bluuebunny/crossref_metadata_2025_split huggingface dataset:
In-Silico analysis reveals lower transcription efficiency of C241T variant of SARS-CoV-2 with host replication factors MADP1 and HNRNP-1
Authors: Chaudhari Armi , Chaudhari Minal , Mahera Sapna , Saiyed Zuber , Nathani Neelam M. , Shukla Shantanu , Patel Chirag , Patel Dhaval , Joshi Madhvi , Joshi Chaitanya G. 
Published: November 2020

ABSTRACTNovel severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has claimed more than 1.5 million lives worldwide and counting. As per the GISAID database, the genomics of SARS-CoV2 is extensively studied with more than 500 genome submissions per day. Out of several hotspot mutations within the SARS-CoV-2 genome, researchers have focused a lot on missense variants but the least work is done on the UTRs. One of the most frequent 5’ UTR variants in the SARS-CoV-2 genome is the C241T with a global frequency of more than 0.9. In the present study, the effect of the C241T mutation has been studied with respect to change in RNA structure and its interaction with the host replication factors MADP1 Zinc finger CCHC-type and RNA-binding motif 1 (hnRNP1). The results obtained from molecular docking and molecular dynamics simulation indicated weaker interaction of C241T mutant stem loops with host transcription factor MADP1 indicating reduced replication efficiency. The results are also correlated with increased recovery rates and decreased death rates of global SARS-CoV-2 cases.
Maximizing statistical power to detect clinically associated cell states with scPOST
Authors: Millard Nghia , Korsunsky Ilya , Weinand Kathryn , Fonseka Chamith Y. , Nathan Aparna , Kang Joyce B. , Raychaudhuri Soumya 
Published: November 2020

AbstractAs advances in single-cell technologies enable the unbiased assay of thousands of cells simultaneously, human disease studies are able to identify clinically associated cell states using case-control study designs. These studies require precious clinical samples and costly technologies; therefore, it is critical to employ study design principles that maximize power to detect cell state frequency shifts between conditions, such as disease versus healthy. Here, we present single-cell Power Simulation Tool (scPOST), a method that enables users to estimate power under different study designs. To approximate the specific experimental and clinical scenarios being investigated, scPOST takes prototype (public or pilot) single-cell data as input and generates large numbers of single-cell datasetsin silico. We use scPOST to perform power analyses on three independent single-cell datasets that span diverse experimental conditions: a batch-corrected 21-sample rheumatoid arthritis dataset (5,265 cells) from synovial tissue, a 259-sample tuberculosis progression dataset (496,517 memory T cells) from peripheral blood mononuclear cells (PBMCs), and a 30-sample ulcerative colitis dataset (235,229 cells) from intestinal biopsies. Over thousands of simulations, we consistently observe that power to detect frequency shifts in cell states is maximized by larger numbers of independent clinical samples, reduced batch effects, and smaller variation in a cell state’s frequency across samples.
SREBP2 delivery to striatal astrocytes normalizes transcription of cholesterol biosynthesis genes and ameliorates pathological features in Huntington’s Disease
Authors: Birolini Giulia , Verlengia Gianluca , Talpo Francesca , Maniezzi Claudia , Zentilin Lorena , Giacca Mauro , Conforti Paola , Cordiglieri Chiara , Caccia Claudio , Leoni Valerio , Taroni Franco , Biella Gerardo , Simonato Michele , Cattaneo Elena , Valenza Marta 
Published: November 2020

AbstractBrain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntington’s Disease (HD). One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP-controlled genes in the cholesterol biosynthesis pathway.Here we evaluated the efficacy of a gene therapy based on the unilateral intra-striatal injection of a recombinant adeno-associated virus 2/5 (AAV2/5) targeting astrocytes specifically and carrying the N-terminal fragment of human SREBP2 (hSREBP2).Robust hSREBP2 expression in striatal glial cells in HD mice activated the transcription of cholesterol biosynthesis pathway genes, restored synaptic transmission, reversedDrd2transcript levels decline, cleared muHTT aggregates and attenuated behavioral deficits. We conclude that glial SREBP2 participates in HD brain pathogenesis in vivo and that AAV-based delivery of SREBP2 to astrocytes counteracts key features of HD.
Two Parallel Pathways Mediate Olfactory-Driven Backward Locomotion
Authors: Israel Shai , Rozenfeld Eyal , Weber Denise , Huetteroth Wolf , Parnas Moshe 
Published: November 2020

