bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACUTE VISION LOSS IN A PATIENT WITH COVID-19
Authors: Selvaraj Vijairam , Sacchetti Daniel , Finn Arkadiy , Dapaah-Afriyie Kwame 
Published: June 2020

AbstractTo date, there have been reports of neurologic manifestations in Covid-19 patients including ischemic strokes, Guillain-Barre Syndrome and anosmia. In this case report, we describe a patient who presented with dysosmia, dysgeusia along with monocular peripheral vision loss after being diagnosed with Covid-19.
Evolutionary conservation and divergence of human brain co-expression networks
Authors: Pembroke WG , Hartl CL , Geschwind DH 
Published: June 2020

AbstractMouse models have allowed for the direct interrogation of genetic effects on molecular, physiological and behavioral brain phenotypes. However, it is unknown to what extent neurological or psychiatric traits may be human or primate-specific and therefore, which components can be faithfully recapitulated in mouse models. We identify robust co-expression modules reflecting whole brain and regional patterns of gene expression and compare conservation of co-expression in 116 independent data sets derived from human, mouse and non-human primate representing more than 15,000 total samples. We observe greater co-expression changes occurring on the human lineage than mouse, and substantial regional variation that highlights cerebral cortex as the most diverged region. Cell type specific modules are the most divergent across the brain, compared with those that represent basic metabolic processes. Among these, glia are the most divergent, three times that of neurons. We show that regulatory sequence divergence explains a significant fraction of co-expression divergence. Similarly, protein coding sequence constraint parallels co-expression conservation, such that genes with loss of function intolerance are enriched in neuronal, rather than glial modules. We also identify dozens of human disease risk genes, such as COMT, PSEN-1, LRRK2, and SNCA, with highly divergent co-expression between mouse and primates or human. We show that 3D human brain organoids recapitulate in vivo co-expression modules representing several human cell types, which along with our analysis of human-mouse disease gene divergence, serve as a foundational resource to guide disease modeling and its interpretation.
Natural killer activation for bladder cancer elimination can be achievedin vitroby heat-killed BCG
Authors: Esteso Gloria , Aguiló Nacho , Julián Esther , Ashiru Omodele , Ho Mei. M. , Martín Carlos , Valés-Gómez Mar 
Published: June 2020

AbstractImmunotherapy, via intravesical instillations ofBacillus Calmette-Guérin(BCG) is the therapy of choice for patients with high risk non-muscle invasive bladder cancer. The subsequent recruitment of lymphocytes and myeloid cells, as well as the release of cytokines and chemokines, induces a local immune response that contributes to eliminate these tumours. The history of BCG development resulted in a large number of genetically diverse BCG substrains which could stimulate the immune system in different ways. Here, while investigating the capacity of different BCG substrains to promote the activation of NK cells, we confirmed that all the evaluated substrains could activate a cytotoxic CD56brightNK cell population which efficiently degranulated against bladder cancer cells; Tice, Connaught and Moreau were the substrains having a stronger effect. Dead mycobacteria also stimulated PBMC cultures and we demonstrate that subcellular fractions of BCG-Tice could contribute to the induction of this NK cell response. Lipids from BCG-Tice, but not fromMycobacterium bovis, stimulated NK cell activation and degranulation, however the aqueous fraction of either bacteria did not activate lymphocytes. Delipidated BCG-Tice activated effector cells (CD3+CD56+and NK). These data suggest that different immune subpopulations could be stimulated using different fractions of mycobacteria for cancer elimination.
Adverse neurological effects of short-term sleep deprivation in aging mice are prevented by SS31 peptide
Authors: Wu Jinzi , Dou Yan , Ladiges Warren C. 
Published: June 2020

