bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fungal symbionts of Arctic zooplankton induce mortality and reduce swimming activity
Authors: Hassett BT , Ershova E , Berge J 
Published: September 2020

ABSTRACTZooplankton are key intermediaries between microbes and higher trophic levels. Elevated temperatures in the Arctic are expected to increase metabolic rates, which in turn will result in increased rates of zooplankton production and foraging. We postulate that this may also be tied to elevated incidence of fungi parasitism in key zooplankton species. We present data ofin-situfungal parasitism in the key Arctic zooplankton species complexCalanusspp. We found that >10% ofCalanusspecimens were internally parasitized by fungi that had 100% molecular identity toPenicillium chrysogenum. Experimental studies with two strains ofP. chrysogenumandCalanusspp. revealed an increased mortality effect suggesting that fungi decrease the survival of overwintering zooplankton, which may have cascading effects on higher trophic levels that feed onCalanus. Moreover,Calanusdemonstrated reduced swimming activity in the presence ofP. chyrsogenum, indicating that fungi could affect predator avoidance and vertical migration patterns of zooplankton. Semi-thin sectioning of live zooplankton incubated withP. chrysogenumrevealed the presence of hyphae throughout the body, underscoring the parasitic nature ofP. chrysogenuminCalanus. We hypothesize that as the Arctic warms, the balance between host and pathogen could shift in favor of pathogen reproduction, resulting in a greater effect of fungal pathogens on zooplankton.
Molecular mechanisms for environmentally induced plasticity in the positioning of meiotic recombination at hotspots
Authors: Mukiza Tresor O. , Protacio Reine U. , Davidson Mari K. , Wahls Wayne P. 
Published: September 2020

AbstractIn meiosis, Spo11/Rec12-initiated homologous recombination is clustered at hotspots that regulate its frequency and distribution across the genome. Intriguingly, the intensities and positions of recombination hotspots can change dramatically in response to intracellular and extracellular conditions, and can display epigenetic memory. Here, using the fission yeastSchizosaccharomyces pombe, we reveal mechanisms for hotspot plasticity. We show that each of six hotspot-activating proteins (transcription factors Atf1, Pcr1, Php2, Php3, Php5, Rst2) is rate-limiting for promoting recombination at its own DNA binding site, allowing each class of hotspot to be regulated independently by agonistic and antagonistic signals. We also discovered that the regulatory protein-DNA complexes can establish a recombinationally poised epigenetic state before meiosis. Notably, Atf1 and Pcr1 controlled the activation of DNA sequence-dependent hotspots to which they do not bind; and they do so by regulating the expression of other hotspot-activating proteins. Thus, while each transcription factor activates its own class of DNA sequence-dependent hotspots directly incis, cross-talk between regulatory networks modulates intransthe frequency and positioning of recombination at other classes of DNA sequence-dependent hotspots. We posit that such mechanisms allow cells to alter the frequency distribution of meiotic recombination in response to metabolic states and environmental cues.
The energetics of social signaling during roost location in Spix’s disc-winged bats
Authors: Chaverri Gloriana , Iturralde-Pólit Paula , Sandoval-Herrera Natalia Ivone , Romero-Vásquez Adarli , Cháves-Ramírez Silvia , Sagot Maria 
Published: September 2020