AbstractAlthough animals switch to backward walking upon sensing an obstacle or danger in their path, the initiation and execution of backward locomotion is poorly understood. The discovery of Moonwalker Descending Neurons (MDNs), madeDrosophilauseful to study neural circuits underlying backward locomotion. MDNs were demonstrated to receive visual and mechanosensory inputs. However, whether other modalities converge onto MDNs and what are the neural circuits activating MDNs are unknown. We show that aversive but not appetitive olfactory input triggers MDN-mediated backward locomotion. We identify in each hemisphere, a single Moonwalker Subesophageal Zone neuron (MooSEZ), which triggers backward locomotion. MooSEZs act both upstream and in parallel to MDNs. Surprisingly, MooSEZs also respond mostly to aversive odor. Contrary to MDNs, blocking MooSEZs activity has little effect on odor-evoked backward locomotion. Thus, this work reveals another important modality input to MDNs in addition to a novel olfactory pathway and MDN-independent backward locomotion pathway.
Splicing modulators elicit global translational repression by condensate-prone proteins translated from introns
Authors: Shrestha Jagat Krishna Chhipi , Schneider-Poetsch Tilman , Suzuki Takehiro , Mito Mari , Khan Khalid , Dohmae Naoshi , Iwasaki Shintaro , Yoshida Minoru 
Published: November 2020

AbstractChemical splicing modulators that bind to the spliceosome have provided an attractive venue for cancer treatment. Splicing modulators induce accumulation and subsequent translation of a subset of intron-retained mRNAs. Yet, the biological effect of proteins containing translated intron sequences remains unclear. Here we identified a number of truncated proteins generated upon treatment with the splicing modulator spliceostatin A (SSA) using genome-wide ribosome profiling and bio-orthogonal non-canonical amino-acid tagging (BONCAT) mass spectrometry. A subset of these truncated proteins has intrinsically disordered regions, forms insoluble cellular condensates, and triggers the proteotoxic stress response through JNK phosphorylation, thereby inhibiting the mTORC1 pathway. In turn, this reduces global translation. These findings indicate that creating an overburden of condensate-prone proteins derived from introns represses translation and prevents further production of harmful truncated proteins. This mechanism appears to contribute to the antiproliferative and proapoptotic activity of splicing modulators.
NK cells promote cancer immunoediting through tumor-intrinsic loss of interferon-stimulated gene expression
Authors: Wong Yung Yu , Riggan Luke , Perez-Reyes Edgar , Huerta Christopher , Moldenhauer Matt , O’Sullivan Timothy E. 
Published: November 2020

AbstractNatural killer (NK) cells are innate lymphocytes that constantly patrol host tissues against transformed cells in a process known as cancer immunosurveillance. Previous evidence in mice has demonstrated that NK cell-derived IFN-γ can promote immunoevasion by sculpting the immunogenicity of developing tumors in a process known as cancer immunoediting. This process involves the elimination of highly immunogenic “unedited” tumor cells followed by the eventual escape of less immunogenic “edited” tumor cell variants that are able to escape recognition or elimination by the immune system. Here, we show that NK cell-edited fibrosarcomas decrease the expression of 17 conserved IFN-γ-inducible genes compared to unedited tumor cells. High expression of 3 of these identified genes (Psmb8, Trim21, Parp12) in human tumor samples correlates with enhanced survival in breast cancer, melanoma, and sarcoma patients. While NK cell-edited fibrosarcomas displayed resistance to IFN-γ growth suppressionin vitro, functional knockouts of individual interferon stimulated genes (ISGs) were not required for outgrowth of unedited tumor cell linesin vitroandin vivocompared to complete loss of IFN signaling. Furthermore, knockout of IFN-γ-intrinsic signaling via deletion ofIfngrin edited B16 F10 and E0771 LMB metastatic cancer cell lines did not impact host survival following lung metastasis. Together, these results suggest that unedited tumors can be selected for decreased IFN-γ signaling to evade immune responsesin vivo, and as a consequence, tumor-extrinsic IFN signaling may be more important for potentiating durable anti-tumor responses to advanced solid tumors.
Obesity-Activated Lung Stomal Cells Promote Myeloid-Lineage Cell Accumulation and Breast Cancer Metastasis
Authors: Hillers-Ziemer Lauren E. , Williams Abbey E. , Janquart Amanda , Grogan Caitlin , Thompson Victoria , Sanchez Adriana , Arendt Lisa M. 
Published: November 2020

