bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACE2 Netlas: In-silico functional characterization and drug-gene interactions of ACE2 gene network to understand its potential involvement in COVID-19 susceptibility
Authors: Pathak Gita A , Wendt Frank R , Goswami Aranyak , De Angelis Flavio ,   COVID-19 Human Genetics Initiative, Polimanti Renato 
Published: October 2020

AbstractAngiotensin-converting enzyme-2 (ACE2) receptor has been identified as the key adhesion molecule for the transmission of the SARS-CoV-2. However, there is no evidence that human genetic variation in ACE2 is singularly responsible for COVID-19 susceptibility. Therefore, we performed a multi-level characterization of genes that interact with ACE2 (ACE2-gene network) for their over-represented biological properties in the context of COVID-19.The phenome-wide association of 51 genes including ACE2 with 4,756 traits categorized into 26 phenotype categories, showed enrichment of immunological, respiratory, environmental, skeletal, dermatological, and metabolic domains (p<4e-4). Transcriptomic regulation of ACE2-gene network was enriched for tissue-specificity in kidney, small intestine, and colon (p<4.7e-4). Leveraging the drug-gene interaction database we identified 47 drugs, including dexamethasone and spironolactone, among others.Considering genetic variants within ± 10 kb of ACE2-network genes we characterized functional consequences (among others) using miRNA binding-site targets. MiRNAs affected by ACE2-network variants revealed statistical over-representation of inflammation, aging, diabetes, and heart conditions. With respect to variants mapped to the ACE2-network, we observed COVID-19 related associations in RORA, SLC12A6 and SLC6A19 genes.Overall, functional characterization of ACE2-gene network highlights several potential mechanisms in COVID-19 susceptibility. The data can also be accessed at https://gpwhiz.github.io/ACE2Netlas/
simplifyEnrichment: an R/Bioconductor package for Clustering and Visualizing Functional Enrichment Results
Authors: Gu Zuguang , Hübschmann Daniel 
Published: October 2020

ABSTRACTFunctional enrichment analysis or gene set enrichment analysis is a basic bioinformatics method that evaluates biological importance of a list of genes of interest. However, it may produce a long list of significant terms with highly redundant information that is difficult to summarize. Current tools to simplify enrichment results by clustering them into groups either still produce redundancy between clusters or do not retain consistent term similarities within clusters. We propose a new method namedbinary cutfor clustering similarity matrices of functional terms. Through comprehensive benchmarks on both simulated and real-world datasets, we demonstrated that binary cut can efficiently cluster functional terms into groups where terms showed more consistent similarities within groups and were more mutually exclusive between groups. We compared binary cut clustering on the similarity matrices obtained from different similarity measures and found that the semantic similarity worked well with binary cut while similarity matrices based on gene overlap showed less consistent patterns. We implemented the binary cut algorithm in the R packagesimplifyEnrichmentwhich additionally provides functionalities for visualizing, summarizing and comparing the clusterings.
In-vitroandin-vivocharacterization of CRANAD-2 for multi-spectral optoacoustic tomography and fluorescence imaging of amyloid-beta deposits in Alzheimer mice
Authors: Ni Ruiqing , Villois Alessia , Dean-Ben Xose Luis , Chen Zhenyue , Vaas Markus , Stavrakis Stavros , Shi Gloria , deMello Andrew , Ran Chongzhao , Razansky Daniel , Arosio Paolo , Klohs Jan 
Published: October 2020

