bluuebunny/crossref_metadata_2025_split huggingface dataset:
A mathematical model of antibiotic resistance gene flow from livestock and spread amongst humans
Authors: Fryer Helen 
Published: March 2022

AbstractThe evolution and spread of antibiotic resistance poses a major threat to human health. The high level of antibiotic use in the rearing of livestock is contributing to the origin and persistence of antibiotic resistance amongst humans. Understanding how resistance genes spread from livestock to humans and investigating the impact of managing antibiotic use in livestock will be important for guiding strategies to reduce the risk to humans. We have developed a mathematical model of the transmission of resistance genes from livestock to humans and their spread amongst the human population. Using this framework we demonstrate that although resistant zoonotic foodborne infections do not contribute significantly to the annual burden of death, they could be a source of resistance amongst other pathogens, including those that exclusively spread between humans. Amongst these pathogens, only livestock-derived resistant strains that are associated with a net fitness cost would be expected to decline in prevalence following control strategies aimed at reducing the impact on humans of antibiotic use in livestock.Author SummaryAntibiotics are an essential component of human health care. They are also used in the rearing of livestock for human consumption, which contributes to the development of antibiotic resistant pathogens. Although humans are known to be at risk from antibiotic resistance that evolves amongst livestock, the number of human lives that are at stake remains unclear. Furthermore, the number of lives that could be saved through interventions to reduce antibiotic use in livestock has not been evaluated. Here, we have developed a mathematical framework to explore these questions. Using this framework we explicitly demonstrate that there are too many uncertainties to calculate the number of preventable human deaths. Nevertheless, the importance of reserving new and currently effective antibiotics for human use is clear. Once resistance genes that do not have a fitness disadvantage have spread from livestock to humans, it is too late for interventions targeted at livestock to affect their prevalence in humans in the long term.
Pre-exposure to mRNA-LNP inhibits adaptive immune responses and alters innate immune fitness in an inheritable fashion
Authors: Qin Zhen , Bouteau Aurélie , Herbst Christopher , Igyártó Botond Z. 
Published: March 2022

ABSTRACTHundreds of millions of SARS-CoV-2 mRNA-LNP vaccine doses have already been administered to humans. However, we lack a comprehensive understanding of the immune effects of this platform. The mRNA-LNP-based SARS-CoV-2 vaccine is highly inflammatory, and its synthetic ionizable lipid component responsible for the induction of inflammation has a long in vivo half-life. Since chronic inflammation can lead to immune exhaustion and non-responsiveness, we sought to determine the effects of pre-exposure to the mRNA-LNP on adaptive immune responses and innate immune fitness. We found that pre-exposure to mRNA-LNPs or LNP alone led to long-term inhibition of the adaptive immune responses, which could be overcome using standard adjuvants. On the other hand, we report that after pre-exposure to mRNA-LNPs, the resistance of mice to heterologous infections with influenza virus increased while Candida albicans decreased. The diminished resistance to Candida albicans correlated with a general decrease in blood neutrophil percentages. Interestingly, mice pre-exposed to the mRNA-LNP platform can pass down the acquired immune traits to their offspring, providing better protection against influenza. In summary, the mRNA-LNP vaccine platform induces long-term unexpected immunological changes affecting both adaptive immune responses and heterologous protection against infections. Thus, our studies highlight the need for more research to determine this platform’s true impact on human health.Authors SummaryWe bring experimental evidence that pre-exposure to mRNA-LNPs or its LNP component affects innate and adaptive immune responses. Pre-exposure to mRNA-LNPs led to long-term inhibition of the adaptive immune responses, which the use of adjuvants could overcome. On the other hand, we report that after pre-exposure to mRNA-LNPs, the resistance of mice to heterologous infections with influenza virus increased while Candida albicans decreased. We also detected a general neutropenia in the mRNA-LNP exposed mice. Interestingly, mice pre-exposed to mRNA-LNPs can pass down the acquired immune traits to their offspring. In summary, the mRNA-LNP vaccine platform induces long-term immunological changes that can affect both adaptive immune responses and heterologous protection against infections, some of which can be inherited by the offspring. More studies are needed to understand the mechanisms responsible for these effects and determine this platform’s impact on human health.
Rapid colour changes in a tiny threatened gecko do not impede computer-assisted individual recognition
Authors: Monnet Cindy , Dokhelar Théo , Renet Julien 
Published: March 2022

