bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer LncRNA Census 2 (CLC2): an enhanced resource reveals clinical features of cancer lncRNAs
Authors: Vancura Adrienne , Lanzós Andrés , Bosch Núria , Torres Mònica , Gutierrez Alejandro Hionides , Haefliger Simon , Johnson Rory 
Published: April 2020

AbstractLong noncoding RNAs play key roles in cancer and are at the vanguard of precision therapeutic development. These efforts depend on large and high-confidence collections of cancer lncRNAs. Here we present the Cancer LncRNA Census 2 (CLC2): at 492 cancer lncRNAs, it is 4-fold greater than its predecessor, without compromising on strict criteria of confident functional / genetic roles and inclusion in the GENCODE annotation scheme. This increase was enabled by leveraging high-throughput transposon insertional mutagenesis (TIM) screening data, yielding 95 novel cancer lncRNAs. CLC2 makes a valuable addition to existing collections: it is amongst the largest, holds the greatest number of unique genes, and carries functional labels (oncogene / tumour suppressor). Analysis of this dataset reveals that cancer lncRNAs are impacted by germline variants, somatic mutations, and changes in expression consistent with inferred disease functions. Furthermore, we show how clinical / genomic features can be used to vet prospective gene sets from high-throughput sources. The combination of size and quality makes CLC2 a foundation for precision medicine, demonstrating cancer lncRNAs’ evolutionary and clinical significance.
Marked Synergy by Vertical Inhibition of EGFR signaling in NSCLC Spheroids: SOS1 as a therapeutic target in EGFR-mutated cancer
Authors: Theard Patricia L. , Sheffels Erin , Sealover Nancy E. , Linke Amanda J. , Pratico David J. , Kortum Robert L. 
Published: April 2020

AbstractDrug treatment of 3D cancer spheroids more accurately reflects in vivo therapeutic responses compared to adherent culture studies. In EGFR-mutated lung adenocarcinoma, EGFR-TKIs show enhanced efficacy in spheroid cultures. Simultaneous inhibition of multiple parallel RTKs further enhances EGFR-TKI effectiveness. We show that the common RTK signaling intermediate SOS1 was required for 3D spheroid growth of EGFR-mutated NSCLC cells. Using two distinct measures of pharmacologic synergy, we demonstrated that SOS1 inhibition strongly synergized with EGFR-TKI treatment only in 3D spheroid cultures. Combined EGFR- and SOS1-inhibition markedly inhibited Raf/MEK/ERK and PI3K/AKT signaling. Finally, broad assessment of the pharmacologic landscape of drug-drug interactions downstream of mutated EGFR revealed synergy when combining an EGFR-TKI with inhibitors of proximal signaling intermediates SOS1 and SHP2, but not inhibitors of downstream RAS effector pathways. These data indicate that vertical inhibition of proximal EGFR signaling should be pursued as a potential therapy to treat EGFR-mutated tumors.
Parental Population Range Expansion Before Secondary Contact Promotes Heterosis
Authors: MacPherson Ailene , Wang Silu , Yamaguchi Ryo , Rieseberg Loren H. , Otto Sarah P. 
Published: April 2020

AbstractPopulation genomic analysis of hybrid zones is instrumental to our understanding of the evolution of reproductive isolation. Many temperate hybrid zones are formed by the secondary contact between two parental populations that have undergone post-glacial range expansion. Here we show that explicitly accounting for historical parental isolation followed by range expansion prior to secondary contact is fundamental for explaining genetic and fitness patterns in these hybrid zones. Specifically, ancestral population expansion can result in allele surfing where neutral or slightly deleterious mutations drift to high frequency at the expansion front. If these surfed deleterious alleles are recessive, they can contribute to substantial heterosis in hybrids produced at secondary contact, counteracting negative effects of Bateson-Dobzhansky-Muller incompatibilities (BDMIs) hence weakening reproductive isolation. When BDMIs are linked to such recessive deleterious alleles the fitness benefit of introgression at these loci can facilitate introgression at the BDMIs. The extent to which this occurs depends on the strength of selection against the linked deleterious alleles and the distribution of recombination across the chromosome. Finally, surfing of neutral loci can alter the expected pattern of population ancestry, thus accounting for historical population expansion is necessary to develop accurate null genomic models of secondary-contact hybrid zones.
Empirical lognormality of biological variation: implications for the ‘zero-force evolutionary law’
Authors: Gingerich Philip D. 
Published: April 2020