AbstractLong-term social aggregations are maintained by multiple mechanisms, including the use of acoustic signals, which may nonetheless entail significant energetic costs. To date, however, no studies have gauged whether there are significant energetic costs to social call production in bats, which heavily rely on acoustic communication for a diversity of social tasks. We measure energetic expenditure during acoustic signaling in Spix’s disc-winged bats (Thyroptera tricolor), a species that commonly uses contact calls to locate the ephemeral furled leaves that they use for roosting. To determine the cost of sound production, we measured oxygen consumption using intermittent-flow respirometry methods, with and without social signaling. Our results show that the emission of contact calls significantly increases oxygen consumption; vocal individuals spent, on average, 12.42 kJ more during social signaling trials than they spent during silent trials. Furthermore, production of contact calls during longer periods increased oxygen consumption for males but not for females. We also found that as resting metabolic rates increased in males, there was a decreasing probability that they would emit response calls. These results provide support to the “allocation model”, which predicts that only individuals with lower self-maintenance costs can afford to spend energy in additional activities. Our results provide a step forward in our understanding of how physiology modulates behavior, specifically how the costs of call production and resting metabolic rates may explain the differences in vocal behavior among individuals.Summary StatementSpix’s disc-winged bats constantly produce contact calls while searching for roosts, which we show significantly increases an individual’s metabolic rate.
Untargeted LC-MS metabolomics for the analysis of micro-scaled extracellular metabolites fromhepatocytes
Authors: Abdalkader Rodi , Chaleckis Romanas , Meister Isabel , Zhang Pei , Wheelock Craig , Kamei Ken-ichrio 
Published: September 2020

AbstractMetabolome analysis in micro physiological models is a challenge due to the low volume of cell culture medium (CCM). Here, we report a LC-MS-based untargeted metabolomics protocol for the detection of hepatocyte extracellular metabolites from micro-scale samples of CCM. Using a single LC-MS method we have detected 57 metabolites of which 27 showed >2-fold shifts after 72-hours incubation. We demonstrate that micro-scale CCM samples can be used for modelling micro-physiological temporal dynamics in metabolite intensities.Graphical Abstract
Cyclooxgenase-2 is induced by SARS-CoV-2 infection but does not affect viral entry or replication
Authors: Chen Jennifer S. , Alfajaro Mia Madel , Wei Jin , Chow Ryan D. , Filler Renata B. , Eisenbarth Stephanie C. , Wilen Craig B. 
Published: September 2020

AbstractIdentifying drugs that regulate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its symptoms has been a pressing area of investigation during the coronavirus disease 2019 (COVID-19) pandemic. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are frequently used for the relief of pain and inflammation, could modulate both SARS-CoV-2 infection and the host response to the virus. NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which mediate the production of prostaglandins (PGs). PGE2, one of the most abundant PGs, has diverse biological roles in homeostasis and inflammatory responses. Previous studies have shown that NSAID treatment or inhibition of PGE2receptor signaling leads to upregulation of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2, thus raising concerns that NSAIDs could increase susceptibility to infection. COX/PGE2signaling has also been shown to regulate the replication of many viruses, but it is not yet known whether it plays a role in SARS-CoV-2 replication. The purpose of this study was to dissect the effect of NSAIDs on COVID-19 in terms of SARS-CoV-2 entry and replication. We found that SARS-CoV-2 infection induced COX-2 upregulation in diverse human cell culture and mouse systems. However, suppression of COX-2/PGE2signaling by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect onACE2expression, viral entry, or viral replication. Our findings suggest that COX-2 signaling driven by SARS-CoV-2 may instead play a role in regulating the lung inflammation and injury observed in COVID-19 patients.ImportancePublic health officials have raised concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating symptoms of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). NSAIDs function by inhibiting the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). These enzymes are critical for the generation of prostaglandins, lipid molecules with diverse roles in maintaining homeostasis as well as regulating the inflammatory response. While COX-1/COX-2 signaling pathways have been shown to affect the replication of many viruses, their effect on SARS-CoV-2 infection remains unknown. We found that SARS-CoV-2 infection induced COX-2 expression in both human cell culture systems and mouse models. However, inhibition of COX-2 activity with NSAIDs did not affect SARS-CoV-2 entry or replication. Our findings suggest that COX-2 signaling may instead regulate the lung inflammation observed in COVID-19 patients, which is an important area for future studies.
CARD8 inflammasome mediates pyroptosis of HIV-1-infected cells by sensing viral protease activity
Authors: Wang Qiankun , Gao Hongbo , Clark Kolin M. , Tang Pengfei , Harlan Gray H. , Kutluay Sebla B. , DeSelm Carl J. , Presti Rachel M. , Shan Liang 
Published: September 2020

