bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heparin-modified alginate microspheres enhance neovessel formation in hiPSC-derived endothelial cells and heterocellularin vitromodels by controlled release of VEGF
Authors: Munarin Fabiola , Kabelac Carly , Coulombe Kareen L.K. 
Published: January 2021

AbstractA formidable challenge in regenerative medicine is the development of stable microvascular networks to restore adequate blood flow or to sustain graft viability and long-term function in implanted or ischemic tissues. In this work, we develop a biomimetic approach to increase the binding affinity of the extracellular matrix for the class of heparin-binding growth factors to localize and control the release of proangiogenic cues while maintaining their bioactivity. Sulfate and heparin moieties are covalently coupled to alginate, and alginate microspheres are produced and used as local delivery depots for vascular endothelial growth factor (VEGF). Release of VEGF from sulfate-alginate and heparin-alginate bulk hydrogels and microspheres was sustained over 14 days.In vitroevaluation with human induced pluripotent stem cell (hiPSC)-derived endothelial cells and aortic ring assay in a chemically-defined hydrogel demonstrates development of primitive three-dimensional vessel-like networks in the presence of VEGF released from the chemically modified alginate microspheres. Furthermore, our results suggest that the sulfate groups available on the chemically modified alginate microspheres promote some new vessel formation even in VEGF-free samples. Based on this evidence, we conclude that sulfate- and heparin-alginate hydrogels are adaptive and bioactive delivery systems for revascularization therapy and translational vascular tissue engineering.
A Network-level Test of the Role of the Co-activated Default Mode Network in Episodic Recall and Social Cognition
Authors: Jackson Rebecca L. , Humphreys Gina F. , Rice Grace E. , Binney Richard J. , Lambon Ralph Matthew A. 
Published: January 2021

AbstractResting-state network research is extremely influential, yet the functions of many networks remain unknown. In part, this is due to typical (e.g., univariate) analyses testing the function of individual regions and not the full set of co-activated regions that form a network. Connectivity is dynamic and the function of a region may change based on its current connections. Therefore, determining the function of a network requires assessment at the network-level. Yet popular theories implicating the default mode network (DMN) in episodic memory and social cognition, rest principally upon analyses performed at the level of individual brain regions. Here we use independent component analysis to formally test the role of the DMN in episodic and social processing at the network level. As well as an episodic retrieval task, two independent datasets were employed to assess DMN function across the breadth of social cognition; a person knowledge judgement and a theory of mind task. Each task dataset was separated into networks of co-activated regions. In each, the co-activated DMN, was identified through comparison to ana prioritemplate and its relation to the task model assessed. This co-activated DMN did not show greater activity in episodic or social tasks than high-level baseline conditions. Thus, no evidence was found to support hypotheses that the co-activated DMN is involved in explicit episodic or social processing tasks at a network-level. The networks associated with these processes are described. Implications for prior univariate findings and the functional significance of the co-activated DMN are considered.
Distinct spermiogenic phenotypes underlie sperm elimination in theSegregation Distortermeiotic drive system
Authors: Herbette Marion , Wei Xiaolu , Chang Ching-Ho , Larracuente Amanda M. , Loppin Benjamin , Dubruille Raphaëlle 
Published: January 2021

AbstractSegregation Distorter(SD) is a male meiotic drive system inDrosophila melanogaster.Males heterozygous for a selfishSDchromosome rarely transmit the homologousSD+chromosome. It is well established that distortion results from an interaction betweenSd, the primary distorting locus on theSDchromosome and its target, a satellite DNA calledRsp,on theSD+chromosome. However, the molecular and cellular mechanisms leading to post-meioticSD+sperm elimination remain unclear. Here we show thatSD/SD+males of different genotypes but with similarly strong degrees of distortion have distinct spermiogenic phenotypes. In some genotypes,SD+spermatids fail to fully incorporate protamines after the removal of histones, and degenerate during the individualization stage of spermiogenesis. In contrast, in otherSD/SD+genotypes, protamine incorporation appears less disturbed, yet spermatid nuclei are abnormally compacted, and mature sperm nuclei are eventually released in the seminal vesicle. Our analyses of differentSD+chromosomes suggest that the severity of the spermiogenic defects associates with the copy number of theRspsatellite. We propose that whenRspcopy number is very high (> 2000), spermatid nuclear compaction defects reach a threshold that triggers a checkpoint controlling sperm chromatin quality to eliminate abnormal spermatids during individualization.
Skin-resident immune cells actively coordinate their distribution with epidermal cells during homeostasis
Authors: Park Sangbum , Matte-Martone Catherine , Gonzalez David G. , Lathrop Elizabeth A. , May Dennis P. , Pineda Cristiana M. , Moore Jessica L. , Boucher Jonathan D. , Marsh Edward D. , Schmitter Axel , Cockburn Katie , Bellaïche Yohanns , Greco Valentina 
Published: January 2021

