bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using machine learning to design a short test from a full-length test of functional health literacy in adults - the development of a short form of the Danish TOFHLA
Authors: Hæsum Lisa Korsbakke Emtekær , Cichosz Simon Lebech , Hejlesen Ole Kristian 
Published: January 2023

AbstractIntroductionPatients are compelled to become more involved in shared decision making with healthcare professionals in the self-management of chronic disease and general adherence to treatment. Therefore, it is valuable to be able to identify patients with low functional health literacy so they can be given special instructions about the management of chronic disease and medications. However, time spent by both patients and clinicians is a concern when introducing a screening instrument in the clinical setting, which raises the need for short instruments for assessing health literacy that can be used by patients without the involvement of healthcare personnel. This paper describes the development of a short version of the full-length Danish TOFHLA (DS-TOFHLA) that is easily applicable in the clinical context and where the use does not require a trained interviewer.Materials and MethodsData were collected as a part of a large-scale telehomecare project (TeleCare North), which was a randomized controlled trial that included 1225 patients with chronic obstructive pulmonary disease.The DS-TOFHLA was developed solely using an algorithm-based selection of variables and multivariable linear regression models. A multivariable regression model was developed using an exhaustive search strategy.ResultsThe exhaustive search showed that the number of items in the full-length TOFHLA could be reduced from 17 numeracy items and 50 reading comprehension items to 20 reading comprehension items while maintaining a correlation of r = 0.90. A generic model-based approach was developed, which is suitable for development of short versions of the TOFHLA in other languages, including the original American version.ConclusionsThis study demonstrated how a generic model-based approach could be applied in the development of a short version of the TOFHLA, thereby reducing the 67 items to 20 items in the short version. Furthermore, this study showed that the inclusion of numeracy items was not necessary. The development of the DS-TOFHLA presents an opportunity to reliably identify patients with inadequate functional health literacy in approximately 5 minutes without involvement of healthcare personnel. The approach may be used in the development of short versions of any scaling questionnaire.
Osseointegration of functionally-graded Ti6Al4V porous implants: Histology of the pore network
Authors: Deering Joseph , Mahmoud Dalia , Rier Elyse , Lin Yujing , do Nascimento Pereira Anna Cecilia , Titotto Silvia , Fang Qiyin , Wohl Gregory R. , Deng Feilong , Grandfield Kathryn , Elbestawi Mohamed A. , Chen Jianyu 
Published: January 2023

AbstractThe additive manufacturing of titanium into porous geometries offers a means to generate low-stiffness endosseous implants with a greater surface area to improve osseointegration. In order to optimize pore size in the scaffolds, it is important to first understand the timeline of osseointegration in pre-clinical models. In this work, selective laser melting was used to produce gyroid-based scaffolds with a uniform pore size of 300 μm or functionally-graded pore size from 600 μm to 300 μm before implantation in New Zealand white rabbit tibiae for 4 and 12 weeks. Initialin vitroassessment with Saos-2 cells showed favourable cell proliferation at pore sizes of 300 and 600 μm. At four weeks, histological observations indicated some residual inflammation alongside neovessel infiltration into the scaffold interior and some early apposition of mineralized bone tissue. At twelve weeks, both scaffolds were filled with a mixture of adipocyte-rich marrow, micro-capillaries, and mineralized bone tissue. X-ray microcomputed tomography showed a higher bone volume fraction (BV/TV) and percentage of bone-implant contact (BIC) in the implants with 300 μm pores than in the functionally-graded specimens, indicating that these smaller pore sizes may be favourable for osseointegration in leporine bone.Graphical Abstract
Automated Enrichment of Phosphotyrosine Peptides for High-Throughput Proteomics
Authors: Chang Alexis , Leutert Mario , Rodriguez-Mias Ricard A. , Villén Judit 
Published: January 2023

