bluuebunny/crossref_metadata_2025 huggingface dataset:
Current and future perspectives for enhancing our understanding of the evolution of plant metabolism
Authors: de Vries Jan , de Vries Sophie , Fernie Alisdair R.
Published: September 2024

The special issue ‘The evolution of plant metabolism’ has brought together original research, reviews and opinions that cover various aspects from the full breath of plant metabolism including its interaction with the environment including other species. Here, we briefly summarize these efforts and attempts to extract a consensus opinion of the best manner in which to tackle this subject both now and in the future.

This article is part of the theme issue ‘The evolution of plant metabolism’.
Cataloguing the postnatal small intestinal transcriptome during the first postnatal month
Authors: Oliveira Luiz Fernando Silva , Khetani Radhika S. , Wu Yu-Syuan , Dasuri Venkata Siva , Harrington Amanda W. , Olaloye Oluwabunmi , Goldsmith Jeffrey , Breault David T. , Konnikova Liza , Ho Sui Shannan J. , O’Connell Amy E.
Published: September 2024

In the first postnatal month, the developing mouse intestine shifts from an immature to a mature intestine that will sustain the organism throughout the lifespan. Here, we surveyed the mouse intestine in C57Bl/6 mice by RNA-Seq to evaluate the changes in gene expression over time from the day of birth through 1 month of age in both the duodenum and ileum. We analyzed gene expression for changes in gene families that correlated with the periods of NEC susceptibility or resistance. We highlight that increased expression of DNA processing genes and vacuolar structure genes, tissue development and morphogenesis genes, and cell migration genes all correlated with NEC susceptibility, while increases in immunity gene sets, intracellular transport genes, ATP production, and intracellular metabolism genes correlated with NEC resistance. Using trends identified in the RNA-Seq analyses, we further evaluated expression of cellular markers and epithelial regulators, immune cell markers, and adenosine metabolism components. We confirmed key changes with qRT-PCR and immunofluorescence. In addition, we compared some findings to humans using human intestinal biopsies and organoids. This dataset can serve as a reference for other groups considering the role of single molecules or molecular families in early intestinal and postnatal development.
PRMT1 Modulates Alternative Splicing to Enhance HPV18 mRNA Stability and Promote the Establishment of Infection
Authors: Williams David E.J. , King Kelly , Jackson Robert , Kuehner Franziska , Arnoldy Christina , Marroquin Jaclyn N. , Tobey Isabelle , Banka Amy , Ragonese Sofia , Van Doorslaer Koenraad
Published: September 2024

Only persistent HPV infections lead to the development of cancer. Thus, understanding the virus-host interplay that influences the establishment of viral infection has important implications for HPV biology and human cancers. The ability of papillomaviruses to establish in cells requires the strict temporal regulation of viral gene expression in sync with cellular differentiation. This control primarily happens at the level of RNA splicing and polyadenylation. However, the details of how this spatio-temporal regulation is achieved still need to be fully understood.

Until recently, it has been challenging to study the early events of the HPV lifecycle following infection. We used a single-cell genomics approach to identify cellular factors involved in viral infection and establishment. We identify protein arginine N-methyltransferase 1 (PRMT1) as an important factor in viral infection of primary human cervical cells. PRMT1 is the main cellular enzyme responsible for asymmetric dimethylation of cellular proteins. PRMT1 is an enzyme responsible for catalyzing the methylation of arginine residues on various proteins, which influences processes such as RNA processing, transcriptional regulation, and signal transduction. In this study, we show that HPV18 infection leads to increased PRMT1 levels across the viral lifecycle. PRMT1 is critical for the establishment of a persistent infection in primary cells. Mechanistically, PRMT1 inhibition leads to a highly dysregulated viral splicing pattern. Specifically, reduced PRMT1 activity leads to intron retention and a change in the E6 and E7 expression ratio. In the absence of PRMT1, viral transcripts are destabilized and subject to degradation via the nonsense-mediated decay (NMD) pathway. These findings highlight PRMT1 as a critical regulator of the HPV18 lifecycle, particularly in RNA processing, and position it as a potential therapeutic target for persistent HPV18 infections.
A hierarchical Bayesian model reveals increased precision weighting for afferent cardiac signals, and reduced anxiety, as a function of interoceptive training
Authors: Suksasilp Chatrin , McLanachan Abigail , Quadt Lisa , Boulton Blaise , Mulcahy James , Critchley Hugo D , Smith Ryan , Garfinkel Sarah N
Published: September 2024

