bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cortical Spheroid Model for Studying the Effects of Ischemic Brain Injury
Authors: McLaughlin Rachel M. , Laguna Amanda , Top Ilayda , Hernandez Christien , Livi Liane L. , Kramer Liana , Zambuto Samantha , Hoffman-Kim Diane 
Published: October 2021

AbstractStroke is a devastating neurological disorder and a leading cause of death and long-term disability. Despite many decades of research, there are still very few therapeutic options for patients suffering from stroke or its consequences. This is partially due to the limitations of current research models, including traditional in vitro models which lack the three-dimensional (3D) architecture and cellular make-up of the in vivo brain. 3D spheroids derived from primary postnatal rat cortex provide an in vivo-relevant model containing a similar cellular composition to the native cortex and a cell-synthesized extracellular matrix. These spheroids are costeffective, highly reproducible, and can be produced in a high-throughput manner, making this model an ideal candidate for screening potential therapeutics. To study the cellular and molecular mechanisms of stroke in this model, spheroids were deprived of glucose, oxygen, or both oxygen and glucose for 24 hours. Both oxygen and oxygen-glucose deprived spheroids demonstrated many of the hallmarks of stroke, including a decrease in metabolism, an increase in neural dysfunction, and an increase in reactive astrocytes. Pretreatment of spheroids with the antioxidant agent N-acetylcysteine (NAC) mitigated the decrease in ATP seen after 24 hours of oxygen-glucose deprivation. Together, these results show the utility of our 3D cortical spheroid model for studying ischemic injury and its potential for screening stroke therapeutics.Significance StatementThose who survive after suffering a stroke often have long-term cognitive or physical disabilities. There is currently only one available therapeutic, tissue plasminogen activator (tPA), and it must be administered within a few hours after the onset of stroke. As stroke prevalence increases with our aging population, there is a growing need for therapies to mitigate or reverse the resulting brain damage. Three-dimensional (3D) culture systems have the potential to screen novel therapeutics more reliably than traditional in vitro models. Here we present a novel 3D cortical spheroid ischemia model which replicates many of the characteristics of stroke and has the potential to be an effective tool in therapeutic development.
Immunogenic potential of neopeptides depends on parent protein subcellular location
Authors: Castro Andrea , Kaabinejadian Saghar , Hildebrand William , Zanetti Maurizio , Carter Hannah 
Published: October 2021

AbstractAntigen presentation via the major histocompatibility complex (MHC) is essential for anti-tumor immunity, however the rules that determine what tumor-derived peptides will be immunogenic are still incompletely understood. Here we investigate whether protein subcellular location driven constraints on accessibility of peptides to the MHC associate with potential for peptide immunogenicity. Analyzing over 380,000 peptides from studies of MHC presentation and peptide immunogenicity, we find clear spatial biases in both eluted and immunogenic peptides. We find that including parent protein location improves prediction of peptide immunogenicity in multiple datasets. In human immunotherapy cohorts, location was associated with response to a neoantigen vaccine, and immune checkpoint blockade responders generally had a higher burden of neopeptides from accessible locations. We conclude that protein subcellular location adds important information for optimizing immunotherapies.HighlightsPeptides eluted from class I and II MHC reflect biases in the subcellular location of the parent proteinsAn embedding-based indicator of parent protein location improves prediction of neoepitope immunogenicity and immunotherapy responseNeoepitope location improves estimation of effective neoantigen burden and stratification of potential for immunotherapy response
SPOT-1D-LM: Reaching Alignment-profile-based Accuracy in Predicting Protein Secondary and Tertiary Structural Properties without Alignment
Authors: Singh Jaspreet , Paliwal Kuldip , Singh Jaswinder , Zhou Yaoqi 
Published: October 2021

ABSTRACTProtein language models have emerged as an alternative to multiple sequence alignment for enriching sequence information and improving downstream prediction tasks such as biophysical, structural, and functional properties. Here we show that a combination of traditional one-hot encoding with the embeddings from two different language models (ProtTrans and ESM-1b) allows a leap in accuracy over single-sequence based techniques in predicting protein 1D secondary and tertiary structural properties, including backbone torsion angles, solvent accessibility and contact numbers. This large improvement leads to an accuracy comparable to or better than the current state-of-the-art techniques for predicting these 1D structural properties based on sequence profiles generated from multiple sequence alignments. The high-accuracy prediction in both secondary and tertiary structural properties indicates that it is possible to make highly accurate prediction of protein structures without homologous sequences, the remaining obstacle in the post AlphaFold2 era.
Identification of electroporation sites in the complex lipid organization of the plasma membrane
Authors: Rems Lea , Tang Xinru , Zhao Fangwei , Pérez-Conesa Sergio , Testa Ilaria , Delemotte Lucie 
Published: October 2021