AbstractSleep deprivation is a potent stress factor that disrupts regulatory pathways in the brain resulting in cognitive dysfunction and increased risk of neurodegenerative disease with increasing age. Prevention of the adverse effects of sleep deprivation could be beneficial in older individuals by restoring healthy brain function. We report here on the ability of SS31, a mitochondrial specific peptide, to attenuate the negative neurological effects of short-term sleep deprivation in aging mice. C57BL/6 female mice, 20 months old, were subcutaneously injected with SS31 (3mg/kg) or saline daily for 4 days. Sleep deprivation was 4 hours daily for the last 2 days of SS31 treatment. Mice were immediately tested for learning ability followed by collection of brain and other tissues. In sleep deprived mice treated with SS31, learning impairment was prevented, brain mitochondrial ATP levels and synaptic plasticity regulatory proteins were restored, and ROS and inflammatory cytokines levels were decreased in the hippocampus. The observations suggest possible therapeutic benefits of SS31 for alleviating adverse neurological effects of acute sleep loss.
Alteration of ribosome function upon 5-fluorouracil treatment favours cancer cell drug-tolerance
Authors: Therizols Gabriel , Bash-Imam Zeina , Panthu Baptiste , Machon Christelle , Vincent Anne , Nait-Slimane Sophie , Garcia Maxime , Chalabi-Dchar Mounira , Lafôrets Florian , Marcel Virginie , Boubaker-Vitre Jihane , Souahlia Guillaume , Albaret Marie-Alexandra , Mertani Hichem C. , Prudhomme Michel , Bertrand Martin , Saurin Jean-Christophe , Bouvet Philippe , Ohlmann Théophile , Guitton Jérôme , Dalla-Venezia Nicole , Pannequin Julie , Catez Frédéric , Diaz Jean-Jacques 
Published: June 2020

AbstractPartial response to chemotherapy leads to disease resurgence. Upon treatment, a subpopulation of cancer cells, called drug-tolerant persistent cells, display a transitory drug tolerance that lead to treatment resistance1,2. Though drug-tolerance mechanisms remain poorly known, they have been linked to non-genomic processes, including epigenetics, stemness and dormancy2–4. 5-fluorouracil (5-FU), the most widely used chemotherapy in cancer treatment, is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways5–9. Here, we show that 5-FU treatment leads to the unexpected production of fluorinated ribosomes, exhibiting altered mRNA translation. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts and human tumours. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs according to the nature of their 5’-untranslated region. As a result, we found that sustained translation ofIGF-1RmRNA, which codes for one of the most potent cell survival effectors, promoted the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that “man-made” fluorinated ribosomes favour the drug-tolerant cellular phenotype by promoting translation of survival genes. This could be exploited for developing novel combined therapies. By unraveling translation regulation as a novel gene expression mechanism helping cells to survive a drug-challenge, our study extends the spectrum of molecular mechanisms driving drug-tolerance.
Lessons learned from bugs in models of human history
Authors: Ragsdale Aaron P. , Nelson Dominic , Gravel Simon , Kelleher Jerome 
Published: June 2020

AbstractSimulation plays a central role in population genomics studies. Recent years have seen rapid improvements in software efficiency that make it possible to simulate large genomic regions for many individuals sampled from large numbers of populations. As the complexity of the demographic models we study grows, however, there is an ever-increasing opportunity to introduce bugs in their implementation. Here we describe two errors made in defining population genetic models using the msprime coalescent simulator that have found their way into the published record. We discuss how these errors have affected downstream analyses and give recommendations for software developers and users to reduce the risk of such errors.
Predicting substitutions to modulate disorder and stability in coiled-coils
Authors: Karami Yasaman , Saighi Paul , Vanderhaegen Rémy , Gerlier Denis , Longhi Sonia , Laine Elodie , Carbone Alessandra 
Published: June 2020