SUMMARYObesity is correlated with increased incidence of breast cancer metastasis, however the mechanisms underlying how obesity promotes metastasis are unclear. In a diet-induced obesity mouse model, obesity enhanced lung metastases in both the presence and absence of primary mammary tumors and increased recruitment of myeloid lineage cells into the lungs. In the absence of tumors, obese mice demonstrated increased numbers of myeloid lineage cells and elevated collagen fibers within the lung stroma, reminiscent of pre-metastatic niches formed by primary tumors. Lung stromal cells isolated from obese non-tumor-bearing mice showed increased proliferation, contractility, and expression of extracellular matrix, inflammatory markers, and TGFβ1. Conditioned media from lung stromal cells from obese mice promoted myeloid lineage cell migrationin vitroin response to CSF2 expression and enhanced invasion of tumor cells. Together, these results suggest that prior to tumor formation, obesity alters the lung microenvironment, creating niches conducive for metastatic growth.
SSB facilitates fork substrate discrimination by PriA
Authors: Tan Hui Yin , Bianco Piero R. 
Published: November 2020

AbstractPriA is a member of the SuperFamily 2 helicase family. Its rolein vivois to reload the primosome onto stalled replication forks resulting in the restart of the previously stalled DNA replication process. SSB is known to play key roles in mediating activities at replication forks and it is known to bind to PriA. To gain mechanistic insight into the PriA-SSB interaction, a coupled spectrophotometric assay was utilized to characterize the ATPase activity of PriAin vitroin the presence of fork substrates. The results demonstrate that SSB enhances the ability of PriA to discriminate between fork substrates 140-fold. This is due to a significant increase in the catalytic efficiency of the helicase induced by DNA-bound SSB. This interaction is species-specific as bacteriophage gene 32 protein cannot substitute for theE.coliprotein. SSB, while enhancing the activity of PriA on its preferred fork, both decreases the affinity of the helicase for other forks and decreases catalytic efficiency. Central to the stimulation afforded by SSB is the unique ability of PriA to bind with high affinity to the 3’-OH placed at the end of the nascent leading strand at the fork. When both the 3’-OH and SSB are present, the maximum effect is observed. This ensures that PriA will only load onto the correct fork, in the right orientation, thereby ensuring that replication restart is directed to only the template lagging strand.
The OCT2 Transporter Regulates Dopamine D1 Receptor Signaling at the Golgi Apparatus
Authors: Puri Natasha M. , Romano Giovanna R. , Lin Ting-Yu , Mai Quynh N. , Irannejad Roshanak 
Published: November 2020