ABSTRACTThe zero-force evolutionary law (ZFEL) of McShea et al. states that independently evolving entities, with no forces or constraints acting on them, will tend to accumulate differences and therefore diverge from each other. McShea et al. quantified the law by assuming normality on an additive arithmetic scale and reflecting negative differences as absolute values, systematically augmenting perceived divergence. The appropriate analytical framework is not additive but proportional, where logarithmic transformation is required to achieve normality. Logarithms and logarithmic differences can be negative but the proportions they represent cannot be negative. Reformulation of ZFEL in a proportional or geometric reference frame indicates that when entities evolve randomly and independently, differences smaller than any initial difference are balanced by differences larger than the initial difference. Total variance increases with each step of a random walk, but there is no statistical expectation of divergence between random-walk lineages.
PD-1 blockade-driven anti-tumor CD8+T cell immunity requires XCR1+dendritic cells
Authors: Mao Tianyang , Song Eric , Iwasaki Akiko 
Published: April 2020

AbstractCD8+T cells are required for effective anti-PD-1 (αPD-1) cancer immunotherapy. Type 1 conventional dendritic cells (cDC1s) bearing XCR1 critically mediate the initiation of protective anti-tumor CD8+T cell responses in mice and humans. However, whether cDC1s contribute to evoking the effector function of CD8+T cells during αPD-1 antibody therapy remains unclear. Here, by deleting cDC1s at the effector phase of αPD-1 therapy, we identify these cells as a crucial innate determinant for effective αPD-1 immunotherapy. αPD-1 treatment unleashed cDC1s to promote anti-tumor CD8+T cell immunity, through the expansion of TCF1+precursors and generation of TIM3+terminally differentiated effectors. Furthermore, tumor cDC1 abundance was predictive of enhanced CD8+T cell infiltration, higher survival, and improved clinical responses to αPD-1 therapy in human cancer patients. Together, this study reveals the requirement for cDC1s in PD-1 blockade therapy, through their ability to elicit CD8+T cell effector responses that mediate tumor control, and highlight cDC1s as an attractive cellular target to be harnessed for novel immunotherapeutics.
Establishment of a stablezg6pdM118-144transgenic zebrafish model of glucose-6-phosphate dehydrogenase deficiency
Authors: Xia Hai-Xiong , Zhou Yan-Hua , Tuo Yuan-Yuan , Ren Ping-Ping , Song Jin , Shang Lu-Jun , Jin Jiao , He Zhi-Xu , Shu Li-Ping 
Published: April 2020

AbstractGlucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common genetic defect and enzymopathy with a wide distribution and increased public health concern, predisposes subjects succumb to oxidative stress. G6PD deficiency has been associated with hemolysis. Clinically, G6PD deficiency is asymptomatic and the clinical manifestations occur with the exposure to certain agents. Due to the lack of suitable animal models that can predict the clinical hemolytic potential of drugs, it needs an appropriate research model to fully recapitulate the manifestations of G6PD deficiency in clinic, to optimize the malaria therapy and promote anti-malarias development. The present study has displayed a stable transgenicTg(zgata1-g6pdM118-144-egfp) zebrafish model with G6PD deficiency which mimics the clinical features of G6PD deficiency phenotypically and functionally. The findings showed that there was an inadequate level of reduced GSH in the transgenicTg(zgata1-g6pdM118-144-egfp) zebrafish line in the presence or absence of α-naphthol, compared to the wildtype zebrafish, indicating an attenuation of g6pd activity in the transgenic zebrafish line. In addition, the observations show that there is a less abundance of g6pd in the transgenicTg(zgata1-g6pdM118-144-egfp) zebrafish line. On the other hand, there is no morphological abnormality in the transgenicTg(zgata1-g6pdM118-144-egfp) zebrafish line. Taken together, our work has delivered a novel stable transgenic zebrafish model of G6PD deficiency that will facilitate the mechanistic and functional elucidation for the role of G6PD in erythrocytic pathophysiology. This model will promote the translational research for the drug development, in particular, for anti-malarias development.
Gromov-Wasserstein optimal transport to align single-cell multi-omics data
Authors: Demetci Pinar , Santorella Rebecca , Sandstede Björn , Noble William Stafford , Singh Ritambhara 
Published: April 2020

