bluuebunny/crossref_metadata_2025_split huggingface dataset:
DNA flexibility regulates transcription factor binding to nucleosomes
Authors: Mariani Luca , Liu Xiao , Lee Kwangwoon , Gisselbrecht Stephen S. , Cole Philip A. , Bulyk Martha L. 
Published: September 2024

ABSTRACTCell fate decisions are controlled by sequence-specific transcription factors (TFs), referred to as ‘pioneer’ factors, that bind their target sites within nucleosomes (’pioneer binding’) and thus initiate chromatin opening. However, pioneers bind just a minority of their recognition sequences present in the genome, suggesting that local sequence context features may regulate pioneer binding. Here, we developed PIONEAR-seq, a highly parallel sequencing-based biochemical assay for high-throughput analysis of TF binding to nucleosomes on nucleosome positioning sequences. Using PIONEAR-seq, we characterized the pioneer binding of 7 human pioneer TFs. Comparison of TF binding to nucleosomes based on the synthetic Widom 601 (W601) model sequence versus three different genomic sequences revealed that the positional preferences of these TFs’ binding to nucleosomes (i.e., dyad, periodic and end binding) is determined by the broader sequence context of the nucleosome, rather than being a property intrinsic to the TF. We propose a model where the flexibility and rigidity within nucleosomal DNA regulate where pioneers bind within nucleosomes. Our results suggest that the broader physical properties of nucleosomal DNA represent another layer ofcis-regulatory information read out by TFs in eukaryotic genomes.
Agar concentration affects the evolution of antibiotic resistance and population genomics in experimental populationsPseudomonas aeruginosa
Authors: Akter Mahfuza , Bailey Susan F. 
Published: September 2024

AbstractBacteria live in a diversity of spatially structured environments, which can impact their evolutionary dynamics via local interactions and environmental variation. Spatial structure is expected to slow the rate of adaptive evolution, increase the amount of clonal competition and so increase diversity of evolutionary trajectories explored as a population evolves. In the lab, agar is a common way in which we add spatial structure to bacterial growth environments. In this study we explored the effects of agar concertation on experimental populations ofPseudomonas aeruginosaevolved in the presence/ absence of a sub-lethal concentration of an antibiotic, ciprofloxacin. We varied agar across four different concentrations which modified viscosity and so the rate at which bacteria move through their environment, as well as potentially shifting the mode of motility. We saw that increasing agar concentration decreased the rate of adaptation, and that the presence of antibiotics, amplified this effect. The number and frequency of evolved mutations also varied with agar concentration and the direction of the effect changed in the presence/ absence of antibiotics – for example, the number of high frequency mutation increased with agar concentration when antibiotics were absent but decreased when antibiotics were present. We also saw an increase in the degree of parallel evolution in populations evolved in the presence of antibiotics and even more so in higher concentrations of agar. Thus, we show that agar concentration, and so spatial structure, can be an important driver of evolutionary dynamics with important impacts on antibiotic resistance evolution including the rate and predictability of adaptation.
Directed disruption of IL2 aggregation sites produces designer biologics with enhanced specificity coupled to improved production capacity
Authors: Dashwood Amy , Makuyana Ntombizodwa , van der Kant Rob , Ghodsinia Arman , Hernandez Alvaro R. , Lienart Stephanie , Burton Oliver , Dooley James , Ali Magda , Kouser Lubna , Naranjo Francisco , Holt Matthew G. , Rousseau Frederic , Schymkowitz Joost , Liston Adrian 
Published: September 2024

AbstractThe pleotropic nature of interleukin-2 (IL2) has allowed it to be used as both a pro-inflammatory and anti-inflammatory therapeutic agent, through promotion of regulatory T cell (Treg) responses via the IL2RA receptor or promotion of CD8 T cell responses via the IL2RB receptor, respectively. However, the utility of IL2 as a treatment is limited by this same pleiotropy, and protein engineering to bias specificity towards either the regulatory T cell (Treg) or CD8 T cell lineage often requires a trade-off in protein production or total bioactivity. Here we use SolubiS, a computational algorithm-based method, to predict mutations within the IL2 structure to improve protein production yield while altering cellular selectivity, to generate a mutein with elevated therapeutic potential. The design and testing process identified the V126R (murine) / V111R (human) mutation as a Treg-enhancing mutein, creating a cation repulsion to inhibit primary binding to IL2RB, with a post-IL2RA confirmational shift enabling secondary IL2RB binding, and hence allowing the trimeric receptor complex to form. In human IL2, additional N110R T151R aggregation-protecting mutations could improve protein yield of the V111R mutation. The approach also generated novel CD8 T cell-promoting mutations. Y79K created a cation-cation repulsion with IL2RA, while Q50W enhanced CD8 T cell activity through potential π-stacking enhancing binding to IL2RB, with the combination highly stimulatory for CD8 T cells. For human IL2, Y65K (homolog to murine Y79K) coupled with E82K prevented IL2RA binding, however it required the aggregation-protecting mutations of N110R T151R to rescue production. These muteins, designed with both cellular specificity and protein production features, have potential as both biological tools and therapeutics.
Don’t bet against the odds! Odd prey in mixed species groups suffer fewer attacks than lone individuals
Authors: Shah Akanksha , Webster Mike M. 
Published: September 2024