AbstractOur organs consist of multiple cell types that ensure proper architecture and function. How different cell types coexist and interact to maintain their homeostasisin vivoremain elusive. The skin epidermis comprises mostly epithelial cells, but also harbors Langerhans cells (LCs) and Dendritic Epidermal T cells (DETCs). In response to injury or infection, LCs and DETCs become activated and play critical immunological roles. During homeostasis, they coexist with epithelial cells in the basal layer of the epidermis. Whether, and how, distributions of LCs and DETCs are regulated during homeostasis is unclear. Here, we addressed this question by tracking LCs, DETCs and epithelial basal cells over time within the skin of live adult mice. We show that LCs and DETCs maintain their overall position despite continuous turnover of neighboring basal epithelial stem cells. Moreover, LCs and DETCs rapidly and maximally explore basal epithelial cell junctions through their dendritic extensions. Altering the epithelial cell density triggers corresponding changes in the immune cell density, but not vice versa, suggesting that epithelial cells determine immune tissue composition in the epidermis. Moreover, LCs and DETCs are organized in a tiling pattern that is actively maintained. When LCs or DETCs are ectopically removed, neighboring epidermal LCs or DETCs, respectively, move into the emptied spaces and re-establish the tiling pattern. Finally, LCs require the GTPase Rac1 to maintain their positional stability, density and tiling pattern. Overall, we discovered that epidermal cells regulate the density of immune cells during homeostasis, and that immune cells actively maintain a non-random spatial distribution, reminiscent of neuronal self-avoidance. We propose that these cellular mechanisms provide the epidermis with an optimal response to environmental insults.
rdrugtrajectory: An R Package for the Analysis of Drug Prescriptions in Electronic Health Care Records
Authors: Nash Anthony , Chang Tingyee E. , Wan Benjamin , Cader M. Zameel 
Published: January 2021

AbstractPrimary care electronic health care records are rich with patient and clinical information. Studying electronic health care records has resulted in marked improvements to national health care processes and patient-care decision making, and is a powerful supplementary source of data for drug discovery effort. We present the R packagerdrugtrajectory, designed to yield demographic and patient-level characteristics of drug prescriptions in the UK Clinical Practice Research Datalink dataset. The package operates over Clinical Practice Research Datalink Gold clinical, referral and therapy datasets and includes features such as first drug prescriptions analysis, cohort-wide prescription information, cumulative drug prescription events, the longitudinal trajectory of drug prescriptions, and a survival analysis timeline builder to identify risks related to drug prescription switching. Therdrugtrajectorypackage has been made freely available via the GitHub repository.
REPEATED INJURY PROMOTES TRACHEOBRONCHIAL TISSUE STEM CELL ATTRITION
Authors: Ghosh Moumita , Hill Cynthia L. , Alsudayri Alfahdah , Lallier Scott W. , Hayes Don , Wijeratne Saranga , Mahoney John E. , Reynolds Susan D. 
Published: January 2021

SUMMARYChronic lung disease has been attributed to stem cell aging and/or exhaustion. To address this issue, we investigated the lifespan of tracheobronchial tissue stem cells (TSC) over time and in response to repeated injury. Chromatin and nucleotide labeling studies in mice indicated that: 1) injury activated a subset of the TSC pool and that this process conserved TSC over time; and 2) activated TSC were predisposed to further proliferation and this activated state lead to terminal differentiation. Analysis of human TSC and clonal isolates indicated that repeated TSC proliferation led to telomere shortening and analysis of TSC from Dyskeratosis Congenita donors indicated that mutations in telomere biology genes accelerated TSC depletion. RNAseq and functional studies indicated that human TSC terminated as a secretory committed cell. These data support a model in which a repeated epithelial injury depletes the TSC pool and initiates the abnormal repair associated with chronic lung disease.
Reconstitution of cargo-induced LC3 lipidation in mammalian selective autophagy
Authors: Chang Chunmei , Shi Xiaoshan , Jensen Liv E. , Yokom Adam L. , Fracchiolla Dorotea , Martens Sascha , Hurley James H. 
Published: January 2021

