bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic exchange shapes ultra-small Patescibacteria metabolic capacities in the terrestrial subsurface
Authors: Gios Emilie , Mosley Olivia E. , Takeuchi Nobuto , Handley Kim M. 
Published: October 2022

ABSTRACTBacterial genomes are highly dynamic entities, mostly due to the extent of horizontal gene transfer (HGT) occurring in these organisms. HGT is thought to be the main driver of genetic variation and adaptation to local environment in bacteria. However, little is known about the modalities of HGT within natural microbial communities, especially the implications of genetic exchange for streamlined microorganisms such as Patescibacteria (Candidate Phyla Radiation). We searched for evidence of genetic exchange in 125 Patescibacteria genomes recovered from aquifer environments and detected the presence of hundreds of genomic islands, individually transferred genes and prophage combined, with up to 29% of genome length attributed to HGT. Results show that most individual gene transfer events occurred between Patescibacteria, but donors were also phylogenetically diverse groundwater microorganisms. Using gene donor-recipient information, we identified one potential host (Omnitrophota) of the ultra-small bacteria, and confirmed this by matching relative abundance patterns across 16 groundwater samples. A wide variety of metabolic functions were introduced in Patescibacteria genomes by HGT including transcription, translation and DNA replication, recombination and repair. This study illustrates the evolutionarily dynamic nature of Patescibacteria genomes despite the constraints of streamlining, and that HGT in these organisms is also mediated via viral infection.
Distinct modes of heat shock transcription factor interactions with mitotic chromosomes
Authors: Price Rachel M. , Budzyński Marek A. , Shen Junzhou , Mitchell Jennifer E. , Kwan James Z.J. , Teves Sheila S. 
Published: October 2022

AbstractA large number of transcription factors have been shown to bind and interact with mitotic chromosomes, which may promote the efficient reactivation of transcriptional programs following cell division. Although the DNA-binding domain (DBD) contributes strongly to TF behavior, TFs from the same DBD family can display distinct binding behaviors during mitosis. To define the mechanisms governing TF behavior during mitosis in mouse embryonic stem cells, we examined two related TFs: Heat Shock Factor 1 and 2 (HSF1 and HSF2). We found that HSF2 maintains site-specific binding genome-wide during mitosis, whereas HSF1 binding is globally decreased. Surprisingly, live-cell imaging shows that both factors appear excluded from mitotic chromosomes, and are similarly more dynamic in mitosis than in interphase. Exclusion from mitotic DNA is not due to extrinsic factors like nuclear import and export mechanisms. Rather, we found that the HSF2 DBD alone can coat mitotic chromosomes, but is insufficient to promote HSF1 coating. These data further confirm that site-specific binding and chromosome coating are independent properties, and that for some TFs, mitotic behavior is largely determined by the non-DBD regions.
GBP2 aggregates LPS and activates the caspase-4 inflammasome independent of the bacterial encapsulation factor GBP1
Authors: Dickinson Mary S. , Kutsch Miriam , Sistemich Linda , Hernandez Dulcemaria , Piro Anthony S. , Needham David , Lesser Cammie F. , Herrmann Christian , Coers Jörn 
Published: October 2022

AbstractSensing and killing of intracellular bacterial pathogens are important features of cell-autonomous immunity. The cytokine gamma-interferon (IFNγ) enhances cell-autonomous immunity through upregulation of interferon stimulated genes such as guanylate binding proteins (GBPs). GBPs promote defense against Gram-negative cytosolic bacteria in part through the induction of an inflammatory cell death pathway called pyroptosis. To activate pyroptosis, GBPs facilitate caspase-4 sensing of the Gram-negative bacterial outer membrane component lipopolysaccharide (LPS). There are seven human GBP paralogs and it is unclear how each GBP contributes to LPS sensing and pyroptosis induction. GBP1 forms a multimeric microcapsule on the surface of cytosolic bacteria through direct interactions with LPS and recruits caspase-4 to bacteria, a process deemed essential for caspase-4 activation. In contrast to GBP1, closely related paralog GBP2 is unable to bind bacteria on its own but requires GBP1 for direct bacterial binding. Unexpectedly, we find that GBP2 overexpression can restore Gram-negative-induced pyroptosis in GBP1KOcells, without GBP2 binding to the bacterial surface. A mutant of GBP1 that lacks the triple arginine motif required for microcapsule formation also rescues pyroptosis in GBP1KOcells, showing that binding to bacteria is dispensable for GBPs to promote pyroptosis. Instead, we find that GBP2, like GBP1, directly binds and aggregates ‘free’ LPS through protein polymerization. This provides a novel mechanistic framework for non-canonical inflammasome activation where GBP1 or GBP2 assemble cytosol-contaminating LPS into a protein-LPS interface for caspase-4 activation as part of a coordinated host response to Gram-negative bacterial infections.Significance StatementSensing Gram-negative bacterial lipopolysaccharide by human caspase-4 is critical for host defense to intracellular Gram-negative bacterial pathogens. Human guanylate binding proteins (GBPs) facilitate caspase-4 activation in response to Gram-negative infections by a poorly understood mechanism. The prevailing model suggests GBP1 binding to bacteria and consequential recruitment of caspase-4 to the bacterial surface are essential for triggering this host response. Here, we show GBP1 binding to bacteria is dispensable for caspase-4 activation and identify GBP2 as an additional lipopolysaccharide-binding protein that can functionally replace GBP1. We demonstrate that GBP1 and GBP2 share the ability to form lipopolysaccharide-protein complexes, which, we propose, allow caspase-4 activation. Our study provides a new mechanistic framework for cytosolic LPS sensing.
The evolution of age-specific resistance to infectious disease
Authors: Buckingham Lydia J. , Bruns Emily L. , Ashby Ben 
Published: October 2022

