bluuebunny/crossref_metadata_2025 huggingface dataset:
KREH2 helicase represses ND7 mRNA editing in procyclic-stageTrypanosoma bruceiby opposite modulation of canonical and “moonlighting” gRNA utilization creating a proposed mRNA structure
Authors: Meehan Joshua , Ivens Alasdair , Grote Scott , Rodshagen Tyler , Chen Zihao , Goode Cody , Sharma Sunil K. , Kumar Vikas , Frese Addison , Goodall Zachary , McCleskey Laura , Sechrist Rebecca , Zeng Lanying , Savill Nicholas J. , Rouskin Silvi , Schnaufer Achim , McDermott Suzanne M. , Cruz-Reyes Jorge
Published: May 2024

Unknown factors regulate mitochondrial U-insertion/deletion (U-indel) RNA editing in procyclic-form (PCF) and bloodstream-form (BSF)T. brucei. This editing, directed by anti-sense gRNAs, creates canonical protein-encoding mRNAs and may developmentally control respiration. Canonical editing by gRNAs that specify protein-encoding mRNA sequences occurs amid massive non-canonical editing of unclear sources and biological significance. We found PCF-specific repression at a major early checkpoint in mRNA ND7, involving helicase KREH2-dependent opposite modulation of canonical and non-canonical “terminator” gRNA utilization. Terminator-programmed editing derails canonical editing and installs proposed repressive structure in 30% of the ND7 transcriptome. BSF-to-PCF differentiationin vitrorecreated this negative control. Remarkably, KREH2-RNAi knockdown relieved repression and increased editing progression by reverting canonical/terminator gRNA utilization. ND7 transcripts lacking early terminator-directed editing in PCF exhibited similar negative editing control along the mRNA sequence, suggesting global modulation of gRNA utilization fidelity. The terminator is a “moonlighting” gRNA also associated with mRNA COX3 canonical editing, so the gRNA transcriptome seems multifunctional. Thus, KREH2 is the first identified repressor in developmental editing control. This and our prior work support a model whereby KREH2 activates or represses editing in a stage and substrate-specific manner. KREH2’s novel dual role tunes mitochondrial gene expression in either direction during development.
The carnivoran adaptive landscape reveals functional trade-offs among the skull, appendicular, and axial skeleton
Authors: Law Chris J. , Hlusko Leslea J. , Tseng Z. Jack
Published: May 2024

Analyses of form-function relationships are widely used to understand links between morphology, ecology, and adaptation across macroevolutionary scales. However, few have investigated functional trade-offs and covariance within and between the skull, limbs, and vertebral column simultaneously. In this study, we investigated the adaptive landscape of skeletal form and function in carnivorans to test how functional trade-offs between these skeletal regions contribute to ecological adaptations and the topology of the landscape. We found that morphological proxies of function derived from carnivoran skeletal regions exhibit trade-offs and covariation across their performance surfaces, particularly in the appendicular and axial skeletons. These functional trade-offs and covariation correspond as adaptations to different adaptive landscapes when optimized by various factors including phylogeny, dietary ecology, and, in particular, locomotor mode. Lastly, we found that the topologies of the optimized adaptive landscapes and underlying performance surfaces are largely characterized as a single gradual gradient rather than as rugged, multipeak landscapes with distinct zones. Our results suggest that carnivorans may already occupy a broad adaptive zone as part of a larger mammalian adaptive landscape that masks the form and function relationships of skeletal traits.
Cdc25A phosphatase is activated and mediates neuronal cell death by PUMA via pRB/E2F1 pathway in a model of Parkinson’s disease
Authors: Das Anoy Kumar , Biswas Subhas C
Published: May 2024

Parkinson’s disease (PD) is a predominant movement disorder caused mainly due to selective loss of the dopaminergic neurons in the substantia nigra pars compacta of the mid brain. There is currently no cure for PD barring treatments to manage symptoms. The reasons might be due to lack of precise understanding of molecular mechanisms leading to neurodegeneration. Aberrant cell cycle activation has been implicated in neuronal death pathways of various neurodegenerative diseases including PD. This study investigates the role of cell cycle regulator Cell division cycle 25A (Cdc25A) in a PD-relevant neuron death model induced by 6-OHDA treatment. We find Cdc25A is rapidly elevated, activated and is playing a key role in neuron death by regulating Rb phosphorylation and E2F1 activity. Knockdown of Cdc25A via shRNA downregulates the levels of pro-apoptotic PUMA, an E2F1 target and cleaved Caspase-3 levels, suggesting Cdc25A may regulate neuronal apoptosis through these effectors. Our work sheds light on the intricate signaling networks involved in neurodegeneration and highlights Cdc25A as a potential therapeutic target for mitigating aberrant cell cycle re-entry underlying PD pathogenesis. These novel insights into molecular mechanisms provide a foundation for future development of neuroprotective strategies to slow or prevent progression of this debilitating disease.
Exploring operational requirements of mixtures for insecticide resistance management in public health using a mathematical model assuming polygenic resistance
Authors: Hobbs Neil Philip , Hastings Ian Michael
Published: May 2024