AbstractCoiled-coils are described as stable structural motifs, where two or more helices wind around each other. However, coiled-coils are associated with local mobility and intrinsic disorder. Intrinsically disordered regions (IDRs) in proteins are characterized by lack of stable secondary and tertiary structure under physiological conditionsin vitro. They are increasingly recognized as important for protein function. However, characterizing their behaviour in solution and determining precisely the extent of disorder of a protein region remains challenging, both experimentally and computationally. In this work, we propose a computational framework to quantify the extent of disorder within a coiled-coil in solution and to help design substitutions modulating such disorder. Our method relies on the analysis of conformational ensembles generated by relatively short all-atom Molecular Dynamics (MD) simulations. We apply it to the phosphoprotein multimerisation domains (PMD) of Measles virus (MeV) and Nipah virus (NiV), both forming tetrameric left-handed coiled-coils. We show that our method can help quantify the extent of disorder of the C-terminus region of MeV and NiV PMDs, without requiring the input MD trajectory to actually sample the unfolded states of these regions. Moreover, this study provided a conceptual framework for the rational design of substitutions aimed at modulating the stability of the coiled-coils. By assessing the impact of four substitutions known to destabilize coiled-coils, we derive a set of rules to control MeV PMD structural stability and cohesiveness. We therefore design two contrasting substitutions, one increasing the stability of the tetramer and the other increasing its flexibility. Consequently, our method can be considered as a platform to reason about how to design substitutions aimed at regulating flexibility and stability.
A burning question: Can savannah fire management generate enough carbon revenue to help save the lion from extinction?
Authors: Tear Timothy H. , Wolff Nicholas H. , Lipsett-Moore Geoffrey J. , Ritchie Mark E. , Ribeiro Natasha S. , Petracca Lisanne S. , Lindsey Peter A. , Hunter Luke , Loveridge Andrew J. , Steinbruch Franziska 
Published: June 2020

SUMMARYLions (Panthera leo) in Africa have lost nearly half their population in just the last two decades, and effective management of the protected areas (PAs) where lions live will cost an estimated USD >$1 B/year in new funding. We explore the potential for launching a fire management and habitat restoration carbon-financing program to help fill this PA management funding gap. We demonstrate how introducing early dry season fire management programs could produce potential carbon revenues (PCR) from either a single carbon-financing method (avoided emissions) or from multiple sequestration methods of USD $59.6-$655.9 M/year (at USD $5/ton) or USD $155.0 M–$1.7 B/year (at USD $13/ton). We highlight variable but significant PCR for PAs with the greatest potential for restoring lion numbers between USD $1.5–$44.4 M per PA. We suggest investing in lion-centric fire management programs to jump-start the United Nations Decade of Ecological Restoration and help preserve African lions across their range.SCIENCE FOR SOCIETYThe United Nation’s recently launched the Decade of Ecological Restoration in response to planet-wide land degradation. This study analyses the potential for savanna fire management programs to restore fire regimes that can generate new sources of revenue from carbon financing for chronically under-funded protected areas in Africa with lions, as lions are a key indicator of savanna ecosystem health. We estimated the amount of carbon saved by shifting fires that normally burn in the late dry season (and emit more carbon) to the early dry season (that accrue more carbon in the soil and woody vegetation). Based on current carbon market values we found substantial potential to eliminate or significantly reduce the $>1B annual funding gap needed to save the lion from extinction. Given additional benefits for nature and people from new savanna fire programs, we recommend integrated conservation and development projects direct more funding to some of the least developed countries with high biodiversity and support fire management programs in Africa.
scNym: Semi-supervised adversarial neural networks for single cell classification
Authors: Kimmel Jacob C. , Kelley David R. 
Published: June 2020

AbstractAnnotating cell identities is a common bottleneck in the analysis of single cell genomics experiments. Here, we present scNym, a semi-supervised, adversarial neural network that learns to transfer cell identity annotations from one experiment to another. scNym takes advantage of information in both labeled datasets and new, unlabeled datasets to learn rich representations of cell identity that enable effective annotation transfer. We show that scNym effectively transfers annotations across experiments despite biological and technical differences, achieving performance superior to existing methods. We also show that scNym models can synthesize information from multiple training and target datasets to improve performance. In addition to high performance, we show that scNym models are well-calibrated and interpretable with saliency methods.
Rewiring PBMC responses to prevent CHIKV infection-specific monocyte subset redistribution and cytokine responses
Authors: Aguilar-Briseño José Alberto , Silva Mariana Ruiz , Moser Jill , Pauzuolis Mindaugas , Smit Jolanda M. , Rodenhuis-Zybert Izabela A. 
Published: June 2020