Perceptual accuracy for interoceptive signals, such as heartbeats, varies in a trait-like manner across individuals and may influence the capacity for emotion regulation and vulnerability to affective symptoms, notably anxiety. Here, we demonstrate that an interoceptive training protocol improved perceptual accuracy in two tasks of heartbeat perception and reduced both state and trait anxiety in a subclinical sample, extending previous findings in autistic adults. Computational modelling indicated that accuracy improvement in the heartbeat discrimination task was associated with increases in the internal reliability estimate for interoceptive signals – their precision weighting – while a lower-level parameter representing noise in the interoceptive signal itself (which influences speed of learning) moderated this precision weighting improvement. Reductions in both state and trait anxiety in the training group were uniquely explained by computational parameter estimates, and not by conventional accuracy measures. These findings indicate that trait-like differences in interoceptive processing are modifiable and can be targeted to alleviate anxiety symptoms, and that interoceptive interventions may be best guided by a computational phenotyping approach.
Genetic requirements ofMycobacterium tuberculosisfor survival under pathogen-specific immunity
Authors: James Kimra S. , Jain Neharika , Witzl Kelly , Cicchetti Nico , Fortune Sarah M. , Ioerger Thomas R. , Martinot Amanda J. , Carey Allison F.
Published: September 2024

Mycobacterium tuberculosis(Mtb), the etiologic agent of tuberculosis (TB), remains a persistent global health challenge due to the lack of an effective vaccine. The only licensed TB vaccine, Bacille Calmette-Guerin (BCG), is a live attenuated strain ofMycobacterium bovis, that protects young children from severe disease but fails to provide protection through adulthood. It is unclear why BCG-induced immunity provides incomplete protection despite inducing a robust CD4+ T cell response, a known critical correlate of protection against Mtb. We set out to interrogate mycobacterial determinants of vaccine escape using a functional genomics approach, TnSeq, to define mycobacterial genes required for survival in mice vaccinated with BCG, the live attenuated Mtb vaccine, ΔLprG, and in mice with Mtb immunity conferred by prior infection. We find that critical virulence genes associated with acute infection and exponential growth are less essential in hosts with adaptive immunity, including genes encoding the Esx-1 and Mce1 systems. Genetic requirements for Mtb growth in vaccinated and previously Mtb-infected hosts mirror the genetic requirements reported for bacteria grown underin vitroconditions that reflect aspects of the adaptive immune response as well as in mouse genetic backgrounds where bacterial growth is restricted. Across distinct immunization conditions, differences in genetic requirements between live attenuated vaccines and vaccination routes are observed, suggesting that different immunization strategies impose distinct bacterial stressors. Collectively, these data support the idea that Mtb requires genes that enable stress adaptation and growth arrest upon encountering the restrictive host environment induced by the adaptive immune response. We demonstrate that TnSeq can be used to understand the bacterial genetic requirements for survival in vaccinated hosts across pre-clinical live attenuated vaccines and therefore may be applied to other vaccine modalities. Understanding how Mtb survives in the setting of vaccine-induced immunity could uncover bacterial vulnerabilities to inform the development and prioritization of new vaccines or adjuvant therapies.
Cannabis smoke and oral Δ9THC enhance working memory in aged but not young adult subjects
Authors: Zequeira Sabrina , Gazarov Emely A , Guvenli Alara A , Berthold Erin C , Senetra Alexandria S , Febo Marcelo , Hiranita Takato , McMahon Lance R , Sharma Abhisheak , McCurdy Christopher R , Setlow Barry , Bizon Jennifer L
Published: September 2024

With increased legalization of recreational and medical cannabis, use of this drug is growing rapidly among older adults. As cannabis use can impair cognition in young adults, it is critically important to understand how consumption interacts with the cognitive profile of aged individuals, who are already at increased risk of decline. The current study was designed to determine how cannabis influences multiple forms of cognition in young adult and aged rats of both sexes when delivered via two translationally-relevant routes of administration. Acute exposure to cannabis smoke enhanced prefrontal cortex-dependent working memory accuracy in aged males, but impaired accuracy in aged females, while having no effects in young adults of either sex. In contrast, the same cannabis smoke exposure regimen had minimal effects on a hippocampus-dependent trial-unique non-matching to location mnemonic task, irrespective of age or sex. In a second set of experiments, chronic oral consumption of Δ9-tetrahydrocannabinol (Δ9THC) enhanced working memory in aged rats of both sexes, while having no effects in young adults. In contrast, the same oral Δ9THC regimen did not affect spatial learning and memory in either age group. Minimal age differences were observed in Δ9THC pharmacokinetics with either route of administration. Together, these results show that cannabis and Δ9THC can attenuate working memory impairments that emerge in aging. While these enhancing effects do not extend to hippocampus-dependent cognition, cannabis does not appear to exacerbate age-associated impairments in this cognitive domain.
Reproducible Sex Differences in Personalized Functional Network Topography in Youth
Authors: Keller Arielle S. , Sun Kevin Y. , Francisco Ashley , Robinson Heather , Beydler Emily , Bassett Dani S. , Cieslak Matthew , Cui Zaixu , Davatzikos Christos , Fan Yong , Gardner Margaret , Kishton Rachel , Kornfield Sara L. , Larsen Bart , Li Hongming , Linder Isabella , Pines Adam , Pritschet Laura , Raznahan Armin , Roalf David R. , Seidlitz Jakob , Shafiei Golia , Shinohara Russell T. , Wolf Daniel H. , Alexander-Bloch Aaron , Satterthwaite Theodore D. , Shanmugan Sheila
Published: September 2024

Background

A key step towards understanding psychiatric disorders that disproportionately impact female mental health is delineating the emergence of sex-specific patterns of brain organization at the critical transition from childhood to adolescence. Prior work suggests that individual differences in the spatial organization of functional brain networks across the cortex are associated with psychopathology and differ systematically by sex.