AbstractInnate, infection-preventing resistance often varies between host life-stages. Juveniles are more resistant than adults in some species, whereas the opposite pattern is true in others. This variation cannot always be explained by prior exposure or physiological constraints and so it has been hypothesised that trade-offs with other life-history traits may be involved. However, little is known about how trade-offs between various life-history traits and resistance at different life-stages affect the evolution of age-specific resistance. Here, we use a mathematical model to explore how trade-offs with natural mortality, reproduction and maturation combine to affect the evolution of resistance at different life-stages. Our results show that certain combinations of trade-offs have substantial effects on whether adults or juveniles are more resistant, with trade-offs between juvenile resistance and adult reproduction inherently more costly than trade-offs involving maturation or mortality (all else being equal), resulting in consistent evolution of lower resistance at the juvenile stage even when infection causes a lifelong fecundity reduction. Our model demonstrates how the differences between patterns of age-structured resistance seen in nature may be explained by variation in the trade-offs involved and our results suggest conditions under which trade-offs tend to select for lower resistance in juveniles than adults.
Risk factors for household transmission of SARS-Cov-2: a modelling study in the French national population-based EpiCov cohort
Authors: Novelli Sophie , Opatowski Lulla , Manto Carmelite , Rahib Delphine , de Lamballerie Xavier , Warszawski Josiane , Meyer Laurence 
Published: October 2022

ABSTRACTBackgroundHouseholds are specific transmission settings, as they involve close and repeated contacts between individuals of different generations. Household surveys provide a unique opportunity to better understand SARS-CoV-2 transmission and the role of individual characteristics.Here, we assessed the risk of SARS-CoV-2 acquisition from household and community exposure according to age, family ties, and socioeconomic and living conditions using data from the nationwide population-based EpiCov cohort/ORCHESTRA collaboration in November-December 2020.MethodsA history of SARS-CoV-2 infection was defined by a positive Euroimmun Anti-SARS-CoV-2 ELISA IgG result in November-December 2020. We applied stochastic chain binomial models fitted to the final distribution of infections in households to data from 17,983 individuals ≥5 years enrolled from 8,165 households. Models estimated the competing risks of being infected from community and household exposure.ResultsYoung adults aged 18-24 years had the highest risk of extra-household infection (8.9%, [95% credible interval, Crl]: 7.5 – 10.4), whereas the oldest (>75) and the youngest (6-10) had the lowest risk, 2.6% (1.8 – 3.5) and 3.4% (1.9 – 5.2), respectively. Extra-household infection was also independently associated with socioeconomic conditions. Within households, the probability of person-to-person transmission increased with age: 10.6% (5.0 – 17.9) among 6-10-year-olds to 43.1% (32.6 – 53.2) among 65-74-year-olds. It was higher between partners 29.9% (25.6 - 34.3) and from mother to child 29.1% (21.4 – 37.3) than between individuals related by other family ties.ConclusionIn 2020 in France, the main factors identified for extra-household infection were age and socioeconomic conditions. Intra-household infection mainly depended on age and family ties.Key MessagesYoung adults aged 18-24 years had the highest probability of extra-household SARS-Cov-2 acquisition over the year 2020: 8.9%, 95% credible interval (95%Crl) 7.5 – 10.4.The probability of extra-household infection increased with family income and population density in the municipality of residence and was higher in the French regions most affected by the waves of SARS-CoV-2.When estimating the probability of person-to-person transmission of SARS-CoV-2, the 65-74 year-olds had the highest susceptibility, i.e. the highest probability of SARS-CoV-2 acquisition when exposed to an infected household member (22.1%, 16.4 – 28.2)The probability of transmission was the highest between partners (29.9%, 25.6 – 34.3). The probability of transmission was higher from mother to child than from father to child: 29.1%, (21.4 – 37.3) and 14.0% (5.9 – 22.8), respectively. The probability of transmission from child to parent was higher from children <12 years than for older children: 11.8% (2.5 – 25.1) and 4.1% (0.9 – 9.0), respectively.
Functional neural architecture of cognitive control mediates the relationship between individual differences in bilingual experience and behaviour
Authors: Carter Felix , DeLuca Vincent , Segaert Katrien , Mazaheri Ali , Krott Andrea 
Published: October 2022

