bluuebunny/crossref_metadata_2025 huggingface dataset:
Cortical nitric oxide required for presynaptic long-term potentiation in the insular cortex
Authors: Yamamoto Kiyofumi , Chen Qi-Yu , Zhou Zhaoxiang , Kobayashi Masayuki , Zhuo Min
Published: June 2024

Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse retrogradely into presynaptic terminals, contributing to the induction of hippocampal long-term potentiation (LTP). Here, we present novel evidence that NO is required for kainate receptor (KAR)-dependent presynaptic form of LTP (pre-LTP) in the adult insular cortex (IC). In the IC, we found that inhibition of NO synthase erased the maintenance of pre-LTP, while the induction of pre-LTP required the activation of KAR. Furthermore, NO is essential for pre-LTP induced between two pyramidal cells in the IC using the double patch-clamp recording. These results suggest that NO is required for homosynaptic pre-LTP in the IC. Our results present strong evidence for the critical roles of NO in pre-LTP in the IC.

This article is part of a discussion meeting issue ‘Long-term potentiation: 50 years on’.
Acanthamoeba castellanii alone is not a growth promoter for Hordeum vulgare
Authors: Sacharow Julia , Ratering Stefan , Schneider Bellinda , Österreicher Cunha-Dupont Alessandra , Schnell Sylvia
Published: June 2024

Protists are important key players in the microbial loop and influence their environment by grazing, which leads to the return of nutrients into the soil and reduces pathogen pressure of plants. Espacially protists on and around plant roots, are important for plant’s development and growth. For this study, the crop Hordeum vulgare was selected, which is the fourth most important crop in the world. Seeds of H. vulgare were inoculated with Acanthamoeba castellanii alone or with additional soil bacteria. The germination of the seedlings and the growth of the plants in pouches was monitored over three weeks, while the plants were reinoculated. No differences were found in leaf growth, root growth, root and leaf nitrogen content or ammonia content of the liquid from the pouches. In contrast, the relative increase in root and leaf dry weight showed a small difference compared to the controls. The results of this experiment demonstrated that seed inoculation with A. castellanii alone or with additional unidentified soil bacteria did not have a major effect on plant growth and development of barley. Nevertheless, small changes in the plant development were detected, indicating that A. castellanii should be considered for further investigation of co-inoculations with plant growth promoting bacteria and additional nutrients.
A study on viruses and bacteria with particular interest on Mycoplasma pneumoniae in children with exacerbation of asthma from a tertiary care hospital in Sri Lanka
Authors: Wijesooriya Lakmini Inoka , Chalker Victoria , Perera Priyantha , Sunil-Chandra N.P.
Published: June 2024

Asthma is a significant public health concern, particularly in children with severe symptoms. Exacerbation of asthma (EOA) is life-threatening and respiratory infections (RIs) play a crucial role. Though viruses  play a significant role in EOA,  patients are empirically treated with antibiotics which contribute to the development of antibiotic resistance. Although there are widely reported association of EOA with viral or M. pneumoniae infections, there are no published data in Sri Lanka. The present study aimed to identify the association of common respiratory viruses, typical respiratory bacterial pathogens, and M. pneumoniae in children with EOA   and relate them with the compatibility of antimicrobial use.
A case-control study was conducted in the pediatric unit of North Colombo Teaching Hospital, Sri Lanka, involving two groups of children between 5-15 years of age. Group-1: children with EOA, Group-2: children with stable asthma (SA). Each group consisted of 100 children. Sputum/throat swabs were tested for common respiratory viruses using virus specific  FITC-labelled monoclonal antibodies (MAbs),  bacteria by routine culture and M. pneumoniae by RT-PCR. Macrolide-resistance in M. pneumoniae was detected using conventional PCR and sequencing specific genetic mutations in the 23S rRNA gene. M. pneumoniae was genotyped using nested multilocus sequence typing (MLST), which targeted eight housekeeping genes  (ppa, pgm, gyrB, gmk, glyA, atpA, arcC, adk).
There was no significant difference in age, gender, demographic or geographical locations   between the two groups. In children with EOA, antibiotics were used in 66% (66/100) and macrolides in 42% (42/100) in children with EOA.  Samples consisted of 78% (78/100)  sputum and 22% (22/100) throat swabs. Adenovirus   was the most common   virus identified, and it was significantly higher in children with EOA compared to those with SA, but no significant difference in typical bacteria findings between the two groups.   M. pneumoniae was detected in one patient    with EOA, with none  detected in the SA group. The  M. pneumoniae was macrolide sensitive, and   it was ST14 by Multi Locus Sequence Typing. This study showed that the empiric use of antibiotics in children with asthma may be better targeted with prior pathogen screening to inform appropriate treatment to minimize antibiotic resistance.
Development of acute Pseudomonas aeruginosa and Acinetobacter baumannii lung infection models in mice using oropharyngeal aspiration.
Authors: Jurado-Martín Irene , Ma Chaoying , Sainz-Mejías Maite , Hou Yueran , Baugh John A. , McClean Siobhán
Published: June 2024

