, we defined an optimal signature of four kinases in a multiple logistic regression diagnostic test for prediction of treatment outcome (AUC=0.926). This kinase signature showed high sensitivity and specificity, indicating its potential as predictive biomarker for treatment success of HER2-targeted therapy.
STEM: A Method for Mapping Single-cell and Spatial Transcriptomics Data with Transfer Learning
Authors: Hao Minsheng , Luo Erpai , Chen Yixin , Wu Yanhong , Li Chen , Chen Sijie , Gao Haoxiang , Bian Haiyang , Wei Lei , Zhang Xuegong 
Published: September 2022

AbstractProfiling spatial variations of cellular composition and transcriptomic characteristics is important for understanding the physiology and pathology of tissues in health or diseases. Spatial transcriptomics (ST) data are powerful for depicting spatial gene expression but the currently dominating high-throughput technology is yet not at single-cell resolution. On the other hand, single-cell RNA-sequencing (SC) data provide high-throughput transcriptomic information at the single-cell level but lack spatial information. Integrating these two types of data would be ideal for revealing transcriptomic landscapes at single-cell resolution. We developed the method STEM (SpaTially aware EMbedding) for this purpose. It uses deep transfer learning to encode both ST and SC data into a unified spatially aware embedding space, and then uses the embeddings to infer the SC-ST mapping and predict pseudo-spatial adjacency between cells in the SC data. Semi-simulation and real data experiments verified that the embeddings preserved the spatial information and eliminated technical biases between SC and ST data. Besides, we can use attribution analysis in STEM to reveal genes whose expressions dominate spatial information. We applied STEM to data of human squamous cell carcinoma and of hepatic lobule to uncover the spatial localization of rare cell types data and reveal cell-type-specific gene expression variation along a spatial axis. STEM is a powerful tool for mapping SC and ST data to build single-cell level spatial transcriptomic landscapes, and can provide mechanistic insights into the spatial heterogeneity and microenvironments of tissues.
INSULIN-LIKE GROWTH FACTOR I REDUCES CORONARY ATHEROSCLEROSIS IN PIGS WITH FAMILIAL HYPERCHOLESTEROLEMIA
Authors: Sukhanov Sergiy , Higashi Yusuke , Yoshida Tadashi , Danchuk Svitlana , Alfortish Mitzi , Goodchild Traci , Scarborough Amy , Sharp Thomas , Jenkins James S. , Garcia Daniel , Ivey Jan , Tharp Darla L. , Schumacher Jeffrey , Rozenbaum Zach , Kolls Jay K. , Bowles Douglas , Lefer David , Delafontaine Patrice 
Published: September 2022

ABSTRACTObjectiveAlthough murine models of coronary atherosclerotic disease (CAD) have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We tested IGF-1 effects in atherosclerotic FH pigs to consider use of IGF-1 to treat CAD in humans. FH pigs were administered with IGF-1 for 6 months. Atherosclerosis was quantified by serial intravascular ultrasound (IVUS) and histology, plaque composition - by immunohistochemistry. We used spatial transcriptomics (ST) analysis to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects.ResultsIGF-1-injected FH pigs had 1.8-fold increase in total circulating IGF-1 levels compared to control. IGF-1 decreased relative coronary atheroma (IVUS) and lesion cross-sectional area (histology). IGF-1 induced vascular hypertrophy and reduced circulating triglycerides, markers of systemic oxidative stress and pro-atherogenic CXCL12 chemokine levels. IGF-1 increased fibrous cap thickness, and reduced necrotic core size, macrophage content, and cell apoptosis, changes consistent with promotion of a stable plaque phenotype. IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1’s effect on atherosclerosis.ConclusionsIGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials. ST profiling of plaques provided novel insights into potential mechanisms.
B lymphocytes in Treatment-Naïve Pediatric Lupus Patients are Epigenetically Distinct from Healthy Children
Authors: Hui-Yuen Joyce S , Jiang Kaiyu , Malkiel Susan , Eberhard B Anne , Walters Heather , Diamond Betty , Jarvis James N. 
Published: September 2022