Aims

We aimed to evaluate the impact of sex on the spatial organization of person-specific functional brain networks.

Method

We leveraged person-specific atlases of functional brain networks defined using non-negative matrix factorization in a sample ofn= 6437 youths from the Adolescent Brain Cognitive Development Study. Across independent discovery and replication samples, we used generalized additive models to uncover associations between sex and the spatial layout (“topography”) of personalized functional networks (PFNs). Next, we trained support vector machines to classify participants’ sex from multivariate patterns of PFN topography. Finally, we leveraged transcriptomic data from the Allen Human Brain Atlas to evaluate spatial correlations between sex differences in PFN topography and gene expression.

Results

Sex differences in PFN topography were greatest in association networks including the fronto-parietal, ventral attention, and default mode networks. Machine learning models trained on participants’ PFNs were able to classify participant sex with high accuracy. Brain regions with the greatest sex differences in PFN topography were enriched in expression of X-linked genes as well as genes expressed in astrocytes and excitatory neurons.

Conclusions

Sex differences in PFN topography are robust, replicate across large-scale samples of youth, and are associated with expression patterns of X-linked genes. These results suggest a potential contributor to the female-biased risk in depressive and anxiety disorders that emerge at the transition from childhood to adolescence.
Metabolic reprogramming of immune cells in HIV infection and treatment
Authors: Xu Phoebe , Wu Di
Published: September 2024

BACKGROUND

Immune cells undergo metabolic reprogramming, altering their energy production in response to HIV infection. During acute HIV infection, CD4+ T cells increase glycolysis to fuel viral replication and defense, but prolonged activation leads to immune exhaustion, with reduced T cell function and impaired pathogen elimination, contributing to AIDS progression. However, the details Metabolic dynamics of Immune Cells during HIV Infection (UT) and after receiving antiretroviral therapy (ART) remains unknown. Communication between Immune cells will be modified to response HIV infection, which can be mediated by metabolites. In this study, we deciphered Metabolic pathway dynamics of all Immune Cells by comparing UT and ART with seronegative controls (SN). Additionally, we investigate alteration of metabolite-mediated cell-cell communications in HIV Infection.

METHODS

Single cell RNA sequencing (scRNA-seq) data of PBMC from SN, UT and ART were analyzed with KEGG Metabolic pathways by irGSEA and algorithm MEBOCOST to study cell-cell communications mediated by metabolites from sender cells and sensor proteins on receiver cells.

RESULTS

lots of differentially expressed Metabolic Pathways were identified for immune cells, including Energy Production and Utilization, Lipid Metabolism, Amino Acid Metabolism, Glycosylation and Glycan Biosynthesis and Oxidative Stress and Antioxidant Defense.

CONCLUSIONS

The analysis highlights the intricate metabolic interplay between monocytes and other immune cells, reflecting their central role in orchestrating immune responses through metabolite exchange. These insights may open avenues for therapeutic interventions, targeting metabolic pathways to enhance immune function or inhibit pathogen survival.
Characterization of alternative mRNA splicing associated with tumor thrombus in clear-cell renal cell carcinoma
Authors: Cohen Zeev , Reinus Harel , Ben-Dov Iddo , Kalisky Tomer
Published: September 2024

Approximately 10% of Renal Cell Carcinoma (RCC) tumors form a thrombus that invades into nearby vasculature and is associated with lower survivability. However, the mechanisms driving tumor thrombus formation and progression are poorly understood. We therefore examined a publicly available RNAseq dataset of samples from RCC patients containing tumors with and without thrombi, as well as associated normal kidney tissues, and compared them. Using cell deconvolution, we found indications that kidney tumors and thrombi are associated with loss of mature kidney-specific cell types and gain of proliferative characteristics. Moreover, we identified a set of transcripts that are alternatively spliced between tumors with and without thrombi. Using motif enrichment analysis for known RNA binding proteins we found putative splicing regulators that are presumably associated with thrombus formation. We believe that this study will assist in unraveling cellular and molecular mechanisms of tumor progression and thrombus formation in RCC.
Functional traits predict outcomes of current and novel competition under warmer climate
Authors: Lyu Shengman , Alexander Jake M.
Published: September 2024

