bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thermal phenotypic plasticity of pre- and post-copulatory male harm buffers sexual conflict in wildDrosophila melanogaster
Authors: Londoño-Nieto Claudia , García-Roa Roberto , Garcia-Co Clara , González Paula , Carazo Pau 
Published: November 2022

ABSTRACTStrong sexual selection frequently leads to sexual conflict and ensuing male harm, whereby males increase their reproductive success at the expense of harming females. Male harm is a widespread evolutionary phenomenon with a strong bearing on population viability. Thus, understanding how it unfolds in the wild is a current priority. Here, we sampled a wildDrosophila melanogasterpopulation and studied male harm across the normal range of temperatures under which it reproduces optimally in nature by comparing female lifetime reproductive success and underlying male harm mechanisms under monogamy (i.e., low male competition/harm) vs. polyandry (i.e., high male competition/harm). While females had equal lifetime reproductive success across temperatures under monogamy, polyandry resulted in a maximum decrease of female fitness at 24°C (35%), reducing its impact at both 20°C (22%), and 28°C (10%). Furthermore, female fitness components and pre- (i.e., harassment) and post-copulatory (i.e., ejaculate toxicity) mechanisms of male harm were asymmetrically affected by temperature. At 20°C, male harassment of females was reduced, and polyandry accelerated female actuarial ageing. In contrast, the effect of mating on female receptivity (a component of ejaculate toxicity) was affected at 28°C, where the mating costs for females decreased and polyandry mostly resulted in accelerated reproductive ageing. We thus show that, across a natural thermal range, sexual conflict processes and their effects on female fitness components are plastic and complex. As a result, the net effect of male harm on overall population viability is likely to be lower than previously surmised. We discuss how such plasticity may affect selection, adaptation and, ultimately, evolutionary rescue under a warming climate.
Selectivity and ranking of tight-binding JAK-STAT inhibitors using Markovian milestoning with Voronoi tessellations
Authors: Ojha Anupam Anand , Srivastava Ambuj , Votapka Lane William , Amaro Rommie E. 
Published: November 2022

AbstractJanus kinases (JAK) are a group of proteins in the non-receptor tyrosine kinase (NRTKs) family that play a crucial role in growth, survival, and angiogenesis. They are activated by cytokines through the Janus kinase - signal transducer and activator of transcription (JAK-STAT) signaling pathway. JAK-STAT signaling pathways have significant roles in the regulation of cell division, apoptosis, and immunity. Identification of the V617F mutation in the Janus homology 2 (JH2) domain of JAK2 leading to myeloproliferative disorders has stimulated great interest in the drug discovery community to develop JAK2-specific inhibitors. However, such inhibitors should be selective towards JAK2 over other JAKs and display an extended residence time. Recently, novel JAK2/STAT5 axis inhibitors (N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives) have displayed extended residence times (hours or longer) on target and adequate selectivity excluding JAK3. To facilitate a deeper understanding of the kinase-inhibitor interactions and advance the development of such inhibitors, we utilize a multiscale Markovian milestoning with Voronoi tessellations (MMVT) approach within the Simulation-Enabled Estimation of Kinetic Rates v.2 (SEEKR2) program to rank-order these inhibitors based on their kinetic properties and further explain the selectivity of JAK2 inhibitors over JAK3. Our approach investigates the kinetic and thermodynamic properties of JAK-inhibitor complexes in a user-friendly, fast, efficient, and accurate manner compared to other brute force and hybrid enhanced sampling approaches.
Wastewater as a back door to serology?
Authors: Agan Marie LittleFawn , Taylor William R. , Young Isaiah , Willis William A. , New Gari D. , Lair Halee , Murphy Anastasia , Marinelli Anna , Juel Md Ariful Islam , Munir Mariya , Dornburg Alex , Schlueter Jessica , Gibas Cynthia 
Published: November 2022