AbstractHIV-1 has high mutation rates and exists as mutant swarms in the host. Rapid evolution of HIV-1 allows the virus to outpace host immune system, leading to viral persistence. Novel approaches to target immutable components are needed to clear HIV-1 infection. Here we report a pattern-recognition receptor CARD8 that senses enzymatic activity of the HIV-1 protease, which is indispensable for the virus. All subtypes of HIV-1 can be sensed by CARD8 despite substantial viral diversity. HIV-1 evades CARD8 sensing because the viral protease remains inactive in infected cells prior to viral budding. Induction of premature intracellular activation of the viral protease triggers CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. This strategy leads to clearance of latent HIV-1 in patient CD4+T cells after virus reactivation. Taken together, our study identifies CARD8 as an inflammasome sensor of HIV-1 that holds promise as a strategy for clearance of persistent HIV-1 infection.
Virus-Like Particle Based-Vaccines Elicit Neutralizing Antibodies against the HIV-1 Fusion Peptide
Authors: Mogus Alemu Tekewe , Liu Lihong , Jia Manxue , Ajayi Diane T. , Xu Kai , Kong Rui , Huang Jing , Yu Jian ,   VRC Production Program, Kwong Peter D. , Mascola John R. , Ho David D. , Tsuji Moriya , Chackerian Bryce 
Published: September 2020

AbstractBroadly neutralizing antibodies (bnAbs) isolated from HIV-infected individuals delineate vulnerable sites on the HIV envelope glycoprotein that are potential vaccine targets. A linear epitope at the N-terminal region of the HIV-1 fusion peptide (FP8) is the primary target of VRC34.01, a bnAb that neutralizes ~50% of primary HIV isolates. FP8 has attracted attention as a potential HIV vaccine target because it is a simple linear epitope. Here, we used platform technologies based on RNA bacteriophage virus-like particles (VLPs) to develop multivalent vaccines targeting the FP8 epitope. We produced recombinant MS2 VLPs displaying the FP8 peptide and we chemically conjugated synthetic FP8 peptides to Qβ VLPs. Both recombinant and conjugated FP8-VLPs induced high titers of FP8-specific antibodies in mice. A heterologous prime-boost-boost regimen employing the two FP8-VLP vaccines and native envelope trimer was the most effective approach for eliciting HIV-1 neutralizing antibodies. Given the potent immunogenicity of VLP-based vaccines, this vaccination strategy – inspired by bnAb-guided epitope mapping, VLP bioengineering, and optimal prime-boost immunization strategies – may be an effective strategy for eliciting bnAb responses against HIV.
METTL3 inhibitors for epitranscriptomic modulation of cellular processes
Authors: Moroz-Omori Elena V. , Huang Danzhi , Bedi Rajiv Kumar , Cheriyamkunnel Sherry J. , Bochenkova Elena , Dolbois Aymeric , Rzeczkowski Maciej D. , Wiedmer Lars , Caflisch Amedeo 
Published: September 2020

AbstractThe methylase METTL3 is the writer enzyme of the N6-methyladenosine (m6A) modification of RNA. Using a structure-based drug discovery approach, we identified a METTL3 inhibitor (UZH1a) with potency in a biochemical assay of 280 nM, while its enantiomerUZH1bis 100 times less active. The crystal structure of the complex of METTL3 withUZH1aillustrates the interactions that make it selective against protein methyltransferases. We observed a dose-dependent reduction in m6A methylation level of mRNA in several cell lines treated withUZH1aalready after 16 h of exposure, as determined by triple-quadrupole LC mass spectrometry, while its enantiomerUZH1bwas essentially inactive at concentrations up to 100 μM. Interestingly, the kinetics of m6A level reduction in mRNAs followed a first-order reaction model, with a half-decay time τ of 1.8 h and a maximum m6A inhibition level of 70%, which is in line with the previously observed shorter half-life of m6A-modified mRNAs. Notably, treatment with the compounds did not alter cellular METTL3 levels, ruling out indirect effects on m6A levels. The effect of the m6A level depletion byUZH1adirectly translated into growth inhibition of MOLM-13 leukemia cells, under short-term and long-term culture. Incubation of the MOLM-13 cells withUZH1a, but not withUZH1b, resulted in increased cell apoptosis and cell cycle arrest already after 16 h of incubation. Interestingly, other cell lines sensitive to METTL3 level (U2Os, HEK293T) did not reveal statistically significant differences betweenUZH1aandUZH1bin a cell viability assay, confirming that the degree of reliance on m6A signalling for survival can vary between cancers/cell types.
The impact of second language immersion: Evidence from a bi-directional longitudinal cross-linguistic study
Authors: Brice Henry , Frost Stephen , Bick Atira S. , Molfese Peter J. , Rueckl Jay G. , Pugh Kenneth R. , Frost Ram 
Published: September 2020

