bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of SARS-CoV-2 induced pathways reveal drug repurposing strategies
Authors: Han Namshik , Hwang Woochang , Tzelepis Konstantinos , Schmerer Patrick , Yankova Eliza , MacMahon Méabh , Lei Winnie , Katritsis Nicholas M , Liu Anika , Schuldt Alison , Harris Rebecca , Chapman Kathryn , McCaughan Frank , Weber Friedemann , Kouzarides Tony 
Published: August 2020

SUMMARYThe global outbreak of SARS-CoV-2 necessitates the rapid development of new therapies against COVID-19 infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein (SIP) network, based on disease signatures defined by COVID-19 multi-omic datasets(Bojkova et al., 2020; Gordon et al., 2020), and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials(Clinicaltrials.gov, 2020) testifying to the validity of the approach. Using artificial neural network analysis we classified these 200 drugs into 9 distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (130) and immune response (70). A subset of drugs implicated in viral replication were tested in cellular assays and two (proguanil and sulfasalazine) were shown to inhibit replication. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.
Highly potent anti-SARS-CoV-2 multivalent DARPin therapeutic candidates
Authors: Walser Marcel , Rothenberger Sylvia , Hurdiss Daniel L. , Schlegel Anja , Calabro Valérie , Fontaine Simon , Villemagne Denis , Paladino Maria , Hospodarsch Tanja , Neculcea Alexandra , Cornelius Andreas , Schildknecht Patricia , Matzner Mirela , Hänggi Martin , Franchini Marco , Kaufmann Yvonne , Schaible Doris , Schlegel Iris , Iss Chloe , Looser Thamar , Mangold Susanne , Herzog Christel , Schiegg Dieter , Reichen Christian , Radom Filip , Bosshart Andreas , Lehmann Andreas , Haeuptle Micha A. , Zürcher Alexander , Vagt Toni , Sigrist Gabriel , Straumann Marcel , Proba Karl , Veitonmäki Niina , Dawson Keith M. , Zitt Christof , Mayor Jennifer , Ryter Sarah , Lyoo Heyrhyoung , Wang Chunyan , Li Wentao , Drulyte Ieva , Du Wenjuan , Binz H. Kaspar , de Waal Leon , Stittelaar Koert J. , Taplin Sarah , Lewis Seth , Steiner Daniel , van Kuppeveld Frank J.M. , Engler Olivier , Bosch Berend-Jan , Stumpp Michael T. , Amstutz Patrick 
Published: August 2020

AbstractGlobally accessible therapeutics against SARS-CoV-2 are urgently needed. Here, we report the generation of the first anti-SARS-CoV-2 DARPin molecules with therapeutic potential as well as rapid large-scale production capabilities. Highly potent multivalent DARPin molecules with low picomolar virus neutralization efficacies were generated by molecular linkage of three different monovalent DARPin molecules. These multivalent DARPin molecules target various domains of the SARS-CoV-2 spike protein, thereby limiting possible viral escape. Cryo-EM analysis of individual monovalent DARPin molecules provided structural explanations for the mode of action. Analysis of the protective efficacy of one multivalent DARPin molecule in a hamster SARS-CoV-2 infection model demonstrated a significant reduction of pathogenesis. Taken together, the multivalent DARPin molecules reported here, one of which has entered clinical studies, constitute promising therapeutics against the COVID-19 pandemic.
Quantification of iPSC-derived vascular networks in novel phototunable angiogenic hydrogels
Authors: Crosby Cody O. , Hillsley Alex , Kumar Sachin , Parekh Sapun H. , Rosales Adrianne , Zoldan Janet 
Published: August 2020