AbstractWastewater surveillance is a powerful tool for monitoring the prevalence of infectious disease. Systems for wastewater monitoring were put in place throughout the world during the COVID-19 pandemic. These systems use viral RNA copies as the basis of estimates of COVID-19 cases in the sewershed area, thereby providing data critical for public health responses. However, the potential to measure other biomarkers in wastewater during outbreaks has not been fully explored. Here we report a novel approach for detecting specific human antibodies from wastewater. We measured the abundance of anti-SARS-CoV-2 spike IgG and IgA from fresh samples of community wastewater and from archived frozen samples dating from 2020-22. The assay described can be performed with readily available reagents, at a moderate per-sample cost. Our findings demonstrate the feasibility of noninvasive serological surveillance via wastewater, enabling a new approach to immunity-based monitoring of populations.
Metabolic Sensing of Extra-cytoplasmic Copper Availability via Translational Control by a Nascent Exported Protein
Authors: Öztürk Yavuz , Andrei Andreea , Blaby-Haas Crysten E. , Daum Noel , Daldal Fevzi , Koch Hans-Georg 
Published: November 2022

AbstractMetabolic sensing is a crucial prerequisite for cells to adjust their physiology to rapidly changing environments. In bacteria, the response to intra- and extra-cellular ligands is primarily controlled by transcriptional regulators, which activate or repress gene expression to ensure metabolic acclimation. Translational control, such as ribosomal stalling can also contribute to cellular acclimation and has been shown to mediate responses to changing intracellular molecules. In the current study, we demonstrate that co-translational export of the protein CutF regulates translation of the down-streamcutO-encoded multi-copper oxidase CutO in response to extracellular copper (Cu). Our data show that CutF, acting as a Cu sensor, is co-translationally exported by the signal recognition particle pathway. Binding of Cu to the periplasmically exposed Cu-binding motif of CutF delays its co-translational export via its C-terminal ribosome stalling-like motif. This allows the unfolding of an mRNA stem-loop sequence that shields the ribosome-binding site ofcutO,which favors its subsequent translation. Bioinformatic analyses reveal that CutF-like proteins are widely distributed in bacteria and often, are located upstream of genes involved in transition metal homeostasis. Our overall findings illustrate a highly conserved control mechanism using co-translational export of a protein acting as a sensor to integrate the changing availability of extracellular nutrients into metabolic acclimation.ImportanceMetabolite sensing is a fundamental biological process, and the perception of dynamic changes in the extracellular environment is of paramount importance for the survival of organisms. Bacteria usually adjust their metabolism to changing environments by transcriptional regulation. Here, we describe an alternative translational mechanism that controls the bacterial response to the presence of copper, a toxic micronutrient. This mechanism involves a co-translationally secreted protein that, in the presence of copper, undergoes a process resembling ribosomal stalling. This allows the unfolding of a downstream mRNA stem-loop and enables translation of the adjacent Cu-detoxifying multicopper oxidase. Bioinformatic analyses reveal that such proteins are widespread, suggesting that metabolic sensing using ribosome-arrested nascent secreted proteins acting as sensors may be a common strategy for integrating environmental signals into metabolic adaptation.
Iron deficiency modulates metabolic landscape of Bacteroidetes promoting its resilience during inflammation
Authors: Lewis Janina P. , Gui Qin 
Published: November 2022

AbstractBacteria have to persist in low iron conditions in order to adapt to host’s nutritional immunity. Since the knowledge of iron stimulon of Bacteroidetes is sparse, we examined oral (Porphyromonas gingivalisandPrevotella intermedia) and gut (Bacteroides thataiotaomicron) representatives for their ability to adapt to iron deplete and iron replete conditions. Our transcriptomics and comparative genomics analysis shows that many iron-regulated mechanisms are conserved within the phylum. Those include genes upregulated in low iron:fldA(flavodoxin), hmu(hemin uptake operon) and loci encoding ABC transporters. Downregulated were:frd(ferredoxin),rbr(rubrerythrin), sdh(succinate dehydrogenase/fumarate reductase),vor(oxoglutarate oxidoreductase/dehydrogenase), andpfor(pyruvate:ferredoxin/ flavodoxin oxidoreductase). Some genus-specific mechanisms, such as theB. thetaiotaomicron’ssuscoding for carbohydrate metabolism and thexusABCcoding for xenosiderophore utilization, were also identified. While all bacteria tested in our study had thenrfAHoperon coding for nitrite reduction and were able to reduce nitrite levels present in culture media, the expression of the operon was iron dependent only inB. thetaiotaomicron.It is noteworthy that we identified a significant overlap between regulated genes found in our study and theB. thetaiotaomicroncolitis study (Zhu et al; Cell Host Microbe 27: 376-388). Many of those commonly regulated genes were also iron regulated in the oral bacterial genera. Overall, this work points to iron being the master regulator enabling bacterial persistence in the host and paves the way for more generalized investigation of the molecular mechanisms of iron homeostasis in Bacteroidetes.
Human and murine neutrophils share core transcriptional programs in both homeostatic and inflamed contexts
Authors: Hackert Nicolaj S. , Radtke Felix A. , Exner Tarik , Lorenz Hanns-Martin , Müller-Tidow Carsten , Nigrovic Peter A. , Wabnitz Guido , Grieshaber-Bouyer Ricardo 
Published: November 2022

