bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Genomic Landscape of Prostate Cancer Brain Metastases
Authors: Rodriguez Antonio , Gallon John , Akhoundova Dilara , Maletti Sina , Ferguson Alison , Cyrta Joanna , Amstutz Ursula , Garofoli Andrea , Paradiso Viola , Tomlins Scott A. , Hewer Ekkehard , Genitsch Vera , Fleischmann Achim , Rushing Elisabeth J. , Grobholz Rainer , Fischer Ingeborg , Jochum Wolfram , Cathomas Gieri , Bubendorf Lukas , Moch Holger , Ng Charlotte K.Y. , Sommer Silke Gillessen , Piscuoglio Salvatore , Rubin Mark A. 
Published: May 2020

AbstractLethal prostate cancer commonly metastasizes to bone, lymph nodes, and visceral organs but with more effective therapies, there is an increased frequency of metastases to the brain. Little is known about the genomic drivers of prostate cancer brain metastases (PCBM). To address this, we conducted a comprehensive multi-regional, genomic, and targeted transcriptomic analysis of PCBM from 28 patients. We compared whole-exome and targeted RNA sequencing with matched primary tumors when available (n = 10) and with publicly available genomic data from non-brain prostate cancer metastases (n = 416). In addition to common alterations inTP53,AR,RB1, andPTEN, we identified highly significant enrichment of mutations inNF1(25% cases (6/28),q= 0.049, 95% CI = 2.38 – 26.52, OR = 8.37) andRICTOR(17.9% cases (5/28),q= 0.01, 95% CI = 6.74 – 480.15, OR = 43.7) in PCBM compared to non-brain prostate cancer metastases, suggesting possible activation of the druggable pathways RAS/RAF/MEK/ERK and PI3K/AKT/mTOR, respectively. Compared to non-brain prostate cancer metastases, PCBM were almost three times as likely to harbor DNA homologous repair (HR) alterations (42.9% cases (12/28), p =0.016, 95% CI = 1.17 – 6.64, OR = 2.8). When considering the combination of somatic mutations, copy number alteration, and Large-scale State Transitions, 64.3% of patients (18/28) were affected. HR alterations may be critical drivers of brain metastasis that potentially provide cancer cells a survival advantage during re-establishment in a special microenvironment. We demonstrate that PCBM have genomic dependencies that may be exploitable through clinical interventions including PARP inhibition.
Construction of mutant heparinase I with significantly increased specific activity
Authors: Kalinina A.N. , Borschevskaya L.N. , Gordeeva T.L. , Patrusheva E. , Sineokiy S.P. 
Published: May 2020

AbstractThe cleavage of heparin by heparin lyases showed great potential as a cost-effective and innoxious method for producing heparin with low molecular weight (LMWH). One of the most studied and sought heparin lyase is heparinase I (HepI). However, the industrial use of HepI was largely hampered by its low specific activity and thermal stability. In this article we describe increasing in specific heparinase I activity by stepwise site-directed mutagenesis. Thus after two cycles of mutagenesis, we obtained mutant heparinase I Flavobacterium heparinum with significantly increased specific activity (25%).
Stress-primed secretory autophagy drives extracellular BDNF maturation
Authors: Martinelli Silvia , Anderzhanova Elmira A. , Wiechmann Svenja , Dethloff Frederik , Weckmann Katja , Bajaj Thomas , Hartmann Jakob , Hafner Kathrin , Pöhlmann Max L. , Jollans Lee , Maccarrone Giuseppina , Hausch Felix , Turck Christoph W , Philipsen Alexandra , Schmidt Mathias V. , Kuster Bernhard , Gassen Nils C 
Published: May 2020

AbstractThe stress response is an essential mechanism that strives to maintain homeostasis, and its disruption is implicated in several psychiatric disorders. As a cellular response to stressors, autophagy is activated to regulate homeostasis through protein degradation and recycling. Secretory autophagy is a recently described pathway where autophagosomes fuse with the plasma membrane rather than lysosomes. In this study, we demonstrate that glucocorticoid-mediated stress enhances secretory autophagy, via the stress-responsive co-chaperone FK506-binding protein 51. We identified the matrix metalloproteinase 9 (MMP9) as one of the stress-induced secreted proteins. Using cellular assays andin vivomicrodialysis, we further found that stress-enhanced MMP9 secretion increases the cleavage of pro-brain derived neurotrophic factor (proBDNF) to its mature form. BDNF is essential for adult synaptic plasticity and its pathway is associated with major depression and posttraumatic stress disorder. These findings unravel a novel mechanistic link between stress, stress adaptation and the development of psychiatric disorders, with possible therapeutic implications.
Data-Driven Modeling of Resource Distribution in Honeybee Swarms
Authors: Fard Golnar Gharooni , Bradley Elizabeth , Peleg Orit 
Published: May 2020