ABSTRACTMixed-species groups are common in nature. Such groups are characterised by the presence of one or more majority species, and smaller numbers of minority species. Minority individuals are expected to be subject to oddity effects; by looking or behaving differently to majority members they should be disproportionately targeted by predators. Given this, why might minority species remain in mixed-species groups? To address this question, we used threespine sticklebacks (Gasterosteus aculeatus) as predators and two ‘species’ of virtual prey presented via videos. We compared predator attacks on solitary prey, and odd and majority grouped prey individuals in groups of different sizes. We found that solitary prey were attacked significantly more than odd and majority grouped prey, while, in fact, odd and majority grouped prey did not differ from each other in terms of attacks received. We also found that prey in smaller groups suffered significantly more attacks than prey in larger groups. These findings provide no evidence for oddity effects but suggest evidence of a confusion effect. Natural mixed-species groups persist for various reasons, for example as foraging guilds, or because some members take advantage of more effective vigilance or alarm calls of others. We suggest, based on these findings, an additional non-mutually exclusive reason; under some circumstances, odd individuals might join larger heterospecific groups because any costs of being odd are greatly outweighed by the predation risk costs of remaining alone.
Spatial structure facilitates evolutionary rescue by drug resistance
Authors: Fruet Cecilia , Müller Ella Linxia , Loverdo Claude , Bitbol Anne-Florence 
Published: September 2024

AbstractBacterial populations often have complex spatial structures, which can impact their evolution. Here, we study how spatial structure affects the evolution of antibiotic resistance in a bacterial population. We consider a minimal model of spatially structured populations where all demes (i.e., subpopulations) are identical and connected to each other by identical migration rates. We show that spatial structure can facilitate the survival of a bacterial population to antibiotic treatment, starting from a sensitive inoculum. Specifically, the bacterial population can be rescued if antibiotic resistant mutants appear and are present when drug is added, and spatial structure can impact the fate of these mutants and the probability that they are present. Indeed, the probability of fixation of neutral or deleterious mutations providing drug resistance is increased in smaller populations. This promotes local fixation of resistant mutants in the structured population, which facilitates evolutionary rescue by drug resistance in the rare mutation regime. Once the population is rescued by resistance, migrations allow resistant mutants to spread in all demes. Our main result that spatial structure facilitates evolutionary rescue by antibiotic resistance extends to more complex spatial structures, and to the case where there are resistant mutants in the inoculum.Author SummaryAntibiotic resistance is a major challenge, since bacteria tend to adapt to the drugs they are subjected to. Understanding what conditions facilitate or hinder the appearance and spread of resistance in a bacterial population is thus of strong interest. Most natural microbial populations have complex spatial structures. This includes host-associated microbiota, such as the gut microbiota. Here, we show that spatial structure can facilitate the survival of a bacterial population to antibiotic treatment, by promoting the presence of resistant bacteria. Indeed, neutral or deleterious mutants giving resistance can take over small populations more easily than large ones, thanks to the increased importance of fluctuations in small populations. Resistant mutants can then spread to the whole structured population. Thus, population spatial structure can be a source of antibiotic treatment failure. This effect of spatial structure is generic and does not require environment heterogeneity.
Phosphatase-independent suppression of mucosal inflammation and disease progression bySalmonellaSopB
Authors: Diab Nour , Stange Eva-Lena , Yong Chiun Huei , Deiwick Jörg , Vucur Mihael , Lüdde Tom , Hensel Michael , Torow Natalia , Zhang Kaiyi , Hornef Mathias W. 
Published: September 2024