AbstractNeutrophils are frequently studied in murine models, but the extent to which findings translate to humans remains poorly defined. Here, we performed an integrative transcriptomic analysis of 11 murine and 13 human datasets. In homeostasis, neutrophils exhibited the highest number of lineage-specific genes and the greatest degree of correlated expression among genes with one-to-one orthologs (r= 0.79,P< 2.2 × 10−16) compared to other leukocytes. In inflammation, neutrophils displayed considerable transcriptional diversity, but shared a core inflammation program across a broad range of conditions which was conserved between species. This core program included genes encoding IL-1 family members, CD14, IL-4R, CD69 and PD-L1. Chromatin accessibility of core inflammation genes increased significantly in blood compared to bone marrow and further with migration from blood to tissue. Transcription factor enrichment analysis nominated members of the NF-κB family and AP-1 complex as important drivers of the core inflammation program, and HoxB8 neutrophils with JUNB knockout showed a significantly reduced expression of core inflammation genes at baseline and upon stimulation. In vitro perturbations confirmed surface protein upregulation of core inflammation members in both species. Together, we demonstrate substantial transcriptional conservation in neutrophils in homeostasis and identify a core inflammation program conserved across species. This systems biology approach can be leveraged to improve transitions between the murine and human context.Key PointsThe transcriptome of resting neutrophils is substantially conserved between humans and miceA core inflammation program in neutrophils is shared across a broad range of conditions and conserved across humans and miceGraphical Abstract
Plethora of QTLs found inArabidopsis thalianareveals complexity of genetic variation for photosynthesis in dynamic light conditions
Authors: Theeuwen Tom P.J.M. , Logie Louise L. , Put Sanne , Bagheri Hedayat , Łosiński Konrad , Drouault Justine , Flood Pádraic J. , Hanhart Corrie , Becker Frank F.M. , Wijfjes Raúl , Hall David , Kramer David M. , Harbinson Jeremy , Aarts Mark G.M. 
Published: November 2022

AbstractThe environments in which plant species evolved are now generally understood to be dynamic rather than static. Photosynthesis has to operate within these dynamic environments, such as sudden changes to light intensities. Plants have evolved photoprotection mechanisms that prevent damage caused by sudden changes to high light intensities. The extent of genetic variation within plants species to deal with these dynamic light conditions remains largely unexplored. Here we show that one accession ofA. thalianahas a more efficient photoprotection mechanism in dynamic light conditions, compared to six other accessions. The construction of a doubled haploid population and subsequent phenotyping in a dynamically controlled high-throughput system reveals up to 15 QTLs for photoprotection. Identifying the causal gene underlying one of the major QTLs shows that an allelic variant ofcpFtsYresults in more efficient photoprotection under high and fluctuating light intensities. Further analyses reveal this allelic variant to be overprotecting, reducing biomass in a range of dynamic environmental conditions. This suggests that within nature, adaptation can occur to more stressful environments and that revealing the causal genes and mechanisms can help improve the general understanding of photosynthetic functioning. The other QTLs possess different photosynthetic properties, and thus together they show how there is ample intraspecific genetic variation for photosynthetic functioning in dynamic environments. With photosynthesis being one of the last unimproved components of crop yield, this amount of genetic variation for photosynthesis forms excellent input for breeding approaches. In these breeding approaches, the interactions with the environmental conditions should however be precisely assessed. Doing so correctly, allows us to tap into nature’s solution to challenging environmental conditions.
Proteome efficiency of metabolic pathways inEscherichia coliincreases along the nutrient flow
Authors: Hu Xiao-Pan , Schroeder Stefan , Lercher Martin J. 
Published: November 2022