Long-lasting insecticide treated nets (LLINs) have been developed which contain two active ingredients. Mixture products for vector control are now an available insecticide resistance management (IRM) strategy. There is a theoretical concern around the use mixtures pertaining to dosing, insecticide decay, initial resistance, and cross resistance. Mixture LLINs all currently have a pyrethroid as one of the partner insecticides. Using previously described mathematical models of polygenic insecticide resistance evolution, which implement selection either by truncation (“polytrucate) or as a probabilistic process (“polysmooth”) mixtures are evaluated for their IRM potential. Scenarios are developed to explore the impact of the initial levels of resistance to the pyrethroid insecticide, insecticide decay rates, and insecticide doses, and cross resistance. Results from our simulations indicate that mixtures should be deployed at full doses. As the initial level of resistance to the pyrethroid increases the benefit of mixture decreases. Insecticide decay was found to be less important than might be thought, with other variables having a greater impact. The mechanism of selection demonstrated consistent results, diverging only at very high levels of resistance to the pyrethroid. Our simulations demonstrate that the impact of positive cross resistance is best mitigated using full-dose mixtures. Insecticide decay less important than previously considered, and opens up the opportunity to mix a wider variety of insecticides. However, as mixtures remain a challenge to develop and therefore strategies which could generate an effect of a “temporal” mixture should be evaluated.
Monitoring of the invasive round goby in an estuarine seascape based on eDNA
Authors: Green Leon , Dahlgren Thomas G. , Axberg Alizz , Panova Marina , Obst Matthias , Sundberg Per
Published: May 2024

0.0

Non-indigenous species (NIS) is one of the five most global concerns when it comes to ecosystem services and threats to native biodiversity. This is especially true in aquatic environments which are harder to monitor than terrestrial environments, and NIS are often found first when they are fully established and basically impossible to eradicate. In marine environments, this is further complicated due to the connectivity and difficulty of eradication. The development and implementation of effective monitoring methods for marine NIS are therefore crucial to enable early detection useful for management strategies. In this study, we develop and evaluate environmental DNA monitoring using quantitative (q)PCR as a means to assess presence of the euryhaline round goby fish (Neogobius melanostomus) in a seascape environment close to Scandinavia’s largest shipping port. We developed a dPCR assay for the species, targeting a region of 12S gene, and verified its specificity compared to other common species from the gobiid-family in the region. We also experimentally determined the decaying rate of round goby DNA in water to a half-life of 9.8 hours in 15 PSU and 15°C with live fish in captivity. Finally, we sampled 10 sites within a 400 km2area for eDNA and presence of the species using fyke-nets and baited remote video to validate the accuracy of the water samples to predict presence, and abundance. We found that the number of DNA copies extracted from the water samples varied strongly at sites where round gobies were caught in nets or on video, but that the average value from four water samples significantly correlated with an average value from four video samples, and also with the total catch at each site. The eDNA assay also detected signals from the species at sites where no fish were caught by fishing or on video. These results show that this method is highly sensitive for the species even in low abundance, and with sufficient amounts of replicates, it can be possible to determine the relative abundance between sites.
Identification of Candidate Diagnostic gene CDC25C for Trametinib-induced Cardiotoxicity by Integrating Bioinformatics and Machine Learning
Authors: Pei Jixiang , Yan Xiong , Guo Qingming , Wang Zhimei , Liu Yukun
Published: May 2024

Trametinib is a MEK inhibitor that has been shown to have considerable efficacy in retarding melanoma progression. However, the exact mechanism of cardiotoxicity induced by trametinib remains unclear. Our study was designed to investigate the underlying mechanisms by which trametinib-induced cardiotoxicity (TIC) might exist, offering novel perspectives and guidance for potential prediction, diagnosis, and treatment of TIC. The GSE217421 dataset indicated 574 up-regulated and 705 down-regulated DEGs. According to the KEGG analysis, these genes were implicated in several pathways and functions, including Cell Cycle, Axon Guidance, Cellular Senescence, and Dilated Cardiomyopathy. The GO analysis suggested their association with Mitotic Cell Cycle, Microtubule Cytoskeleton and Adenyl Nucleotide Binding. The hub genes (CDC25C) for TIC were screened through Multiple machine learning algorithms. Next, The expression level of CDC25C was verified using the GSE217423 validation set. Nomogram model based on CDC25C demonstrated excellent diagnostic capability according to three different evaluation measures. To further explore the regulatory mechanism of CDC25C in TIC, we constructed a multi-regulatory network using miRNAs-lncRNAs-TFs-CDC25C and conducted an immunoinfiltration analysis. Our study suggests that CDC25C may be a candidate diagnostic gene and a potential therapeutic target for the early occurrence and development of TIC. This provides new ideas for the prediction, diagnosis and treatment strategies for TIC.
Native Korean wild mice (Mus musculus): molecular phylogeny and morphometrics
Authors: Kim Daewoo , Oh Jooseong , Oh Jang Geun , Yang Hee-Young , Kim Geun-Joong , Lee Tae-Hoon , Lee Bae-Geun , Park Chungoo , Nam Dong-Ha
Published: May 2024