Functional traits offer a potential avenue to generalize and forecast the impacts of changing competition on plant communities, including changing outcomes of competition among species that currently interact (current competition) or that will interact in the future following range shifts (novel competition). However, it remains unclear how well traits explain variation in the outcomes of current and novel competition, as well as the underlying processes determining coexistence or competitive exclusion, under changing climate. Here, we conducted a field experiment in which pairs of high and low-elevation species interacted in three sites across an elevation gradient in the Swiss Alps. For each species pair, we quantified the population-level outcomes of competition (invasion growth rates), relative fitness differences and niche overlap and related these to 15 functional traits that were measured in each site. Most traits were significantly associated with invasion growth rates at the low elevation, where species had greater relative fitness differences, but these associations were much weaker towards higher elevations. This appears to be because traits, particularly those associated with light competition, captured species’ relative fitness differences at lower elevations, but not at the high elevation site. Greater relative fitness differences towards lower elevations suggest that climate warming may increase the likelihood of competitive exclusion of species that are poor competitors for light. In addition, novel competitors tended to show greater niche overlap than current competitors, leading to stronger overall competitive effects. But in general, trait differences predicted competitive outcomes of novel and current competitors similarly well, suggesting that traits can be used to predict interactions between species that do not yet interact. Our study reinforces the importance of considering changing interactions for predicting species responses to climate change and provides experimental evidence supporting the usefulness of functional trait differences in forecasting the impacts of future plant interactions under changing climate.
Viral epidemic potential is not uniformly distributed across the bat phylogeny
Authors: Cummings Caroline A. , Vicente-Santos Amanda , Carlson Colin J. , Becker Daniel J.
Published: September 2024

Characterizing host–virus associations is critical due to the rising frequency of emerging infectious diseases originating from wildlife. Past analyses have evaluated zoonotic risk as binary, but virulence and transmissibility can vary dramatically. Recent work suggests bats harbor more viruses with high virulence in humans than other taxa. However, it remains unknown whether all bats harbor viruses of equal zoonotic potential. We used phylogenetic factorization to flexibly identify clades of mammals (at any taxonomic level) associated with low or high viral epidemic potential, and found virulence and transmissibility only cluster within bat subclades, often among cosmopolitan families. Mapping the geographic distributions of these bat clades with spatial data on anthropogenic footprint suggests high zoonotic risk in coastal South America, Southeast Asia, and equatorial Africa. Our results deepen understanding of the host– virus network and identify clades to prioritize for viral surveillance, risk mitigation, and future studies characterizing mechanisms of viral tolerance.
A Collagen Triple Helix without the Super Helical Twist
Authors: Kreutzberger Mark A. B. , Yu Le Tracy , Hancu Maria C. , Purdy Michael D. , Osinski Tomasz , Kasson Peter , Egelman Edward H. , Hartgerink Jeffrey D.
Published: September 2024

Collagens are ubiquitous in biology functioning as the backbone of the extracellular matrix, forming the primary structural components of key immune system complexes, and fulfilling numerous other structural roles in a variety of systems. Despite this, there is limited understanding of how triple helices, the basic collagen structural units, pack into collagenous assemblies. Here we use a peptide self-assembly system to design collagenous assemblies based on the C1q collagen-like region. Using cryo-EM we solve a structure of one assembly to 3.5 Å resolution and build an atomic model. From this, we identify a triple helix conformation with no superhelical twist, starkly in contrast to the canonical right-handed triple helix. This non-twisting region allows for unique hydroxyproline stacking between adjacent triple helices and also results in the formation of an exposed cavity with rings of hydrophobic amino acids packed symmetrically. We find no precedent for such an arrangement of collagen triple helices and have designed mutant assemblies to probe key stabilizing amino acid interactions in the complex. The mutations behave as predicted by our atomic model. Our findings, combined with the extremely limited experimental structural data on triple helix packing in the literature, suggest that collagen and collagen-like assemblies may adopt a far more varied conformational landscape than previously appreciated. We hypothesize that this is particularly likely adjacent to the termini of these helices and at discontinuities to the required Xaa-Yaa-Gly repeating primary sequence; a discontinuity found in the majority of this class of proteins and in many collagen-associated diseases.
Estimating sampling and laboratory capacity for a simulated African swine fever outbreak in the United States
Authors: Galvis Jason A. , Satici Muhammed Y. , Sykes Abagael L. , O’Hara Kathleen C. , Rochette Lisa , Roberts David , Machado Gustavo
Published: September 2024

The introduction of African swine fever virus (ASFV) into uninfected countries can impact economic and animal welfare. Rapid detection and control of the outbreak contribute to successful eradication and promote business continuity. We developed a model to determine the number of samples, sample collectors, laboratory capacity, and processing times following an ASFV introduction into the U.S. We simulated the spread of ASFV in one densely populated swine region, generating a median of 27 (range = 1-68) outbreaks in 150 days, resulting 616 (range = 1-15,011) sampling events with a total of 3,068 barns (range = 7-69,118) sampled. We calculated the total sample collectors needed, considering daily working hours, sampling and driving time, and laboratory capabilities with and without blood sample pooling. Samples included 31 blood samples and five oral fluid samples per barn, which equal 84,830 (range = 52-2,066,831) and 14,195 (range = 10-345,590) blood and oral fluid samples, respectively. The median number of sample collectors needed to prevent sampling delay varied from 136 to 367 and, in the worst epidemic scenarios, from 833 to 3,115. Notably, excluding downtime–which prevented the sampler from visiting additional farms for 24 or 72 hours–reduced the number of sample collectors needed between 28% and 75%, while switching from blood to oral fluid samples reduced this number between 47% and 75%. At a laboratory processing daily capacity of 1,000 samples, the median days for sample processing without pooling were 92 days, with a maximum of 5.7 years. We demonstrated a need to redistribute 10,062 (range = 2-67,940) unprocessed samples daily to other laboratories to prevent processing delays. Our study addresses the challenge of efficiently organizing resources for managing a potential ASFV outbreak, providing information about the number of sample collectors and laboratory capacity needed for one densely populated swine region in the U.S.
Enzymatic protein fusions with 100% product yield
Authors: Fuchs Adrian C. D.
Published: September 2024