AbstractThe abnormal deposition of fibrillar beta-amyloid (Aβ) deposits in the brain is one of the major histopathological hallmarks of Alzheimer’s disease (AD). Here we characterize curcumin-derivative CRANAD-2 for multi-spectral optoacoustic tomography (MSOT) and fluorescence imaging of brain Aβ deposits in the arcAβ mouse model of AD cerebral amyloidosis. CRANAD-2 shows a specific and quantitative detection of A fibrilsin vitro,even in complex mixtures, and it is capable to distinguish between monomeric and fibrillar forms of A.In vivoepifluorescence and MSOT after intravenous CRANAD-2 administration demonstrated higher retention in arcAβ compared to non-transgenic littermate mice. Immunohistochemistry showed co-localization of CRANAD-2 and Aβ deposits in arcAβ mouse brain sections, thus verifying the specificity of the probe. In conclusion, we demonstrate suitability of CRANAD-2 for fluorescence- and MSOT-based detection of Aβ deposits in animal models of AD pathology, which facilitates mechanistic studies and the monitoring of putative treatments targeting Aβ deposits.
Applications of machine learning to solve genetics problems
Authors: Sowunmi Kehinde , Nweze Victor Nnanna , Abiola Soyebo Titilayo , Ajibike Okosesi Ebunoluwa , Lawal Adesiyan Ayobami , Adejoke Olademeji Kafayat , Adekunle Ajibola Oluwaseun , Ogunlana Yusuf Olayinka , Wasiu Agboola Olamilekan , Kaur Gurpreet , Hameed Atoromola , Abidemi Oladipupo Temitope 
Published: October 2020

AbstractThe development of precise DNA editing nucleases that induce double-strand breaks (DSBs) - including zinc finger nucleases, TALENs, and CRISPR/Cas systems - has revolutionized gene editing and genome engineering. Endogenous DNA DSB repair mechanisms are often leveraged to enhance editing efficiency and precision. While the non-homologous end joining (NHEJ) and homologous recombination (HR) DNA DSB repair pathways have already been the topic of an excellent deal of investigation, an alternate pathway, microhomology-mediated end joining (MMEJ), remains relatively unexplored. However, the MMEJ pathway’s ability to supply reproducible and efficient deletions within the course of repair makes it a perfect pathway to be used in gene knockouts. (Microhomology Evoked Deletion Judication EluciDation) may be a random forest machine learning-based method for predicting the extent to which the location of a targeted DNA DSB are going to be repaired using the MMEJ repair pathway. On an independent test set of 24 HeLa cell DSB sites, MEDJED achieved a Pearson coefficient of correlation (PCC) of 81.36%, Mean Absolute Error (MAE) of 10.96%, and Root Mean Square Error (RMSE) of13.09%. This performance demonstrates MEDJED’s value as a tool for researchers who wish to leverage MMEJ to supply efficient and precise gene knock outs.
Cell size is a determinant of stem cell potential during aging
Authors: Lengefeld Jette , Cheng Chia-Wei , Maretich Pema , Blair Marguerite , Hagen Hannah , McReynolds Melanie R. , Sullivan Emily , Majors Kyra , Roberts Christina , Kang Joon Ho , Steiner Joachim D. , Miettinen Teemu P. , Manalis Scott R. , Antebi Adam , Morrison Sean J. , Lees Jacqueline A. , Boyer Laurie A. , Yilmaz Ömer H. , Amon Angelika 
Published: October 2020

AbstractStem cells are remarkably small in size. Whether small size is important for stem cell function is unknown. We find that murine hematopoietic stem cells (HSCs) enlarge under conditions known to decrease stem cell function. This decreased fitness of large HSCs is due to reduced proliferative potential. Preventing HSC enlargement by inhibiting macromolecule biosynthesis or reducing large HSCs size by shortening G1averts the loss of stem cell potential under conditions causing stem cell exhaustion. Finally, we show that a fraction of murine and human HSCs enlarge during aging. Preventing this age-dependent enlargement improves HSC function. We conclude that small cell size is important for stem cell functionin vivoand propose that stem cell enlargement contributes to their functional decline during aging.One Sentence SummarySize increase drives stem cell aging.
The PfAP2-G2 transcription factor is a critical regulator of gametocyte maturation
Authors: Singh Suprita , Santos Joana M. , Orchard Lindsey M. , Yamada Naomi , van Biljon Riëtte , Painter Heather J. , Mahony Shaun , Llinás Manuel 
Published: October 2020