ABSTRACTVascularization of engineered scaffolds remains a critical obstacle hindering the translation of tissue engineering from the bench to the clinic. Previously, we demonstrated the robust micro-vascularization of collagen hydrogels with induced pluripotent stem cell (iPSC)-derived endothelial progenitors; however, physically cross-linked collagen hydrogels compact rapidly and exhibit limited strength. To address these challenges, we synthesized an interpenetrating polymer network (IPN) hydrogel comprised of collagen and norbornene-modified hyaluronic acid (NorHA). This dual-network hydrogel combines the natural cues presented by collagen’s binding sites and extracellular matrix (ECM)-mimicking fibrous architecture with thein situmodularity and chemical cross-linking of NorHA. We modulated the stiffness and degradability of this novel IPN hydrogel by varying the concentration and sequence, respectively, of the NorHA peptide cross-linker. Rheological characterization of the photo-mediated gelation process revealed that the stiffness of the IPN hydrogel increased with cross-linker concentration and was decoupled from the bulk NorHA content. Conversely, the swelling of the IPN hydrogel decreased linearly with increasing cross-linker concentration. Collagen microarchitecture remained relatively unchanged across cross-linking conditions, although the mere addition of NorHA delayed collagen fibrillogenesis. Upon iPSC-derived endothelial progenitor encapsulation, robust, lumenized microvascular networks developed in IPN hydrogels over two weeks. Subsequent computational analysis showed that an initial rise in stiffness increased the number of branch points and vessels, but vascular growth was suppressed in high stiffness IPN hydrogels. These results suggest that an IPN hydrogel consisting of collagen and NorHA is highly tunable, compaction resistant, and capable of stimulating angiogenesis.STATEMENT OF SIGNIFICANCEWe have synthesized the first tunable collagen and norbornene functionalized hyaluronic acid (NorHA) interpenetrating polymer network hydrogel. This unique biomaterial allows for control over hydrogel stiffness, independent of the total polymer concentration, by varying the concentration of a peptide cross-linker and was specifically designed to produce a biomimetic vasculogenic microenvironment. Using the system, we performed a detailed study of the vasculogenesis of induced pluripotent stem cell-derived (iPSC) endothelial progenitors, a poorly studied cell source with considerable therapeutic potential. Our results show that vascular growth can be tuned by altering the stiffness and degradability of the scaffolds independently. Finally, we improved upon our open-source computational pipeline programmed in ImageJ and MATLAB to further quantify vascular topologies in three dimensions.Graphical abstract
Cell line-specific network models of ER+ breast cancer identify PI3Kα inhibitor sensitivity factors and drug combinations
Authors: Tejeda Zañudo Jorge Gómez , Mao Pingping , Alcon Clara , Kowalski Kailey J. , Johnson Gabriela N. , Xu Guotai , Baselga José , Scaltriti Maurizio , Letai Anthony , Montero Joan , Albert Reka , Wagle Nikhil 
Published: August 2020

AbstractDurable control of invasive solid tumors necessitates identifying therapeutic resistance mechanisms and effective drug combinations. A promising approach to tackle the cancer drug resistance problem is to build mechanistic mathematical models of the signaling network of cancer cells, and explicitly model the dynamics of information flow through this network under distinct genetic conditions and in response to perturbations.In this work, we used a network-based mathematical model to identify sensitivity factors and drug combinations for the PI3Kα inhibitor alpelisib, which was recently approved for ER+PIK3CAmutant breast cancer. We experimentally validated the model-predicted efficacious combination of alpelisib and BH3 mimetics (e.g. MCL1 inhibitors) in ER+ breast cancer cell lines. We also experimentally validated the reduced sensitivity to alpelisib caused by FOXO3 knockdown, which is a novel potential resistance mechanism. Our experimental results showed cell line-specific sensitivity to the combination of alpelisib and BH3 mimetics, which was driven by the choice of BH3 mimetics. We find that cell lines were sensitive to the addition of either MCL1 inhibitor s63845 alone or in combination with BCL-XL/BCL-2 inhibitor navitoclax, and that the need for the combination of both BH3 mimetics was predicted by the expression of BCL-XL. Based on these results, we developed cell line-specific network models that are able to recapitulate the observed differential response to alpelisib and BH3 mimetics, and also incorporate the most recent knowledge on resistance and response to PI3Kα inhibitors.Overall, we present an approach for the development, experimental testing, and refining of mathematical models, which we apply to the context of PI3Kα inhibitor drug resistance in breast cancer. Our approach predicted and validated PI3Kα inhibitor sensitivity factors (FOXO3 knockdown) and drug combinations (BH3 mimetics), and illustrates that network-based mathematical models can contribute to overcoming the challenge of cancer drug resistance.
Assessing distribution changes of selected native and alien invasive plant species under changing climatic conditions in Nyeri County, Kenya
Authors: Waititu Julius Maina , Mundia Charles Ndegwa , Sichangi Arthur W 
Published: August 2020