AbstractTrophallaxis is the mutual exchange and direct transfer of liquid food among eusocial insects such as ants, termites, wasps, and bees. This process allows efficient dissemination of nutrients and is crucial for the colony’s survival. In this paper, we present a data-driven agent-based model and use it to explore how the interactions of individual bees, following simple, local rules, affect the global food distribution. We design the rules in our model using laboratory experiments on honeybees. We validate its results via comparisons with the movement patterns in real bees. Using this model, we demonstrate that the efficiency of food distribution is affected by the density of the individuals, as well as the rules that govern their behavior: e.g., how they move and whether or not they aggregate. Specifically, food is distributed more efficiently when donor bees do not always feed their immediate neighbors, but instead prioritize longer motions, sharing their food with more-distant bees. This non-local pattern of food exchange enhances the overall probability that all of the bees, regardless of their position in the colony, will be fed efficiently. We also find that short-range attraction improves the efficiency of the food distribution in the simulations. Importantly, this model makestestablepredictions about the effects of different bee densities, which can be validated in experiments. These findings can potentially contribute to the design of local rules for resource sharing in swarm robotic systems.
Dynamics of transposable elements in recently diverged fungal pathogens: lineage-specific transposable element content and efficiency of genome defences
Authors: Lorrain Cécile , Feurtey Alice , Möller Mareike , Haueisen Janine , Stukenbrock Eva 
Published: May 2020

AbstractTransposable elements (TEs) impact genome plasticity, architecture and evolution in fungal plant pathogens. The wide range of TE content observed in fungal genomes reflects diverse efficacy of host-genome defence mechanisms that can counter-balance TE expansion and spread. Closely related species can harbour drastically different TE repertoires, suggesting variation in the efficacy of genome defences. The evolution of fungal effectors, which are crucial determinants of pathogenicity, has been linked to the activity of TEs in pathogen genomes. Here we describe how TEs have shaped genome evolution of the fungal wheat pathogenZymoseptoria triticiand four closely related species. We comparedde novoTE annotations and Repeat-Induced Point mutation signatures in thirteen genomes from theZymoseptoriaspecies-complex. Then, we assessed the relative insertion ages of TEs using a comparative genomics approach. Finally, we explored the impact of TE insertions on genome architecture and plasticity. The thirteen genomes ofZymoseptoriaspecies reflect different TE dynamics with a majority of recent insertions. TEs associate with distinct genome compartments in allZymoseptoriaspecies, including chromosomal rearrangements, genes showing presence/absence variation and effectors. EuropeanZ. triticiisolates have reduced signatures of Repeat-Induced Point mutations compared to Iranian isolates and closely related species. Our study supports the hypothesis that ongoing but moderate TE mobility inZymoseptoriaspecies shapes pathogen genome evolution.
Rapid selection of a human monoclonal antibody that potently neutralizes SARS-CoV-2 in two animal models
Authors: Li Wei , Drelich Aleksandra , Martinez David R. , Gralinski Lisa , Chen Chuan , Sun Zehua , Schäfer Alexandra , Leist Sarah R. , Liu Xianglei , Zhelev Doncho , Zhang Liyong , Peterson Eric C. , Conard Alex , Mellors John W. , Tseng Chien-Te , Baric Ralph S. , Dimitrov Dimiter S. 
Published: May 2020