AbstractDopamine is the main catecholamine in the brain and the kidney, where it controls a number of physiological functions such as locomotion, cognition, emotion, endocrine regulation and renal function. As a membrane impermeant hormone and neurotransmitter, dopamine is thought to signal by binding and activating dopamine receptors, members of the G protein couple receptor (GPCR) family, only on the plasma membrane. Here, using novel nanobody-based biosensors, we demonstrate for the first time that the dopamine D1 receptor (D1DR), the primary mediator of dopaminergic signaling in the brain and kidney, not only functions on the plasma membrane but becomes activated at the Golgi apparatus in the presence of its ligand. We present evidence that activation of the Golgi pool of D1DR is dependent on Organic Cation Transporter 2 (OCT2), a dopamine transporter, providing an explanation for how the membrane impermeant dopamine accesses subcellular pools of D1DR. We further demonstrate that dopamine activates Golgi-D1DR in the striatal medium spiny neurons (MSN) and this activity depends on OCT2 function. We also introduce a new approach to selectively interrogate compartmentalized D1DR signaling by inhibiting Gαs coupling, using a nanobody-based chemical recruitment system. Using this strategy, we show that Golgi-localized D1DRs regulate cAMP production and mediate local protein kinase A activation. Together, our data suggest that spatially compartmentalized signaling hubs are previously unappreciated regulatory aspects of D1DR signaling. Our data also provide further evidence for the role of transporters in regulating subcellular GPCR activity.
Demogenomic modeling of the timing and the processes of early European farmers differentiation
Authors: Marchi Nina , Winkelbach Laura , Schulz Ilektra , Brami Maxime , Hofmanová Zuzana , Blöcher Jens , Reyna-Blanco Carlos S. , Diekmann Yoan , Thiéry Alexandre , Kapopoulou Adamandia , Link Vivian , Piuz Valérie , Kreutzer Susanne , Figarska Sylwia M. , Ganiatsou Elissavet , Pukaj Albert , Struck Travis J. , Gutenkunst Ryan N. , Karul Necmi , Gerritsen Fokke , Pechtl Joachim , Peters Joris , Zeeb-Lanz Andrea , Lenneis Eva , Teschler-Nicola Maria , Triantaphyllou Sevasti , Stefanović Sofija , Papageorgopoulou Christina , Wegmann Daniel , Burger Joachim , Excoffier Laurent 
Published: November 2020

AbstractThe precise genetic origins of the first Neolithic farming populations, as well as the processes and the timing of their differentiation, remain largely unknown. Based on demogenomic modeling of high-quality ancient genomes, we show that the early farmers of Anatolia and Europe emerged from a multiphase mixing of a Near Eastern population with a strongly bottlenecked Western hunter-gatherer population after the Last Glacial Maximum. Moreover, the population branch leading to the first farmers of Europe and Anatolia is characterized by a 2,500-year period of extreme genetic drift during its westward range expansion. Based on these findings, we derive a spatially explicit model of the population history of Southwest Asia and Europe during the late Pleistocene and early Holocene.One-Sentence Summary:Early European farmers emerged from multiple post LGM mixtures and experienced extreme drift during their westward expansion.
Sensory-based quantification of male colour patterns in Trinidadian guppies reveals nonparallel phenotypic evolution across an ecological transition in multivariate trait space
Authors: Yong Lengxob , Croft Darren P. , Troscianko Jolyon , Ramnarine Indar , Wilson Alastair 
Published: November 2020

ABSTRACTParallel evolution, in which independent populations evolve along similar phenotypic trajectories, offers insights into the repeatability of adaptive evolution. Here, we revisit a classic example of parallelism, that of repeated evolution of brighter males in the Trinidadian guppy. In guppies, colonisation of low predation habitats is associated with emergence of ‘more colourful’ phenotypes since predator-induced viability selection for crypsis weakens while sexual selection by female preference for conspicuity remains strong. Our study differs from previous investigations in three respects. First, we adopt a multivariate phenotyping approach to characterise parallelism in multi-trait space. Second, we use ecologically-relevant colour traits defined by the visual systems of the two selective agents (i.e. guppy, predatory cichlid). Third, we estimate population genetic structure to test for adaptive (parallel) evolution against a model of neutral phenotypyc divergence. We find strong phenotypic differentiation that is inconsistent with a neutral model, but only limited support for the predicted pattern of greater conspicuity at low predation. Effects of predation regime on each trait were in the expected direction, but weak, largely non-significant, and explained little among-population variation. In multi-trait space, phenotypic trajectories of lineages colonising low from high predation regimes were not parallel. Our results are consistent with reduced predation risk facilitating adaptive differentiation by female choice, but suggest that this proceeds in (effectively) independent directions of multi-trait space across lineages. Pool-sequencing data also revealed SNPs showing greater differentiation than expected under neutrality and/or associations with known colour genes in other species, presenting opportunities for future genetic study.
Quench me if you can: Alpha-2-macroglobulin trypsin complexes enable serum biomarker analysis by MALDI mass spectrometry
Authors: Taraskin Aleksandr S. , Semenov Konstantin K. , Protasov Aleksandr V. , Lozhkov Alexey A. , Tyulin Alexandr A. , Shaldzhyan Aram A. , Ramsay Edward S. , Mirgorodskaya Olga A. , Klotchenko Sergey A. , Zabrodskaya Yana A. 
Published: November 2020