The protein ligase Connectase can be used to fuse proteins to small molecules, solid carriers, or other proteins. Compared to other protein ligases, it offers greater substrate specificity, higher catalytic efficiency, and catalyzes no side reactions. However, its reaction is reversible, resulting in only 50% fusion product from two equally abundant educts. Here, we present a simple method to reliably obtain 100% fusion product in 1:1 conjugation reactions. This method is efficient for protein-protein or protein-peptide fusions at the N-or C-termini. It enables the generation of defined and completely labeled antibody conjugates with one fusion partner on each chain. The reaction requires short incubation times with small amounts of enzyme and is effective even at low substrate concentrations and at low temperatures. With these characteristics, it presents a valuable new tool for bioengineering.
Connectivity in the Dorsal Visual Stream is Enhanced in Action Video Game Players
Authors: Cahill Kyle , Jordan Timothy , Dhamala Mukesh
Published: September 2024

Action video games foster competitive environments that demand rapid spatial navigation and decision-making. Action video gamers often exhibit faster response times and slightly improved accuracy in vision-based sensorimotor tasks. However, the underlying functional and structural changes in the two visual streams of the brain that may be contributing to these cognitive improvements have been unclear. Using functional and diffusion MRI data, this study investigated the differences in connectivity between gamers who play action video games and nongamers in the dorsal and ventral visual streams. We found that action video gamers have enhanced functional and structural connectivity, especially in the dorsal visual stream. Specifically, there is heightened functional connectivity—both undirected and directed—between the left Superior Occipital Gyrus and the left Superior Parietal Lobule during a moving-dots discrimination decision-making task. This increased connectivity correlates with response time in gamers. The structural connectivity, as quantified by diffusion fractional anisotropy and quantitative anisotropy measures of the axonal fiber pathways between the same regions was also enhanced for gamers compared to nongamers. These findings provide valuable insights into how action video gaming can induce targeted neuroplastic changes, enhancing structural and functional connectivity between specific brain regions in the visual processing pathways. These connectivity changes in the dorsal visual stream underpin the superior performance of action video gamers compared to non-gamers in tasks requiring rapid and accurate vision-based decision-making.

GRAPHICAL ABSTRACT

Impact Statement

Understanding the neural mechanisms underlying how observed cognitive alterations due to video game playing are achieved has potential implications for future cognitive training, rehabilitation, and education. The structural and functional MRI analysis in this study provides a quantitative basis by which the underlying neural connectivity changes due to video game playing in the visual streams may be assessed and linked to observed behavioral differences. These methods are extendible and provide insight into underlying neural network enhancements associated with improved cognitive performance due to video game playing. The findings of this study support enhanced functional and structural connectivity in the dorsal visual stream among gamers due to video game playing in the behavioral paradigm of vision-based sensorimotor decision-making. Functional connectivity measures that were considered were significantly correlated with the participants’ response times.
Inter-Kingdom Interactions and Environmental Influences on the Oral Microbiome in Severe Early Childhood Caries
Authors: Weng Lingjia , Cui Yuqi , Jian Wenting , Zhang Yuwen , Pang Liangyue , Cao Yina , Zhou Yan , Liu Wei , Lin Huancai , Tao Ye
Published: September 2024

Dental caries arise from intricate interactions among oral microorganisms, impacting ecological stability and disease progression. This study delves into the bacterial-fungal dynamics in severe early childhood caries (S-ECC) among 61 children aged 3-4 years with complete deciduous dentition. We evaluated environmental factors such as saliva pH, buffering capacity, and trace elements (iron, fluoride). We examined the performance of 16S rRNA V1-V9 regions gene and internal transcribed spacer (ITS) primers for bacteria and fungi from plaque and saliva to characterize community compositions and diversity. Saliva pH and buffering capacity were also measured. Findings revealed significant shifts in bacterial diversity in S-ECC saliva samples, marked by decreased diversity and elevated abundance of cariogenic species, particularlyStreptococcus mutans.Candida albicanswas notably more prevalent in the S-ECC group, implicating its potential role in pathogenesis. Iron and fluoride concentrations showed no significant correlation with microbial community structure. Network analyses uncovered complex intra- and inter-kingdom interactions, underscoring cooperative and competitive dynamics. S-ECC children exhibited higher abundances of bacteria (Streptococcus mutans,Granulicatella,Actinomyces) and fungi (Candida albicans), with specific microbial taxa associated with reduced saliva pH.

Importance

This study illuminates the intricate relationship between bacteria and fungi within the oral microbial community of children, specifically highlighting differences between those with severe early childhood caries (S-ECC) and those without caries. Through an extensive analysis of the microbial composition in both saliva and dental plaque, we identified a significant increase in the abundance of specific bacterial taxa (e.g., S. mutans, Granulicatella, Actinomyces) and fungal species (e.g., C. albicans) in the oral cavities of children with S-ECC. This finding underscores the potential role of these microorganisms in the development of caries.