Taxonomic status of house mice in the Korean Peninsula remains poorly understood. Here, we analyze genetic and morphological characteristics of mice from Korea and evaluate their phylogenetic relationships to the well-known primary subspecies. Using a comprehensive set of publicly available genetic data (mtDNAcytbgene), Korean mice including our specimens from islands, mountains, and agricultural fields were identified toMus mus musculus. External morphology, such as tail ratios of our specimens, resembled previously assigned subspecies (e.g.,M. m. molossinus,M. m. utsuryonis, andM. m. yamashinai), suggesting a single subspecific group withinM. m. musculus. Korean mice displayed a distinctive landmark configuration around the snout, with a relatively short and slender premaxillary tooth-patch width (PMXW) and a larger maxillary tooth-row length (MXTL) compared to laboratory strains derived fromM. m. domesticus. Our investigation provides insights into the phylogenetic relationships and taxonomic status of Korean mice relative to the primary lineages ofM. musculussubspecies. Understanding the evolutionary history of KoreanM. m. musculussheds new light on how their spatiotemporal dynamics led to diversification, with the Korean Peninsula serving as an ecological bridge between East Eurasia and neighboring regions.
A synthetic method to assay polycystin channel biophysics
Authors: Larmore Megan , Esarte Palomero Orhi , Kamat Neha P. , DeCaen Paul G.
Published: May 2024

Ion channels are biological transistors that control ionic flux across cell membranes to regulate electrical transmission and signal transduction. They are found in all biological membranes and their conductive state kinetics are frequently disrupted in human diseases. Organelle ion channels are among the most resistant to functional and pharmacological interrogation. Traditional channel protein reconstitution methods rely upon exogenous expression and/or purification from endogenous cellular sources which are frequently contaminated by resident ionophores. Here we describe a fully synthetic method to assay functional properties of polycystin channels that natively traffic to primary cilia and endoplasmic reticulum organelles. Using this method, we characterize their oligomeric assembly, membrane integration, orientation and conductance while comparing these results to their endogenous channel properties. Outcomes define a novel synthetic approach that can be applied broadly to investigate channels resistant to biophysical analysis and pharmacological characterization.
The utility of whole-genome sequencing to identify likely transmission pairs for pathogens with slow and variable evolution
Authors: Wood A. J. , Benton C. H. , Delahay R. J. , Marion G. , Palkopoulou E. , Pooley C. M. , Smith G. C. , Kao R. R.
Published: May 2024

Pathogen whole-genome sequencing (WGS) has been used to track the transmission of infectious diseases in extraordinary detail, especially for pathogens that undergo fast and steady evolution, as is the case with many RNA viruses. However, for other pathogens evolution is less predictable, making interpretation of these data to inform our understanding of their epidemiology more challenging and the value of densely collected pathogen genome data uncertain. Here, we assess the utility of WGS for one such pathogen, in the “who-infected-whom” identification problem. We study samples from hosts (130 cattle, 111 badgers) with confirmed infection ofM. bovis(causing bovine Tuberculosis), which has an estimated clock rate as slow as ∼0.1–1 variations per year. For each potential pathway between hosts, we calculate the relative likelihood that such a transmission event occurred. This is informed by an epidemiological model of transmission, and host life history data. By including WGS data, we shrink the number of plausible pathways significantly, relative to those deemed likely on the basis of life history data alone. Despite our uncertainty relating to the evolution ofM. bovis, the WGS data are therefore a valuable adjunct to epidemiological investigations, especially for wildlife species whose life history data are sparse.
Evidence for a push-pull interaction between superior colliculi in monocular dynamic vision mode
Authors: Gil Rita , Valente Mafalda , Fernandes Francisca F. , Shemesh Noam
Published: May 2024

Visual perception can operate in two distinct vision modes - static and dynamic - that have been associated with different neural activity regimes in the superior colliculus (SC). The static vision mode (low flashing frequencies) is associated with strong SC activation modulated by cortical gain and inhibitory intertectal effects, while the dynamic vision mode (high flashing frequencies) evokes the continuity illusion, with associated suppression of SC neural activity. However, the pathway-wide mechanisms underpinning the dynamic vision mode remain poorly understood, especially in terms of corticotectal and tectotectal feedback. Here, we harness rat functional MRI combined with brain lesions to investigate whole-pathway interactions in the dynamic vision mode. In the SC, we find contralateral suppression of activity opposing positive ipsilateral neural activation upon monocular visual stimulation in the dynamic vision mode. A cortical amplification effect was confirmed for both static and dynamic vision modes through cortical lesions, while further lesioning ipsilateral SC led to a boost in the contralateral negative signals, suggesting an active push-pull interaction between ipsilateral and contralateral SCs during the dynamic vision mode regime. This push-pull interaction is specific to the dynamic vision mode; in the static vision mode, both SCs show similar response polarities. These results highlight hitherto unreported frequency-dependent modulations in the tectotectal pathway and further challenge the contemporary notion that intertectal connections solely serve as reciprocal inhibitory mechanisms for avoiding visual blur during saccade occurrence.