AbstractThe plasma membrane of a biological cell is a complex assembly of lipids and membrane proteins, which tightly regulate transmembrane transport. When a cell is exposed to a strong electric field, the membrane integrity becomes transiently disrupted by formation of transmembrane pores. This phenomenon, termed electroporation, is already utilized in many rapidly developing applications in medicine including gene therapy, cancer treatment, and treatment of cardiac arrythmias. However, the molecular mechanisms of electroporation are not yet sufficiently well understood; in particular, it is unclear where exactly pores form in the complex organization of the plasma membrane. In this study we combine coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis to identify how formation of pores depends on the local lipid organization. We show that pores do not form homogeneously across the membrane, but colocalize with domains that have specific features, the most important being high density of polyunsaturated lipids. We further show that knowing the lipid organization is sufficient to reliably predict poration sites with machine learning. However, by analysing poration kinetics with Bayesian survival analysis we then show that poration does not depend solely on local lipid arrangement, but also on membrane mechanical properties and the polarity of the electric field. Finally, we discuss how the combination of atomistic and coarse-grained molecular dynamics simulations, machine learning methods, and Bayesian survival analysis can guide the design of future experiments and help us to develop an accurate description of plasma membrane electroporation on the whole-cell level. Achieving this will allow us to shift the optimization of electroporation applications from blind trial-and-error approaches to mechanistic-driven design.
Single-cell transcriptomics unveils xylem cell development and evolution
Authors: Tung Chia-Chun , Kuo Shang-Che , Yang Chia-Ling , Huang Chia-En , Yu Jhong-He , Sun Ying-Hsuan , Shuai Peng , Su Jung-Chen , Ku Chuan , Lin Ying-Chung Jimmy 
Published: October 2021

AbstractAs the most abundant tissue on Earth1, xylem is responsible for lateral growth in plants. Typical xylem has a radial system composed of ray parenchyma cells and an axial system of fusiform cells2. In most angiosperms, fusiform cells are a combination of vessel elements for water transportation and libriform fibers for mechanical support, while both functions are performed together by tracheids in other vascular plants2. However, little is known about the developmental programs and evolutionary relationships of these xylem cell types. Through both single-cell and laser-capture microdissection transcriptomic profiling, here we demonstrate the developmental lineages of ray and fusiform cells in stem-differentiating xylem across four divergent woody angiosperms. Cross-species analyses of single-cell trajectories reveal highly conserved ray, yet variable fusiform, lineages across angiosperms. Core eudicots Populus trichocarpa and Eucalyptus grandis share nearly identical fusiform lineages. The tracheids in the basal eudicot Trochodendron aralioides, an evolutionarily reversed character3, 4, exhibit strong transcriptomic similarity to vessel elements but not libriform fibers, suggesting that water transportation, instead of mechanical support, is the major feature. We also found that the more basal angiosperm Liriodendron chinense has a fusiform lineage distinct from that in core eudicots. This evo-developmental framework provides a comprehensive understanding of the formation of xylem cell lineages across multiple plant species spanning over a hundred million years of evolutionary history5.
Nanopore microscope identifies RNA isoforms with structural colors
Authors: Bošković Filip , Keyser Ulrich Felix 
Published: October 2021

AbstractIdentifying RNA transcript isoforms requires intricate protocols that suffer from various enzymatic biases. Here we design three-dimensional molecular constructs that enable identification of transcript isoforms at the single-molecule level using solid-state nanopore microscopy. We refold target RNA into RNA identifiers (IDs) with designed sets of complementary DNA strands. Each reshaped molecule carries a unique sequence of structural (pseudo)colors. Structural colors consist of DNA structures, protein labels, native RNA structures, or a combination of all three. The sequence of structural colors of RNA IDs enables simultaneous identification and relative quantification of multiple RNA targets without prior amplification. Our Amplification-free RNA TargEt Multiplex Isoform Sensing (ARTEMIS) reveals structural arrangements in native transcripts in agreement with published variants. ARTEMIS discriminates circular and linear transcript isoforms in a one step, enzyme-free reaction in a complex human transcriptome using single-molecule readout.One sentence summaryHere we show enzyme-free identification and relative quantification of RNA isoforms using a nanopore microscope and structural colors.
Automatic identification and annotation of MYB gene family members in plants
Authors: Pucker Boas 
Published: October 2021