Contrary to previous studies that emphasize the importance of iron and fluoride in oral health, our research found no significant correlation between the concentrations of these elements and the composition of oral microbial communities. This result challenges conventional understanding and opens new avenues for future research. Additionally, we discovered an association between certain microbial species and reduced salivary pH, offering fresh insights into the relationship between the oral microenvironment and caries development.

The implications of our findings are substantial for the development of prevention and intervention strategies targeting childhood caries. They also underscore the critical need for a deeper exploration of oral microbial interactions and their environmental influences.
Oncogenic and teratogenic effects ofTrp53Y217C, an inflammation-prone mouse model of the human hotspot mutantTP53Y220C
Authors: Jaber Sara , Eldawra Eliana , Rakotopare Jeanne , Simeonova Iva , Lejour Vincent , Gabriel Marc , Cañeque Tatiana , Volochtchouk Vitalina , Licaj Monika , Fajac Anne , Rodriguez Raphaël , Morillon Antonin , Bardot Boris , Toledo Franck
Published: September 2024

Missense “hotspot” mutations localized in six p53 codons account for 20% ofTP53mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether and how they may gain additional functions promoting tumorigenesis remain controversial. Here we generatedTrp53Y217C, a mouse model of the human hotspot mutantTP53Y220C. DNA damage responses were lost inTrp53Y217C/Y217Ccells, andTrp53Y217C/Y217Cfibroblasts exhibited increased chromosome instability compared toTrp53-/-cells. Furthermore,Trp53Y217C/Y217Cmale mice died earlier thanTrp53-/-males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes inTrp53Y217C/Y217Cthymic cells compared toTrp53-/-cells. Surprisingly, we recovered only oneTrp53Y217C/Y217Cfemale for 22Trp53Y217C/Y217Cmales at weaning, a skewed distribution explained by a high frequency ofTrp53Y217C/Y217Cfemale embryos with exencephaly and the death of mostTrp53Y217C/Y217Cfemale neonates. Strikingly however, when we treated pregnant females with the anti-inflammatory drug supformin (LCC-12) we observed a five-fold increase in the proportion of viableTrp53Y217C/Y217Cweaned females in their progeny. Together, these data suggest that the p53Y217Cmutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.
Paralog protein compensation preserves protein-protein interaction networks following gene loss in cancer
Authors: Venkatesh Anjan , Quinn Niall , Upadhya Swathi Ramachandra , De Kegel Barbara , Carrancio Alfonso Bolado , Lefeivre Thomas , Dennler Olivier , Wynne Kieran , von Kriegsheim Alexander , Ryan Colm J.
Published: September 2024

Proteins operate within dense interconnected networks, where interactions are necessary both for stabilising proteins and for enabling them to execute their molecular functions. Remarkably, protein-protein interaction networks operating within tumour cells continue to function despite widespread genetic perturbations. Previous work has demonstrated that tumour cells tolerate perturbations of paralogs better than perturbations of singleton genes, but the mechanisms behind this genetic robustness remains poorly understood. Here, we systematically profile the proteomic response of tumours and tumour cell lines to gene loss. We find many examples of active compensation, where deletion of one paralog results in increased abundance of another, and collateral loss, where deletion of one paralog results in reduced abundance of another. Compensation is enriched among sequence-similar paralog pairs that are central in the protein-protein interaction network and widely conserved across evolution. Compensation is also significantly more likely to be observed for gene pairs with a known synthetic lethal relationship. Our results support a model whereby loss of one gene results in increased protein abundance of its paralog, stabilising the protein-protein interaction network. Consequently, tumour cells may become dependent on the paralog for survival, creating potentially targetable vulnerabilities.
Metabolic Stress Accelerates Dysregulated Synovial Macrophage-Fibroblast Communication and Htra1 Overproduction in Osteoarthritis
Authors: Blackler Garth , Klapak Joseph , Guo Qinli , Philpott Holly T. , Jiang HanYu , Ocica Dariana , Sordo Luigi Del , Fiset Benoit , Walsh Logan A. , Appleton C. Thomas
Published: September 2024

Biomechanical and metabolic factors increase the risk for osteoarthritis (OA) by causing supraphysiological stresses on joint tissues. Chronic exposure to these stresses contributes to failure of the joint organ system, resulting in pain and loss of function for patients with OA. The synovium is vital for joint organ health but during OA, synovial inflammation and damage are associated with worse outcomes including pain. Unfortunately, the separate and combined effects of metabolic and biomechanical stresses on synovial tissues are not well understood. In this study, metabolic syndrome (MetS) was associated with worse knee pain in patients with early-stage knee OA, suggesting that metabolic stress may act on synovial tissues during early-stage OA, exacerbating outcomes. In a rat model of experimental knee OA, the combined effects of biomechanical and metabolic stresses induced worse knee pain, cartilage damage, and synovial inflammation than biomechanical stress alone. Further, single-cell RNA sequencing of synovial macrophages and fibroblasts identified earlier metabolic (glycolytic and respiratory) shifts, neurogenesis, dysregulated communication, and cell activation when metabolic and biomechanical stresses were combined. Lastly, using a direct contact co-culture system, we showed that metabolic stress alters macrophage-fibroblast communication leading to increased expression of Htra1, a pathogenic protease in OA. This study identifies novel mechanisms that may represent amenable therapeutic targets for patients experiencing MetS and OA.