AbstractChanges in climatic conditions increases the risks of native and alien taxa expanding in geographical range and causing habitat transformations. The role of climate change in enhancing bio-invasions in local natural environments need to be assessed to guide on effective species management policy formulations. In this present study, we used species presence records, predictor variables and an ensemble of General Circulation Models data to predict suitable ecological niches for five of the selected invasive plant species within Nyeri County, Kenya. We predicted species distributions under RCP2.6, RCP4.5, and RCP8.5 emission scenarios for the years 2050 and 2070. We analysed species distribution changes to identify invasive species requiring immediate management action. Our analysis indicated that three of the five study species were suitable in ~50% of the study area while the other two were suitable in ~30% under the current climate.Lantana camara L.andSolanum campylacanthum Hochst. ex A. Richspecies would experience the largest range shift distance of ~6 – 10km and the largest habitat gain of ~12 – 33% in the future.Caesalpinia decapetala (Roth) Alston, Opuntia stricta (Haw.) Haw.andSenna didymobotrya (Fresen.) H.S. Irwin & Barnebyspecies on the other hand would have a decline in habitat range under future climate change scenarios. Although,S. didymobotryais considered a native species, it would lose half of its current suitable habitat in the future. Range shift analysis showed all study species would generally shift to the north west direction or towards the Aberdare ranges. From this study we conclude thatinvasive species management programs for smaller geographical areas ought to consider projecting species distributions under climate change scenarios to identify areas with high possible biodiversity changes. This would be important to conservationists when prioritizing management actions of invasive species in the region where data on invasive species is still limited.
Resveratrol induces H2A.X phosphorylation and H4K16 de-acetylation inToxoplasma gondii
Authors: Contreras Susana M. , Ganuza Agustina , Corvi María M. , Angel Sergio O. 
Published: August 2020

AbstractResveratrol (RSV) is a multi-target drug that demonstrated activity againstToxoplasma gondiiin macrophage and HFF cell line infection models. In addition to modulate redox homeostasis, RSV is also an activator of Sir2, a type III HDAC. RSV inhibited intracellularT. gondiitachyzoite growth at concentrations below the toxic effect on host cells. The IC50value in a 24-hours treatment was 53 μM. After 96 hours of treatment the maximum non-toxic concentration for host cell, 20 μM, only inhibitedT. gondiigrowth a 50%. RSV induced a reduction in H4K16 acetylation (H4K16ac), a mark associated to transcription, DNA replication and homologous recombination repair, without any effect on H3 acetylation (H3ac). RSV also enhanced the SQE motif phosphorylation onT. gondiiH2A.X (termed γH2A.X), a DNA damage associated PTM. Sirtinol, a specific Sir2 inhibitor also inhibitedT. gondiibut did not altered the acetylation status of H3 and H4K16 as well as H2A.X phosphorylation. Our findings suggest a possible link between RSV and DNA damage or DNA repair process maybe due to DNA replication stress and/or another undetermined mechanism.
Highly redundant neuropeptide volume co-transmission underlying episodic activation of the GnRH neuron dendron
Authors: Liu Xinhuai , Yeo Shel-Hwa , McQuillan H. James , Herde Michel K. , Hessler Sabine , Cheong Isaiah , Porteous Robert , Herbison Allan E. 
Published: August 2020

AbstractThe necessity and functional significance of neurotransmitter co-transmission remains unclear. The glutamatergic “KNDy” neurons co-express kisspeptin, neurokinin B (NKB) and dynorphin and exhibit a highly stereotyped synchronized behavior that reads out to the gonadotropin-releasing hormone (GnRH) neuron dendrons to drive episodic hormone secretion. Using expansion microscopy, we show that KNDy neurons make abundant close but non-synaptic appositions with the GnRH neuron dendron. Confocal GCaMP6 calcium imaging demonstrated that, of the neurotransmitters co-expressed by KNDy neurons, only kisspeptin was able to activate the GnRH neuron dendron. The selective deletion of kisspeptin from KNDy neurons resulted in mice in which the synchronized behavior of the KNDy neurons was maintained but their ability to drive episodic hormone secretion was abolished. This indicates that KNDy neurons drive episodic hormone secretion through converse modes of highly redundant neuropeptide co-transmission orchestrated by differential postsynaptic neuropeptide receptor expression at their two target sites.
Frequent lineage-specific substitution rate changes support an episodic model for protein evolution
Authors: Prabh Neel , Tautz Diethard 
Published: August 2020