AbstractBilinguals have often, but not always, been found to outperform monolinguals on domain-general attentional control. Inconsistent findings have been argued to stem, at least partly, from treating bilingualism as a uniform category and from not considering how neural adaptations to bilingual experiences modulate behavioural outcomes. The present study investigated how patterns of language experience, including language switching behaviour, duration and intensity/diversity of bilingual language use, influence the brain processes underlying cognitive control, and how these in turn translate to cognitive control performance. We examined reaction times and spectral dynamics of the electroencephalograms (EEG) of two-hundred-and-thirty-nine participants (about 70% bilinguals) with diverse language experiences during two cognitive control paradigms testing interference suppression (flanker and Simon task). Using structural equation modelling, we found that different bilingual experience factors were related with neurocognitive measures, which in turn were related with behavioural interference effects, for the flanker but not the Simon task. More specifically, increased frequency of language switching and intensity / diversity of bilingual language usage was negatively related to induced top-down control measures (especially midline-frontal theta), which in turn was beneficial for interference control. In contrast, duration of bilingual engagement correlated negatively with evoked bottom-up control measures (especially P3) and was therefore detrimental to interference control. We demonstrate here for the first time how the different factors of bilingual experience lead to different neural adaptations which impact behavioural outcomes.Significance statementLike other intensive experiences, bilingualism leads to brain adaptations. It results in structural changes in language areas, and, due to demands on language control, in brain areas associated with domain-general cognitive control. Related to this, bilinguals often outperform monolinguals on cognitive control tasks. But what is often ignored is that bilingualism is a multi-dimensional phenomenon, with variations such as diversity of language usage and duration of language use. The present large-scale study of neural functioning in bilingualism revealed for the first time how individual differences in bilingual experience lead to adaptations to brain functioning which in turn affect cognitive control behaviour. It exemplifies how the complexity of individual experiences plays a fundamental role in brain function.
Natural variation in Arabidopsis responses toPlasmodiophora brassicaereveals an essential role for RPB1
Authors: Ochoa Juan Camilo , Mukhopadhyay Soham , Bieluszewski Tomasz , Jedryczka Malgorzata , Malinowski Robert , Truman William 
Published: October 2022

ABSTRACTDespite the identification of clubroot resistance genes in various Brassica crops our understanding of the genetic basis of immunity toPlasmodiophora brassicaeinfection in the model plantArabidopsis thalianaremains limited. To address this issue we performed a screen of 142 natural accessions and identified 11 clubroot resistant Arabidopsis lines. Genome wide association analysis identified several genetic loci significantly linked with resistance. Three genes from two of these loci were targeted for deletion by CRISPR/Cas9 mutation in resistant accessions Est-1 and Uod-1. Deletion ofResistance to Plasmodiophora brassicae 1(RPB1) rendered both lines susceptible to theP. brassicaepathotype P1+. Further analysis ofrpb1knock-out Est-1 and Uod-1 lines showed that the RPB1 protein is required for activation of downstream defence responses, such as the expression of phytoalexin biosynthesis geneCYP71A13. RPB1 has no known functional domains or homology to previously characterised proteins. The clubroot susceptible Arabidopsis accession Col-0 lacks a functionalRPB1gene; when Col-0 is transformed withRPB1expression driven by its native promoter it is capable of activatingRPB1expression in response to infection but this is not sufficient to confer resistance. Constitutive over-expression ofRPB1in Col-0 leads to drastically reduced growth and activation of stress-responsive genes. Furthermore, we found that transient expression ofRPB1inNicotiana tabacuminduced programmed cell death in leaves. We conclude that RPB1 is a critical component of the defence response toP. brassicaeinfection in Arabidopsis, acting downstream of pathogen recognition but required for the elaboration of effective resistance.
Atomic force microscopy evidences the underlying fibrillar formation mechanism of S100A9 neurodegenerative protein family
Authors: Marcuello Carlos 
Published: October 2022

Withdrawn reasonThe author has withdrawn the manuscript because additional results with complementary techniques are expected to complement the already gathered data and thus, having a more complete overview of the impact of several conditions of interest on the S100A9 fibrillation processes. Therefore, the author do not wish this work to be cited as reference for the project. If you have any questions, please contact with the author.
Mechanisms underlying divergent relationships between Ca2+and YAP/TAZ signaling
Authors: Khalilimeybodi A. , Fraley S.I. , Rangamani P. 
Published: October 2022

