bluuebunny/crossref_metadata_2025_split huggingface dataset:
A synthetic communication system uncovers extracellular immunity that self-limits bacteriophage transmission
Authors: Pathania Amit , Hopper Corbin , Pandi Amir , Függer Matthias , Nowak Thomas , Kushwaha Manish 
Published: May 2022

AbstractUnderstanding how delivery and exchange of genetic information by bacteriophages shapes bacterial populations is important for designing applications for phage therapy, biocontrol, and microbiome engineering. Here, we present a synthetic intercellular communication system that repurposes phage M13 for genetic exchange between Escherichia coli cells and build mathematical models of the communication behaviour. Our models, based on Chemical Reaction Networks, capture the growth burden, cell density, and growth phase dependence of phage secretion and infection kinetics and predict the stochasticity characterising phage-bacterial interactions at low numbers. In co-cultures of phage sender and receiver cells, resource sharing and selection pressure determine the choice of horizontal versus vertical phage transmission. Surprisingly, we discover that a phage-encoded immunity factor confers extracellular protection to uninfected bacteria, reducing infection rates by 70%. In a simulated gut environment, this novel “self-jamming” mechanism enables the phage to farm uninfected bacteria for future infections, increasing the overall success of both M13 and E. coli. The synthetic system developed here lays the groundwork for implementing population level controls in engineered bacterial communities, using phage signals for communication.
An expanding arsenal of immune systems that protect bacteria from phages
Authors: Millman Adi , Melamed Sarah , Leavitt Azita , Doron Shany , Bernheim Aude , Hör Jens , Lopatina Anna , Ofir Gal , Hochhauser Dina , Stokar-Avihail Avigail , Tal Nitzan , Sharir Saar , Voichek Maya , Erez Zohar , Ferrer Jose Lorenzo M. , Dar Daniel , Kacen Assaf , Amitai Gil , Sorek Rotem 
Published: May 2022

AbstractBacterial anti-phage defense systems are frequently clustered in microbial genomes, forming defense islands. This genomic property enabled the recent discovery of multiple defense systems based on their genomic co-localization with known systems, but the full arsenal of anti-phage mechanisms in bacteria is still unknown. In this study we report the discovery of 21 new defense systems that protect bacteria from phages, based on computational genomic analyses and phage infection experiments. We find multiple systems with protein domains known to be involved in eukaryotic anti-viral immunity, including ISG15-like proteins, dynamin-like proteins, and SEFIR domains, and show that these domains participate in bacterial defense against phages. Additional systems include protein domains predicted to manipulate DNA and RNA molecules, as well as multiple toxin-antitoxin systems shown here to function in anti-phage defense. The systems we discovered are widely distributed in bacterial and archaeal genomes, and in some bacteria form a considerable fraction of the immune arsenal. Our data substantially expand the known inventory of defense systems utilized by bacteria to counteract phage infection.
Intermittent fasting mitigates cognitive deficits in Alzheimer’s disease via the gut-brain axis
Authors: Jia Mengzhen , Shi Lin , Zhao Yihang , Hu Xinyu , Zhao Junhe , Ding Chen , Shang Yiqiu , Li Xin , Jin Xin , Dai Xiaoshuang , Liu Xuebo , Liu Zhigang 
Published: May 2022

SummaryIntermittent fasting (IF) is suggested to mitigate cognitive impairment in Alzheimer’s disease (AD). We detailed the effects of IF in AD development and assessed the contribution of the gut microbiota-metabolite-brain axis in promoting the effects of fasting. A 16-week IF regimen significantly improved spatial memory and cognitive function in AD transgenic mice; this improvement was accompanied by decreased Aβ accumulation and suppression of neuroinflammation. IF reshaped the microbiota and beneficially altered the microbial metabolites related to cognitive function. Multi-OMICs integration demonstrated a strong connection between IF induced changes in hippocampus gene expression, the composition of the gut microbes, and the serum metabolites beneficial for cognitive function. Removal of gut microbes with antibiotics abolished the neuroprotective effects of IF. These findings suggest new avenues for therapy and nutritional intervention to prevent the development of AD and other neurodegenerative diseases.
Global early replication disrupts gene expression and chromatin conformation in a single cell cycle
Authors: Santos Miguel M. , Johnson Mark C. , Fiedler Lukáš , Zegerman Philip 
Published: May 2022