AbstractPhoto-identification is a non-invasive method used for recognising wild animals with distinctive and stable patterns over time. This method is now widely used for capture-recapture wildlife monitoring. However, in species exhibiting rapid colouration changes, the evolving body patterns can lead to errors in individual recognition. In this study, we assessed the effect of dorsal physiological colour change of the tiny threatened European leaf-toed gecko (Euleptes europaea) on the performance of Wild-ID and Hotspotter, the two most commonly used individual recognition software for wildlife monitoring. We exposed 30 European leaf-toed geckos to several semi-controlled parameters (substrate type, temperature and light from natural diurnal/nocturnal cycles) in order to characterise the extent of variation in dorsal colouration, by standardised reflectance measurements. The colour of the substrate had a significant effect on individual reflectance changes. Body temperature also seemed to significantly affect the reflectance but the experimental conditions did not allow us to clearly distinguish the effect of temperature and light. For each of the 30 geckos, four photographic databases (n= 4*280) were then analysed by both software packages, under two extreme reflectance conditions. Despite the large changes in individual reflectance, Wild-ID and Hotspotter proved to be extremely reliable with a 100% recognition rate. The analysis of similarity scores suggests that Hotspotter is less sensitive to chromatic variation than Wild-ID. We provide here the first evidence that physiological colour change is not a barrier to computer-assisted individual recognition. This study advocates the use of Hotspotter for monitoring populations of European leaf-toed geckos and other saurians that generate significant colouration change over a short time.
The exchange dynamics of biomolecular condensates
Authors: Zhang Yaojun , Pyo Andrew G.T. , Kliegman Ross , Jiang Yoyo , Brangwynne Clifford P. , Stone Howard A. , Wingreen Ned S. 
Published: March 2022

AbstractA hallmark of biomolecular condensates formed via liquid-liquid phase separation is that they dynamically exchange material with their surroundings, and this process can be crucial to condensate function. Intuitively, the rate of exchange can be limited by the flux from the dilute phase or by the mixing speed in the dense phase. Surprisingly, a recent experiment suggests that exchange can also be limited by the dynamics at the droplet interface, implying the existence of an “interface resistance”. Here, we first derive an analytical expression for the timescale of condensate material exchange, which clearly conveys the physical factors controlling exchange dynamics. We then utilize sticker-spacer polymer models to show that interface resistance can arise when incident molecules transiently touch the interface without entering the dense phase, i.e., the molecules “bounce” from the interface. Our work provides insight into condensate exchange dynamics, with implications for both natural and synthetic systems.
Distilling complex evolutionary histories with shiftPlot
Authors: Miller Eliot T , Martin Bruce S 
Published: March 2022

AbstractPhylogenies form the backbone of many modern comparative methods and are integral components of contemporary science communication. Recent years have seen drastic increases in both the size and complexity of phylogenetic data as computational resources and genetic/trait databases expand. Graphical representations of these massive phylogenetic datasets push against the limits of legibility, often veering closer to artwork than scientific figures optimized to communicate results. While attractive scientific illustrations are certainly a laudable goal, researchers may want to opt for simpler representations to communicate results more concisely. Here, we introduce a new R package, shiftPlot, which implements methods for simplifying and plotting phylogenetic comparative data on discrete traits. Specifically, shiftPlot automatically finds and collapses clades exhibiting the same character state, effectively creating smaller phylogenies that may be more legibly rendered on standard page sizes. Further, these visualizations more clearly communicate evolutionary dynamics by emphasizing state shifts over tip states. While there are undoubtedly situations where this graphical approach will not be suitable (e.g., continuous traits), we believe shiftPlot will prove useful for modern researchers faced with the task of communicating the results of complex phylogenetic analyses.
Chlamydia trachomatisinduces the transcriptional activity of host YAP in a Hippo-independent fashion
Authors: Caven Liam T. , Brinkworth Amanda J. , Carabeo Rey T. 
Published: March 2022