AbstractData integration of single-cell measurements is critical for understanding cell development and disease, but the lack of correspondence between different types of measurements makes such efforts challenging. Several unsupervised algorithms can align heterogeneous single-cell measurements in a shared space, enabling the creation of mappings between single cells in different data domains. However, these algorithms require hyperparameter tuning for high-quality alignments, which is difficult in an unsupervised setting without correspondence information for validation. We present Single-Cell alignment using Optimal Transport (SCOT), an unsupervised learning algorithm that uses Gromov Wasserstein-based optimal transport to align single-cell multi-omics datasets. We compare the alignment performance of SCOT with state-of-the-art algorithms on four simulated and two real-world datasets. SCOT performs on par with state-of-the-art methods but is faster and requires tuning fewer hyperparameters. Furthermore, we provide an algorithm for SCOT to use Gromov Wasserstein distance to guide the parameter selection. Thus, unlike previous methods, SCOT aligns well without using any orthogonal correspondence information to pick the hyperparameters. Our source code and scripts for replicating the results are available athttps://github.com/rsinghlab/SCOT.
Controlling the SARS-CoV-2 outbreak, insights from large scale whole genome sequences generated across the world
Authors: Phelan Jody , Deelder Wouter , Ward Daniel , Campino Susana , Hibberd Martin L. , Clark Taane G 
Published: April 2020

ABSTRACTBackgroundSARS-CoV-2 most likely evolved from a bat beta-coronavirus and started infecting humans in December 2019. Since then it has rapidly infected people around the world, with more than 4.5 million confirmed cases by the middle of May 2020. Early genome sequencing of the virus has enabled the development of molecular diagnostics and the commencement of therapy and vaccine development. The analysis of the early sequences showed relatively few evolutionary selection pressures. However, with the rapid worldwide expansion into diverse human populations, significant genetic variations are becoming increasingly likely. The current limitations on social movement between countries also offers the opportunity for these viral variants to become distinct strains with potential implications for diagnostics, therapies and vaccines.MethodsWe used the current sequencing archives (NCBI and GISAID) to investigate 15,487 whole genomes, looking for evidence of strain diversification and selective pressure.ResultsWe used 6,294 SNPs to build a phylogenetic tree of SARS-CoV-2 diversity and noted strong evidence for the existence of two major clades and six sub-clades, unevenly distributed across the world. We also noted that convergent evolution has potentially occurred across several locations in the genome, showing selection pressures, including on the spike glycoprotein where we noted a potentially critical mutation that could affect its binding to the ACE2 receptor. We also report on mutations that could prevent current molecular diagnostics from detecting some of the sub-clades.ConclusionThe worldwide whole genome sequencing effort is revealing the challenge of developing SARS-CoV-2 containment tools suitable for everyone and the need for data to be continually evaluated to ensure accuracy in outbreak estimations.
The CRISPR-Cas9 crATIC HeLa transcriptome: Characterization of a novel cellular model of ATIC deficiency and ZMP accumulation
Authors: Mazzarino Randall C , Baresova Veronika , Zikánová Marie , Duval Nathan , Wilkinson Terry G. , Patterson David , Vacano Guido N. 
Published: April 2020