AbstractPhosphotyrosine (pY) enrichment is critical for expanding fundamental and clinical understanding of cellular signaling by mass spectrometry-based proteomics. However, current pY enrichment methods exhibit a high cost per sample and limited reproducibility due to expensive affinity reagents and manual processing. We present rapid-robotic phosphotyrosine proteomics (R2-pY), which uses a magnetic particle processor and pY superbinders or antibodies. R2-pY handles 96 samples in parallel, requires 2 days to go from cell lysate to mass spectrometry injections, and results in global proteomic, phosphoproteomic and tyrosine specific phosphoproteomic samples. We benchmark the method on HeLa cells stimulated with pervanadate and serum and report over 4000 unique pY sites from 1 mg of peptide input, strong reproducibility between replicates, and phosphopeptide enrichment efficiencies above 99%. R2-pY extends our previously reported R2-P2 proteomic and global phosphoproteomic sample preparation framework, opening the door to large-scale studies of pY signaling in concert with global proteome and phosphoproteome profiling.
ConDoR: Tumor phylogeny inference with a copy-number constrained mutation loss model
Authors: Sashittal Palash , Zhang Haochen , Iacobuzio-Donahue Christine A. , Raphael Benjamin J. 
Published: January 2023

AbstractTumors consist of subpopulations of cells that harbor distinct collections of somatic mutations. These mutations range in scale from single nucleotide variants (SNVs) to large-scale copy-number aberrations (CNAs). While many approaches infer tumor phylogenies using SNVs as phylogenetic markers, CNAs that overlap SNVs may lead to erroneous phylogenetic inference. Specifically, an SNV may be lost in a cell due to a deletion of the genomic segment containing the SNV. Unfortunately, no current single-cell DNA sequencing (scDNA-seq) technology produces accurate measurements of both SNVs and CNAs. For instance, recenttargetedscDNA-seq technologies, such as Mission Bio Tapestri, measure SNVs with high fidelity in individual cells, but yield much less reliable measurements of CNAs. We introduce a new evolutionary model, theconstrained k-Dollo model, that uses SNVs as phylogenetic markers and partial information about CNAs in the form of clustering of cells with similar copy-number profiles. This copy-number clustering constrains where loss of SNVs can occur in the phylogeny. We develop ConDoR (Constrained Dollo Reconstruction), an algorithm to infer tumor phylogenies from targeted scDNA-seq data using the constrainedk-Dollo model. We show that ConDoR outperforms existing methods on simulated data. We use ConDoR to analyze a new multi-region targeted scDNA-seq dataset of 2153 cells from a pancreatic ductal adenocarcinoma (PDAC) tumor and produce a more plausible phylogeny compared to existing methods that conforms to histological results for the tumor from a previous study. We also analyze a metastatic colorectal cancer dataset, deriving a more parsimonious phylogeny than previously published analyses and with a simpler monoclonal origin of metastasis compared to the original study.Code availabilitySoftware is available athttps://github.com/raphael-group/constrained-Dollo
The maternal microbiome regulates infant respiratory disease susceptibility via intestinal Flt3L expression and plasmacytoid dendritic cell hematopoiesis
Authors: Sikder Md. Al Amin , Rashid Ridwan B. , Ahmed Tufael , Sebina Ismail , Howard Daniel , Ullah Md. Ashik , Rahman Muhammed Mahfuzur , Lynch Jason P. , Curren Bodie , Werder Rhiannon B. , Simpson Jennifer , Bissell Alec , Morrison Mark , Walpole Carina , Radford Kristen J. , Kumar Vinod , Woodruff Trent M. , HuiYing Tan , Ali Ayesha , Kaiko Gerard E. , Upham John W. , Hoelzle Robert D. , Cuív Páraic Ó , Holt Patrick G. , Dennis Paul G. , Phipps Simon 
Published: January 2023