One Sentence Summary

Opposing signals between superior colliculi in the dynamic vision mode suggest an active push-pull interaction within the tectotectal commissural pathway.
Biological mechanisms are necessary to improve projections of species range shifts
Authors: Van der Meersch Victor , Armstrong Edward , Mouillot Florent , Duputié Anne , Davi Hendrik , Saltré Frédérik , Chuine Isabelle
Published: May 2024

The recent acceleration of global climate warming has created an urgent need for reliable projections of species distributions, widely used by natural resource managers. Such projections, however, are produced using various modeling approaches with little information on their relative performances under expected novel climatic conditions. Here, we hindcast the range shifts of five forest tree species across Europe over the last 12,000 years to compare the performance of three different types of species distribution models and determine the source of their robustness. We show that the performance of correlative models (CSDMs) decreases twice as fast as that of process-based models (PBMs) when climatic dissimilarity rises, and that PBM projections are likely to be more reliable than those made with CSDMs, at least until 2060 under scenario SSP245. These results demonstrate for the first time the well-established albeit so far untested idea that explicit description of mechanisms confers models robustness, and highlight a new avenue to improve model projections in the future.
An efficient biochemical method for characterizing and classifying potentially amyloidogenic and therapeutic peptides
Authors: Pradeau-Phélut Lucas , Alvès Stacy , Le Tareau Léo , Larralde Cyann , Bernard Emma , Kee Him Josephine Lai , Lepvrier Eléonore , Bron Patrick , Delamarche Christian , Garnier Cyrille
Published: May 2024

Amyloidosis are proteinopathies characterized by systemic or organ-specific deposition of proteins in the form of amyloid fibers. Nearly forty proteins have been identified to play a role in these pathologies and the structures of the associated fibers are beginning to be determined by Cryo-EM. However, the molecular events underlying the process, such as fiber nucleation and elongation, are poorly understood, which impairs developing efficient therapies. In most cases, only a few dozen amino acids of the pathological protein are found in the final structure of the fibers, while amyloid peptides comprising 5 to 10 amino acids are involved in fibers nucleation process. The identification and biochemical characterization of these peptides is therefore of major scientific and clinical importance.In silicoapproaches are limited due to the peptides’ small size and long-distance intra- and intermolecular interactions that occur during nucleation. To address this problem, we developed a novel biochemical method for characterizing and classifying batches of related peptides. Initial work to optimize our approach is based on the reference peptide PHF6 (ß1) from Microtubule Associated Protein Tau (MAPT) as compared to 22 related peptides. We classified these peptides into groups displaying different biochemical properties, and thereby identified new amyloid peptides and peptides with therapeutic potential. We underline that our method is applicable to any family of peptides and could be scaled up for high-throughput analyses.
Comprehensive Assessment of Force-Field Performance in Molecular Dynamics Simulations of DNA/RNA Hybrid Duplexes
Authors: Knappeová Barbora , Mlýnský Vojtěch , Pykal Martin , Šponer Jiří , Banáš Pavel , Otyepka Michal , Krepl Miroslav
Published: May 2024

Mixed double helices formed by RNA and DNA strands, commonly referred to as hybrid duplexes or hybrids, are essential in biological processes like transcription and reverse transcription. They are also important for their applications in CRISPR gene editing and nanotechnology. Yet, despite their significance, the hybrids have been seldom modeled by atomistic molecular dynamics methodology, and there is no benchmark study systematically assessing the force-field performance. Here, we present an extensive benchmark study of the hybrids using contemporary and commonly utilized pairwise additive and polarizable nucleic acid force fields. Our findings indicate that none of the available force-field choices accurately reproduces all the characteristic structural details of the hybrids. The AMBER force fields are unable to populate the C3′-endo (north) pucker of the DNA strand and underestimate inclination. CHARMM force field accurately describes the C3′-endo pucker and inclination but shows base pair instability. The polarizable force fields struggle with accurately reproducing the helical parameters. Some force-field combinations even demonstrate a discernible conflict between the RNA and DNA parameters. In this work, we offer a candid assessment of the force-field performance for mixed DNA/RNA duplexes. We provide guidance on selecting utilizable force-field combinations, as well as highlight potential pitfalls and best practices for obtaining optimal performance.
Sex-specific Dominance and Its Effects on Allelic Diversity in Sexually Antagonistic Loci
Authors: Siljestam Mattias , Rueffler Claus , Arnqvist Göran
Published: May 2024

Sexually antagonistic (SA) selection, favouring different alleles in males and females, can contribute to the maintenance of genetic diversity. Current theory predicts that biallelic polymorphism can be maintained in SA loci under strong selection or dominance reversal in the sexes. Yet, selection should often be weak, several candidate SA loci harbour more than two segregating alleles and dominance reversal may not be common. We present a general model to explore the evolution of alleles at autosomal and X-linked loci under SA selection, affecting a quantitative trait with distinct female and male optima. We confirm that additive allelic effects predict biallelic polymorphism, but only under symmetric and relatively strong selection. However, polyallelic polymorphism can evolve under conditions of sex-specific or X-linked dominance for the trait, particularly under weak selection, such that several alleles coexist in a single population through balancing selection. Our analysis furthermore shows that sex-specific dominance and X-linked dominance evolve when permitted, thus polyallelic polymorphism is a likely evolutionary outcome. We conclude that SA selection can drive the co-evolution of differences in dominance between the sexes and polyallelic polymorphism, particularly under weak selection, an outcome reducing the gender load. To assess these findings, we analyse segregating variation in three populations of an insect model system and find that (1) loci with the strongest signal of polyallelic polymorphism are enriched with functions associated with known SA phenotypes and (2) both candidate SA loci and loci exhibiting sex-specific dominance show a stronger signal of polyallelic polymorphism.
The dorsal thalamic lateral geniculate nucleus is required for visual control of head direction cell firing direction in rats
Authors: Street James S , Jeffery Kate J
Published: May 2024