AbstractInfection with the mosquito-borne Chikungunya virus (CHIKV) causes acute or chronic arthritis in humans. Inflammatory responses mediated by monocytes, the primary target cells of CHIKV infection in the blood, are considered to play an important role in CHIKV pathogenesis. A recent study revealed that the acute phase of CHIKV infection is characterized by a monocyte-driven response, with an expansion of the intermediate monocyte (IM) subset. In this study, we adopted a previously established in vitro model of CHIKV infection in peripheral blood mononuclear cells, to elucidate the mechanism and relevance of IM expansion in CHIKV replication and associated inflammatory responses. Our data show that infectious but not replication-incompetent CHIKV increases the frequency of IM and to a lesser extent, non-classical (NM) monocytes while reducing the number of classical monocytes (CM). The increase of IM or NM frequency coincided with the activation of inflammatory response and occurred in the absence of lymphocytes implying that monocyte-derived cues are sufficient to drive this effect. Importantly, priming of monocytes with LPS prevented expansion of IM and NM but had no effect on viral replication. It did however alter CHIKV-induced cytokine signature. Taken together, our data delineate the role of IM in CHIKV infection-specific innate immune responses and provide insight for the development of therapeutic strategies that may focus on rewiring monocyte immune responses to prevent CHIKV-mediated arthralgia and arthritis.
Altered Huntingtin-Chromatin Interactions Predict Transcriptional and Epigenetic Changes in Huntington’s Disease Mouse Models
Authors: Pearl Jocelynn R , Shetty Amol C , Cantle Jeffrey P , Bergey Dani E , Bragg Robert M. , Coffey Sydney R. , Kordasiewicz Holly B. , Hood Leroy E , Price Nathan D , Ament Seth A , Carroll Jeffrey B 
Published: June 2020

AbstractProgressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntington’s disease (HD), but the mechanistic basis remains poorly understood. Using chromatin immunoprecipitation and sequencing (ChIP-seq), we show that the huntingtin protein (HTT) reproducibly occupies specific locations in the mouse genome. Moreover, many genomic loci were differentially occupied by HTT in striatal tissue from a homozygous knock-in mouse model of HD (B6.HttQ111/Q111) when compared to wildtype controls. Huntingtin ChIP-seq peaks were enriched in the coding regions of cell identity genes important for striatal function, with many of these genes found to have reduced expression in the striata of HD patients and mouse models, as well as reduced HTT occupancy inHttQ111/Q111mice compared to controls. Conversely, HTT ChIP-seq peaks were depleted near genes that are up-regulated in HD. ChIP-seq of bulk striatal histone modifications, generated in parallel, revealed genotype-specific colocalization of HTT with active chromatin marks (H3K4me3 and H3K27ac), and with enhancer of zeste homolog 2 (EZH2), a key enzymatic component of the PRC2 complex. Near genes that are differentially regulated in HD, greater HTT occupancy inHttQ111/Q111vs. wildtype mice was associated with increased EZH2 binding, increased histone H3 lysine 4 (H3K4me3), and decreased histone H3 lysine 27 (H3K27me3). Our study suggests that huntingtin-chromatin interactions may play a direct role in organizing chromatin and promoting cell type-specific gene expression, with loss of HTT occupancy predicting decreased gene expression in HD.
A Tumbling Magnetic Microrobot System for Biomedical Applications
Authors: Niedert Elizabeth E. , Bi Chenghao , Adam Georges , Lambert Elly , Solorio Luis , Goergen Craig J. , Cappelleri David J. 
Published: June 2020