Bacterial infections caused by antimicrobial resistant pathogens such as Pseudomonas aeruginosa and Acinetobacter baumannii can cause potentially fatal infections in susceptible individuals, with respiratory tract infections among the most common presentation. There is a real need to develop novel treatments or prophylactic interventions to combat these infections. The development of any new treatment or vaccine requires robust, reliable animal models for their preclinical evaluation. In particular, the bacterial burden needs to be accurately determined before and after administration of the potential therapy under evaluation to quantitate the effectiveness of the treatment. We provide a reliable non-invasive murine model of acute lung infection with either P. aeruginosa or A. baumannii using an oropharyngeal aspiration technique. This non-surgical technique to deliver suspensions into mouse lungs is less stressful to animals than other techniques. It allowed uniform bilateral distribution of the bacterial dose resulting in even colonisation of both lungs. The optimal timepoint for humane killing and organ harvest was 24 h after challenge for both pathogens, and at least 4x106 and 107 CFU/mouse were needed to establish P. aeruginosa or A. baumannii infection, respectively. These optimised mouse pneumonia models offer a valuable tool for studying P. aeruginosa and A. baumannii infections and evaluating therapeutic interventions against them.
Increased Osteoblastic and Osteocytic in Vitro Cell Viability by Yerba Mate (Ilex paraguariensis)
Authors: Villarreal Laureana , Sanz Natasha , Fagalde Florencia Buiatti , D’Andrea Florencia , Lombarte Mercedes , Rico María J. , Rozados Viviana R. , Scharovsky O. Graciela , Plotkin Lilian I. , Di Loreto Verónica E. , Brun Lucas R.
Published: June 2024

Background: Yerba mate (YM, Ilex paraguariensis) consumption beneficially affects the bones. However, whether YM components exert their effect on bone cells directly remains elusive.Methods: We evaluated how main YM components affect osteoblastic (MC3T3-E1) and osteocytic (MLO-Y4) cells in vitro when administered separately or in an aqueous extract. MC3T3-E1 and MLO-Y4 cells were exposed to three different experimental conditions: (1) Caffeine, chlorogenic acid, and their combinations; (2) Caffeine, rutin, and their combinations; (3) Aqueous YM extract.Results: All polyphenol and caffeine concentrations as well as that of their tested combinations significantly increased MC3T3-E1 cell viability from 16.6% to 34.8% compared to the control. In MLO-Y4 cells, the lowest rutin and the two highest caffeine concentrations significantly increased cell viability by 11.9, 14.9, and 13.7%, respectively. While rutin and caffeine combinations tended to increase MLO-Y4 cell viability, different chlorogenic acid and caffeine combinations did not affect it. Finally, the aqueous YM extract significantly increased MLO-Y4, MC3T3-E1, and differentiated MC3T3-E1 cell viability compared to the control without treatment.Conclusions: YM components (rutin, chlorogenic acid, and caffeine) positively affected bone cells, mainly pre-osteoblast cells. Moreover, the aqueous YM extract significantly increased MLO-Y4, MC3T3-E1, and differentiated MC3T3-E1 cell viabilities indicating an additional relevant nutritional property of YM infusion. Further studies would be required to elucidate the underlying effector mechanism of YM on the bones and its relationship with previously described in vivo positive effects.
Systematic Review and Meta-Analysis of the Effect of Osteoporosis on Reoperation Rates and Complications after Surgical Management of Lumbar Degenerative Disease
Authors: Lechtholz-Zey Elizabeth A. , Ayad Mina , Gettleman Brandon S. , Mills Emily S. , Shelby Hannah , Ton Andy T. , Shah Ishan , Wang Jeffrey C. , Hah Raymond J. , Alluri Ram K.
Published: June 2024