AbstractThe early embryonic divisions of many organisms, including fish, flies and frogs are characterised by a very rapid S-phase caused by high rates of replication initiation. In somatic cells, S-phase is much longer due to both a reduction in the total number of initiation events and the imposition of a temporal order of origin activation. The physiological importance of changes in the rate and timing of replication initiation in S-phase remains unclear. Here we assess the importance of the temporal control of replication initiation using a conditional system in budding yeast to drive the early replication of all origins in a single cell cycle. We show that global early replication disrupts the expression of over a quarter of all genes. By deleting individual origins, we show that delaying replication is sufficient to restore normal gene expression, directly establishing replication timing control in this regulation. Global early replication disrupts nucleosome positioning and transcription factor binding during S-phase, suggesting that the rate of S-phase is important to regulate the chromatin landscape. Together these data provide new insight into the role of a temporal order of origin firing for coordinating replication, gene expression and chromatin establishment as occurs in the early embryo.
Long-term ecological and evolutionary dynamics in the gut microbiomes of carbapenemase-producing Enterobacteriaceae colonized subjects
Authors: Kang Jonathan T. L. , Teo Jonathan , Bertrand Denis , Ng Amanda , Ravikrishnan Aarthi , Yong Melvin , Tek Ng Oon , Marimuthu Kalisvar , Chen Swaine , Rei Chng Kern , Yunn-Hwen Gan , Nagarajan Niranjan 
Published: May 2022

AbstractLong-term colonization of the gut microbiome by carbapenemase-producing Enterobacteriaceae (CPE) is a growing area of public health concern as it can lead to community transmission and rapid increase in cases of life-threatening CPE infections. Leveraging the observation that many subjects are decolonized without interventions within a year, we used longitudinal shotgun metagenomics (up to 12 timepoints) for detailed characterization of ecological and evolutionary dynamics in the gut microbiome of a cohort of CPE-colonized subjects and family members (n=46; 361 samples). Subjects who underwent decolonization exhibited a distinct ecological shift marked by recovery of microbial diversity, key commensals and anti-inflammatory pathways. In addition, colonization was marked by elevated but unstable Enterobacteriaceae abundances, which exhibited distinct strain-level dynamics for different species (Escherichia coli and Klebsiella pneumoniae). Finally, comparative analysis with whole genome sequencing data from CPE isolates (n=159) helped identify sub-strain variation in key functional genes and the presence of highly similar E. coli and K. pneumoniae strains with variable resistance profiles and plasmid sharing. These results provide an enhanced view into how colonization by multi-drug resistant bacteria associates with altered gut ecology and can enable transfer of resistance genes, even in the absence of overt infection and antibiotic usage.
Gateway Identity and Spatial Remapping in a Combined Grid and Place Cell Attractor
Authors: Baumann Tristan , Mallot Hanspeter A. 
Published: May 2022

AbstractThe spatial specificities of hippocampal place cells, i.e., their firing fields, are subject to change if the rat enters a new compartment in the experimental maze. This effect is known as remapping. It cannot be explained from path integration (grid cell activity) and local sensory cues alone but requires additional knowledge of the different compartments in the form of context recognition at the gateways between them. Here we present a model for the hippocampalentorhinal interplay in which the activity of place and grid cells follows a joint attractor dynamic. Place cells depend on the current grid cell activity but can also reset the grid cell activity in the remapping process. Remapping is triggered by the passage through a gateway. When this happens, a previously stored pattern of place cell activity associated with the gateway is reactivated from a “gateway database”. The joint attractor will then reinstate the grid cell pattern that was active when the gateway had first been learned and path integration can proceed from there. The model is tested with various mazes used in the experimental literature and reproduces the published results, and we make predictions for remapping in a new maze type. We propose the involvement of memory in the form of “gate cells” that drive the place cells and with them the joint hippocampal-entorhinal loop into the corresponding attractor whenever a compartment is entered.
A label-free method to track individuals and lineages of budding cells
Authors: Pietsch Julian M. J. , Muñoz Alán F. , Adjavon Diane-Yayra A. , Farquhar Iseabail , Clark Ivan B. N. , Swain Peter S. 
Published: May 2022