ABSTRACTOne of the main functions of alpha-2-macroglobulin (A2M) in human blood serum is the binding of all classes of protease. It is known that trypsin, after such interaction, possesses modified proteolytic activity. Trypsin first hydrolyzes two bonds in A2M’s ‘bait region’, and the peptide705VGFYESDVMGR715is released from A2M. In this work, specifics of the A2M-trypsin interaction were used to determine A2M concentration directly in human blood serum using MALDI mass-spectrometry. Following exogenous addition of trypsin to human blood serumin vitro, the concentration of the VGFYESDVMGR peptide was measured, using its isotopically-labeled analogue (18O), and A2M concentration was calculated. The optimized mass spectrometric approach was verified using a standard method for A2M concentration determination (ELISA) and the relevant statistical analysis methods. It was also shown that trypsin’s modified proteolytic activity in the presence of serum A2M can be used to analyze other serum proteins, including potential biomarkers of pathological processes. Thus, this work describes a promising approach to serum biomarker analysis that can be technically extended in several useful directions.
Study of unsteady separated fluid flows using a multi-block lattice Boltzmann method
Authors: Ezzatneshan Eslam 
Published: November 2020

Purpose
Numerical simulations are performed for studying the vorticity dynamics of a dipole colliding with the wall in a bounded flow and the wake structure and separated flow properties past a circular cylinder at the values of Reynolds numbers.

Design/methodology/approach
The near wake statistics of separated fluid flows are investigated by using the lattice Boltzmann method (LBM) in a two-dimensional framework. A multi-block technique is applied to accurately resolve the flow characteristics by the grid refinement near the wall and preserve the stability of the numerical solution at relatively high Reynolds numbers.

Findings
The results show that the rolling-up of the boundary layer occurs due to the shear-layer instabilities near the surface which causes a boundary layer detachment from the wall and consequently leads to the formation of small-scale vortices. These shear-layer vortices shed at higher frequencies than the large-scale Strouhal vortices which result in small-scale high-frequency fluctuations in the velocity field in the very near wake. The present study also demonstrates that the efficiency of the multi-block LBM used for predicting the statistical features of flow problems is comparable with the solvers based on the Navier-Stokes equations.

Practical implications
Studying the separated flow characteristics in aerospace applications.

Originality/value
Applying a multi-block lattice Boltzmann method (LBM) for simulation of separated fluid flows at high-Reynolds numbers. Studying of the near wake statistics of unsteady separated fluid flows using the multi-block LBM. Comparison of flow characteristics obtained based on the LBM with those of reported based on the Navier-Stokes equations.
Teaching and discussing mental health among university students: a pilot arts-based study
Authors: Atayero Sarah , Dunton Kate , Mattock Sasha , Gore Amanda , Douglas Sarah , Leman Patrick , Zunszain Patricia 
Published: November 2020

PurposeInterdisciplinary approaches to health education are becoming increasingly common. Here, the authors describe an arts-based approach designed by academics and artists to both supplement the study of mental illness and support the individual mental health of undergraduate and postgraduate university students, by raising the visibility of mental illness in an innovative way.Design/methodology/approachThrough workshops, university students were guided in a sensory and physical way to discuss psychological health and vulnerability. This was followed by the creation of physical representations of mental distress through art pieces.FindingsStudents were able to design their own art pieces and discuss mental health issues in an open and creative way. Students reported that the arts-based initiative was beneficial to their practice as future professionals and provided a holistic learning experience. At the same time, artists were able to generate powerful images which facilitated further discussions within the faculty.Practical implicationsThis project provides an innovative model for workshops which could be employed to raise the visibility of common mental health disorders among university students while providing a safe space to discuss and support wellbeing. Additionally, variations could be implemented to enhance the teaching of affective disorders within a university curriculum.Originality/valueThis paper presents the results of collaboration between academics and artists, who together generated an innovative way to both support students' mental health and provide an alternative way to supplement experiential learning about common mental health conditions such as anxiety and depression.