Head direction (HD) neurons, signalling facing direction, generate a signal that is primarily anchored to the outside world by visual inputs. We investigated the route for visual landmark information into the HD system in rats. There are two candidates: an evolutionarily older, larger subcortical (retino-tectal) pathway specialised for coarse vision, and a smaller cortical (retino-geniculo-striate) pathway for higher acuity vision. We disrupted the cortical pathway by lesioning the dorsal lateral geniculate (dLGN) thalamic nuclei bilaterally, and recorded HD cells in postsubicular (PoS) cortex as rats foraged in a visual-cue-controlled enclosure. In dLGN-lesioned rats we found the expected number of PoS HD cells. Although directional tuning curves were broader across a trial, this was due to increased instability of otherwise normal-width tuning curves. Tuning curves were also poorly responsive to polarizing visual landmarks, and did not distinguish cues based on their visual pattern. Thus, the retino-geniculo-striate pathway is not critical for generation of an underlying, tightly-tuned directional signal, but does provide the main route for vision-based anchoring of the signal to the outside world, even when visual cues are high-contrast and low in detail.
Species interactions and food-web context drive temperature-dependent prey evolution
Authors: Han Ze-Yi , Yuan Yaning , DeWitt Katrina , Yammine Andrea , Wieczynski Daniel J. , Onishi Masayuki , Gibert Jean P.
Published: May 2024

Understanding how global warming shapes species evolution within communities is a pressing goal of ecology. Temperature affects interacting species and can lead to changes in species interactions, but how that will alter species evolutionary trajectories within complex food webs is poorly understood. Here we address 1) whether different predators affect prey evolution differentially, 2) whether the food web context in which this happens influences prey evolution, 3) whether temperature affects prey evolution directly, and 4) whether ecological interactions mediate how temperature affects prey evolution. We use a combination of mathematical modeling and experimental evolution assays in microbial food webs composed of prey algae and their protists predators. We found that temperature alone doesn’t drive prey evolution unless predators are involved. Importantly, the influence of temperature through predation is contingent on the food web structure. This leads to distinct evolutionary trajectories when prey evolves with predators alone or with a competing predator present. Our findings indicate that the species evolution to warming is likely contingent on their specific ecological contexts, suggesting that similar species across different food webs could exhibit diverse evolutionary responses to new climates.
GPT-4 based AI agents – the new expert system for detection of antimicrobial resistance mechanisms?
Authors: Giske Christian G. , Bressan Michelle , Fiechter Farah , Hinic Vladimira , Mancini Stefano , Nolte Oliver , Egli Adrian
Published: May 2024

Background

EUCAST recommends a two-step process for beta-lactamases in Gram-negative bacteria. Screening with minimal inhibitory concentrations (MICs) or inhibition zone diameters for potential extended spectrum beta-lactamase (ESBL), plasmid-mediated AmpC beta-lactamase, or carbapenemase production is followed by confirmatory tests. GPT-4 and its newly released customized GPT-agent may support the initial EUCAST-screening process. We aimed to validate a customized GPT-agent to identify potential resistance mechanisms.

Methods

We used 225 Gram-negative isolates. Based on phenotypic resistances against beta-lactam antibiotics, we formed four categories: “none”, “ESBL”, “AmpC”, or “carbapenemase”. We included 862 phenotypic categories. Next, we customized a GPT-agent with EUCAST-guidelines, expert rules, and EUCAST-breakpoint table (v13.1). We compared routine diagnostic outputs (reference) to (i) EUCAST-GPT-expert, (ii) medical microbiologists, and (iii) GPT-4 without customization. We determined performance as sensitivities and specificities to flag suspect resistance mechanisms.

Results

Three human readers showed concordance in 814/862 (94.4%) phenotypic categories and used in median eight words (IQR 4-11) for reasoning. Median sensitivity and specificity for ESBL, AmpC, and carbapenemase were 98%/99.1%, 96.8%/97.1%, and 95.5%/98.5%, respectively. Three independent prompting rounds of the GPT-agent showed concordance in 706/862 (81.9%) categories but used in median 158 words (IQR 140-174) for reasoning,. Median sensitivity and specificity for ESBL, AmpC, and carbapenemase prediction were 95.4%/69.23%, 96.9%/86.3%, and 100%/98.8%, respectively. In the non-customized GPT-4, 169/862 (19.6%) categories could be interpreted. Of these 137/169 (81.1%) categories agreed with routine diagnostic. The non-customized GPT-4 used in median 85 words (IQR 72-105) for reasoning.

Conclusion

Human experts showed higher concordance and shorter argumentations compared to GPT-agents. Human experts showed comparable median sensitivities and higher specificities compared to GPT-agents. GPT-agents showed more unspecific flagging of ESBL and AmpC, potentially, resulting in additional testing, diagnostic delays, and higher costs. GPT-4 and GPT-agents are not IVDR/FDA-approved, but validation of LLMs is critical and datasets for benchmarking are needed.
The distribution of regions of homozygosity (ROH) among consanguineous populations - implications for a routine genetic counseling service
Authors: Gafni-Amsalem Chen , Warwar Nasim , Khayat Morad , Tatour Yasmin , Abuleil-Zuabi Olfat , Campisi-Pinto Salvatore , Carmi Shai , Shalev Stavit A.
Published: May 2024

Background

Regions of homozygosity (ROH) increase the risk of recessive disorders, and guidelines recommend reporting of excessive ROH in prenatal testing. However, ROH are common in populations that practice endogamy or consanguinity, and cutoffs for reporting ROH in such populations may not be evidence-based.