ABSTRACTInde novopurine biosynthesis (DNPS), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (2.1.2.3) / inosine monophosphate cyclohydrolase (3.5.4.10) (ATIC) catalyzes the last two reactions of the pathway: conversion of 5-aminoimidazole-4-carboxamide ribonucleotide [aka Z-nucleotide monophosphate (ZMP)] to 5-formamido-4-imidazolecarboxamide ribonucleotide (FAICAR) then to inosine monophosphate (IMP). ZMP is an adenosine monophosphate (AMP) mimetic and a known activator of AMP-activated protein kinase (AMPK). Recently, a HeLa cell line null mutant for ATIC was constructed via CRISPR-Cas9 mutagenesis. This mutant, crATIC, accumulates ZMP during purine starvation. Given that the mutant can accumulate ZMP in the absence of treatment with exogenous compounds, crATIC is likely an important cellular model of DNPS inactivation and ZMP accumulation. In the current study, we characterize the crATIC transcriptome versus the HeLa transcriptome in purine-supplemented and purine-depleted growth conditions. We report and discuss transcriptome changes with particular relevance to Alzheimer’s disease and in genes relevant to lipid and fatty acid synthesis, neurodevelopment, embryogenesis, cell cycle maintenance and progression, extracellular matrix, immune function, TGFβ and other cellular processes.
Investigation of the anti-TB potential of selected alkaloid constituents using molecular docking approach
Authors: Siam Mohammad Kawsar Sharif , Shohan Mohammad Umer Sharif , Zafroon Zaira 
Published: April 2020

AbstractMycobacterium tuberculosis, the leading bacterial killer disease worldwide, causes Human tuberculosis (TB). Due to the growing problem of drug resistantMycobacterium tuberculosisstrains, new anti-TB drugs are urgently needed. Natural sources such as plant extracts have long played an important role in tuberculosis management and can be used as a template to design new drugs. A wide screening of natural sources is time consuming but the process can be significantly sped up using molecular docking. In this study, we used a molecular docking approach to investigate the interactions between selected natural constituents and three proteins MtPanK, MtDprE1 and MtKasA involved in the physiological functions of Mycobacterium tuberculosis which are necessary for the bacteria to survive and cause disease. The molecular docking score, a score that accounts for the binding affinity between a ligand and a target protein, for each protein was calculated against 150 chemical constituents of different classes to estimate the binding free energy. The docking scores represent the binding free energy. The best docking scores indicates the highest ligand protein binding which is indicated by the lowest energy value. Among the natural constituents, Shermilamine B showed a docking score of - 8.5kcal/mol, Brachystamide B showed a docking score of −8.6 kcal/mol with MtPanK, Monoamphilectine A showed a score of −9.8kcal/mol with MtDprE1.These three compounds showed docking scores which were superior to the control inhibitors and represent the opportunity of in vitro biological evaluation and anti-TB drug design. Consequently, all these compounds belonged to the alkaloid class. Specific interactions were studied to further understand the nature of intermolecular bonds between the most active ligands and the protein binding site residues which proved that among the constituents monoamphilectine A and Shermilamine B show more promise as Anti-TB drugs. Furthermore, the ADMET properties of these compounds or ligands showed that they have no corrosive or carcinogenic parameters.Graphical Abstract
Proteasome activator PA200 maintains stability of histone marks during transcription and aging
Authors: Jiang Tian-Xia , Ma Shuang , Han Xia , Luo Zi-Yu , Zhu Qian-Qian , Chiba Tomoki , Xie Wei , Chen Su-Ren , Lin Kui , Qiu Xiao-Bo 
Published: April 2020

