bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractDental 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.ImportanceThis 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

AbstractMissense “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

AbstractProteins 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

AbstractBiomechanical 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

AbstractObjectiveBone 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).MethodsSubchondral 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.ResultsSubchondral 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.ConclusionOur 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

AbstractAll 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

AbstractBackgroundBacillus 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.ResultsWe 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.ConclusionDisruption 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

AbstractRodent 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

AbstractRegulatory 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.
Amphetamine increases timing variability by degrading prefrontal ramping activity
Authors: Weber Matthew A. , Sivakumar Kartik , Kirkpatrick Braedon Q. , Stutt Hannah R. , Tabakovic Ervina E. , Bova Alexandra S , Kim Young-cho , Narayanan Nandakumar S. 
Published: September 2024

AbstractBackgroundAmphetamine is a commonly abused psychostimulant that increases synaptic catecholamine levels and impairs executive functions. However, it is unknown how acute amphetamine affects brain areas involved in executive control, such as the prefrontal cortex. We studied this problem in mice using interval timing, which requires participants to estimate an interval of several seconds with a motor response. Rodent prefrontal cortex ensembles are required for interval timing. We tested the hypothesis that amphetamine disrupts interval timing by degrading prefrontal cortex temporal encoding.MethodsWe first quantified the effects of amphetamine on interval timing performance by conducting a meta-analysis of 11 prior rodent studies. We also implanted multielectrode recording arrays in the dorsomedial prefrontal cortex of 7 mice and then examined the effects of 1.5 mg/kgD-amphetamine injected intraperitoneally on interval timing behavior and prefrontal neuronal ensemble activity.ResultsA meta-analysis of previous literature revealed that amphetamine produces a large effect size on interval timing variability across studies but only a medium effect size on central tendencies of interval timing. We found a similar effect on interval timing variability in our task, which was accompanied by greater trial-to-trial variability in prefrontal ramping, attenuated interactions between pairs of ramping neurons, and dampened low-frequency oscillations.ConclusionsThese findings suggest that amphetamine alters prefrontal temporal processing by increasing the variability of prefrontal ramping. Our work provides insight into how amphetamine affects timing-related brain activity, which may be useful in developing new neurophysiological markers for amphetamine use and novel treatments targeting the prefrontal cortex.
Rhythmic Sampling and Competition of Target and Distractor in a Motion Detection Task
Authors: Xiong Changhao , Petro Nathan M. , Bo Ke , Cui Lihan , Keil Andreas , Ding Mingzhou 
Published: September 2024

AbstractIt has been suggested that the visual system samples attended information rhythmically. Does rhythmic sampling also apply to distracting information? How do attended information and distracting information compete temporally for neural representations? We recorded electroencephalography from participants who detected instances of coherent motion in a random dot kinematogram (RDK; the target stimulus), overlayed on different categories (pleasant, neutral, and unpleasant) of affective images from the International Affective System (IAPS) (the distractor). The moving dots were flickered at 4.29 Hz whereas the IAPS pictures were flickered at 6 Hz. The time course of spectral power at 4.29 Hz (dot response) was taken to index the temporal dynamics of target processing. The spatial pattern of the power at 6 Hz was similarly extracted and subjected to a MVPA decoding analysis to index the temporal dynamics of processing pleasant, neutral, or unpleasant distractor pictures. We found that (1) both target processing and distractor processing exhibited rhythmicity at ∼1 Hz and (2) the phase difference between the two rhythmic time courses were related to task performance, i.e., relative phase closer to π predicted a higher rate of coherent motion detection whereas relative phase closer to 0 predicted a lower rate of coherent motion detection. These results suggest that (1) in a target-distractor scenario, both attended and distracting information were sampled rhythmically and (2) the more target sampling and distractor sampling were separated in time within a sampling cycle, the less distraction effects were observed, both at the neural and the behavioral level.
Microfluidic Modulation of Microvasculature in Microdissected Tumors
Authors: Nguyen Tran N. H. , Horowitz Lisa F. , Nguyen Brandon , Lockhart Ethan , Zhu Songli , Gujral Taranjit S. , Folch Albert 
Published: September 2024

ABSTRACTThe microvasculature within the tumor microenvironment (TME) plays an essential role in cancer signaling beyond nutrient delivery. However, it has been challenging to control the generation and/or maintenance of microvasculature inex vivosystems, a critical step for establishing cancer models of high clinical biomimicry. There have been great successes in engineering tissues incorporating microvasculaturede novo(e.g., organoids and organs-on-chip), but these reconstituted tissues are formed with non-native cellular and molecular components that can skew certain outcomes such as drug efficacy. Microdissected tumors, on the other hand, show promise in preserving the TME, which is key for creating cancer models that can bridge the gap between bench and bedside. However, microdissected tumors are challenging to perfuse. Here, we developed a microfluidic platform that allows for perfusing the microvasculature of microdissected tumors. We demonstrate that, compared to diffusive transport, microfluidically perfused tissues feature larger and longer microvascular structures, with a better expression of CD31, a marker for endothelial cells, as analyzed by 3D imaging. This study also explores the effects of nitric oxide pathway-related drugs on endothelial cells, which are sensitive to shear stress and can activate endothelial nitric oxide synthase, producing nitric oxide. Our findings highlight the critical role of controlled perfusion and biochemical modulation in preserving tumor microvasculature, offering valuable insights for developing more effective cancer treatments.