AbstractSince the inception of the molecular clock model for sequence evolution, the investigation of protein divergence has revolved around the question of a more or less constant rate of overall sequence information change. Although anomalies in clock-like divergence are described for some proteins, nowadays, the assumption of a constant decay rate for a given protein family is taken as the null model for protein evolution. Still, so far, a systematic test of this null model has not been done at a genome-wide scale despite the databases’ enormous growth. We focus here on divergence rate comparisons between closely related lineages, since this allows clear orthology assignments by synteny and unequivocal alignments, which are crucial for the determination of substitution rate changes. Thus, we generated a high-confidence dataset of syntenic orthologs from four ape species, including humans. Further analysis revealed that despite the appearance of an overall clock-like substitution pattern, a substantial number of proteins show lineage-specific acceleration and deceleration in divergence rates, or combinations of both in different lineages. Interestingly, when aggregated, even the families showing large lineage-specific rate perturbations can show overall rate equality. Our analysis uncovers a much more dynamic history of substitution rate changes in protein families. Which invalidates a pan-genome null model of constant decay, on the one hand, but remains compatible with the existing notion that aggregated data can be reliably used to estimate species splitting time. Ultimately, our data shows that a null model of constant change is not suitable to predict the evolutionary trajectories of individual proteins.
RDC complex executes a dynamic piRNA program duringDrosophilaspermatogenesis to safeguard male fertility
Authors: Chen Peiwei , Luo Yicheng , Aravin Alexei A. 
Published: August 2020

SUMMARYpiRNAs are small non-coding RNAs that guide the silencing of transposons and other targets in animal gonads. InDrosophilafemale germline, many piRNA source loci dubbed ‘piRNA clusters’ lack hallmarks of active genes and exploit an alternative path for transcription, which relies on the Rhino-Deadlock-Cutoff (RDC) complex. It remains to date unknown how piRNA cluster transcription is regulated in the male germline. We found that components of RDC complex are expressed in male germ cells during early spermatogenesis, from germline stem cells (GSCs) to early spermatocytes. RDC is essential for expression of dual-strand piRNA clusters and transposon silencing in testis; however, it is dispensable for expression of Y-linkedSuppressor of StellatepiRNAs and thereforeStellatesilencing. Despite intactStellaterepression,rhimutant males exhibited compromised fertility accompanied by germline DNA damage and GSC loss. Thus, piRNA-guided repression is essential for normal spermatogenesis beyondStellatesilencing. While RDC associates with multiple piRNA clusters in GSCs and early spermatogonia, its localization changes in later stages as RDC concentrates on a single X-linked locus,AT-chX. Dynamic RDC localization is paralleled by changes in piRNA cluster expression, indicating that RDC executes a fluid piRNA program during different stages of spermatogenesis.
Global historic pandemics caused by the FAM-1 genotype of the Irish potato pathogenPhytophthora infestans
Authors: Saville Amanda C. , Ristaino Jean B. 
Published: August 2020

AbstractThe FAM-1 genotype ofPhytophthora infestanscaused late blight in the 1840s in the US and Europe and was responsible for the Irish famine. We examined 140 herbarium specimens collected between 1845 and 1991 from six continents and used 12-plex microsatellite genotyping (SSR) to identify FAM-1 and the mtDNA lineage (Herb-1/ Ia) present in historic samples. FAM-1 was detected in approximately 73% of the historic specimens and was found on 6 continents. The US-1 genotype was found in only 27% of the samples and was found later on all continents except Australia/Oceania. FAM-1 was the first genotype detected in almost all the former British colonies from which samples were available. The data from historic samples suggest the FAM-1 genotype was widespread, diverse, and spread more widely than US-1. The famine lineage spread to six continents over 140 years, and likely spread during global colonization from Europe.
BAX is necessary for neuronal death following exposure to isoflurane during the neonatal period
Authors: Slupe Andrew M. , Villasana Laura , Wright Kevin M. 
Published: August 2020