AbstractBackgroundMYBs are among the largest transcription factor families in plants. Consequently, members of this family are involved in a plethora of processes including development and specialized metabolism. The MYB families of many plant species were investigated in the last two decades since the first investigation looked at Arabidopsis thaliana. This body of knowledge and characterized sequences provide the basis for the identification, classification, and functional annotation of candidate sequences in new genome and transcriptome assemblies.ResultsA pipeline for the automatic identification and functional annotation of MYBs in a given sequence data set was implemented in Python. MYB candidates are identified, screened for the presence of a MYB domain and other motifs, and finally placed in a phylogenetic context with well characterized sequences. In addition to technical benchmarking based on existing annotation, the transcriptome assembly of Croton tiglium and the annotated genome sequence of Castanea crenata were screened for MYBs. Results of both analyses are presented in this study to illustrate the potential of this application. The analysis of one species takes only a few minutes depending on the number of predicted sequences and the size of the MYB gene family. This pipeline, the required bait sequences, and reference sequences for a classification are freely available on github: https://github.com/bpucker/MYB_annotator.ConclusionsThis automatic annotation of the MYB gene family in novel assemblies makes genome-wide investigations consistent and paves the way for comparative studies in the future. Candidate genes for in-depth analyses are presented based on their orthology to previously characterized sequences which allows the functional annotation of the newly identified MYBs with high confidence. The identification of orthologs can also be harnessed to detect duplication and deletion events.
iHypoxia: an integrative database of the expression dynamics of proteins in response to hypoxia in animals
Authors: Liu Ze-Xian , Wang Panqin , Zhang Qingfeng , Li Shihua , Zhang Yuxin , Guo Yutong , Jia Chongchong , Shao Tian , Li Lin , Cheng Han , Wang Zhenlong 
Published: October 2021

AbstractDecreased oxygen concentrations (hypoxia) outside of the physiological range may severely subvert cell, tissue, and organism survival. Mammals have evolved mechanisms to sense hypoxia and induce a series of hypoxic responses. In recent years, high-throughput techniques have greatly promoted global perturbation studies of protein expression during hypoxia, and these studies have contributed to the understanding of the complex regulatory networks of hypoxia. In this study, we developed an integrated resource for the expression dynamics of proteins in response to hypoxia (iHypoxia), which contains 1,629 expression events of 1,215 proteins identified by low-throughput experiments (LTEs) and 154,953 quantitative expression events of 36,194 proteins identified by high-throughput experiments (HTEs) from five mammals that exhibit a response to hypoxia. Various experimental details such as the hypoxic experimental conditions, expression patterns, and samples were carefully collected and integrated. In addition, we conducted an orthologous search and identified 581,763 proteins that may respond to hypoxia among 50 animals. An enrichment analysis of human proteins identified from LTEs showed that these proteins were enriched in certain drug targets and cancer genes. The annotation of known posttranslational modification (PTM) sites to proteins identified by LTEs revealed that these proteins underwent extensive PTMs, particularly phosphorylation, ubiquitination and acetylation. Based on the results, iHypoxia provides a convenient and user-friendly method for users to obtain hypoxia-related information of interest. We anticipate that iHypoxia, which is freely accessible at http://ihypoxia.omicsbio.info, will advance the understanding of hypoxia and serve as a valuable data resource.
RIG-I immunotherapy overcomes radioresistance in p53-positive malignant melanoma
Authors: Lambing Silke , Holdenrieder Stefan , Müller Patrick , Tan Yu Pan , Hagen Christian , Garbe Stephan , Schlee Martin , van den Boorn Jasper G. , Bartok Eva , Hartmann Gunther , Renn Marcel 
Published: October 2021

AbstractRadiation therapy induces cytotoxic DNA damage, which results in cell-cycle arrest and activation of cell-intrinsic death pathways, but its application has been limited by the radioresistance of tumors, such as in malignant melanoma. RIG-I is a cytosolic immune receptor expressed in all somatic cells, including tumor cells, with a key role in sensing viral RNA. RIG-I specific oligonucleotide ligands elicit a robust cell-intrinsic antiviral response and immunogenic cell death in tumor cells and are being tested in clinical trials. Nonetheless, their potential to overcome radioresistance has not yet been explored. Here, we demonstrate that activation of RIG-I enhances the extent and immunogenicity of irradiation-induced tumor cell death in human and murine melanoma cell lines in vitro and improved survival in the murine B16 melanoma model. Pathway analysis of transcriptomic data revealed a central role for p53 downstream of the combination treatment, which was corroborated using p53-/- B16 cells. In vivo, the effect of irradiation on immune-cell activation and inhibition of tumor growth was absent in mice carrying p53-/- B16 tumors, while the response to RIG-I stimulation in those mice was maintained. Our results identify p53 as pivotal for the synergistic antitumoral effect of RIG-I and irradiation, resulting in potent induction of immunogenic tumor-cell death. Thus, the administration of RIG-I ligands in combination with radiotherapy is a promising therapeutic approach to treating radioresistant tumors with a functional p53 pathway, such as malignant melanoma.
Pharmacological mechanisms on the anti-breast cancer property of Coix lacryma-jobi: A network-based analysis
Authors: Ferrer Angelu Mae , David Janella Rayne , Taquiqui Arvin , Bautista Arci , Deocaris Custer C. , Alinsug Malona V. 
Published: October 2021