AbstractSalmonella entericasubsp.entericaserovar Typhimurium (S.Typhimurium) translocates effector molecules via itsSalmonellapathogenicity island (SPI)1 encoded type 3 secretion system (T3SS) to induce internalization by intestinal epithelial cells and manipulate cellular responses. Among these effector molecules, theSalmonellaouter protein B (SopB) was shown to possess phosphatidyl-inositol phosphatase activity and induce bacterial internalisation, promote cell survival, influence endosomal trafficking and alter host cell signalling. Using a neonatalS.Typhimurium infection model, we here show that SopBin vivosuppresses early epithelial chemokine expression, delays mucosal immune cell recruitment, reduces barrier impairment by enterocyte necroptosis, and prevents disease progression and premature death. Unexpectedly, this immunosuppressive effect was independent of the phosphatidyl-inositol phosphatase and phosphotransferase activity of SopB but required an intact N-terminal domain. Thus, SopB exerts a potent phosphatase-independent immunosuppressive effect to delay local tissue inflammation and disease progression likely to promote host transmission.
Are you talking to me? How the choice of speech register impacts listeners’ hierarchical encoding of speech
Authors: Piazza Giorgio , Carta Sara , Ip Emily , Pérez-Navarro Jose , Kalashnikova Marina , Martin Clara D. , Di Liberto Giovanni M. 
Published: September 2024

SummarySpeakers accommodate their speech to meet the needs of their listeners, producing different speech registers. One such register is Foreigner-Directed Speech (FDS), which is the way native speakers address non-native listeners, typically characterized by features such as slow speech rate and phonetic exaggeration. Here, we investigated how register impacts the cortical encoding of speech at different levels of language integration. Specifically, we tested the hypothesis that enhanced comprehension of FDS compared with Native-Directed Speech (NDS) involves more than just a slower speech rate, influencing speech processing from acoustic to semantic levels. Electroencephalography (EEG) signals were recorded from Spanish native listeners, who were learning English (L2 learners), and English native listeners (L1 listeners) as they were presented with audio-stories. Speech was presented in English in three different speech registers: FDS, NDS and a control register (Slow-NDS) which is slowed down version of NDS. We measured the cortical tracking of acoustic, phonological, and semantic information with a multivariate temporal response function analysis (TRF) on the EEG signals. We found that FDS promoted L2 learners’ cortical encoding at all the levels of speech and language processing considered. First, FDS led to a more pronounced encoding of the speech envelope. Second, phonological encoding was more refined when listening to FDS, with phoneme perception getting closer to that of L1 listeners. Finally, FDS also enhanced the TRF- N400, a neural signature of lexical expectations. Conversely FDS impacted acoustic but not linguistic speech encoding in L1 listeners. Taken together, these results support our hypothesis that FDS accommodates speech processing in L2 listeners beyond what can be achieved by simply speaking slowly, impacting the cortical encoding of sound and language at different abstraction levels. In turn, this study provides objective metrics that are sensitive to the impact of register on the hierarchical encoding of speech, which could be extended to other registers and cohorts.
SAM-based Automatic Workflow for Histology Cyst Segmentation in Autosomal Dominant Polycystic Kidney Disease
Authors: Delgado-Rodriguez Pablo , Kinakh Roman , Aldabe Rafael , Munoz-Barrutia Arrate 
Published: September 2024

AbstractAutosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder characterized by the development of numerous cysts in the kidneys, ultimately leading to significant structural alterations and renal failure. Detailed investigations of this disease frequently utilize histological analyses of kidney sections across various stages of ADPKD progression. In this paper, we introduce an automated workflow leveraging the Segment Anything Model (SAM) neural network, complemented by a series of post-processing steps, to autonomously segment cysts in histological images. This approach eliminates the need for manual annotations or preliminary training phases and enables precise quantification of cystic changes over entire kidney sections. Application of this method to sequential histology images across the development timeline of ADPKD in mice demonstrated a notable increase in the proportion of diseased tissue from 8 to 12 weeks and from 12 to 16 weeks, with the cysts appearing progressively lighter. Our workflow not only surpasses the performance of the existing Cystanalyser tool but also offers enhanced flexibility and accuracy in full-image segmentation. The developed workflow is made publicly accessible to facilitate its adoption as an efficient tool for rapid and reliable cyst segmentation in histological studies.
Is criticality a unified set-point of brain function?
Authors: Hengen Keith B. , Shew Woodrow L. 
Published: September 2024

ABSTRACTBrains face selective pressure to optimize computation, broadly defined. This optimization is achieved by myriad mechanisms and processes that influence the brain’s computational state. These include development, plasticity, homeostasis, and more. Despite enormous variability over time and between individuals, do these diverse mechanisms converge on the same set-point? Is there a universal computational optimum around which the healthy brain tunes itself? The criticality hypothesis posits such a unified computational set-point. Criticality is a special dynamical brain state, defined by internally-generated multi-scale, marginally-stable dynamics which maximize many features of information processing. The first experimental support for this hypothesis emerged two decades ago, and evidence has accumulated at an accelerating pace, despite a contentious history. Here, we lay out the logic of criticality as a general computational end-point and systematically review experimental evidence for the hypothesis. We perform a meta-analysis of 143 datasets from manuscripts published between 2003 and 2024. To our surprise, we find that a long-standing controversy in the field is the product of a simple methodological choice that has no bearing on underlying dynamics. Our results suggest that a new generation of research can leverage the concept of criticality—as a unifying principle of brain function–to accelerate our understanding of behavior, cognition, and disease.
Life stage- and sex-specific sensitivity to nutritional stress in a holometabolous insect
Authors: Brueggemann Leon , Singh Pragya , Müller Caroline 
Published: September 2024