AbstractA microrobot system comprised of an untethered tumbling magnetic microrobot, a two degree of freedom rotating permanent magnet, and an ultrasound imaging system has been developed forin vitroandin vivobiomedical applications. The microrobot tumbles end-over-end in a net forward motion due to applied magnetic torque from the rotating magnet. By turning the rotational axis of the magnet, two-dimensional directional control is possible and the microrobot was steered along various trajectories, including a circular path and P-shaped path. The microrobot is capable of moving over the unstructured terrain within a murine colon inin vitro,in situ, andin vivoconditions, as well as a porcine colon inex vivoconditions. High frequency ultrasound imaging allows for real-time determination of the microrobot’s position while it is optically occluded by animal tissue. When coated with a fluorescein payload, the microrobot was shown to release the majority of the payload over a one hour time period in phosphate-buffered saline. Cytotoxicity tests demonstrated that the microrobot’s constituent materials, SU-8 and polydimethylsiloxane (PDMS), did not show a statistically significant difference in toxicity to murine fibroblasts from the negative control, even when the materials were doped with magnetic neodymium microparticles. The microrobot system’s capabilities make it promising for targeted drug delivery and otherin vivobiomedical applications.
Induction of intracellular wild-type p53 amyloids leading to cellular transformation and tumor formation in mice
Authors: Navalkar Ambuja , Pandey Satyaprakash , Singh Namrata , Dey Amit Kumar , Saha Sandhini , Patel Komal , Mohanty Bhabani , Jadhav Sachin , Chaudhari Pradip , Maiti Tushar K. , Maji Samir K. 
Published: June 2020

AbstractTumor suppressor p53 mutations, with subsequent loss-of-tumor suppressive function and gain-of oncogenic functions, are associated with more than 50% of human cancers. Aggregation and amyloid formation are also mechanisms by which wild type and mutant p53 might be involved in cancer, but the direct evidence of how aggregated p53 acts as an oncogene is lacking. In this study, we directly demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to normal cells. Cells with p53 amyloids show enhanced survival, apoptotic resistance with increased proliferation and migration rates. The tumorigenic potential of p53 amyloid transformed cells is further confirmed in a mice xenograft model, wherein the tumor showed p53 amyloid aggregates. Gene-expression analysis and proteomic profiling suggest that p53 amyloid formation triggers aberrant expression of pro-oncogenes while downregulating the tumor-suppressive genes. Interestingly, disaggregating p53 rescues the cellular transformation and also inhibits tumor development in mice. We propose that wild-type p53 amyloid formation can potentially contribute to the initiation of tumor development.
A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes
Authors: Kroll François , Powell Gareth T , Ghosh Marcus , Antinucci Paride , Hearn Timothy J , Tunbak Hande , Lim Sumi , Dennis Harvey W , Fernandez Joseph M , Whitmore David , Dreosti Elena , Wilson Stephen W , Hoffman Ellen J , Rihel Jason 
Published: June 2020

ABSTRACTHundreds of human genes are associated with neurological diseases, but translation into tractable biological mechanisms is lagging. Larval zebrafish are an attractive model to investigate genetic contributions to neurological diseases. However, current CRISPR-Cas9 methods are difficult to apply to large genetic screens studying behavioural phenotypes. To facilitate rapid genetic screening, we developed a simple sequencing-free tool to validate gRNAs and a highly effective CRISPR-Cas9 method capable of converting >90% of injected embryos directly into F0 biallelic knockouts. We demonstrate that F0 knockouts reliably recapitulate complex mutant phenotypes, such as altered molecular rhythms of the circadian clock, escape responses to irritants, and multi-parameter day-night locomotor behaviours. The technique is sufficiently robust to knockout multiple genes in the same animal, for example to create the transparent triple knockoutcrystalfish for imaging. Our F0 knockout method cuts the experimental time from gene to behavioural phenotype in zebrafish from months to one week.
Regulation of Iron Homeostasis Through Parkin-mediated Lactoferrin Ubiquitylation
Authors: Gholkar Ankur A. , Schmollinger Stefan , Velasquez Erick F. , Lo Yu-Chen , Cohn Whitaker , Capri Joseph , Dharmarajan Harish , Deardorff William J. , Gao Lucy W. , Abdusamad Mai , Whitelegge Julian P. , Torres Jorge Z. 
Published: June 2020

ABSTRACTSomatic mutations that perturb Parkin ubiquitin ligase activity and the misregulation of iron homeostasis have both been linked to Parkinson’s disease. Lactotransferrin is a member of the transferrin iron binding proteins that regulate iron homeostasis and increased levels of Lactotransferrin and its receptor have been observed in neurodegenerative disorders like Parkinson’s disease. Here, we report that Parkin binds to Lactotransferrin and ubiquitylates it to regulate iron homeostasis.