Background: There is considerable heterogeneity in findings and a lack of consensus regarding the interplay between osteoporosis and outcomes in patients with lumbar degenerative spine disease. Therefore, the purpose of this systematic review and meta-analysis was to gather and analyze existing data on the effect of osteoporosis on radiographic, surgical, and clinical outcomes following surgery for lumbar degenerative spinal disease.Methods: A systematic review was performed to determine the effect of osteoporosis on the incidence of adverse outcomes after surgical intervention for lumbar degenerative spinal diseases. The approach focused on the radiographic outcomes, reoperation rates, and other medical and surgical complications. Subsequently, a meta-analysis was performed on the eligible studies.Results: The results of the meta-analysis suggested that osteoporotic patients experienced increased rates of adjacent segment disease (ASD; p=0.015) and cage subsidence (p=0.001) while demonstrating lower reoperation rates than non-osteoporotic patients (7.4% vs. 13.1%; p=0.038). The systematic review also indicated that the length of stay, overall costs, rates of screw loosening, and rates of wound and other medical complications may increase in patients with a lower bone mineral density. Fusion rates, as well as patient-reported and clinical outcomes, did not differ significantly between osteoporotic and non-osteoporotic patients.Conclusions: Osteoporosis was associated with an increased risk of ASD, cage migration, and possibly postoperative screw loosening, as well as longer hospital stays, incurring higher costs and an increased likelihood of postoperative complications. However, a link was not established between osteoporosis and poor clinical outcomes.
TORC1 reactivation by pheromone signaling revealed by phosphoproteomics of fission yeast sexual reproduction
Authors: Bérard Melvin , Merlini Laura , Martin Sophie G
Published: June 2024

Starvation, which is associated with inactivation of the growth-promoting TOR complex 1 (TORC1), is a strong environmental signal for cell differentiation. In the fission yeastSchizosaccharomyces pombe, nitrogen starvation has distinct physiological consequences depending on the presence of mating partners. In their absence, cells enter quiescence, and TORC1 inactivation prolongs their life. In presence of compatible mates, TORC1 inactivation is essential for sexual differentiation. Gametes engage in paracrine pheromone signaling, grow towards each other, fuse to form the diploid zygote, and form resistant, haploid spore progenies. To understand the signaling changes in the proteome and phospho-proteome during sexual reproduction, we developed cell synchronization strategies and present (phospho-)proteomic datasets that dissect pheromone from starvation signals over the sexual differentiation and cell-cell fusion processes. Unexpectedly, these datasets reveal phosphorylation of ribosomal protein S6 during sexual development, which we establish requires TORC1 activity. We demonstrate that TORC1 is re-activated by pheromone signaling, in a manner that does not require autophagy. Mutants with low TORC1 re-activation exhibit compromised mating and poorly viable spores. Thus, while inactivated to initiate the mating process, TORC1 is reactivated by pheromone signaling in starved cells to support sexual reproduction.
MAXTEMP: A method to maximize precision of the temporal method for estimatingNein genetic monitoring programs
Authors: Waples Robin S. , Masuda Michele M. , LaCava Melanie E.F. , Finger Amanda J.
Published: June 2024