AbstractOver the course of their lives, organisms can be repeatedly exposed to stress, which shapes their phenotype. At certain life stages, known as sensitive phases, individuals might be more receptive to such stress than at others. One of these stresses is nutritional stress, such as food limitation. However, little is known about how plastic responses differ between individuals experiencing nutritional stress early versus later in life or repeatedly, particularly in species with distinct ontogenetic niches. Moreover, there may be sex-specific differences due to distinct physiology.The turnip sawfly,Athalia rosae (Hymenoptera: Tenthredinidae), is a holometabolous herbivore, whose larvae consume leaves and flowers, while the adults take up nectar. We examined the effects of starvation experienced at different life stages on life-history traits as well as adult behavioural and metabolic traits to determine which life-stage may be more sensitive to nutritional stress and how specific these traits respond. We exposed individuals to four distinct nutritional regimes, no, larval, or adult starvation, or starvation periods during both larval and adult stage.Larvae exposed to starvation had a prolonged developmental time, and starved females reached a lower initial adult body mass than non-starved individuals. However, males did not differ in initial adult body mass regardless of larval starvation, suggesting the ability to conform well to poor nutritional conditions, possibly through changes in development and metabolism.Adult behaviour, measured as activity, was not significantly impacted by larval or adult starvation in either sex. Individuals starved as larvae had similar carbohydrate and lipid (i.e. fatty acid) contents as non-starved individuals, potentially due to building up energy reserves during their prolonged development, while starvation during adulthood or at both stages led to reduced energy reserves in males.This study indicates that the sensitivity of a life stage to nutritional stress depends on the specific trait under consideration. Life-history traits were mainly affected by larval nutritional stress, while activity appeared to be more robust and metabolism mostly impacted by the adult nutritional conditions. Individuals differed in their ability to conform to the given environment, with the responses being life stage- and sex-specific.
CIZ1 regulates G1 length and the CDK threshold for initiation of DNA replication to prevent DNA replication stress
Authors: Tollitt James , Briggs Tiernan , Allinson Sarah L. , Staples Christopher J. , Parsons Jason L. , Mort Richard L. , Copeland Nikki A. 
Published: September 2024

AbstractEukaryotic cell division is regulated by oscillating CDK activity, which must reach critical CDK threshold activity levels to progress through cell cycle stages. In low mitogen, low CDK environments cells exit the cell cycle into a non-proliferative quiescent state, G0, that plays essential roles in stem cell maintenance and cellular homeostasis. CIZ1 regulates cell cycle and epigenetic programmes, and CIZ1 ablation enhances genomic instability after release from quiescence. Here, we determined the mechanisms that promote genome instability in CIZ1 ablated cells using a combination of Fucci(CA) live cell imaging, cell-free DNA replication assays and DNA combing. Cell cycle dynamics are unaffected inCIZ1−/−(CIZ1 KO) fibroblasts; however, a specific post-quiescent phenotype is observed resulting in a reduced G1 phase and cell cycle length. The reduction in G1 length in CIZ1 KO cells is associated with increased cyclin E1/E2 and A2 expression, and enhanced phosphorylation of Rb leading to early restriction point bypass.CIZ1−/−cells are deficient in cyclin A chromatin binding and required increased cyclin-CDK activity for the initiation of DNA replication, which is associated with DNA replication stressin vitroandin vivo. Significantly, the CDK threshold for initiation of DNA replication was 2-fold higher in CIZ1 KO nuclei than parental controls. Importantly, addition of recombinant CIZ1in vitroandin vivopromotes recruitment of cyclin A to chromatin and reinstates the CDK threshold for initiation of DNA replication, reversing DNA replication stress and increasing replication fork rates. Loss of CIZ1 is associated with dysregulated cyclin-CDK signalling, resulting in reduced G1 length, an increased CDK activity threshold required to promote initiation of DNA replication that results in DNA replication stress. These data suggest that CIZ1 facilitates recruitment of cyclin-CDK complexes to chromatin and contributes to the mechanisms that determine the threshold CDK activity required for the G1/S transition in post-quiescent cells. Taken together the data support a role for CIZ1 in the prevention of DNA replication stress and maintenance of genome stability.