AbstractBrice et al. (2019) presented data from the first epoch of a longitudinal study of the neurobiological underpinnings of first-language (L1) and second-language (L2) processing. Results showed a similar network of activation for reading across L1 and L2, as well as significant convergence of print and speech processing across a network of left-hemisphere regions in both L1 and L2 with greater activation and convergence for L2 in anterior regions, and greater activation and convergence for L1 in posterior regions of the reading network. Here, we present the first look at longitudinal changes in these effects. L2 showed relatively few changes in activation, with some shifts in the weighting between ventral and dorsal processing. L1, however, showed more widespread differences in processing, suggesting that the neurobiological footprint of reading is dynamic, with both L1 and L2 impacting each other. Print/speech convergence showed very little longitudinal change, suggesting that it is a stable marker of the differences in L1 and L2 processing.
Reduced competence to arboviruses following the sustainable invasion ofWolbachiainto nativeAedes aegyptifrom Niterói, Southeastern Brazil
Authors: Gesto João Silveira Moledo , Ribeiro Gabriel Sylvestre , Rocha Marcele Neves , Dias Fernando Braga Stehling , Peixoto Julia , Carvalho Fabiano Duarte , Pereira Thiago Nunes , Moreira Luciano Andrade 
Published: September 2020

AbstractField release ofWolbachia-infectedAedes aegyptihas emerged as a promising solution to manage the transmission of dengue, Zika and chikungunya in endemic areas across the globe. Through an efficient self-dispersing mechanism, and the ability to induce virus-blocking properties,Wolbachiaoffers an unmatched potential to gradually modify wildAe. aegyptipopulations turning them unsuitable disease vectors. Here in this work, a proof-of-concept field trial was carried out in a small community of Niterói, greater Rio de Janeiro. Following the release ofWolbachia-infected eggs, we reported a successful invasion and long-term establishment of the bacterium across the territory, as denoted by stable high-infection indexes (>80%). We have also demonstrated that refractoriness to dengue and Zika viruses, either thorough oral-feeding or intra-thoracic saliva challenging assays, were maintained over the adaptation to the natural environment of Southeastern Brazil. These findings further supportWolbachia’s ability to invade localAe. aegyptipopulations and impair disease transmission, and shall pave the way for future epidemiological and economic impact assessments.
Intrinsic and extrinsic noise are distinguishable in a synthesis – export – degradation model of mRNA production
Authors: Gorin Gennady , Pachter Lior 
Published: September 2020

AbstractIntrinsic and extrinsic noise sources in gene expression, originating respectively from transcriptional stochasticity and from differences between cells, complicate the determination of transcriptional models. In particularly degenerate cases, the two noise sources are altogether impossible to distinguish. However, the incorporation of downstream processing, such as the mRNA splicing and export implicated in gene expression buffering, recovers the ability to identify the relevant source of noise. We report analytical copy-number distributions, discuss the noise sources’ qualitative effects on lower moments, and provide simulation routines for both models.
Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C
Authors: Posada-Céspedes Susana , Van Zyl Gert , Montazeri Hesam , Kuipers Jack , Rhee Soo-Yon , Kouyos Roger , Günthard Huldrych F. , Beerenwinkel Niko 
Published: September 2020