SummarySevere lower respiratory infection (sLRI) are a major cause of infant morbidity and mortality, and predispose to later chronic respiratory diseases such as asthma. Poor maternal diet during pregnancy is a risk factor for sLRI in the offspring. Here we demonstrate in mice that a maternal low-fibre diet (LFD) disrupts plasmacytoid and conventional dendritic cell (DC) hematopoiesis in the offspring, predisposing to sLRI and subsequent asthma. The LFD alters the composition of the maternal milk microbiome and assembling infant gut microbiome, ablating the induction of a developmental wave of the non-redundant DC growth factor Flt3L by neonatal intestinal epithelial cells. Therapy with a propionate-producing bacteria isolated from the milk of high-fibre diet-fed mothers, or supplementation with propionate, confers protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that regulates pDC hematopoiesis in early life and confers disease resistance.
Environmental constraints can explain clutch size differences between urban and forest blue tits: insights from an egg removal experiment
Authors: Pitt Mark D. , Capilla-Lasheras Pablo , Alhowiti Norah S.S. , Branston Claire J. , Carlon Eugenio , Boonekamp Jelle J. , Dominoni Davide M. 
Published: January 2023

AbstractUrban environments present novel ecological challenges to wild species. Understanding whether species responses to urban living are adaptive or maladaptive is critical to predicting the impacts of urbanisation on biodiversity. In birds, urban populations generally exhibit reduced reproductive investment (clutch size) compared to forest populations. However, whether smaller clutches are adaptive, or a result of environmental constraints is unclear. Here, to investigate these two hypotheses, we quantified the ability of urban and forest blue tits (Cyanistes caeruleus) to lay new eggs upon egg removal. Consistent with the constraint hypothesis, our results suggest that urban females do not lay new eggs, at least to the same extent as forest birds. Meanwhile, forest birds laid approximately two additional eggs. As urban blue tits did not lay replacement eggs, our experiment resulted in a brood reduction and nestlings from urban experimental nests had higher survival than those from urban control nests, suggesting that females may be misjudging urban habitat quality and produce a clutch too large to be sustained. Taken together, our results suggest that urban females may experience constraints that limit egg formation and/or exacerbate the trade-off between female survival and egg production. This has important implications for urban green space management.
Rupture Strength of Living Cell Monolayers
Authors: Duque Julia , Bonfanti Alessandra , Fouchard Jonathan , Baldauf Lucia , Azenha Sara R. , Ferber Emma , Harris Andrew , Barriga Elias H. , Kabla Alexandre J. , Charras Guillaume 
Published: January 2023

AbstractThe ability of tissues to sustain mechanical stress and avoid rupture is a fundamental pillar of their function. Rupture in response to physiological levels of stress can be undesired, for example resulting from disease or genetic mutations, or be an integral part of developmental processes, such as during blastocoel formation in mouse or leg eversion in flies. Despite its importance, we know very little about rupture in cellularised tissues because it is a multi-scale phenomenon that necessitates comprehension of the interplay between mechanical forces and processes at the molecular and cellular scales. Using a combination of mechanical measurements, live imaging and computational modelling, we characterise rupture in epithelial monolayers. We show that, despite consisting of only a single layer of cells, monolayers can withstand surprisingly large deformations, often accommodating several-fold increases in their length before rupture. At large deformation, epithelia increase their stiffness multiple-fold in a process controlled by a supracellular network of keratin filaments. Perturbing keratin organisation fragilised monolayers and prevented strain stiffening. Using computational approaches, we show that, although the kinetics of adhesive bond rupture ultimately control tissue strength, tissue rheology and the history of deformation prior to failure set the strain and stress that the tissue reaches at the onset of fracture. Our data paint a picture of epithelia as versatile materials that combine resistance to shocks with deformability when subjected to low strain rates.
Subclonal somatic copy number alterations emerge and dominate in recurrent osteosarcoma
Authors: Kinnaman Michael D. , Zaccaria Simone , Makohon-Moore Alvin , Arnold Brian , Levine Max , Gundem Gunes , Arango Ossa Juan E. , Glodzik Dominik , Rodríguez-Sánchez M. Irene , Bouvier Nancy , Li Shanita , Stockfisch Emily , Dunigan Marisa , Cobbs Cassidy , Bhanot Umesh , You Daoqi , Mullen Katelyn , Melchor Jerry , Ortiz Michael V. , O’Donohue Tara , Slotkin Emily , Wexler Leonard H. , Dela Cruz Filemon S. , Hameed Meera , Glade Bender Julia L. , Tap William D. , Meyers Paul A. , Papaemmanuil Elli , Kung Andrew L. , Iacobuzio-Donahue Christine A 
Published: January 2023