AbstractDifferentiation from asexual blood stages to sexual gametocytes is required for transmission of malaria parasites from the human to the mosquito host. Preventing gametocyte commitment and development would block parasite transmission, but the underlying molecular mechanisms behind these processes remain poorly understood. Here, we report that the ApiAP2 transcription factor, PfAP2-G2 (PF3D7_1408200) plays a critical role in the maturation ofPlasmodium falciparumgametocytes. PfAP2-G2 binds to the promoters of a wide array of genes that are expressed at many stages of the parasite life cycle. Interestingly, we also find binding of PfAP2-G2 within the gene body of almost 3000 genes, which strongly correlates with the location of H3K36me3 and several other histone modifications as well as Heterochromatin Protein 1 (HP1), suggesting that occupancy of PfAP2-G2 in gene bodies may serve as an alternative regulatory mechanism. Disruption ofpfap2-g2does not impact asexual development, parasite multiplication rate, or commitment to sexual development but the majority of sexual parasites are unable to mature beyond stage III gametocytes. The absence ofpfap2-g2leads to overexpression of 28% of the genes bound by PfAP2-G2 and none of the PfAP2-g2 bound are downregulated, suggesting that it is a repressor. We also find that PfAP2-G2 interacts with chromatin remodeling proteins, a microrchidia (MORC) protein, and another ApiAP2 protein (PF3D7_1139300). Overall our data demonstrate that PfAP2-G2 is an important transcription factor that establishes an essential gametocyte maturation program in association with other chromatin-related proteins.
Annual phytoplankton dynamics in coastal waters from Fildes Bay, Western Antarctic Peninsula
Authors: Trefault Nicole , De la Iglesia Rodrigo , Moreno-Pino Mario , dos Santos Adriana Lopes , Ribeiro Catherine Gérikas , Cristi Antonia , Marie Dominique , Vaulot Daniel 
Published: October 2020

AbstractYear-round reports of phytoplankton dynamics in the West Antarctic Peninsula are rare and mainly limited to microscopy and/or pigment-based studies. We analyzed the phytoplankton community from coastal waters of Fildes Bay in the West Antarctic Peninsula between January 2014 and 2015 using metabarcoding of the nuclear and plastidial 18/16S rRNA gene from both size-fractionated and flow cytometry sorted samples. Each metabarcoding approach yielded a different image of the phytoplankton community with for example Prymnesiophyceae more prevalent in plastidial metabarcodes and Mamiellophyceae in nuclear ones. Overall 14 classes of photosynthetic eukaryotes were present in our samples with the following dominating: Bacillariophyta (diatoms), Pelagophyceae and Dictyochophyceae for division Ochrophyta, Mamiellophyceae and Pyramimonadophyceae for division Chlorophyta, Prymnesiophyceae and Cryptophyceae. Diatoms were dominant in the larger size fractions and during summer, while Prymnesiophyceae and Cryptophyceae were dominant in colder seasons. Pelagophyceae were particularly abundant towards the end of autumn (May). In addition ofMicromonas polarisandMicromonassp. clade B3, both previously reported in Arctic waters, we detected a newMicromonas18S rRNA sequence signature, close to but clearly distinct fromM. polaris, which potentially represent a new clade specific of the Antarctic. These results highlight the need for complementary strategies as well as the importance of year-round monitoring for a comprehensive description of phytoplankton communities in Antarctic coastal waters.
CRISPR-based knockin mutagenesis of the pioneer transcription factor FOXA1; optimization of strategies for multi-allelic proteins in cancer cells
Authors: Li Shen , Garay Joseph P. , Tubbs Colby A. , Franco Hector L. 
Published: October 2020