AbstractMuch of biochemical regulation ultimately controls growth rate, particularly in microbes. Although time-lapse microscopy visualises cells, determining their growth rates is challenging because cells often overlap in images, particularly for those that divide asymmetrically, like Saccharomyces cerevisiae. Here we present the Birth Annotator for Budding Yeast (BABY), an algorithm to determine single-cell growth rates from label-free images. Using a convolutional neural network, BABY resolves overlaps through separating cells by size and assigns buds to mothers by identifying bud necks. BABY uses machine learning to track cells and determine lineages, estimates growth rates as the rate of change of volumes, and identifies cytokinesis by how growth varies. Using BABY and a microfluidic device, we show that bud growth is first sizer- then timer-controlled, that the nuclear concentration of Sfp1, a regulator of ribosome biogenesis, varies before the growth rate does, and that growth rate can be used for real-time control. Growth rate and fitness are strongly correlated, and BABY should therefore generate much biological insight.
Activation of TnSmu1, an integrative and conjugative element, by an ImmR-like transcriptional regulator in Streptococcus mutans
Authors: King Shawn , Quick Allison , King Kalee , Walker Alejandro R. , Shields Robert C. 
Published: May 2022

AbstractIntegrative and conjugative elements (ICEs) are chromosomally encoded mobile genetic elements that can transfer DNA between bacterial strains. Recently, as part of efforts to determine hypothetical gene functions, we have discovered an important regulatory module encoded on an ICE known as TnSmu1 on the Streptococcus mutans chromosome. The regulatory module consists of a cI-like repressor with a helix-turn-helix DNA binding domain immRSmu (immunity repressor) and a metalloprotease immASmu (anti-repressor). It is not possible to create an in-frame deletion mutant of immRSmu and repression of immRSmu with CRISPRi causes substantial cell defects. We used a bypass of essentiality (BoE) screen to discover genes that allow deletion of the regulatory module. This revealed that conjugation genes, located within TnSmu1, can restore the viability of an immRSmu mutant. Deletion of immRSmu also leads to production of a circular intermediate form of TnSmu1, that is also inducible by the genotoxic agent mitomycin C. To gain further insights into potential regulation of TnSmu1 by ImmRSmu and broader effects on S. mutans UA159 physiology we used CRISPRi and RNA-seq. Strongly induced genes included all the TnSmu1 mobile element, genes involved in amino acid metabolism, transport systems, and a Type I-C CRISPR-Cas system. Lastly, bioinformatic analysis shows that the TnSmu1 mobile element and its associated genes are well distributed across S. mutans isolates. Taken together, our results show that activation of TnSmu1 is controlled by the immRASmu module, and that activation is deleterious to S. mutans, highlighting the complex interplay between mobile elements and their host.
SbCYP79A61 Produces Phenylacetaldoxime, a Precursor of Benzyl Cyanide and Phenylacetic Acid in Sorghum bicolor
Authors: Perez Veronica C. , Dai Ru , Tomiczek Breanna , Mendoza Jorrel , Wolf Emily S.A. , Grenning Alexander , Vermerris Wilfred , Block Anna K. , Kim Jeongim 
Published: May 2022