One-sentence summary:Metabolic stress may cause worse outcomes in OA through dysregulated synovial cell communication that activates synovial fibroblasts and increases Htra1 production.
Subchondral bone marrow adipose tissue lipolysis regulates bone formation in hand osteoarthritis
Authors: Maniglio Mauro , Loisay Léa , de Haro Diego , Antoniadis Alexander , Hügle Thomas , Geurts Jeroen
Published: September 2024

Objective

Bone marrow adipose tissue (BMAT) is emerging as an important regulator of bone formation and energy metabolism. Lipolysis of BMAT releases glycerol and fatty acid substrates that are catabolized by osteoblasts. Here, we investigated whether BMAT lipolysis is involved in subchondral bone formation in hand osteoarthritis (OA).

Methods

Subchondral BMAT lipolysis and bone marrow adipocyte (BMAd) morphology were studied in clinical specimens of carpo-metacarpal (CMC1) ans distal interphalangeal joint (DIP) OA. BMAd size, osteoblast numbers and expression of lipolysis enzymes (ATGL, phospho-HSL, MGLL) were compared between regions of low and high bone formation. Free fatty acids, glycerol and bone biomarkers were measured in osteochondral explants.

Results

Subchondral BMAd size was positively correlated with BMI and reduced in regions of high bone formation. Osteoblast numbers were negatively correlated with BMAd size. ATGL, phoshpo-HSL and MGLL were expressed in both in BMAds and activated osteoblasts and increased in regions of high bone formation. Secreted glycerol levels, but not free fatty acids, were correlated with bone formation markers pro-collagen type I and alkaline phosphatase.

Conclusion

Our findings reveal a previously unrecognized role of BMAT lipolysis in regulating bone formation in hand OA, which may be modulated by BMI.
Cave Adaptation Favors Aging Resilience in the Mexican Tetra
Authors: Cobham Ansa E. , Kenzior Alexander , Morales-Sosa Pedro , Javier Jose Emmanuel , Swanson Selene , Wood Christopher , Rohner Nicolas
Published: September 2024

All animals age, but the rate at which some species age varies widely. What environmental pressures and what molecular factors underlie the remarkable diversity in aging and lifespan across species remains largely enigmatic. The Mexican tetra,Astyanax mexicanus, serves as an intriguing new model to study how adaptations to different environments can change aging. This species exists as two morphotypes: the river-dwelling surface fish, which inhabits environments rich in food and light, and the blind cave-adapted cavefish, that thrive in dark, nutrient-limited but predator free environments. Nutrient limitation and lack of predation are known to impact lifespan, however, how adaption to such environments changes the aging trajectory in this species remains unknown. Here, we compared aging markers between surface and cavefish populations, focusing on morphological and behavioral changes, as well as molecular signatures, and found that aging markers are pronounced and evident in surface fish, whereas these signatures are less distinct in aged cavefish. Using zebrafish, we explored the contribution of the cavefish insulin receptor mutation to longevity. Although the insulin receptor mutation is sufficient to increase lifespan in fish, our findings suggest its impact is limited. Instead, our data indicate that metabolic shifts, particularly those related to mitochondrial function, may be key contributors to the extended longevity observed in cavefish.
Knockout of theSfVipR1gene confers high-level resistance toBacillus thuringiensisVip3Aa toxin inSpodoptera frugiperda
Authors: Zhang Zheng , Wang Lisi , Pang Xinru , Tay Wee Tek , Gordon Karl H. J. , Walsh Tom K. , Yang Yihua , Wu Yidong
Published: September 2024

Background

Bacillus thuringiensis(Bt) insecticidal proteins, including Cry proteins and vegetative insecticidal proteins (Vips), are extensively utilized in transgenic crops due to their efficacy and safety. The fall armyworm,Spodoptera frugiperda, has evolved practical resistance to Cry1Fa, yet no practical resistance to Vip3Aa has been documented. However, both laboratory selection and field screen studies indicate a high potential for this pest to evolve resistance to Vip3Aa, making it crucial to evaluate potential resistance genes. HaVipR1 has recently been identified as a key determinant of Vip3Aa resistance in the cotton bollworm,Helicoverpa armigera. This study investigated whether theHaVipR1-homologous gene inS. frugiperda(SfVipR1) is similarly involved in Vip3Aa resistance.

Results

We employed CRISPR/Cas9 technology to generate a homozygous knockout strain ofSfVipR1. In comparison with the parent susceptible YJ-19 strain, the knockout strain (Sfru-KO) exhibited high-level resistance to Vip3Aa (>1875-fold) but showed no resistance to Cry1Fa. This acquired resistance to Vip3Aa is autosomal, recessive, and genetically linked to the deletion mutation inSfVipR1within the Sfru-KO strain ofS. frugiperda.