Methods

We reviewed prenatal testing results (based on cytogenetic microarrays) from 2191 pregnancies in the Jewish and non-Jewish populations of Northern Israel and estimated the prevalence of ROH according to self-reported ethnicity and parental relationships.

Results

The proportion of the genome in ROH, ROH rate, was higher in non-Jews [Mean(SD)=2.91%(3.92%); max=25.54%; N=689] than in Jews [Mean(SD)=0.81%(0.49%); max=3.93%; N=1502]. In the non-Jewsih populations, consanguineous marriages had the highest ROH rates [Mean(SD)=7.14%(4.55%), N=217], followed by endogamous [Mean(SD)=1.13%(1.09%), N=283]) and non-endogamous [Mean(SD)=0.69%(0. 56%), N=189]) marriages. ROH rates were greater than 5%, the ACMG-recommended cutoff, in 149/689 (21.63%) of the non-Jewish samples. Within the Jewish populations, the rates were similar between Ashkenazi, North African, and Middle Eastern Jews, but were higher for six consanguineous unions [Mean(SD)=2.38%(1.23%)] and when spouses belonged to the same sub-population.

Conclusions

Given the high ROH rates we observed in some subjects, we suggest that assessing the risk for recessive conditions in consanguineous/endogamous populations should be done before the first pregnancy, through genetic counseling and sequencing. Such an approach will: (1) identify couples who are at risk and counsel them on reproductive options; and (2) avoid the stress that couples who are not at risk may experience due to a prenatal ROH report.
Early adulthood socioeconomic trajectories contribute to inequalities in adult diet quality, independent of childhood and adulthood socioeconomic position
Authors: Tao Yinhua , Maddock Jane , Howe Laura D , Winpenny Eleanor M
Published: May 2024

Background

Diet is an important risk factor for cardiovascular disease and shows well-established socioeconomic patterning among adults. However, less clear is how socioeconomic inequalities in diet develop across the life course. This study assessed the associations of early adulthood socioeconomic trajectories (SETs) with adult diet quality, adjusting for childhood socioeconomic position (SEP) and testing for mediation by adulthood SEP.

Methods

Participants from the 1970 British Cohort Study with socioeconomic data in early adulthood were included (n=12434). Diet quality at age 46 years, evaluated using the Mediterranean diet pyramid, was regressed on six previously identified classes of early adulthood SETs between ages 16 and 24 years, including a Continued Education class, four occupation-defined classes, and an Economically Inactive class. Causal mediation analyses tested the mediation of the association via household income and neighbourhood deprivation at age 46 years separately. Models were adjusted for sex, childhood SEP, adolescent diet quality and adolescent health.

Results

The Continued Education class showed the best diet quality at age 46 years, while little difference in diet quality was found among the remaining SET classes. The association between the Continued Education class and adult diet quality was independent of parental SEP in childhood, and was largely not mediated by household income or neighbourhood deprivation (0.7% and 3.7% of the total effect mediated, respectively) in mid-adulthood.

Conclusions

Early adulthood SETs independently contribute to adult diet quality, with continuing education associated with better adherence to Mediterranean diet. Early adulthood therefore represents a critical period for intervention to alleviate dietary inequalities in later life.

Key Messages

Life course epidemiology research aims to identify potential windows of change in life to prevent the establishment of socioeconomic inequalities in diet and diet-related cardiovascular health.

Early adulthood socioeconomic trajectories contributed to adult diet quality independent of childhood and adulthood socioeconomic position, with continuing education between ages 16 and 24 years associated with better diet quality at age 46 years.

Early adulthood represents a critical period for intervention to alleviate socioeconomic inequalities in diet persisting into adulthood.
Novel phages ofPseudomonas syringaeunveil numerous potential auxiliary metabolic genes
Authors: Feltin Chloé , Garneau Julian R. , Morris Cindy E. , Bérard Annette , Torres-Barceló Clara
Published: May 2024

Relatively few phages that infect plant pathogens have been isolated and investigated. ThePseudomonas syringaespecies complex is present in various environments, including plants. It can cause major crop diseases, such as bacterial canker on apricot trees. This study presents a collection of 25 unique phages genomes that infectP. syringae. These phages were isolated from apricot orchards with bacterial canker symptoms after enrichment with 21 strains ofP. syringae. This collection comprises mostly virulent phages, with only three being temperate. They belong to 14 genera, 11 of which are newly discovered, and 18 new species, revealing great genetic diversity within this collection. Novel DNA packaging systems have been identified bioinformatically in one of the new phage species, but experimental confirmation is required to define the precise mechanism. Additionally, many phage genomes contain numerous potential auxiliary metabolic genes with diversified putative functions. At least three phages encode genes involved in bacterial tellurite resistance, a toxic metalloid. This suggests that viruses could play a role in bacterial stress tolerance. This research emphasises the significance of continuing the search for new phages in the agricultural ecosystem to unravel novel ecological diversity and new gene functions. This work contributes to the foundation for future fundamental and applied research on phages infecting phytopathogenic bacteria.
Inducing aggresome and stable tau aggregation in Neuro2a cells with an optogenetic tool
Authors: Sakuragi Shigeo , Uchida Tomoya , Kato Naoki , Zhao Boxiao , Takahashi Toshiki , Hattori Akito , Sakata Yoshihiro , Soeda Yoshiyuki , Takashima Akihiko , Yoshimura Hideaki , Matsumoto Gen , Bannai Hiroko
Published: May 2024