ABSTRACTAldoximes are amino acid derivatives that serve as intermediates for numerous specialized metabolites including cyanogenic glycosides, glucosinolates, and auxins. Aldoxime formation is mainly catalyzed by cytochrome P450 monooxygenases of the 79 family (CYP79s) that can have broad or narrow substrate specificity. Aldoxime biosynthesis in the cereal sorghum (Sorghum bicolor) is not well characterized. This study identified nine CYP79-encoding genes in the genome of sorghum. A phylogenetic analysis of CYP79 showed that SbCYP79A61 formed a subclade with maize ZmCYP79A61, previously characterized to be involved in aldoxime biosynthesis. Functional characterization of this sorghum enzyme using transient expression in Nicotiana benthamiana and stable overexpression in Arabidopsis thaliana revealed that SbCYP79A61 catalyzes the production of phenylacetaldoxime (PAOx) from phenylalanine, but unlike the maize enzyme, displays no detectable activity against tryptophan. Additionally, targeted metabolite analysis after stable isotope feeding assays revealed that PAOx can serve as a precursor of phenylacetic acid (PAA) in sorghum and identified benzyl cyanide as an intermediate of PAOx-derived PAA biosynthesis in both sorghum and maize. Taken together, our results demonstrate that SbCYP79A61 produces PAOx in sorghum and may serve in the biosynthesis of other nitrogen-containing phenylalanine-derived metabolites involved in mediating biotic and abiotic stresses.HighlightIdentification of SbCYP79A61, an enzyme catalyzing the production of phenylacetaldoxime (PAOx) in sorghum, and identification of benzyl cyanide as an intermediate of PAOx-derived phenylacetic acid (PAA) biosynthesis in monocots.
Geodesics to Characterize the Phylogenetic Landscape
Authors: Khodaei Marzieh , Owen Megan , Beerli Peter 
Published: May 2022

AbstractPhylogenetic trees are fundamental for understanding evolutionary history. However, finding maximum likelihood trees is challenging due to the complexity of the likelihood landscape and the size of tree space. Based on the Billera-Holmes-Vogtmann (BHV) distance between trees, we describe a method to generate intermediate trees on the shortest path between two trees, called pathtrees. These pathtrees give a structured way to generate and visualize treespace in an area of interest. They allow investigating intermediate regions between trees of interest, exploring locally optimal trees in topological clusters of treespace, and potentially finding trees of high likelihood unexplored by tree search algorithms. We compared our approach against other tree search tools (Paup*, RAxML, and RevBayes) in terms of generated highest likelihood trees, new topology proportions, and consistency of generated treespace. We assess our method using two datasets. The first consists of 23 primate species (CytB, 1141 bp), leading to well-resolved relationships. The second is a dataset of 182 milksnakes (CytB, 1117 bp), containing many similar sequences and complex relationships among individuals. Our method visualizes the treespace using log likelihood as a fitness function. It finds similarly optimal trees as heuristic methods and presents the likelihood landscape at different scales. It revealed that we could find trees that were not found with MCMC methods. The validation measures indicated that our method performed well mapping treespace into lower dimensions. Our method complements heuristic search analyses, and the visualization allows the inspection of likelihood terraces and exploration of treespace areas not visited by heuristic searches.
Systemic coagulopathy drives host lethality in a new Drosophila tumor model
Authors: Hsi Tsai-Ching , Ong Katy L , Sepers Jorian J , Kim Jung , Bilder David 
Published: May 2022

ABSTRACTMalignant tumors trigger a complex network of inflammatory and wound repair responses, prompting Dvorak’s characterization of tumors as ‘wounds that never heal’ 1. Some of these responses lead to profound defects in blood clotting, such as Disseminated Intravascular Coagulopathy (DIC), which correlate with poor prognoses 2–4. Here, we demonstrate that a new tumor model in Drosophila provokes phenotypes that recapitulate coagulopathies observed in patients. Fly ovarian tumors overproduce multiple secreted components of the clotting cascade and trigger hypercoagulation of fly blood (hemolymph). Hypercoagulation occurs shortly after tumor induction and is transient; it is followed by a hypocoagulative state that is defective in wound healing. Cellular clotting regulators accumulate on the tumor over time and are depleted from the body, suggesting that hypocoagulation is caused by malignant growth exhaustion of host clotting components. Interestingly, clinical studies have suggested that lethality in patients with high serum levels of clotting components can be independent of thrombotic events 5,6. We show that rescuing coagulopathy improves survival of tumor-bearing flies, despite the fact that flies have an open circulatory system. Our work establishes a platform for identifying alternative mechanisms by which tumor-driven coagulopathy triggers early mortality, as well as exploring other conserved mechanisms of host responses to chronic wounds.
Potent activation of NAD+-dependent deacetylase Sirt7 by nucleosome binding
Authors: Kuznetsov Vyacheslav I. , Liu Wallace H. , Klein Mark A. , Denu John M. 
Published: May 2022