AbstractThe obligate intracellular pathogenChlamydia trachomatisis the causative agent of the most common bacterial sexually transmitted disease worldwide. While the host response to infection by this pathogen has been well characterized, it remains unclear to what extent host gene expression during infection is the product ofChlamydia-directed modulation of host transcription factors. In this report, we show the transcriptome ofChlamydia-infected epithelial cells exhibits gene expression consistent with activity of YAP, a transcriptional coactivator implicated in cell proliferation, organ morphogenesis, wound healing, and fibrosis. After confirming induction of YAP target genes during infection, we observed increased YAP nuclear translocation inChlamydia-infected epithelial cells. We show that increased YAP activation is aChlamydia-directed process occurring during midcycle infection; critically, this phenotype is sensitive to inhibition of protein synthesis by the pathogen. Infection-mediated YAP activation bypasses YAP inhibition by the Hippo kinase cascade, instead involving YAP tyrosine phospho-activation and the activity of host Src family kinases. Taken together, our results define a mechanism forChlamydia-directed modulation of host gene expression independent of the host inflammatory response to infection, as well as introduce novel therapeutic targets for treatment of this pervasive disease.
Prioritized single-cell proteomics reveals molecular and functional polarization across primary macrophages
Authors: Huffman R Gray , Leduc Andrew , Wichmann Christoph , di Gioia Marco , Borriello Francesco , Specht Harrison , Derks Jason , Khan Saad , Khoury Luke , Emmott Edward , Petelski Aleksandra A. , Perlman David H , Cox Jürgen , Zanoni Ivan , Slavov Nikolai 
Published: March 2022

Major aims of single-cell proteomics include increasing the consistency, sensitivity, and depth of protein quantification, especially for proteins and modifications of biological interest. To simultaneously advance all these aims, we developed prioritized Single Cell ProtEomics (pSCoPE). pSCoPE consistently analyzes thousands of prioritized peptides across all single cells (thus increasing data completeness) while analyzing identifiable peptides at full duty-cycle, thus increasing proteome depth. These strategies increased the sensitivity, data completeness, and proteome coverage over 2-fold. The gains enabled quantifying protein variation in untreated and lipopolysaccharide-treated primary macrophages. Within each condition, proteins covaried within functional sets, including phagosome maturation and proton transport. This protein covariation within a treatment condition was similar across the treatment conditions and coupled to phenotypic variability in endocytic activity. pSCoPE also enabled quantifying proteolytic products, suggesting a gradient of cathepsin activities within a treatment condition. pSCoPE is freely available and widely applicable, especially for analyzing proteins of interest without sacrificing proteome coverage. Support for pSCoPE is available at: scp.slavovlab.net/pSCoPEAbstract Figure
High-fidelity dendritic sodium spike generation in human layer 2/3 neocortical pyramidal neurons
Authors: Gooch Helen M. , Bluett Tobias , Perumal Madhusoothanan B. , Vo Hong D. , Fletcher Lee N. , Papacostas Jason , Jeffree Rosalind L. , Wood Martin , Colditz Michael J. , McMillen Jason , Tsahtsarlis Tony , Amato Damian , Campbell Robert , Gillinder Lisa , Williams Stephen R. 
Published: March 2022