Tauopathy is a spectrum of diseases characterized by fibrillary tau aggregate formation in neurons and glial cells in the brain. Tau aggregation originates in the brainstem and entorhinal cortex and then spreads throughout the brain in Alzheimer’s disease (AD), which is the most prevalent type of tauopathy. Understanding the mechanism by which locally developed tau pathology propagates throughout the brain is crucial for comprehending AD pathogenesis. Therefore, a novel model of tau pathology that artificially induces tau aggregation in targeted cells at specific times is essential. This study describes a novel optogenetic module, OptoTau, which is a human tau with the P301L mutation fused with a photosensitive protein CRY2olig, inducing various forms of tau according to the temporal pattern of blue light illumination pattern. Continuous blue light illumination for 12 h to Neuro2a cells that stably express OptoTau (OptoTauKI cells) formed clusters along microtubules, many of which eventually accumulated in aggresomes.

Conversely, methanol-resistant tau aggregation was formed when alternating light exposure and darkness in 30-min cycles for 8 sets per day were repeated over 8 days. Methanol-resistant tau was induced more rapidly by repeating 5-min illumination followed by 25-min darkness over 24 h. These results indicate that OptoTau induced various tau aggregation stages based on the temporal pattern of blue light exposure. Thus, this technique exhibits potential as a novel approach to developing specific tau aggregation in targeted cells at desired time points.

Significance

This study developed an approach to manipulate tau aggregation in a blue light-dependent manner using cells that stably express OptoTau, which is an optogenetic tool based on the CRY2olig module. Tau accumulation in aggresomes or stable tau aggregation were selectively induced by blue light illumination conditions. These results are crucial as they provide a new technological basis for establishing a singular point of tau aggregation in specific targeted cells at a particular time.
A phylogenetic host range index reveals contrasted relationships between phage virulence and specialisation
Authors: Torres-Barceló Clara , Boyer Claudine , Garneau Julian R. , Poussier Stéphane , Robène Isabelle , Moury Benoit
Published: May 2024

Phages are typically known for having a limited host range, targeting various strains within a specific bacterial species. However, factors like the phylogeny or epidemiology of host bacteria are often disregarded, despite their potential influence on phage specialization and virulence. This research utilizes a new “phylogenetic host range index” that accounts for the genetic diversity of bacterial hosts, to classify phages into specialists and generalists accurately. We provide evidence that the CRISPR-Cas immune system of bacteria more frequently targets generalist phages than specialist phages. We explore the hypothesis that generalist phages might exhibit lower virulence than specialist ones due to potential evolutionary trade-offs between host range breadth and virulence. Importantly, contrasted correlations between phage virulence and host range depend on the epidemiological context. A trade-off was confirmed in a homogeneous bacterial epidemiology situation, but not in more complex epidemiological scenario, where no apparent costs were detected for phages adapted to a wide range of hosts. This study highlights the need for genetic analyses in phage host range and of investigating ecological trade-offs that could improve their applications in biocontrol or therapy.
Convergent evolution associated with the loss of developmental diapause may promote extended lifespan in bees
Authors: Santos Priscila K. F. , Kapheim Karen M.
Published: May 2024

Diapause has long been proposed to play a significant role in the evolution of eusociality in Hymenoptera. Recent studies have shown that shifts in the diapause stage precede social evolution in wasps and bees, however, the genomic basis remains unknown. Given the overlap in molecular pathways that regulate diapause and lifespan, we hypothesized that the evolutionary loss of developmental diapause may lead to extended lifespan among adults, which is a prerequisite for the evolution of eusociality. To test this, we compared 27 bee genomes with or without prepupal diapause. Our results point to several potential mechanisms for lifespan extension in species lacking prepupal diapause, including the loss of the growth hormone PTTH and its receptor TORSO, along with convergent selection in genes known to regulates lifespan in animals. Specifically, we observed purifying selection of pro-longevity genes and relaxed selection of anti-longevity genes within the IIS/TOR pathway in species that have lost prepupal diapause. Changes in selection pressures on this pathway may lead to the evolution of new phenotypes, such as lifespan extension and altered responses to nutritional signals, that are crucial for social evolution.