AbstractSelective autophagy of damaged mitochondria, intracellular pathogens, protein aggregates, endoplasmic reticulum, and other large cargoes is essential for health. The presence of cargo initiates phagophore biogenesis, which entails the conjugation of ATG8/LC3 family proteins to membrane phosphatidylethanolamine. Current models suggest that the presence of clustered ubiquitin chains on a cargo triggers a cascade of interactions from autophagic cargo receptors through the autophagy core complexes ULK1 and class III PI 3-kinase complex I (PI3KC3-C1), WIPI2, and the ATG7, ATG3, and ATG12-ATG5-ATG16L1 machinery of LC3 lipidation. This model was tested using giant unilamellar vesicles (GUVs), GST-Ub4as a model cargo, the cargo receptors NDP52, TAX1BP1, and OPTN, and the autophagy core complexes. All three cargo receptors potently stimulated LC3 lipidation on GUVs. NDP52- and TAX1BP1-induced LC3 lipidation required the ULK1 complex together with all other components, however, ULK1 kinase activity was dispensable. In contrast, OPTN bypassed the ULK1 requirement completely. These data show that the cargo-dependent stimulation of LC3 lipidation is a common property of multiple autophagic cargo receptors, yet the details of core complex engagement vary considerably and unexpectedly between the different receptors.
Effects of Ihand TASK-like shunting current on dendritic impedance in layer 5 pyramidal-tract neurons
Authors: Kelley Craig , Dura-Bernal Salvador , Neymotin Samuel A. , Antic Srdjan D. , Carnevale Nicholas T. , Migliore Michele , Lytton William W 
Published: January 2021

AbstractPyramidal neurons in neocortex have complex input-output relationships that depend on their morphologies, ion channel distributions, and the nature of their inputs, but which cannot be replicated by simple integrate-and-fire models. The impedance properties of their dendritic arbors, such as resonance and phase shift, shape neuronal responses to synaptic inputs and provide intraneuronal functional maps reflecting their intrinsic dynamics and excitability. Experimental studies of dendritic impedance have shown that neocortical pyramidal tract neurons exhibit distance-dependent changes in resonance and impedance phase with respect to the soma. We therefore investigated how well several biophysically-detailed multi-compartment models of neocortical layer 5 pyramidal tract neurons reproduce the location-dependent impedance profiles observed experimentally. Each model tested here exhibited location-dependent impedance profiles, but most captured either the observed impedance amplitude or phase, not both. The only model that captured features from both incorporates HCN channels and a shunting current, like that produced by Twik-related acid-sensitive K+(TASK) channels. TASK-like channel activity in this model was dependent on local peak HCN channel conductance (Ih). We found that while this shunting current alone is insufficient to produce resonance or realistic phase response, it modulates all features of dendritic impedance, including resonance frequencies, resonance strength, synchronous frequencies, and total inductive phase. We also explored how the interaction ofIhand a TASK-like shunting current shape synaptic potentials and produce degeneracy in dendritic impedance profiles, wherein different combinations ofIhand shunting current can produce the same impedance profile.New & NoteworthyWe simulated chirp current stimulation in the apical dendrites of 5 biophysically-detailed multi-compartment models of neocortical pyramidal tract neurons and found that a combination of HCN channels and TASK-like channels produced the best fit to experimental measurements of dendritic impedance. We then explored how HCN and TASK-like channels can shape the dendritic impedance as well as the voltage response to synaptic currents.
A Bacterial Bile Acid Metabolite Modulates TregActivity through the Nuclear Hormone Receptor NR4A1
Authors: Li Wei , Hang Saiyu , Fang Yuan , Bae Sena , Zhang Yancong , Wang Gang , McCurry Megan D. , Bae Munhyung , Franzosa Eric A. , Huttenhower Curtis , Yao Lina , Devlin A. Sloan , Huh Jun R. 
Published: January 2021