AbstractThe epigenetic inheritance relies on stability of histone marks, but various diseases, including aging-related diseases, are usually associated with alterations of histone marks. How the stability of histone marks is maintained still remains unclear. The core histones can be degraded by the atypical proteasome, which contains the proteasome activator PA200, in an acetylation-dependent manner during somatic DNA damage response and spermiogenesis. Here we show that PA200 promotes the transcription-coupled degradation of the core histones, and plays an important role in maintaining the stability of histone marks. Degradation of the histone variant H3.3, which is incorporated into chromatin during transcription, was much faster than that of its canonical form H3.1, which is incorporated during DNA replication. This degradation of the core histones could be suppressed by the transcription inhibitor, the proteasome inhibitor or deletion of PA200. The histone deacetylase inhibitor accelerated the degradation rates of H3 in general, especially its variant H3.3, while the mutations of the putative acetyl-lysine-binding region of PA200 abolished histone degradation in the G1-arrested cells, supporting that acetylation is involved in the degradation of the core histones. Deletion of PA200 dramatically altered deposition of the active transcriptional hallmarks (H3K4me3 and H3K56ac) and transcription, especially during cellular aging. Furthermore, deletion of PA200 or its yeast ortholog Blm10 accelerated cellular aging. Notably, the PA200-deficient mice displayed a range of aging-related deteriorations, including immune malfunction, anxiety-like behaviors and shorter lifespan. Thus, the proteasome activator PA200 is critical to the maintenance of the stability of histone marks during transcription and aging.
Cell culture NAIL-MS allows insight into human RNA modification dynamicsin vivo
Authors: Heiss Matthias , Hagelskamp Felix , Kellner Stefanie 
Published: April 2020

AbstractIn the last years, studies about the dynamics of RNA modifications are among the most controversially discussed. As the main reason, we have identified the unavailability of a technique which allows to follow the temporal dynamics of RNA transcripts in human cell culture. Here, we present a NAIL-MS (nucleic acid isotope labeling coupled mass spectrometry) scheme for efficient stable isotope labeling in both RNA and DNA (>95% within 7 days) in common human cell lines and growth media. Validation experiments reveal that the labeling procedure itself does neither interfere with the isotope dilution MS quantification nor with RNA modification density. We design pulse chase NAIL-MS experiments and apply the new tool to study the temporal placement of modified nucleosides ine.g.tRNAPheand 18S rRNA. In existing RNAs, we observe a constant loss of modified nucleosides over time which is masked by a post-transcriptional methylation mechanism and thus not detectable without NAIL-MS. During alkylation stress, NAIL-MS reveals an adaptation of tRNA modifications in new transcripts but not existing transcripts.Overall, we present a fast and reliable stable isotope labeling strategy which allows a more detailed study of RNA modification dynamics in human cell culture. With cell culture NAIL-MS it is finally possible to study the speed of both modification and demethylation reactions inside human cells. Thus it will be possible to study the impact of external stimuli and stress on human RNA modification kinetics and processing of mature RNA.
Adaptations accumulated under prolonged resource exhaustion are highly transient
Authors: Avrani Sarit , Katz Sophia , Hershberg Ruth 
Published: April 2020

AbstractMany non-sproulating bacterial species can survive for years within exhausted growth media in a state termed long-term stationary phase (LTSP). We have been carrying out evolutionary experiments aimed at elucidating the dynamics of genetic adaptation under LTSP. We showed thatEscherichia coliadapts to prolonged resource exhaustion through the highly convergent acquisition of mutations. In the most striking example of such convergent adaptation, we observed that across all independently evolving LTSP populations, over 90% ofE. colicells carry mutations to one of three specific sites of the RNA polymerase core enzyme (RNAPC). These LTSP adaptations reduce the ability of the cells carrying them to grow once fresh resources are again provided. Here, we examine how LTSP populations recover from costs associated with their adaptation, once resources are again provided to them. We demonstrate that due to the ability of LTSP populations to maintain high levels of standing genetic variation during adaptation, costly adaptations are very rapidly purged from the population once they are provided with fresh resources. We further demonstrate that recovery from costs acquired during adaptation under LTSP occurs much more rapidly than would be possible if LTSP adaptations had fixed during the time populations spent under resource exhaustion. Finally, we previously reported that under LTSP, some clones develop a mutator phenotype, greatly increasing their mutation accumulation rates. Here, we show that the mechanisms, by which populations recover from costs associated with fixed adaptations, may depend on mutator status.