AbstractAlthough combination antiretoviral therapies seem to be effective at controlling HIV-1 infections regardless of the viral subtype, there is increasing evidence for subtype-specific drug resistance mutations. The order and rates at which resistance mutations accumulate in different subtypes also remain poorly understood. Here, we present a methodology for the comparison of mutational pathways in different HIV-1 subtypes, based on Hidden Conjunctive Bayesian Networks (H-CBN), a probabilistic model for inferring mutational pathways from cross-sectional genotype data. We introduce a Monte Carlo sampling scheme for learning H-CBN models on a large number of resistance mutations and develop a statistical test to assess differences in the inferred mutational pathways between two groups. We apply this method to the temporal progression of mutations conferring resistance to the protease inhibitor lopinavir in a large cross-sectional data set of South African individuals living with HIV-1 subtype C, as well as a genotype data set of subtype B infections derived from the Stanford HIV Drug Resistance Database and the Swiss HIV Cohort Study. We find strong support for different initial mutational events in the protease, namely at residue 46 in subtype B and at residue 82 in subtype C. Our results also show that mutations can accumulate along various alternative paths within subtypes, as opposed to a unique total temporal ordering. Furthermore, the maximum likelihood mutational networks for subtypes B and C share only 7 edges (Jaccard distance 0.802) and imply many different evolutionary pathways. Beyond HIV drug resistance, the statistical methodology is applicable more generally for the comparison of inferred mutational pathways between any two groups.Author summaryThere is a disparity in the distribution of infections by HIV-1 subtype in the world. Subtype B is predominant in America, Western Europe and Australia, and most therapeutic strategies are based on research and clinical studies on this subtype. However, non-B subtypes represent the majority of global HIV-1 infections; e.g., subtype C alone accounts for nearly half of all HIV-1 infections. We present a statistical framework enabling the comparison of patterns of accumulating mutations in different HIV-1 subtypes. Specifically, we study lopinavir resistance pathways in HIV-1 subtypes B versus C, but the methodology can be generally applied to compare the temporal ordering of genetic events in different subgroups.
Modulation of metabolic hormone signalingviaa circadian hormone and a biogenic amine inDrosophila melanogaster
Authors: Braco Jason T. , Saunders Cecil J. , Nelson Jonathan M. , Johnson Erik C. 
Published: September 2020

ABSTRACTIn insects, Adipokinetic hormone is the primary hormone responsible for the mobilization of stored energy. While a growing body of evidence has solidified AKH’s role in modulating the physiological and behavioral responses to metabolic stress, little is known about the upstream endocrine circuit that directly regulates AKH release. We evaluated the AKH-expressing cell transcriptome to identify potential regulatory elements controlling AKH cell activity, and found that a number of receptors show consistent expression levels, including all known dopamine receptors, dopamine ecdysone receptor (DopEcR), Dopamine 2-like receptor (D2R), Dopamine 1-like receptor 2 (DopR2), DopR, and the Pigment Dispersing Factor (PDFR). We tested the consequences of targeted genetic knockdown and found that RNAi elements targeting each dopamine receptor caused a significant reduction in survival under starvation. In contrast, PDFR knockdown significantly extended lifespan under starvation whereas expression of a tethered PDF in AKH cells resulted in a significantly shorter lifespan during starvation. These manipulations also caused various changes in locomotor activity under starvation. Specifically, there were higher amounts of locomotor activity in dopamine receptor knockdowns, in both replete and starved states. PDFR knockdown resulted in increased locomotion during replete conditions and locomotion levels that were comparable to wild-type during starvation. Expression of a membrane-tethered PDF led to decreased locomotion under baseline and starvation. Next, we used live-cell imaging to evaluate the acute effects of the ligands for these receptors (dopamine, ecdysone, and Pigment Dispersing Factor) on AKH cell activation. Dopamine application led to a transient increase in intracellular calcium in a sugar-dependent manner. Furthermore, we found that co-application of dopamine and ecdysone led to a complete loss of this response, suggesting that these two hormones are acting antagonistically. We also found that PDF application directly led to an increase in cAMP in AKH cells, and that this response was dependent on expression of the PDFR in AKH cells. Together these results suggest a complex circuit in which multiple hormones act on AKH cells to modulate metabolic state.