We introduce a new software program,MAXTEMP, that maximizes precision of the temporal method for estimating effective population size (Ne) in genetic monitoring programs, which are increasingly used to systematically track changes in global biodiversity. Scientists and managers are typically most interested inNefor individual generations, either to match with single-generation estimates of census size (N) or to evaluate consequences of specific management actions or environmental events. Systematically sampling every generation produces a time series of single-generation estimates of temporal, which can then be used to estimateNe; however, these estimates have relatively low precision because each reflects just a single episode of genetic drift. Systematic sampling also produces an array of multigenerational temporal estimates that collectively contain a great deal of information about genetic drift that, however, can be difficult to interpret. Here we show how additional information contained in multigenerational temporal estimates can be leveraged to increase precision offor individual generations. Using information from one additional generation before and after a target generation can reduce the standard deviation ofby up to 50%, which not only tightens confidence intervals aroundbut also reduces the incidence of extreme estimates. Practical application ofMAXTEMPis illustrated with data for a long-term genetic monitoring program for California delta smelt. A second feature ofMAXTEMP, which allows one to estimateNein an unsampled generation using a combination of temporal and single-sample estimates ofNefrom sampled generations, is also described and evaluated.
Estradiol Modulates Resting-State Connectivity in Perimenopausal Depression
Authors: Hynd Megan , Gibson Kathryn , Walsh Melissa , Phillips Rachel , Prim Julianna , Eisenlohr-Moul Tory , Walsh Erin , Dichter Gabriel , Schiller Crystal
Published: June 2024

The perimenopausal transition is marked by an increased risk for affective dysregulation and major depressive disorder (MDD), with hormone replacement therapy using estradiol (E2) showing promise for alleviating symptoms of perimenopausal-onset MDD (PO-MDD). Although E2’s effectiveness is recognized, its mechanisms underlying mood symptom modulation remain to be fully elucidated. Building on previous research suggesting that E2 may influence mood by altering cortico-subcortical connectivity, this study investigates the effects of transdermal E2 on resting-state functional connectivity (rsFC) in perimenopausal women with and without PO-MDD, focusing on rsFC changes using seed regions within emotion and reward processing networks. In this pharmaco-fMRI study, sixteen participants with PO-MDD and eighteen controls underwent rsFC analysis before and after three weeks of transdermal E2 administration. Pre-E2 results showed that the PO-MDD group, compared to controls, exhibited increased connectivity between the right amygdala (seed) and medial prefrontal cortex and anterior cingulate cortex, and decreased connectivity with the supplementary motor area. Post-E2 results revealed several significant E2-induced changes in connectivity between the PO-MDD and control groups: PO-MDD showed increased connectivity between the right caudate nucleus (seed) and left insula, and decreased connectivity between the right putamen (seed) and left hippocampus, and the right amygdala (seed) and left ventromedial prefrontal cortex. Notably, changes in connectivity were predictive of symptom trajectory across anhedonia, depressive mood, somatic, and vasomotor domains in the PO-MDD group. These findings enrich our understanding of PO-MDD by highlighting distinct rsFC patterns characteristic of the disorder and their shifts in response to E2 treatment, suggesting potential neural mechanisms underlying E2’s mood-modulating effects.
Economic evaluation of a wearable-based intervention to increase physical activity among insufficiently active middle-aged adults
Authors: Ching Jack H. , Duff Steve , Hernandez John
Published: June 2024

Background

Physical activity levels worldwide have declined over recent decades, with the average number of daily steps decreasing steadily since 1995. Given that physical inactivity is a major modifiable risk factor for chronic disease and mortality, increasing the level of physical activity is a clear opportunity to improve population health on a broad scale. The current study aims to assess the cost-effectiveness and budget impact of a Fitbit-based intervention among healthy, but insufficiently active, adults to quantify the potential clinical and economic value for a commercially insured population in the U.S.