AbstractUnderstanding the allocation of the cellular proteome to different cellular processes is central to unraveling the organizing principles of bacterial physiology. Proteome allocation to protein translation itself is maximally efficient, i.e., it represents the minimal allocation of dry mass able to sustain the observed protein production rate. In contrast, recent studies on bacteria have demonstrated that the concentrations of many proteins exceed the minimal level required to support the observed growth rate, indicating some heterogeneity across pathways in their proteome efficiency. Here, we systematically analyze the proteome efficiency of metabolic pathways, which together account for more than half of theE. coliproteome during exponential growth. Comparing the predicted minimal and the observed proteome allocation to different metabolic pathways across growth conditions, we find that the most costly biosynthesis pathways – those for amino acid biosynthesis and cofactor biosynthesis – are expressed for near optimal efficiency. Overall, proteome efficiency increases along the carbon flow through the metabolic network: proteins involved in pathways of nutrient uptake and central metabolism tend to be highly over-abundant, while proteins involved in anabolic pathways and in protein translation are much closer to the expected minimal abundance across conditions. Our work thus provides a bird’s-eye view of metabolic pathway efficiency, demonstrating systematic deviations from optimal cellular efficiency at the network level.ImportanceProtein translation is the most expensive cellular process in fast-growing bacteria, and efficient proteome usage should thus be under strong natural selection. However, recent studies show that a considerable part of the proteome is unneeded for instantaneous cell growth inE. coli. We still lack a systematic understanding of how this excess proteome is distributed across different pathways as a function of the growth conditions. We estimated the minimal required proteome across growth conditions inE. coliand compared the predictions with experimental data. We found that the proteome allocated to the most expensive internal pathways, including translation and the synthesis of amino acids and cofactors, are near the minimally required levels. In contrast, transporters and central carbon metabolism show much higher proteome levels than the predicted minimal abundance. Our analyses show that the proteome fraction unneeded for instantaneous cell growth decreases along the nutrient flow inE. coli.
The bone ecosystem facilitates multiple myeloma relapse and the evolution of heterogeneous proteasome inhibitor resistant disease
Authors: Bishop Ryan T. , Miller Anna K. , Froid Matthew , Nerlakanti Niveditha , Li Tao , Frieling Jeremy , Nasr Mostafa , Nyman Karl , Sudalagunta Praneeth R , Canevarolo Rafael , Silva Ariosto Siqueira , Shain Kenneth H. , Lynch Conor C. , Basanta David 
Published: November 2022

AbstractMultiple myeloma (MM) is an osteolytic plasma cell malignancy that, despite being responsive to therapies such as proteasome inhibitors, frequently relapses. Understanding the mechanism and the niches where resistant disease evolves remains of major clinical importance. Cancer cell intrinsic mechanisms and bone ecosystem factors are known contributors to the evolution of resistant MM but the exact contribution of each is difficult to define with currentin vitroandin vivomodels. However, mathematical modeling can help address this gap in knowledge. Here, we describe a novel biology-driven hybrid agent-based model that incorporates key cellular species of the bone ecosystem that control normal bone remodeling and, in MM, yields a protective environment under therapy. Critically, the spatiotemporal nature of the model captures two key features: normal bone homeostasis and how MM interacts with the bone ecosystem to induce bone destruction. We next used the model to examine how the bone ecosystem contributes to the evolutionary dynamics of resistant MM under control and proteasome inhibitor treatment. Our data demonstrates that resistant disease cannot develop without MM intrinsic mechanisms. However, protection from the bone microenvironment dramatically increases the likelihood of developing intrinsic resistance and subsequent relapse. The spatial nature of the model also reveals how the bone ecosystem provides a protective niche for drug sensitive MM cells under treatment, consequently leading to the emergence of a heterogenous and drug resistant disease. In conclusion, our data demonstrates a significant role for the bone ecosystem in MM survival and resistance, and suggests that early intervention with bone ecosystem targeting therapies may prevent the emergence of heterogeneous drug resistant MM.
Development of Accurate Long-lead COVID-19 Forecast
Authors: Yang Wan , Shaman Jeffrey 
Published: November 2022