AbstractBackgroundSystemic lupus erythematosus (SLE) is a complex disease likely triggered by gene-environment interactions. We have shown that most of the SLE-associated haplotypes encompass genomic regions enriched for epigenetic marks associated with enhancer function in neutrophils, and T and B cells, suggesting that genetic risk is exerted through altered gene regulation. Data remain scarce on how epigenetic variance contributes to disease risk in pediatric SLE (pSLE). We aim to identify differences in epigenetically-regulated chromatin architecture in treatment-naïve pSLE patients compared to healthy children.MethodsUsing the assay for transposase-accessible chromatin with sequencing (ATACseq), we surveyed open chromatin in 8 treatment-naïve pSLE patients, with at least moderate disease severity, and 5 healthy children. We investigated whether regions of open chromatin unique to pSLE patients demonstrate enrichment for specific transcriptional regulators, using standard computational approaches to identify unique peaks and a false discovery rate of <0.05. Further analyses for differential transcription factor binding, histone modification enrichment, and variant calling were performed using multiple bioinformatics packages in R and Linux.ResultsThere were 30,139 differentially accessible regions (DAR) identified unique to pSLE B cells, of which 64.3% are more accessible in pSLE than B cells from healthy children. Many of these DAR are found in distal, intergenic regions, and are enriched for enhancer histone marks (p=0.027). When we compared B cells from pSLE patients to those of untreated adults, we found more regions of inaccessible chromatin, and fewer DAR within 10-100kb of known SLE haplotypes. In pSLE B cells, 65.2% of the DAR are located within or near known SLE haplotypes. Further analysis revealed enrichment of several transcription factor binding motifs within these DAR that may regulate genes involved in the pro-inflammatory responses and cellular adhesion.ConclusionsThis is the first report describing differences in chromatin architecture between pSLE patients and healthy children. We demonstrate an epigenetically-distinct profile in pSLE B cells when compared to those from healthy children and adults with lupus, indicating that pSLE B cells are predisposed for disease onset and development. Increased chromatin accessibility in non-coding genomic regions controlling activation of inflammation and the immune response suggest that transcriptional dysregulation by regulatory elements that control B cell activation plays an important role in the pathogenesis of pSLE.
Neurophysiological basis of hemodynamic responses in the developing human brain before the time of normal birth
Authors: Poppe Tanya , Willers Moore Jucha , Rupawala Mohammed , Price Anthony N. , Godinez Felipe , Whitehead Kimberley , Dall’Orso Sofia , Edwards A. David , Fabrizi Lorenzo , Arichi Tomoki 
Published: September 2022

ABSTRACTNeurovascular coupling that links neural activity to localized increases in blood flow is essential both for brain function and to prevent tissue injury. In the healthy human brain, this underlies an association between the duration of EEG microstates, which represent coordinated and metastable activation of neuronal ensembles, and increases in hemodynamic activity. However, in early human life it is not clear whether neurovascular coupling is functional as the underlying physiological mechanisms may be too immature to effectively support it. Here, we combined MRI compatible robotics with simultaneous EEG and fMRI data acquisition in 13 preterm infants to assess whether the relationship between neural activity and hemodynamic responses is present in this critical period of early life. Passive sensorimotor stimulation elicited both a distinct sequence of four EEG microstates and a significant rise in the blood oxygen level dependent (BOLD) fMRI signal in the left primary sensorimotor cortex. Furthermore, EEG microstate duration was significantly related to BOLD response amplitude. These results suggest that effective neurovascular coupling is present in the human brain even before the normal time of birth and reveal a complex relationship between EEG and fMRI signals underpinned by patterns of activity across distinct neural ensembles.
Leaf traits predict water-use efficiency in U.S. Pacific Northwest grasslands under rain exclusion treatment
Authors: Dawson Hilary Rose , Maxwell Toby M. , Reed Paul B. , Bridgham Scott D. , Silva Lucas C. R. 
Published: September 2022