SUMMARYBile acids act as signaling molecules that regulate immune homeostasis, including the differentiation of CD4+T cells into distinct T cell subsets. The bile acid metabolite isoallolithocholic acid (isoalloLCA) enhances the differentiation of anti-inflammatory regulatory T cells (Treg cells) by facilitating the formation of a permissive chromatin structure in the promoter region of the transcription factor forkhead box P3 (Foxp3). Here, we identify gut bacteria that synthesize isoalloLCA from 3-oxolithocholic acid and uncover a gene cluster responsible for the conversion in members of the abundant human gut bacterial phylum Bacteroidetes. We also show that the nuclear hormone receptor NR4A1 is required for the effect of isoalloLCA on Treg cells. Moreover, the levels of isoalloLCA and its biosynthetic genes are significantly reduced in patients with inflammatory bowel diseases, suggesting that isoalloLCA and its bacterial producers may play a critical role in maintaining immune homeostasis in humans.
Fungal Ice2p is in the same superfamily as SERINCs, restriction factors for HIV and other viruses
Authors: Alli-Balogun Ganiyu O. , Levine Tim P. 
Published: January 2021

AbstractIce2p is an integral endoplasmic reticulum (ER) membrane protein in budding yeastS. cerevisiaenamed ICE because it is required for Inheritance of Cortical ER. Ice2p has also been reported to be involved in an ER metabolic branch-point that regulates the flux of lipid either to be stored in lipid droplets or to be used as membrane components. Alternately, Ice2p has been proposed to act as a tether that physically bridges the ER at contact sites with both lipid droplets and the plasma membrane via a long loop on the protein’s cytoplasmic face that contains multiple predicted amphipathic helices. Here we carried out a bioinformatic analysis to increase understanding of Ice2p. Firstly, regarding topology, we found that diverse members of the fungal Ice2 family have ten transmembrane helices, which places the long loop on the exofacial face of Ice2p, where it cannot form inter-organelle bridges. Secondly, we identified Ice2 as a full-length homologue of SERINC (serine incorporator), a family of proteins with ten transmembrane helices found universally in eukaryotes. Since SERINCs are potent restriction factors for HIV and other viruses, study of Ice2p may reveal functions or mechanisms that shed light on viral restriction by SERINCs.
Trans-channel fluorescence learning improves high-content screening for Alzheimer’s disease therapeutics
Authors: Wong Daniel R. , Conrad Jay , Johnson Noah , Ayers Jacob , Laeremans Annelies , Lee Joanne C. , Lee Jisoo , Prusiner Stanley B. , Bandyopadhyay Sourav , Butte Atul J. , Paras Nick , Keiser Michael J. 
Published: January 2021

AbstractIn microscopy-based drug screens, fluorescent markers carry critical information on how compounds affect different biological processes. However, practical considerations may hinder the use of certain fluorescent markers. Here, we present a deep learning method for overcoming this limitation. We accurately generated predicted fluorescent signals from other related markers and validated this new machine learning (ML) method on two biologically distinct datasets. We used the ML method to improve the selection of biologically active compounds for Alzheimer’s disease (AD) from high-content high-throughput screening (HCS). The ML method identified novel compounds that effectively blocked tau aggregation, which would have been missed by traditional screening approaches unguided by ML. The method improved triaging efficiency of compound rankings over conventional rankings by raw image channels. We reproduced this ML pipeline on a biologically independent cancer-based dataset, demonstrating its generalizability. The approach is disease-agnostic and applicable across diverse fluorescence microscopy datasets.
GSDMD Deficiency Protects Against Aortic Rupture
Authors: Ye Dien , Howatt Deborah A. , Li Zhenyu , Daugherty Alan , Lu Hong S. , Wu Congqing 
Published: January 2021