AbstractPrecise genome engineering of living cells has been revolutionized by the introduction of the highly specific and easily programmable properties of CRISPR-Cas9 technology. This has greatly accelerated research into human health and has facilitated the discovery of novel therapeutics. CRISPR-Cas9 is most widely employed for its ability to inactivate, or knockout, specific genes, but can be also used to introduce subtle site-specific substitutions of DNA sequences that can lead to changes in the amino acid composition of proteins. Despite the proven success of CRISPR-based knockin strategies of genes in typical diploid cells (i.e. cells containing two sets of chromosomes), precise editing of cancer cells, that typically have unstable genomes and multiple copies of chromosomes, is more challenging and not adequately addressed in the literature. Herein we detail our methodology for replacing endogenous proteins with intended knockin mutants in polyploid cancer cells and discuss our experimental design, screening strategy, and facile allele-frequency estimation methodology. As proof of principle, we performed genome editing of specific amino acids within the pioneer transcription factor FOXA1, a critical component of estrogen and androgen receptor signaling, in MCF-7 breast cancer cells. We confirm proper levels of mutant FOXA1 protein expression and intended amino acids substitutions via western blotting and mass spectrometry. In addition, we show that mutant allele-frequency estimation is easily achieved by TOPO cloning combined with allele-specific PCR, which we later confirmed by next-generation RNA-sequencing. Typically, there are 4 - 5 copies (alleles) of FOXA1 in breast cancer cells making the editing of this protein inherently challenging. As a result, most studies that focus on FOXA1 mutants rely on ectopic overexpression of FOXA1 from a plasmid. Therefore, we provide an optimized methodology for replacing endogenous wildtype FOXA1 with precise knockin mutants to enable the systematic analysis of its molecular mechanisms within the appropriate physiological context.
Winter wheat adapts to environmental pH by changing H+net flux in roots at the seedling stage
Authors: Wang Guangtao , Feng Suwei , Ding Weihua , Hu Tiezhu , Ru Zhengang 
Published: October 2020

AbstractChanges in rhizosphere pH play an important role in wheat growth. To investigate the relationship between changes in rhizosphere pH and the growth of winter wheat roots and to explore the regulatory mechanism of acid and alkali resistance in winter wheat roots, the semi-winter wheat varieties Aikang 58 (AK58) and Bainong 4199 (BN4199) were used as materials for hydroponic experiments. Three pH levels (4.0, 6.5, and 9.0, with 6.5 as control) were applied during the wheat seedling stage. The results showed that the shoot and root biomass of the plants significantly decreased compared with the control under acid-base stress, with a more significant decrease with acid stress than alkali stress. Compared with the control, the root/shoot ratio increased under alkali stress and decreased under acid stress. The wheat root system showed H+net efflux at pH 6.5 and 9.0, and the H+net efflux rate at pH 4.0 was significantly lower than the control. The root activity of wheat was higher than the control at pH 9.0 and lower at pH4.0. The change of root pH was showed pH 4.0 < pH 6.5 < pH 9.0. Correlation analysis showed that changes in H+net flux were significantly positively correlated to root activity and root pH. The H+efflux rate and root activity of BN4199 were highe r than AK58 under acid and alkali stress, and the root/shoot ratio was relatively high, indicating strong acid and alkali resistance. We conclude that wheat could adapt to poor acid-base environments by adjusting root H+net flux, and in practice, the root/shoot ratio could be used as index for the rapid determination of acid-base tolerance in wheat at the seedling stage.
Genomic structural variation in ‘Nebbiolo’ grapevines at the individual, clonal and cultivar levels
Authors: Maestri Simone , Gambino Giorgio , Minio Andrea , Perrone Irene , Cosentino Emanuela , Giovannone Barbara , Lopatriello Giulia , Marcolungo Luca , Cantu Dario , Rossato Marzia , Delledonne Massimo , Calderón Luciano 
Published: October 2020

AbstractStructural Variants (SVs) are a widely unexplored source of genetic variation, both due to methodological limitations and because they are generally associated to deleterious effects. However, with the advent of long-range genomic platforms, it has become easier to directly detect SVs. In the same direction, clonally propagated crops provide a unique opportunity to study SVs, offering a suitable genomic environment for their accumulation in heterozygosis. In particular, it has been reported that SVs generate drastic levels of heterozygosity in grapevines. ‘Nebbiolo’ (Vitis viniferaL.) is a grapevine cultivar typical of north-western Italy, appreciated for its use in producing high-quality red wines. Here, we aimed to analyze the frequency of SVs in ‘Nebbiolo’, at three different organizational levels. For this purpose, we generated genomic data based on long-reads, linked-reads and optical mapping. We assembled a reference genome for this cultivar and compared two different clones, includingV. viniferareference genome (PN40024) in our comparisons. Our results indicate that SVs differentially occurring between ‘Nebbiolo’ clones might be rare, while SVs differentiating haplotypes of the same individual are as abundant as those that occur differentially between cultivars.
Poly-ADP-ribosylation drives loss of protein homeostasis in ATM and Mre11 deficiency
Authors: Lee Ji-Hoon , Ryu Seung W. , Ender Nicolette A. , Paull Tanya T. 
Published: October 2020