AbstractExposure to volatile anesthetics during the neonatal period results in acute neuronal death in rodent and non-human primate models, potentially leading to lasting cognitive deficits. We usedBax-/-mice to show that neuronal death following neonatal exposure to isoflurane is mediated by the apoptotic pathway, and that GABAergic interneurons are selectively vulnerable. NeonatalBax-/-mice also showed attenuated microglial activation after exposure to isoflurane, indicating that neuroinflammatory response is secondary to neuronal apoptosis. Isoflurane-induced neuronal apoptosis in neonates appeared to have little effect on seizure threshold or cognitive function later in life. Collectively, these findings define the acute injury mechanism of volatile anesthetics during the neonatal period.
Longitudinal changes in brain metabolites in healthy subjects and patients with first episode psychosis (FEP): a 7-Tesla MRS study
Authors: Wang Min , Barker Peter B. , Cascella Nicola , Coughlin Jennifer M. , Nestadt Gerald , Nucifora Frederick C. , Sedlak Thomas W. , Kelly Alexandra , Younes Laurent , Geman Donald , Sawa Akira , Yang Kun 
Published: August 2020

AbstractObjective7 Tesla (T) longitudinal magnetic resonance spectroscopy (MRS) offers a precise measurment of metabolic levels in human brain via a non-invasive approach. Studying longitudinal changes in neurometabolites could help identify trait and state markers for diseases and understand inconsistent findings from different researchers due to differences in the age of study participants and duration of illness. This study is the first to report novel longitudinal patterns in young adulthood from both physiological and pathological viewpoints using 7T MRS.MethodsUtilizing a four-year longitudinal cohort with 38 first episode psychosis (FEP) patients (onset within 2 years) and 48 healthy controls (HC), the authors examined the annual percentage changes of 9 neurometabolites in 5 brain regions.ResultsBoth FEP patients and HC subjects were found to have significant longitudinal reductions in glutamate (Glu) in the anterior cingulate cortex (ACC). Only FEP patients were found to have a significant decrease over time in γ-aminobutyric acid (GABA), N-acetyl aspartate (NAA), myo-inositol (mI), and total choline (tCho: phosphocholine plus glycerophosphocholine) in the ACC. Uniquely, glutathione (GSH) was found to have a near zero annual percentage change in both FEP patients and HC subjects in all 5 brain regions over a four-year timespan in young adulthood.ConclusionsGSH could be a trait marker for diagnostic applications at least in young adulthood. Glu, GABA, NAA, mI, and tCho in the ACC are associated with the patient’s status and could be state markers for mechanistic studies of psychotic disorders, including those for progressive pathological changes and medication effects in young adulthood.
Genome-wide haplotype association study in imaging genetics using whole-brain sulcal openings of 16,304 UK Biobank subjects
Authors: Karkar Slim , Dandine-Roulland Claire , Mangin Jean-François , Guen Yann Le , Philippe Cathy , Deleuze Jean-François , Pierre-Jean Morgane , Floch Edith Le , Frouin Vincent 
Published: August 2020

AbstractNeuroimaging-genetics cohorts gather two types of data: brain imaging and genetic data. They allow the discovery of associations between genetic variants and brain imaging features. They are invaluable resources to study the influence of genetics and environment in the brain features variance observed in normal and pathological populations. This study presents a genome wide haplotype analysis for 123 brain sulcus opening value (a measure of sulcal width) across the whole brain that include 16,304 subjects from UK Biobank. Using genetic maps, we defined 119,548 blocks of low recombination rate distributed along the 22 autosomal chromosomes, and analyzed 1,051,316 haplotypes. To test associations between haplotypes and complex traits, we designed three statistical approaches. Two of them use a model that includes all the haplotypes for a sin gle block, while the last approach considers one model by haplotype. All the statistics produced were assessed as rigorously as possible. Thanks to the rich imaging dataset at hand, we used resampling techniques to assess False Positive Rate for each statistical approach in a genome-wide and brain-wide context. The results on real data show that genome-wide haplotype analyses are more sensitive than single-SNP approach and account for local complex Linkage Disequilibrium (LD) structure, which makes genome-wide haplotype analysis an interesting and statistically sound alternative to the single-SNP counterpart.