AbstractYes-associated protein (YAP) and its homolog TAZ are transducers of several biochemical and biomechanical signals, serving to integrate multiplexed inputs from the microenvironment into higher-level cellular functions such as proliferation, differentiation, apoptosis, migration, and hemostasis. Emerging evidence suggests that Ca2+is a key second messenger that closely connects microenvironmental input signals and YAP/TAZ regulation. However, studies that directly modulate Ca2+have reported contradictory YAP/TAZ responses: In some studies, a reduction in Ca2+influx increases the activity of YAP/TAZ, while in others, an increase in Ca2+influx activates YAP/TAZ. Importantly, Ca2+and YAP/TAZ exhibit distinct spatiotemporal dynamics, making it difficult to unravel their connections from a purely experimental approach. In this study, we developed a network model of Ca2+-mediated YAP/TAZ signaling to investigate how temporal dynamics and crosstalk of signaling pathways interacting with Ca2+can alter YAP/TAZ response, as observed in experiments. By including six signaling modules (e.g., GPCR, IP3-Ca2+, Kinases, RhoA, F-actin, and Hippo-YAP/TAZ) that interact with Ca2+, we investigated both transient and steady-state cell response to Angiotensin II and thapsigargin stimuli. The model predicts stimuli, Ca2+transient, and frequency-dependent relationships between Ca2+and YAP/TAZ primarily mediated by signaling species like cPKC, DAG, CaMKII, and F-actin. Model results illustrate the role of Ca2+dynamics and CaMKII bistable response in switching the direction of changes in Ca2+-induced YAP/TAZ activity for different stimuli. Frequency-dependent YAP/TAZ response revealed the competition between upstream regulators of LATS1/2, leading to the YAP/TAZ non-monotonic response to periodic GPCR stimulation. This study provides new insights into the underlying mechanisms responsible for the controversial Ca2+-YAP/TAZ relationship observed in experiments.
Manganese-dependent microRNA trimming by 3’→5’ exonucleases generates 14-nucleotide or shorter tiny RNAs
Authors: Sim GeunYoung , Kehling Audrey C. , Park Mi Seul , Secor Jackson , Divoky Cameron , Zhang Huaqun , Malhotra Nipun , Bhagdikar Divyaa , El-Wahaband Ekram Abd , Nakanishi Kotaro 
Published: October 2022

AbstractMicroRNAs (miRNAs) are about 22-nucleotide (nt) non-coding RNAs forming the effector complexes with Argonaute (AGO) proteins to repress gene expression. Although tiny RNAs (tyRNAs) shorter than 19 nt have been found to bind to plant and vertebrate AGOs, their biogenesis remains a long-standing question. Here, our in vivo and in vitro studies show several 3’→5’ exonucleases, such as interferon-stimulated gene 20 kDa (ISG20), three prime repair exonuclease 1 (TREX1), and ERI1 (enhanced RNAi, also known as 3’hExo), capable of trimming AGO-associated full-length miRNAs to 14 nt or shorter tyRNAs. Their guide trimming occurs in a manganese-dependent manner but independently of the guide sequence and the loaded four human AGO paralogs. We also show that ISG20-mediated guide trimming makes Argonaute3 (AGO3) a slicer. Given the high Mn2+ concentrations in stressed cells, virus-infected cells, and neurodegeneration, our study sheds light on the roles of the Mn2+-dependent exonucleases in remodeling gene silencing.
Machine Learning Optimization of Candidate Antibodies Yields Highly Diverse Sub-nanomolar Affinity Antibody Libraries
Authors: Li Lin , Gupta Esther , Spaeth John , Shing Leslie , Jaimes Rafael , Caceres Rajmonda Sulo , Bepler Tristan , Walsh Matthew E. 
Published: October 2022

AbstractTherapeutic antibodies are an important and rapidly growing drug modality. However, the design and discovery of early-stage antibody therapeutics remain a time and cost-intensive endeavor. In this work, we present an end-to-end Bayesian, language model-based method for designing large and diverse libraries of high-affinity single-chain variable fragments (scFvs). We integrate target-specific binding affinities with information from millions of natural protein sequences in a probabilistic machine learning framework to design thousands of scFvs that are then empirically measured. In a head-to-head comparison with a directed evolution approach, we show that the best scFv generated from our method represents a 28.8-fold improvement in binding over the best scFv from the directed evolution. Additionally, 99% of the designed scFvs in our most successful library are improvements over the initial candidate scFv. By comparing a library’s predicted success to actual measurements, we demonstrate our method’s ability to explore tradeoffs between library success and diversity during the design phase and prior to experimental testing. The results of our work highlight the significant impact machine learning models can have on scFv development. We expect our end-to-end method to be broadly applicable and able to provide value to other protein engineering tasks.