SummaryLoss of the ataxia-telangiectasia mutated (ATM) kinase causes cerebellum-specific neurodegeneration in humans. We previously demonstrated that deficiency in ATM activation via oxidative stress generates high levels of insoluble protein aggregates in human cells, reminiscent of protein dysfunction in common neurodegenerative disorders. Here we show that this process is driven by poly-ADP-ribose polymerases (PARPs) and that the insoluble protein species arise from intrinsically disordered proteins associating with PAR-associated genomic sites in ATM-deficient cells. The lesions implicated in this process are single-strand DNA breaks dependent on reactive oxygen species, transcription, and R-loops. Human cells expressing Mre11 A-T-like disorder (ATLD) mutants also show PARP-dependent aggregation identical to that of ATM deficiency. Lastly, analysis of A-T patient cerebellum samples shows widespread protein aggregation as well as loss of proteins known to be critical in human spinocerebellar ataxias. These results provide a new hypothesis for loss of protein integrity and cerebellum function in A-T.
Real-Time Linear Prediction of Simultaneous and Independent Movements of Two Finger Groups Using an Intracortical Brain-Machine Interface
Authors: Nason Samuel R. , Mender Matthew J. , Vaskov Alex K. , Willsey Matthew S. , Patil Parag G. , Chestek Cynthia A. 
Published: October 2020

SUMMARYModern brain-machine interfaces can return function to people with paralysis, but current hand neural prostheses are unable to reproduce control of individuated finger movements. Here, for the first time, we present a real-time, high-speed, linear brain-machine interface in nonhuman primates that utilizes intracortical neural signals to bridge this gap. We created a novel task that systematically individuates two finger groups, the index finger and the middle-ring-small fingers combined, presenting separate targets for each group. During online brain control, the ReFIT Kalman filter demonstrated the capability of individuating movements of each finger group with high performance, enabling a nonhuman primate to acquire two targets simultaneously at 1.95 targets per second, resulting in an average information throughput of 2.1 bits per second. To understand this result, we performed single unit tuning analyses. Cortical neurons were active for movements of an individual finger group, combined movements of both finger groups, or both. Linear combinations of neural activity representing individual finger group movements predicted the neural activity during combined finger group movements with high accuracy, and vice versa. Hence, a linear model was able to explain how cortical neurons encode information about multiple dimensions of movement simultaneously. Additionally, training ridge regressing decoders with independent component movements was sufficient to predict untrained higher-complexity movements. Our results suggest that linear decoders for brain-machine interfaces may be sufficient to execute high-dimensional tasks with the performance levels required for naturalistic neural prostheses.
Identifying the functions of two biomarkers in human oligodendrocyte progenitor cell development
Authors: Zhou Haipeng , He Ying , Yang Yinxiang , Wang Zhaoyan , Wang Qian , Hu Caiyan , Wang Xiaohua , Lu Siliang , Li Ke , Luan Zuo 
Published: October 2020

AbstractNG2 and A2B5 are important biological markers of human oligodendrocyte progenitor cells. To study their functional differences during the development of human oligodendrocyte progenitor cells to oligodendrocytes, we used cell sorting technology and obtained a large number of sterile, high-purity NG2+/- and A2B5+/- cells with high viability. Further research was then conducted viain vitrocell proliferation and migration assays, single-cell sequencing, mRNA sequencing, and cell transplantation into shiverer mice. The results showed that the migration ability of the cells was inversely proportional to the myelination ability. NG2 may be a marker of early oligodendrocyte progenitor cells and is conducive to cell migration and proliferation, while A2B5 may be a marker of slightly mature oligodendrocyte progenitor cells and is conducive to cell differentiation. Further, cell migration, proliferation, and myelination capacity of the negative cell population were stronger than those of the positive cell population. In summary, these results suggest that oligodendrocyte progenitor cells in the mid-stage may be more suitable for clinical cell transplantation to treat demyelinating diseases.Summary statementThis research found that oligodendrocyte progenitor cells in the middle developmental stages may be more suitable for cell transplantation to treat demyelinating diseases.