AbstractEffective therapies are urgently needed for the SARS-CoV-2/COVID19 pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from eight large phage-displayed Fab, scFv and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) glycoprotein. One high affinity mAb, IgG1 ab1, specifically neutralized replication competent SARS-CoV-2 with exceptional potency as measured by two different assays. There was no enhancement of pseudovirus infection in cells expressing Fcγ receptors at any concentration. It competed with human angiotensin-converting enzyme 2 (hACE2) for binding to RBD suggesting a competitive mechanism of virus neutralization. IgG1 ab1 potently neutralized mouse ACE2 adapted SARS-CoV-2 in wild type BALB/c mice and native virus in hACE2 expressing transgenic mice. The ab1 sequence has relatively low number of somatic mutations indicating that ab1-like antibodies could be quickly elicited during natural SARS-CoV-2 infection or by RBD-based vaccines. IgG1 ab1 does not have developability liabilities, and thus has potential for therapy and prophylaxis of SARS-CoV-2 infections. The rapid identification (within 6 days) of potent mAbs shows the value of large antibody libraries for response to public health threats from emerging microbes.
Polymer Stiffness Regulates Multivalent Binding and Liquid-Liquid Phase Separation
Authors: Zumbro E. , Alexander-Katz A. 
Published: May 2020

AbstractMultivalent binding is essential to many biological processes because it builds high affinity bonds by using several weak binding interactions simultaneously. Multivalent polymers have shown promise as inhibitors of toxins and other pathogens, and they are important components in the formation of biocondensates. Explaining how structural features of these polymers change their binding and subsequent control of phase separation is critical to designing better pathogen inhibitors and also to understanding diseases associated with membraneless organelles. In this work, we will examine the binding of a multivalent polymer to a small target. This scenario could represent a polymeric inhibitor binding to a toxic protein or RNA binding to an RNA-binding protein in the case of liquid-liquid phase separation. We use simulation and theory to show that flexible random-coil polymers bind more strongly than stiff rod-like polymers and that flexible polymers nucleate condensed phases at lower energies than their rigid analogues. We hope these results will provide insight into the rational design of polymeric inhibitors and improve understanding of membraneless organelles.Statement of SignificanceMultivalent polymers are essential for many biological systems, including targeting pathogens and controlling the formation of liquid-liquid phase separated biocondensates. Here, we explain how increasing polymer stiffness can reduce multivalent binding affinity to a small target such as a toxic protein and how modulating polymer stiffness can change the phase boundary for liquid-liquid phase separation. These results have implications for designing stronger pathogen inhibitors and provide insights on neurodegenerative diseases associated with abnormal biocondensate formation.
ERH as a component of the Microprocessor facilitates the maturation of suboptimal microRNAs
Authors: Kwon S. Chul , Jang Harim , Yang Jihye , Kim Jeesoo , Baek S. Chan , Kim Jong-Seo , Kim V. Narry 
Published: May 2020

ABSTRACTThe Microprocessor complex cleaves the primary transcript of microRNA (pri-miRNA) to initiate miRNA maturation. Microprocessor is known to consist of RNase III DROSHA and dsRNA-binding DGCR8. Here we identify Enhancer of Rudimentary Homolog (ERH) as a new component of the Microprocessor. ERH binds to a conserved region in the N-terminus of DGCR8. Knockdown of ERH or deletion of the DGCR8 N-terminus results in a decrease of processing of primary miRNAs with suboptimal hairpin structures that reside in polycistronic miRNA clusters. ERH increases the processing of suboptimal pri-miR-451 in a manner dependent on its neighboring pri-miR-144. Thus, the ERH dimer may mediate “cluster assistance” in which the Microprocessor is loaded onto a poor substrate with help from a high-affinity substrate in the same cluster. Our study reveals a role of ERH in the miRNA pathway.
Surface display of designer protein scaffolds on genome-reduced strains ofPseudomonas putida
Authors: Dvořák Pavel , Bayer Edward A. , de Lorenzo Víctor 
Published: May 2020

AbstractThe bacteriumPseudomonas putidaKT2440 is gaining considerable interest as a microbial platform for biotechnological valorization of polymeric organic materials, such as waste lignocellulose or plastics. However,P. putidaon its own cannot make much use of such complex substrates, mainly because it lacks an efficient extracellular depolymerizing apparatus. We seek to meet this challenge by adopting a recombinant cellulosome strategy for this attractive host. Here, we report an essential step in this endeavor – a display of designer enzyme-anchoring protein “scaffoldins”, encompassing cohesin binding domains from divergent cellulolytic bacterial species on theP. putidasurface. TwoP. putidachassis strains, EM42 and EM371, with streamlined genomes and substantial differences in the composition of the outer membrane were employed in this study. Scaffoldin variants were delivered to their surface with one of four tested autotransporter systems (Ag43 fromEscherichia coli), and the efficient display was confirmed by extracellular attachment of chimeric β-glucosidase and fluorescent proteins. Our results highlight the importance of cell surface engineering for display of recombinant proteins in Gram-negative bacteria and pave the way towards designer cellulosome strategies, tailored forP. putida.
Transcriptomic profiling of human effector and regulatory T cell subsets identifies predictive population signatures
Authors: Höllbacher Barbara , Duhen Thomas , Motley Samantha , Klicznik Maria M. , Gratz Iris K. , Campbell Daniel J. 
Published: May 2020