AbstractDoes drought stress in temperate grasslands alter the relationship between plant structure and function? Here we report data from an experiment focusing on growth form and species traits that affect the critical functions of water- and nutrient-use efficiency in prairie and pasture plant communities. A total of 139 individuals of 12 species (11 genera and four families) were sampled in replicated plots maintained for three years across a 520 km latitudinal gradient in the Pacific Northwest, USA. Rain exclusion did not alter the interspecific relationship between foliar traits and stoichiometry or intrinsic water-use efficiency. Rain exclusion reduced intrinsic water-use efficiency in grasses, an effect was primarily species-specific, although leaf morphology, life history strategy, and phylogenetic distance predicted intrinsic water-use efficiency for all twelve species when analyzed together. Variation in specific leaf area explained most of the variation in intrinsic water-use efficiency between different functional groups, with annual forbs and annual grasses at opposite ends of the resource-use spectrum. Our findings are consistent with expected trait-driven tradeoffs between productivity and resource-use efficiency, and provide insight into strategies for the sustainable use and conservation of temperate grasslands.Plain language summaryScientists have previously shown that plant leaf form (e.g., shape, width, size) has a predictable relationship to leaf function (e.g., how it can perform biological processes). When we deprive plants of water, does this relationship break down? We grew prairie and pasture plants at three sites in Oregon and Washington, USA, spanning a broad range of climate and water availability. At each site, we built shelters over half our plots to keep out some of the rain, reducing how much water our plants received. Leaf form-function relationships did not change between plots with more or less water. However, each species had a different water use efficiency and nutrient content, and some grasses had an unusual response, that is, they became less efficient at using water under less rain. Overall, we were pretty good at predicting water and nutrient use based on leaf form, whether plants were annual or perennial, and how related they were. Our findings match expectations about leaf structure-function relationships and people who manage temperate grasslands can use our results to decide which plants will work best for using and conserving their systems.Key pointsFoliar structure-function relationships did not change under experimental drought.Leaf morphology, life history, and phylogenetics predicted resource-use for 12 species.
Selection leads to remarkable variability in the outcomes of hybridization across replicate hybrid zones
Authors: McFarlane S. Eryn , Jahner Joshua P. , Lindtke Dorothea , Buerkle C. Alex , Mandeville Elizabeth G. 
Published: September 2022

AbstractHybrid zones have been viewed as an opportunity to see speciation in action. When hybrid zones are replicated, it is assumed that if the same genetic incompatibilities are maintaining reproductive isolation across all instances of secondary contact, those incompatibilities should be identifiable by consistent patterns in the genome. In contrast, changes in allele frequencies due to genetic drift should be idiosyncratic for each hybrid zone. To test this assumption, we simulated 20 replicates of each of 12 hybrid zone scenarios with varied genetic incompatibilities, rates of migration, selection and different starting population size ratios of parental species. We found remarkable variability in the outcomes of hybridization in replicate hybrid zones, particularly with Bateson-Dobzhansky-Muller incompatibilities and strong selection. We found substantial differences among replicates in the overall genomic composition of individuals, including admixture proportions, inter-specific ancestry complement, and number of ancestry junctions. Additionally, we found substantial variation in genomic clines among replicates at focal loci, regardless of locus-specific selection. We conclude that processes other than selection are responsible for some consistent outcomes of hybridization, whereas selection on incompatibilities can lead to genomically widespread and highly variable outcomes. We highlight the challenge of mapping between pattern and process in hybrid zones and call attention to how selection against incompatibilities will commonly lead to variable outcomes. We hope that this study informs future research on replicate hybrid zones and encourages further development of statistical techniques, theoretical models, and exploration of additional axes of variation to understand reproductive isolation.