AbstractMultiple large-scale tumor genomic profiling efforts have been undertaken in osteosarcoma, however, little is known about the spatial and temporal intratumor heterogeneity and how it may drive treatment resistance. We performed whole-genome sequencing of 37 tumor samples from eight patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. We identified subclonal copy number alterations in all but one patient. We observed that in five patients, a subclonal copy number clone from the primary tumor emerged and dominated at subsequent relapses.MYCgain/amplification was enriched in the treatment-resistant clone in 6 out of 7 patients with more than one clone. Amplifications in other potential driver genes, such asCCNE1,RAD21,VEGFA, andIGF1R, were also observed in the resistant copy number clones. Our study sheds light on intratumor heterogeneity and the potential drivers of treatment resistance in osteosarcoma.SignificanceSubclonal copy number clones emerged and dominated in relapsed osteosarcoma, withMYCgain/amplification being the defining characteristic in our cohort. Selective pressure from neoadjuvant chemotherapy revealed this clone at the time of primary resection, highlighting that genomic profiling at this time may identify clones that are selected for, or determine innate resistance to primary chemotherapy.
A Novel Protein for the Bioremediation of Gadolinium Waste
Authors: Lee Harvey D. , Grady Connor J. , Krell Katie , Strebeck Cooper , Good Nathan M. , Martinez-Gomez N. Cecilia , Gilad Assaf A. 
Published: January 2023

AbstractSeveral hundreds of tons of gadolinium-based contrast agents (GBCAs) are being dumped into the environment every year. Although macrocyclic GBCAs exhibit superior stability compared to their linear counterparts, we have found that the structural integrity of chelates are susceptible to ultraviolet light, regardless of configuration. In this study, we present a synthetic protein termed GLamouR that binds and reports gadolinium in an intensiometric manner. We then explore the extraction of gadolinium from GBCA-spiked artificial urine samples and investigate if the low picomolar concentrations reported in gadolinium-contaminated water sources pose a barrier for bioremediation. Based on promising results, we anticipate GLamouR can be used for detecting and mining REEs beyond gadolinium as well and hope to expand the biological toolbox for such applications.
Persistent confined migration confers permanent nuclear and functional changes in migrating cells
Authors: Lope-Planelles Ana de , González-Novo Raquel , Madrazo Elena , Zamora-Carreras Héctor , Torrano Verónica , López-Menéndez Horacio , Roda-Navarro Pedro , Monroy Francisco , Redondo-Muñoz Javier 
Published: January 2023

AbstractNuclear deformability plays a critical role in cell migration. During this process, the remodeling of internal components of the nucleus has a direct impact on DNA damage and cell behavior; however, how persistent migration promotes nuclear changes leading to phenotypical and functional consequences remains poorly understood. Here, we described that the persistent migration through physical barriers was sufficient to promote permanent modifications in migratory-altered cells. We found that lamin B1 altered its localization, concomitant with morphological and transcriptional changes. Migratory-altered cells showed alterations in cellular functions such as DNA repair and cell migration. We applied biochemical and biophysical approaches to identify that confined conditions altered the biomechanical response of the nucleus. Mechanistically, we determined that actin dynamics controlled the redistribution of lamin, and the basal levels of DNA damage in migratory-altered cells. Our observations reveal a novel role for confined cell conditions in consistent nuclear and genomic alterations that might handle the genetic instability and cellular heterogeneity in aging diseases and cancer.HighlightsPersistent confined migration promotes permanent mophological changes.Lamin B1 is redistribution in the nucleus of migratory altered cells.Migratory-altered cells exhibit transcriptional and functional changes related to cell migration and survival.Actin polymerization controls nuclear changes induced by cell migration.
Apelin-VEGF-C mRNA delivery as therapeutic for the treatment of secondary lymphedema
Authors: Lamaa A. , Creff J. , Benuzzi E. , Pujol f. , Draia-Nicolau T. , Nougué M. , Verdu L. , Morfoisse F. , Lacazette E. , Valet P. , Chaput B. , Gross F. , Gayon R. , Bouillé P. , Malloizel-Delaunay J. , Bura-Rivière A. , Prats A.C. , Garmy-Susini B. 
Published: January 2023

ABSTRACTSecondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in lymphedematous arm compared to normal arm in patients. The role of APLN in LD was confirmed in APLN-knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of safe and non-integrative RNA-delivery LentiFlash®vector that will be evaluated for phase I/IIa clinical trial.
Transcriptome analysis reveals novel regulators of the Scots pine stilbene pathway
Authors: Paasela Tanja , Lim Kean-Jin , Pavicic Mirko , Harju Anni , Venäläinen Martti , Paulin Lars , Auvinen Petri , Kärkkäinen Katri , Teeri Teemu H. 
Published: January 2023

AbstractStilbenes are developmentally induced metabolites in Scots pine heartwood where they have important role in protecting wood from decaying fungi. The stilbene pathway is also stress inducible, and ultraviolet (UV)-C radiation was among the first discovered artificial stress activators of the pathway. Many conditions that activate the pathway are known, but the specific transcriptional regulators and the biosynthetic enzyme responsible for activating the stilbene precursor cinnamate in the pathway are unknown.Here we describe the first large-scale transcriptomic analysis of pine needles in response to UV-C exposure and treatment with translational inhibitor cycloheximide, both activating the transcription of stilbene pathway genes, to uncover the candidates for the transcriptional regulation of the pathway and the cinnamate activating CoA ligase. We show that the regulation of pine stilbene pathway has shared features with grapevine stilbene pathway. In both species, the stilbene pathway was transcriptionally activated after UV-C treatment, protein phosphatase inhibitors and plant hormones ethylene and jasmonate.The pine stilbene synthase promoter retains its inducibility when transformed in plants that normally do not synthesize stilbenes. Pine stilbene synthase promoter was able to activate the expression of a reporter gene in Arabidopsis in response to UV-C exposure and phosphatase inhibitors, but not as response to plant hormone treatment. This indicates that stilbene synthase gene regulation occurs both via ancient stress-response pathway(s) but also via species specific regulators. With transcriptomic approach we identified candidate enzymes for cinnamate acting CoA ligase and transcription factors regulating the pathway.
Type I IFN stimulates lymph node stromal cells from adult and old mice during a West Nile virus infection
Authors: Bennett Allison K. , Richner Michelle , Mun Madeline D. , Richner Justin M. 
Published: January 2023

ABSTRACTAdvanced age is a significant risk factor during viral infection due to an age-associated decline in the immune response. Older individuals are especially susceptible to severe neuroinvasive disease after West Nile virus (WNV) infection. Previous studies have characterized age-associated defects in hematopoietic immune cells during WNV infection that culminate in diminished antiviral immunity. Situated amongst immune cells in the draining lymph node (DLN) are structural networks of nonhematopoietic lymph node stromal cells (LNSCs). LNSCs are comprised of numerous, diverse subsets, with critical roles in the coordination of robust immune responses. The contributions of LNSCs to WNV immunity and immune senescence are unclear. Here, we examine LNSC responses to WNV within adult and old DLNs. Acute WNV infection triggered cellular infiltration and LNSC expansion in adult. Comparatively, aged DLNs exhibited diminished leukocyte accumulation, delayed LNSC expansion, and altered fibroblast and endothelial cell subset composition, signified by fewer LECs. We established anex vivoculture system to probe LNSC function. Adult and old LNSCs both recognized an ongoing viral infection primarily through type I IFN signaling. Gene expression signatures were similar between adult and old LNSCs. Aged LNSCs were found to constitutively upregulate immediate early response genes. Collectively, these data suggest LNSCs uniquely respond to WNV infection. We are the first to report age-associated differences in LNSCs on the population- and gene expression-level during WNV infection. These changes may compromise antiviral immunity, leading to increased WNV disease in older individuals.