AbstractAfter activation, CD4+T helper (Th) cells differentiate into functionally specialized populations that coordinate distinct immune responses and protect against different types of pathogens. In humans, these effector and memory Th cell subsets can be readily identified in peripheral blood based on their differential expression of chemokine receptors that govern their homeostatic and inflammatory trafficking. Foxp3+regulatory T (Treg) cells can also be divided into subsets that phenotypically mirror each of these effector populations, and share expression of key transcription factors and effector cytokines. In this study, we performed comprehensive transcriptional profiling of 11 phenotypically distinct Th and Treg cell subsets sorted from peripheral blood of healthy individuals. Despite their shared phenotypes, we found that mirror Th and Treg subsets were transcriptionally dissimilar, and that Treg cell populations showed limited transcriptional diversity compared to Th cells. We identified core transcriptional signatures shared across all Th and Treg cell populations, and unique signatures that define each of the Th or Treg populations. Finally, we applied these signatures to bulk Th and Treg RNA-seq data and found enrichment of specific Th and Treg cell populations in different human tissues. These results further define the molecular basis for the functional specialization and differentiation of Th and Treg cell populations, and provide a new resource for examining Th and Treg specialization in RNA-seq data.
Combined knockout ofLrrk2andRab29does not result in behavioral abnormalitiesin vivo
Authors: Mazza Melissa Conti , Nguyen Victoria , Beilina Alexandra , Ding Jinhui , Cookson Mark R. 
Published: May 2020

AbstractCoding mutations in theLRRK2gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, leading to the suggestion that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci aroundLRRK2and one of its proposed substrates,RAB29, as contributors towards the lifetime risk of sporadic PD. Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, here we generated a double knockout mouse model and determined whether there are any consequences on brain function with aging. From a battery of motor and non-motor behavioral tests, we noted only that 18-24 monthRab29-/-and double (Lrrk2-/-/Rab29-/-) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in number of substantia nigra pars compacta (SNc) dopamine neurons or in tyrosine hydroxylase levels in the SNc and striatum, which might reflect a PD-like pathology. These results suggest that depletion of both Lrrk2 and Rab29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans.Significance statementGenetic variation in LRRK2 that result in elevated kinase activity can cause Parkinson’s disease (PD), suggesting LRRK2 inhibition as a therapeutic strategy. RAB29, a substrate of LRRK2, has also been associated with increased PD risk. Evidence exists for an interactive relationship between LRRK2 and RAB29. Mouse models lacking either LRRK2 or RAB29 do not show brain pathologies. We hypothesized that the loss of both targets would result in additive effects acrossin vivoand post-mortem assessments in aging mice. We found that loss of both LRRK2 and RAB29 did not result in significant behavioral deficits or dopamine neuron loss. This evidence suggests that chronic inhibition of this pathway should be tolerated clinically.
Expansion Sequencing: Spatially PreciseIn SituTranscriptomics in Intact Biological Systems
Authors: Alon Shahar , Goodwin Daniel R , Sinha Anubhav , Wassie Asmamaw T , Chen Fei , Daugharthy Evan R , Bando Yosuke , Kajita Atsushi , Xue Andrew G , Marrett Karl , Prior Robert , Cui Yi , Payne Andrew C , Yao Chun-Chen , Suk Ho-Jun , Wang Ru , Yu Chih-Chieh (Jay) , Tillberg Paul , Reginato Paul , Pak Nikita , Liu Songlei , Punthambaker Sukanya , Iyer Eswar P. R. , Kohman Richie E , Miller Jeremy A , Lein Ed S , Lako Ana , Cullen Nicole , Rodig Scott , Helvie Karla , Abravanel Daniel L , Wagle Nikhil , Johnson Bruce E , Klughammer Johanna , Slyper Michal , Waldman Julia , Jané-Valbuena Judit , Rozenblatt-Rosen Orit , Regev Aviv ,   IMAXT Consortium, Church George M , Marblestone Adam H , Boyden Edward S 
Published: May 2020