AbstractDendritic computations have a central role in rodent neocortical circuit function, which are signaled into neuronal output by the initiation and propagation of regenerative dendritic spikes. However, it remains poorly explored whether these mechanisms are operational in the human neocortex. To directly examine the dendritic computational properties of the most numerous class of pyramidal neuron in the human and rat neocortex we made simultaneous electrical recordings from the soma and apical dendrites of layer 2/3 pyramidal neurons maintained in acute brain slices of analogous cortical areas under identical experimental conditions. In both species correlated dendritic excitatory input led to the initiation of sodium channel-mediated dendritic spikes with conserved biophysical properties. Dendritic sodium spikes in human and rat layer 2/3 pyramidal neurons could be generated across a similar wide input range, exhibited a similar frequency range of activation, and forward propagated with high fidelity to drive neuronal output to implement stereotyped computations. Our findings therefore reveal that the dendritic computational properties of human layer 2/3 pyramidal neurons are phylogenetically conserved.
Proteochemometric method for pIC50 prediction of Flaviviridae
Authors: Singh Divye , Mahadik Avani , Surana Shraddha , Arora Pooja 
Published: March 2022

AbstractViruses remain an area of concern despite constant development of antiviral drugs and therapies. One of the contributors among others is the flaviviridae family of viruses. Like other spaces, antiviral peptides (AVP) are gaining importance for studying flaviviridae family. Along with antiviral properties of peptides, information about bioactivity takes it even closer to accurate predictions of peptide capabilities. Experimental identification of bioactivity of each potential peptide is an expensive and time consuming task. Computational methods like Proteochemometric modelling (PCM) are promising for prediction of bioactivity based on peptide and target sequence. The additional edge PCM methods bring in is the aspect of considering both peptide and target properties instead of only looking at peptide properties. In this study, we propose prediction of pIC50 for AVP against flaviviridae family target proteins. The target proteins were manually curated from literature. Here we utilize the PCM descriptors as peptide descriptors, target descriptors and cross term descriptors. We observe taking peptide and target information improves the results qualitatively and gives better pIC50 predictions. The R2 and MAPE values are 0.85 and 8.44 % respectively
TARGET-HF: Developing a model for detecting incident heart failure among symptomatic patients in general practice using routine health care data
Authors: De Clercq Lukas , Schut Martijn C. , Bossuyt Patrick , van Weert Henk , Handoko M. Louis , Harskamp Ralf 
Published: March 2022

AbstractBackgroundTimely diagnosis of heart failure (HF) is essential to optimize treatment opportunities that improve symptoms, quality of life, and survival. While most patients consult their general practitioner (GP) prior to HF, early stages of HF may be difficult to identify. An integrated clinical support tool may aid in identifying patients at high risk of HF. We therefore constructed a prediction model using routine health care data.MethodsOur study involved a dynamic cohort of patients (≥35 years) who consulted their GP with either dyspnea and/or peripheral edema within the Amsterdam metropolitan area in 2011-2020. The outcome of interest was incident HF, verified by an expert panel. We developed a regularized multivariable proportional hazards model (TARGET-HF). The model was evaluated with bootstrapping on an isolated validation set and compared to an existing model developed with hospital insurance data as well as patient age as a sole predictor.ResultsData from 31,905 patients were included (40% male, median age 60) of whom 1,301 (4.1%) were diagnosed with HF over 124,676 person-years of follow-up. Data were allocated to a development (n=25,524) and validation (n=6,381) set. TARGET-HF attained a C-statistic of 0.853 (95%-CI:0.834-0.872) on the validation set, which proved to provide a better discrimination than C=0.822 for age alone (95% CI:0.801-0.842, p<0.001) and C=0.824 for the hospital-based model (95% CI:0.802-0.843, p<0.001).ConclusionThe TARGET-HF model illustrates that routine consultation codes can be used to build a performant model to identify patients at risk for HF at time of GP consultation.
An immune dysfunction score for stratification of patients with acute infection based on whole blood gene expression
Authors: Cano-Gamez Eddie , Burnham Katie L , Goh Cyndi , Malick Zunaira H , Kwok Andrew , Smith David A , Peters-Sengers Hessel , Antcliffe David ,   GAinS Investigators, McKechnie Stuart , Scicluna Brendon P , van der Poll Tom , Gordon Anthony C , Hinds Charles J , Davenport Emma E , Knight Julian C 
Published: March 2022

AbstractDysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of deaths globally each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole blood transcriptomics for stratification of patients with severe infection by integrating data from 3,149 samples of sepsis patients and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 19-gene signature. Finally, we built a machine learning framework, SepstratifieR, to deploy SRSq in sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, thus bringing us closer to precision medicine in infection.
Bone morphogenetic protein 2 is a new molecular target linked to nonalcoholic fatty liver disease with potential value as non-invasive screening tool
Authors: Marañón Patricia , Fernández-García Carlos Ernesto , Isaza Stephania C , Rey Esther , Gallego-Durán Rocío , Montero-Vallejo Rocío , Rodríguez de Cía Javier , Ampuero Javier , Romero-Gómez Manuel , García-Monzón Carmelo , González-Rodríguez Águeda 
Published: March 2022

ABSTRACTNonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide, being nonalcoholic steatohepatitis (NASH) its most clinically relevant form. Given the risks associated with taking a liver biopsy, the design of accurate non-invasive methods to identify NASH patients is of upmost importance. BMP2 plays a key role in metabolic homeostasis; however, little is known about its involvement in NAFLD onset and progression. This study aimed to elucidate the impact of BMP2 in NAFLD pathophysiology. Hepatic and circulating levels of BMP2 were quantified in serum and liver specimens from 115 biopsy-proven NAFLD patients and 75 subjects with histologically normal liver (NL). In addition, BMP2 content and release was determined in cultured human hepatocytes upon palmitic acid (PA) overload. We found that BMP2 expression was abnormally increased in livers from NAFLD patients than in subjects with NL and this was reflected in higher serum BMP2 levels. Notably, we observed that PA upregulated BMP2 expression and secretion by human hepatocytes. An algorithm based on serum BMP2 levels and clinically relevant variables to NAFLD showed an AUROC of 0.886 (95%CI, 0.83–0.94) to discriminate NASH. We used this algorithm to develop SAN (Screening Algorithm for NASH): a SAN < 0.2 implied a low risk and a SAN ≥ 0.6 indicated high risk of NASH diagnosis. This proof-of-concept study shows BMP2 as a new molecular target linked to NAFLD and introduces SAN as a simple and efficient algorithm to screen individuals at risk for NASH.
Plasma iron controls neutrophil production and function
Authors: Frost Joe N. , Wideman Sarah K. , Preston Alexandra E. , Teh Megan R , Ai Zhichao , Wang Lihui , Cross Amy , White Natasha , Yazicioglu Yavuz , Bonadonna Michael , Clarke Alexander J. , Armitage Andrew E. , Galy Bruno , Udalova Irina A. , Drakesmith Hal 
Published: March 2022

SummaryLow plasma iron (hypoferremia) induced by hepcidin is a conserved inflammatory response that protects against infections but inhibits erythropoiesis. How hypoferremia influences leukocytogenesis is unclear. Using proteomic data, we predicted that neutrophil production would be profoundly more iron-demanding than generation of other white blood cell types. Accordingly in mice, hepcidin-mediated hypoferremia substantially reduced numbers of granulocytes but not monocytes, lymphocytes or dendritic cells. Neutrophil rebound after anti-GR1-induced neutropenia was blunted during hypoferremia, but was rescued by supplemental iron. Similarly, hypoferremia markedly inhibited pharmacologically-stimulated granulopoiesis mediated by GCSF and inflammation-induced accumulation of neutrophils in the spleen and peritoneal cavity. Furthermore, hypoferremia specifically altered neutrophil effector functions, suppressing antibacterial mechanisms but enhancing mitochondrial ROS-dependent NETosis associated with chronic inflammation. Notably, antagonising endogenous hepcidin during acute inflammation enhanced production of neutrophils. We propose plasma iron modulates the profile of innate immunity by controlling monocyte-to-neutrophil ratio and neutrophil activity in a therapeutically targetable system.