AbstractCoronavirus disease 2019 (COVID-19) will likely remain a major public health burden; accurate forecast of COVID-19 epidemic outcomes several months into the future is needed to support more proactive planning. Here, we propose strategies to address three major forecast challenges, i.e., error growth, the emergence of new variants, and infection seasonality. Using these strategies in combination we generate retrospective predictions of COVID-19 cases and deaths 6 months in the future for 10 representative US states. Tallied over >25,000 retrospective predictions through September 2022, the forecast approach using all three strategies consistently outperformed a baseline forecast approach without these strategies across different variant waves and locations, for all forecast targets. Overall, probabilistic forecast accuracy improved by 64% and 38% and point prediction accuracy by 133% and 87% for cases and deaths, respectively. Real-time 6-month lead predictions made in early October 2022 suggested large attack rates in most states but a lower burden of deaths than previous waves during October 2022 – March 2023; these predictions are in general accurate compared to reported data. The superior skill of the forecast methods developed here demonstrate means for generating more accurate long-lead forecast of COVID-19 and possibly other infectious diseases.Author SummaryInfectious disease forecast aims to reliably predict the most likely future outcomes during an epidemic. To date, reliable COVID-19 forecast remains elusive and is needed to support more proactive planning. Here, we pinpoint the major challenges facing COVID-19 forecast and propose three strategies. Comprehensive testing shows the forecast approach using all three strategies consistently outperforms a baseline approach without these strategies across different variant waves and locations in the United States for all forecast targets, improving the probabilistic forecast accuracy by ∼50% and point prediction accuracy by ∼100%. The superior skills of the forecast methods developed here demonstrate means for generating more accurate long-lead COVID-19 forecasts. The methods may be also applicable to other infectious diseases.One sentence summary:To support more proactive planning, we develop COVID-19 forecast methods that substantially improve accuracy with lead time up to 6 months.
Phenotypic, molecular and functional characterisation of humanin vitro-generated IL-17A+ CD8+ T-cells
Authors: Gray Elizabeth H. , Srenathan Ushani , Durham Lucy E. , Lalnunhlimi Sylvine , Steel Kathryn J. A. , Catrina Anca , Kirkham Bruce W. , Taams Leonie S. 
Published: November 2022

AbstractIL-17A+ CD8+ T-cells, often referred to as Tc17 cells, have been identified at sites of inflammation in several immune-mediated inflammatory diseases including psoriasis and spondyloarthritis. Whilst much of our understanding of IL-17A+ CD8+ T-cells has been discerned from murine studies, human IL-17A+ CD8+ T-cells remain less-well characterised. We optimised anin vitropolarisation protocol to expand human IL-17A+ CD8+ T-cells from PBMC or bulk CD8+ T-cell populations for phenotypic and functional assessment. We show that T-cell activation in the presence of IL-1β and IL-23 significantly increased the frequencies of IL-17A+ CD8+ T-cells, which was not further enhanced by the addition of IL-6, IL-2 or anti-IFNγ mAb.In vitro-generatedIL-17A+ CD8+ T-cells from healthy donors displayed a distinct type-17 profile compared with IL-17A- CD8+ T-cells, as defined by transcriptional signature (IL17A, IL17F, RORC, RORA, MAF, IL23R, CCR6, CXCR6); high surface expression of CCR6 and CD161; and polyfunctional production of IL-17A, IL-17F, IL-22, IFNγ, TNFα and GM-CSF. A significant proportion ofin vitro-induced IL-17A+ CD8+ T-cells expressed TCRVα7.2 and bound MR1 tetramers, indicative of a MAIT CD8+ T-cell population. Using an IL-17A secretion assay, we demonstrate that thein vitro-generated IL-17A+ CD8+ T-cells were biologically functional and induced pro-inflammatory IL-6 and IL-8 production by synovial fibroblasts from patients with psoriatic arthritis. Collectively, we report anin vitroculture system to expand IL-17A+ CD8+ T-cells and further characterise their phenotype, transcriptional regulation and functional relevance to human health and disease.