AbstractSirtuin-7 (Sirt7) is a nuclear NAD+-dependent deacetylase with a broad spectrum of biological functions. Sirt7 overexpression is linked to several pathological states and enhances anticancer drug resistance, making the enzyme a promising target for the development of novel therapeutics. Despite a plethora of reported in vivo functions the biochemical characterization of recombinant Sirt7 remains inadequate for the development of novel drug candidates. Here, we conduct an extensive biochemical analysis of Sirt7 using newly developed binding and kinetic assays to reveal that the enzyme preferentially interacts with and is activated by nucleosomes. Sirt7 activation by nucleic acids alone is effective towards long-chain acylated hydrophobic substrates while only nucleosome binding leads to 105-fold activation of deacetylase activity. Using endogenous chromatin and recombinant acetylated nucleosomes, we reveal that Sirt7 is one of the most efficient deacetylases in the sirtuin family and that its catalytic activity is limited by the rate of dissociation from deacetylated nucleosomes.
A Mathematical Model of the Within-Host Kinetics of SARS-CoV-2 Neutralizing Antibodies Following COVID-19 Vaccination
Authors: de Pillis Lisette , Caffrey Rebecca , Chen Ge , Dela Mark D. , Eldevik Leif , McConnell Joseph , Shabahang Shahrokh , Varvel Stephen A. 
Published: May 2022

AbstractCompelling evidence continues to build to support the idea that SARS-CoV-2 Neutralizing Antibody (NAb) levels in an individual can serve as an important indicator of the strength of protective immunity against infection. It is not well understood why NAb levels in some individuals remain high over time, while in others levels decline rapidly. In this work, we present a two-population mathematical model of within-host NAb dynamics in response to vaccination. By fitting only four host-specific parameters, the model is able to capture individual-specific NAb levels over time as measured by the AditxtScore™ for NAbs. The model can serve as a foundation for predicting NAb levels in the long-term, understanding connections between NAb levels, protective immunity, and break-through infections, and potentially guiding decisions about whether and when a booster vaccination may be warranted.
Reconstruction and deconstruction of human somitogenesis in vitro
Authors: Miao Yuchuan , Djeffal Yannis , De Simone Alessandro , Zhu Kongju , Silberfeld Andrew , Lee Jong Gwan , Rao Jyoti , Tarazona Oscar A. , Mongera Alessandro , Rigoni Pietro , Diaz-Cuadros Margarete , Song Laura Min Sook , Di Talia Stefano , Pourquié Olivier 
Published: May 2022

AbstractThe body of vertebrates displays a segmental organization which is most conspicuous in the periodic organization of the vertebral column and peripheral nerves. This metameric organization is first implemented when somites, which contain the precursors of skeletal muscles and vertebrae, are rhythmically generated from the presomitic mesoderm (PSM). Somites then become subdivided into anterior and posterior compartments essential for vertebral formation and segmental patterning of the peripheral nervous system1–4. How this key somitic subdivision is established remains poorly understood. Here we introduce novel tridimensional culture systems of human pluripotent stem cells (PSCs), called Somitoids and Segmentoids, which can recapitulate the formation of epithelial somite-like structures with antero-posterior (AP) identity. Using these systems, we identified a key organizing function of the segmentation clock in converting temporal rhythmicity into the spatial regularity of anterior and posterior somitic compartments. We show that an initial salt-and-pepper expression pattern of the segmentation gene MESP2 in the newly formed segment is transformed into defined compartments of anterior and posterior identity via an active cell sorting mechanism. Moreover, we demonstrate a large degree of independence of the various patterning modules involved in somitogenesis including the segmentation clock, somite epithelialization and AP polarity patterning. Together we put forward a novel framework accounting for the symmetry breaking process initiating somite polarity patterning. Our work provides a valuable platform to decode general principles of somitogenesis and advance knowledge of human development.