Significance

Diapause has long been proposed to play a significant role in the evolution of eusociality in Hymenoptera. Recent studies have shown that the loss of diapause during the prepupal stage precedes social evolution in wasps and bees. However, the genomic mechanisms underlying this phenomenon remain unknown. Through comparative genomics, we showed that the convergent loss of prepupal diapause is associated with mechanisms that may promote lifespan extension, a prerequisite for social evolution. These mechanisms include genes losses and signals of selection on genes related to aging.
Biochemical characterization ofBacillus anthracissortase B: Use in sortase-mediated ligation and substrate recognition dependent on residues beyond the canonical pentapeptide binding motif for sortase enzymes
Authors: Jackson Sophie N. , Blount Jadon M. , Croney Kayla A. , Lee Darren E. , Ibershof Justin W. , Whitham Kyle M. , McCarty James , Antos John M. , Amacher Jeanine F.
Published: May 2024

Sortases are cysteine transpeptidases located on the surface of Gram-positive bacteria. These critical enzymes facilitate the attachment of proteins to the cell wall, and are potential targets for novel antibiotic development, as well as versatile tools in protein engineering applications. Although there are six classes of sortases recognized, class A sortases (SrtA) are the most widely studied and utilized. SrtA enzymes recognize the canonical Cell Wall Sorting Signal (CWSS), LPXTG, where X=any amino acid, although work in recent years identified additional promiscuity in multiple positions of this recognition motif. Much less is known about Class B sortases (SrtB), which target a distinct sequence, typically with an N-terminal Asn, e.g., variations of NPXTG or NPQTN. Although understudied overall, two SrtB enzymes have previously been shown to be specific for heme transporter proteins, andin vitroexperiments with the catalytic domains of these enzymes reveal activities significantly worse than SrtA from the same organisms. Here, we use protein biochemistry, structural analyses, and computational simulations to better understand and characterize these enzymes, specifically investigatingBacillus anthracisSrtB (baSrtB) as a model SrtB protein. Structural modeling predicts a plausible enzyme-substrate complex, which is verified by mutagenesis of binding cleft residues at several positions. Furthermore, residues N- and C-terminal to the pentapeptide recognition motif are critical for observed activity. We also use chimeric proteins to identify a single site that improves baSrtB activity by ∼4-fold and use purified protein substrates to validate sortase-mediated ligation of two proteins using SrtB enzymes for the first time. Taken together, these studies provide insight into SrtB-target binding as well as evidence that SrtB enzymes can be modified to be of potential use in protein engineering.
OncogenicKRASMutations Confer a Unique Mechanotransduction Response to Peristalsis in Colorectal Cancer Cells
Authors: Clevenger Abigail J. , Collier Claudia A. , Gorley John Paul M. , McFarlin Maygan K. , Solberg Spencer C. , Kopetz E. Scott , Stratman Amber N. , Raghavan Shreya A.
Published: May 2024

Colorectal cancer (CRC) tumors start as precancerous polyps on the inner lining of the colon or rectum, where they are exposed to the mechanics of colonic peristalsis. Our previous work leveraged a custom-built peristalsis bioreactor to demonstrate that colonic peristalsis led to cancer stem cell enrichment in colorectal cancer cells. However, this malignant mechanotransductive response was confined to select CRC lines that harbored an oncogenic mutation in theKRASgene. In this work, therefore, we explored the involvement of activatingKRASmutations on peristalsis-associated mechanotransduction in CRC. Peristalsis enriched the cancer stem cell marker LGR5 inKRASmutant (G13D, etc.) lines, in a Wnt-independent manner. Conversely, LGR5 enrichment in wild typeKRASlines exposed to peristalsis were minimal. LGR5 enrichment downstream of peristalsis translated to increased tumorigenicityin vivoinKRASmutant vs. wild type lines. Differences in mechanotransduction response was additionally apparent via unbiased gene set enrichment analysis, where many unique pathways were enriched in wild type vs. mutant lines, in response to peristalsis. Interestingly, peristalsis also triggered β-catenin nuclear localization independent of Wnt, particularly inKRASmutant lines. The central involvement of KRAS in the mechanotransductive responses was validated via gain and loss of function strategies. β-catenin activation and LGR5 enrichment downstream of peristalsis converged to the activation of the MEK/ERK kinase cascade, that remains active in cells that harbor oncogenicKRASmutations. Taken together, our results demonstrated that oncogenicKRASmutations conferred a unique peristalsis-associated mechanotransduction response to colorectal cancer cells, resulting in cancer stem cell enrichment and increased tumorigenicity. These mechanosensory connections can be leveraged in improving the sensitivity of emerging therapies that target oncogenic KRAS.
Transversity generalized parton distributions in spin-
3/2
particles
Authors: Fu Dongyan , Dong Yubing , Kumano S.
Published: May 2024

The definitions of the quark and gluon transversity generalized parton distributions (GPDs) in spin-3/2 particles are obtained in the light-cone gauge. It is found that they contain 16 independent components for each parton. Their even or odd property is found in terms of a skewness variable, and the odd transversity GPDs vanish in the forward limit. There are 16 amplitudes with helicity flip of quark or gluon. We conclude that all the amplitudes, unpolarized, polarized, and transversity amplitudes, have a common factor F(ζ) carrying all the complex parts. Here, the variable ζ is the helicity difference ζ=(λ′−λ)−(μ′−μ) for the amplitude Aλ′μ′,λμ. This kinematical factor is associated with the transfer of the orbital angular momentum in the quark- and gluon-spin-3/2 particle scattering amplitudes. We also derive another main physical quantity, transversity distribution, from the transversity GPDs in the forward limit for the spin-3/2 particles.

Published by the American Physical Society
2024