Conclusion

Disruption of SfVipR1 results in high-level resistance to Vip3Aa, highlighting SfVipR1 has a critical role in Vip3Aa toxicity inS. frugiperda, despite the exact mechanism remaining unclear. Early detection ofSfVipR1mutant alleles in the field is essential for developing adaptive resistance management strategies againstS. frugiperda.
A Kinematic Deviation Index (KDI) for Evaluation of Forelimb Function in Rodents
Authors: Torres-Espin Abel , Bernstein Amanda , Soliman Marwa , Jara Juan Sebastián , Moreno-López Yunuen , Hollis Edmund
Published: September 2024

Rodent models are widely used to study neurological conditions and assess forelimb movement to measure function performance, deficit, recovery and treatment effectiveness. Traditional assessment methods based on endpoints such as whether the task is accomplished, while easy to implement, provide limited information on movement patterns important to assess different functional strategies. On the other side, detailed kinematic analysis provides granular information on the movement patterns but is difficult to compare across laboratories, and may not translate to clinical metrics of upper limb function. To address these limitations, we developed and validated a kinematic deviation index (KDI) for rodents that mimics current trends in clinical research. The KDI is a unitless summary score that quantifies the difference between an animal movement during a task and its optimal performance derived from spatiotemporal marker sequences without pre-specifying movements. We demonstrate the utility of KDI in assessing reaching and grasping in mice and validate its discrimination between trial endpoints in healthy animals. Furthermore, we show KDI sensitivity to interventions, including acute and chronic spinal cord injury and optogenetic disruption of sensorimotor circuits. The KDI provides a comprehensive measure of motor function that bridges the gap between detailed kinematic analysis and simple success/failure metrics, offering a valuable tool for assessing recovery and compensation in rodent models of neurological disorders.
An amphiregulin reporter mouse enables transcriptional and clonal expansion analysis of reparative lung Treg cells
Authors: Loffredo Lucas F. , Kaiser Katherine A. , Kornberg Adam , Rao Samhita , de los Santos-Alexis Kenia , Han Arnold , Arpaia Nicholas
Published: September 2024

Regulatory T (Treg) cells are known to play critical roles in tissue repair via provision of growth factors such as amphiregulin (Areg). Areg-producing Treg cells have previously been difficult to study because of an inability to isolate live Areg-producing cells. In this report, we created a novel reporter mouse to detect Areg expression in live cells (AregThy1.1). We employed influenza A and bleomycin models of lung damage to sort Areg-producing and –non-producing Treg cells for transcriptomic analyses. Single cell RNA-seq revealed distinct subpopulations of Treg cells and allowed transcriptomic comparisons of damage-induced populations. Single cell TCR sequencing showed that Treg cell clonal expansion is biased towards Areg-producing Treg cells, and largely occurs within damage-induced subgroups. Gene module analysis revealed functional divergence of Treg cells into immunosuppression-oriented and tissue repair–oriented groups, leading to identification of candidate receptors for induction of repair activity in Treg cells. We tested these using an ex vivo assay for Treg cell–mediated tissue repair, identifying 4-1BB agonism as a novel mechanism for reparative activity induction. Overall, we demonstrate that theAregThy1.1mouse is a promising tool for investigating tissue repair activity in leukocytes.
Deep learning facilitates precise identification of disease-resistance genes in plants
Authors: Liu Zhenya , Wang Xu , Cao Shuo , Lei Tingyue , Chenzhu Yifu , Zhang Mengyan , Liu Zhongqi , Lu Jianzhong , Ma Wenqi , Su Bingxiong , Wang Yiwen , Zhou Yongfeng
Published: September 2024

The identification of plant disease-resistance genes is essential for understanding the plant immune system and accelerating crop breeding with disease resistance. Therefore, there is a pressing need for a method capable of accurately and comprehensively annotating resistance genes at a genome-wide scale. In this study, we propose Evolutionary Scale Modeling for LRR (ESM-LRR), a novel approach based on the deep protein language model to accurately identify LRR domains which are substantially variable structures in disease-resistance proteins. ESM-LRR achieved its highest F1 score of 0.80 on a test set using the 90% identity as the matching threshold. Building upon ESM-LRR, we developed the Plant Disease-Resistance Gene Predictor (R-Predictor), a framework designed to simultaneously annotate 15 diverse domain topologies, extensively covering recently characterised resistance genes across the entire genome. R-Predictor integrates four modules, each employing superior methods that outperform existing methods (F1 score of 0.89 for RLKs and 0.88 for NLRs), demonstrating its high accuracy and practicality in annotating disease-resistance genes (R genes). R-Predictor were also applied to identify R genes in rice, tomato, and grapevine. Furthermore, AlphaFold3 was employed to screen interactions between 1,116 protein pairs involving three NLRs identified exclusively by R-Predictor and 372 literature-reported plant-pathogen effectors, resulting in the identification of 15 putative NLR-effector complexes. Overall, this study presents a novel approach for advancing our understanding of plant immune mechanisms.