ABSTRACTObjectiveAortic ruptures are fatal consequences of aortic aneurysms with macrophage accumulation being a hallmark at the site of ruptures. Pyroptosis is critical in macrophage-mediated inflammation. This study determined effects of pyroptosis on aortic dilation and rupture using GSDMD deficient mice.Approach and ResultsIn an initial study, maleGsdmd+/+andGsdmd-/-mice in C57BL/6J background (8 – 10 weeks old) were infected with adeno-associated viral vectors encoding mouse PCSK9D377Y gain-of-function mutation and fed a Western diet to induce hypercholesterolemia. After two weeks of AAV infection, angiotensin II (AngII, 1 µg/kg/min) was infused. During the 4 weeks of AngII infusion, 5 of 13Gsdmd+/+mice died of aortic rupture, whereas no aortic rupture occurred inGsdmd-/-mice. In surviving mice, no differences in either ascending or abdominal aortic dilation were observed betweenGsdmd+/+andGsdmd-/-mice. To determine whether protection of GSDMD deficiency against aortic rupture is specific to AngII infusion, we subsequently examined aortic pathologies in mice administered beta-aminopropionitrile (BAPN). BAPN (0.5% wt/vol) was administered in drinking water to maleGsdmd+/+andGsdmd-/-mice (4 weeks old) for 4 weeks. Six of 13Gsdmd+/+mice died of aortic rupture, whereas no aortic rupture occurred inGsdmd-/-mice. In mice survived, no differences of diameters in the ascending, arch, or abdominal aortic regions were observed betweenGsdmd+/+andGsdmd-/-mice.ConclusionsGSDMD deficiency protects against AngII or BAPN-induced aortic ruptures in mice.HighlightsGSDMD deficiency protects against angiotensin II-induced aortic rupture in hypercholesterolemic mice.GSDMD deficiency protects against beta-aminopropionitrile (BAPN)-induced aortic dissection and rupture in C57BL/6J mice.
CRY2missense mutations suppress P53 and enhance cell growth
Authors: Chan Alanna B. , Parico Gian Carlo G. , Fribourgh Jennifer L. , Ibrahim Lara H. , Bollong Michael J. , Partch Carrie L. , Lamia Katja A. 
Published: January 2021

AbstractDisruption of circadian rhythms increases the risk of several types of cancer. Mammalian cryptochromes (CRY1 and CRY2) are circadian transcriptional repressors that are related to DNA repair enzymes. While CRYs lack DNA repair activity, they modulate the transcriptional response to DNA damage, and CRY2 can promote SCFFBXL3-mediated ubiquitination of c-MYC and other targets. Here, we characterize five mutations in CRY2 observed in human cancers in The Cancer Genome Atlas. We demonstrate that two orthologous mutations of mouse CRY2 (D325H and S510L) accelerate the growth of primary mouse fibroblasts expressing high levels of c-MYC. Neither mutant affects steady state levels of overexpressed c-MYC, and they have divergent impacts on circadian rhythms and on the ability of CRY2 to interact with SCFFBXL3. Unexpectedly, stable expression of either CRY2 D325H or of CRY2 S510L robustly suppresses P53 target gene expression, suggesting that this is the primary mechanism by which they influence cell growth.
iRGD-liposomes enhance tumor delivery and therapeutic efficacy of antisense oligonucleotide drugs against primary prostate cancer and bone metastasis
Authors: Guan Jibin , Guo Hong , Tang Tang , Wang Yihan , Wei Yushuang , Seth Punit , Li Yingming , Dehm Scott M , Ruoslahti Erkki , Pang Hong-Bo 
Published: January 2021

AbstractNucleotide-based drugs, such as antisense oligonucleotides (ASOs), have unique advantages in treating human diseases as they provide virtually unlimited ability to target any gene. However, their clinical translation faces many challenges, one of which is poor delivery to the target tissuein vivo. This problem is particularly evident in solid tumors. Here, we functionalized liposomes with a tumor-homing and -penetrating peptide, iRGD, as a carrier of an ASO against androgen receptor (AR) for prostate cancer treatment. The iRGD-liposomes exhibited a high loading efficiency of AR-ASO, and an efficient knockdown of AR gene products was achievedin vitro, including AR splice variants.In vivo, iRGD-liposomes significantly increased AR-ASO accumulation in the tumor tissue and decreased AR expression relative to free ASOs in prostate tumors established as subcutaneous xenografts. Similar results were obtained with intra-tibial xenografts modeling metastasis to bones, the predominant site of metastasis for prostate cancer. In treatment studies, iRGD-liposomes markedly improved the AR-ASO efficacy in suppressing the growth of both subcutaneous xenografts and intra-tibial xenografts. The inhibitory effect on tumor growth was also significantly prolonged by the delivery of the AR-ASO in the iRGD-liposomes. Meanwhile, iRGD-liposomes did not increase ASO accumulation or toxicity in healthy organs. Overall, we provide here a delivery system that can significantly increase ASO accumulation and efficacy in solid tumors. These benefits are achieved without significant side effects, providing a way to increase the antitumor efficacy of ASOs.