Abstract:Methods for highly multiplexed RNA imaging are limited in spatial resolution, and thus in their ability to localize transcripts to nanoscale and subcellular compartments. We adapt expansion microscopy, which physically expands biological specimens, for long-read untargeted and targetedin situRNA sequencing. We applied untargeted expansion sequencing (ExSeq) to mouse brain, yielding readout of thousands of genes, including splice variants and novel transcripts. Targeted ExSeq yielded nanoscale-resolution maps of RNAs throughout dendrites and spines in neurons of the mouse hippocampus, revealing patterns across multiple cell types; layer-specific cell types across mouse visual cortex; and the organization and position-dependent states of tumor and immune cells in a human metastatic breast cancer biopsy. Thus ExSeq enables highly multiplexed mapping of RNAs, from nanoscale to system scale.One Sentence SummaryIn situsequencing of physically expanded specimens enables multiplexed mapping of RNAs at nanoscale, subcellular resolution.
Detection of Viral RNA Fragments in Human iPSC-Cardiomyocytes following Treatment with Extracellular Vesicles from SARS-CoV-2 Coding-Sequence-Overexpressing Lung Epithelial Cells
Authors: Kwon Youjeong , Nukala Sarath Babu , Srivastava Shubhi , Miyamoto Hiroe , Ismail Nur Izzah , Rehman Jalees , Ong Sang-Bing , Lee Won Hee , Ong Sang-Ging 
Published: May 2020

ABSTRACTThe novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a worldwide pandemic. Early data suggest that the prevalence and severity of COVID-19 appear to be higher among patients with underlying cardiovascular risk factors. Despite the expression of angiotensin-converting enzyme 2 (ACE2), a functional receptor for SARS-CoV-2 infection, in cardiomyocytes, there has been no conclusive evidence of direct viral infection although the presence of inflammation and viral genome within the hearts of COVID-19 patients have been reported. Here we transduced A549 lung epithelial cells with lentivirus overexpressing selected genes of the SARS-CoV-2. We then isolated extracellular vesicles (EVs) from the supernatant of A549 cells and detected the presence of viral RNA within the purified EVs. Importantly, we observed that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were able to actively uptake these EVs and viral genes were subsequently detected in the cardiomyocytes. Accordingly, uptake of EVs containing viral genes led to an upregulation of inflammation-related genes in hiPSC-CMs. Thus, our findings indicate that SARS-CoV-2 RNA-containing EVs represent an indirect route of viral RNA entry into cardiomyocytes.
Unveiling diffusion pattern and structural impact of the most invasive SARS-CoV-2 spike mutation
Authors: Trucchi Emiliano , Gratton Paolo , Mafessoni Fabrizio , Motta Stefano , Cicconardi Francesco , Bertorelle Giorgio , D’Annessa Ilda , Di Marino Daniele 
Published: May 2020

ABSTRACTStarting in Wuhan, China, SARS-CoV-2 epidemics quickly propagated worldwide in less than three months, geographically sorting genomic variants in newly established propagules of infections. Stochasticity in transmission within and between countries and/or actual advantage in virus transmissibility could explain the high frequency reached by some genomic variants during the course of the outbreak.Using a suite of statistical, population genetics, and theoretical approaches, we show that the globally most represented spike protein variant (i.e., the G clade, A → G nucleotide change at genomic position 23,403; D → G amino acid change at spike protein position 614)i)underwent a significant demographic expansion in most countries not explained by stochastic effects or enhanced pathogenicity;ii)affects the spike S1/S2 furin-like site increasing its conformational plasticity (short range effect), andiii)modifies the internal motion of the receptor-binding domain affecting its cross-connection with other functional domains (long-range effect).Our study unambiguously links the spread of the G614 with a non-random process, and we hypothesize that this process is related to the selective advantage produced by a specific structural modification of the spike protein. We conclude that the different conformation of the S1/S2 proteolytic site is at the basis of the higher transmission rate of this invasive SARS-CoV-2 variant, and provide structural information to guide the design of selective and efficient drugs.