AbstractBreast cancer is considered as one of the three most common cancers around the world and the second leading cause of cancer deaths among women. Coix lachrymal jobi, commonly known as Job’s tears or adlay has been reported to possess anti-cancer properties. Despite evidences provided by clinical data, the usage of Coix lacryma-jobi in treating cancer, particularly breast cancer, has been scarce. Thus, this study was conducted to determine the pharmacological mechanisms underlying its anti-breast cancer property using various network pathway analyses. Bioactive compounds from Coix lacryma-jobi and its potential target genes were obtained from SymMap. Breast cancer-related target genes were collected from CTD. Protein-protein interaction network was analyzed using the STRING database. GO and KEGG pathway enrichment analyses were performed using DAVID to further explore the mechanisms of Coix lacryma-jobi in treating breast cancer. PPI and compound-target-pathway were visualized using Cytoscape. A total of 26 bioactive compounds, 201 corresponding targets, 36625 breast cancer-associated targets were obtained, and 200 common targets were considered potential therapeutic targets. The 9 bioactive compounds identified were berberine, oleic acid, beta-sitosterol, sitosterol, linoleic acid, berberrubine, jatrorrhizine, thalifendine, and stigmasterol. The identified 5 core targets were ESR1, JUN, MAPK14, and RXRA. Coix lacryma-jobi targets enriched in GO terms were mostly involved in regulation of transcription from RNA polymerase II promoter, drug response, steroid hormone receptor activity, and protein binding. This study elucidates on the pharmacological underpinnings on the potency of adlay against breast cancer. Its subsequent drug development will be worth a step forward for a breast cancer-free society.
Formation of multinucleated globoid cells in Krabbe iPSC-derived microglia cultures: a preliminary investigation
Authors: Lieberman Richard , Gao Grace , Hunter Robert B. , Leonard John P. , Cortes Leslie K. , Barker Robert H. 
Published: October 2021

AbstractGloboid cell leukodystrophy (Krabbe disease) is a severe demyelinating, neurodegenerative lysosomal storage disorder caused by deficiency in glycosphingolipid catabolic enzyme galactosylceramidase (GALC). Histologically, Krabbe disease is characterized by the appearance of large multinucleated globoid cells that express classical macrophage markers (both of brain-resident microglia and peripheral monocyte-derived). Globoid cells reside near areas of degeneration; however, their functional significance in disease progression remains unclear. In the current study, we differentiated microglia-like cells from iPSCs from a donor with infantile Krabbe disease and compared them to microglia generated from two healthy controls and two donors with the lysosomal storage disorder metachromatic leukodystrophy (MLD), which is genetically distinct from Krabbe disease but presents similarly in terms of severity of demyelination and neurodegeneration. We report the novel finding of prominent formation of giant multinucleated globoid cells from the microglia derived from the Krabbe donor, but not from healthy control or MLD donors. The Krabbe microglia displayed reduced IL-6 protein expression upon stimulation with lipopolysaccharide, and the multinucleated globoid cells themselves appeared deficient in phagocytosis of both disease-relevant myelin debris and E. coli, together hinting at an impairment of normal function. The formation of the globoid cells could be attenuated by fully replacing the medium following passaging, suggesting that yet-to-be determined secreted factors are influencing cell fusion in our culture system. While preliminary, our results imply that globoid cells may be detrimental in Krabbe disease by hindering the normal function of brain-residing macrophages.
Cutaneous manifestations and dermoscopic findings are important clues to the diagnosis of Talaromyces marneffei in HIV patients with immune reconstitution inflammatory syndrome: A case report and literature review
Authors: Chaisuwannarak Kornkanok , Chularojanamontri Leena , Junsuwan Natachaya , Eimpunth Sasima 
Published: October 2021

AbstractTalaromyces (formerly Penicillium) marneffei is a dimorphic fungus that causes talaromycosis (formerly penicilliosis). The condition is predominantly found in patients with HIV. Important diagnostic clues are a history of living or travelling in endemic areas, and central umbilicated skin lesions. Dermoscopy is particularly useful for providing rapid bedside information, with a round, whitish, amorphous structure being the most common finding. Immune reconstitution inflammatory syndrome (IRIS) may occur. Driven by the initiation of antiretroviral therapy, IRIS is an exaggerated response of T cells to pathogens. Although mycobacterial and cryptococcal opportunistic infections are common with IRIS, a linkage between T. marneffei and IRIS has rarely been reported. Here, we report on a literature review of patients with HIV who developed IRIS associated with talaromycosis. Dermatologists should be aware of the cutaneous and dermoscopic findings of talaromycosis as they provide important clues that enable its early diagnosis and treatment.