Methods

An economic model was developed to compare physical activity levels, health outcomes, costs, and quality-adjusted life-years (QALYs) associated with usual care and a Fitbit-based inter-vention that consists of a consumer wearable device alongside goal setting and feedback features provided in a companion software application. Improvement in physical activity was measured in terms of mean daily step count. The effects of increased daily step count were characterized as reduced short-term healthcare costs and decreased incidence of chronic diseases with corresponding improvement in health utility and reduced disease costs. Published literature, standardized costing resources, and data from a National Institutes of Health-funded research program were utilized. Cost-effectiveness and budget impact analyses were performed for a hypothetical cohort of middle-aged adults.

Results

The base case cost-effectiveness results found the Fitbit intervention to be dominant (less costly and more effective) compared to usual care. Discounted 15-year incremental costs and QALYs were -$1,257 and 0.011, respectively. In probabilistic analyses, the Fitbit intervention was dominant in 93% of simulations and either dominant or cost-effective (defined as less than $150,000/QALY gained) in 99.4% of simulations. For budget impact analyses conducted from the perspective of a U.S. Commercial payer, the Fitbit intervention was estimated to save approximately $6.5 million dollars over 2 years and $8.5 million dollars over 5 years for a cohort of 8,000 participants. Although the economic analysis results were very robust, the short-term healthcare cost savings were the most uncertain in this population and warrant further research.

Conclusions

There is abundant evidence documenting the benefits of wearable activity trackers when used to increase physical activity as measured by daily step counts. Our research provides additional health economic evidence supporting implementation of wearable-based interventions to improve population health, and offers compelling support for payers to consider including wearable-based physical activity interventions as part of a comprehensive portfolio of preventive health offerings for their insured populations.
VILOCA: Sequencing quality-aware haplotype reconstruction and mutation calling for short- and long-read data
Authors: Fuhrmann Lara , Langer Benjamin , Topolsky Ivan , Beerenwinkel Niko
Published: June 2024

RNA viruses exist in large heterogeneous populations within their host. The structure and diversity of virus populations affects disease progression and treatment outcomes. Next-generation sequencing allows detailed viral population analysis, but inferring diversity from error-prone reads is challenging. Here, we present VILOCA, a method for mutation calling and reconstruction of local haplotypes from short- and long-read viral sequencing data. Local haplotypes refer to genomic regions that have approximately the length of the input reads. VILOCA recovers local haplotypes by using a Dirichlet process mixture model to cluster reads around their unobserved haplotypes and leveraging quality scores of the sequencing reads. We assessed the performance of VILOCA in terms of mutation calling and haplotype reconstruction accuracy on simulated and experimental Illumina, PacBio, and Oxford Nanopore data. On simulated and experimental Illumina data, VILOCA performed better or similar to existing methods. On the simulated long-read data, VILOCA is able to recover on average 82% of the ground truth mutations with perfect precision compared to only 64% recall and 90% precision of the second-best method. In summary, VILOCA provides significantly improved accuracy in mutation and haplotype calling, especially for long-read sequencing data, and therefore facilitates the comprehensive characterization of heterogeneous within-host viral populations.
Beyond Pre-Post Surveys: Exploring Validity Evidence For The Use Of Experience Sampling Methods To Measure Student Anxiety In Introductory Biology
Authors: Weatherton Maryrose , Rosenberg Joshua M. , Rocconi Louis , Schussler Elisabeth E.
Published: June 2024

Classroom experiences elicit many emotions in students. Of these emotions, anxiety, or the feeling of uncertainty about a prospective event, has outsized impacts on students’ academic achievement and persistence. To understand the effects of student anxiety on student outcomes, education researchers often utilize single or dual-time point (e.g., pre-post) surveys. However, we posit that these methods have significant limitations, including the potential to miss variation in student emotions across time. One methodological solution to this problem is using experience sampling methods (ESM), or short, frequent surveys that capture student experiences as they occur. This study sought to provide evidence of validity for the use of ESM to measure student anxiety in Introductory Biology courses. We compared student anxiety data gathered via ESM and traditional survey methods (i.e., pre-post surveys) in terms of 1) differences in participant recruitment, 2) students’ experience of anxiety, and 3) the predictive ability on end-of-course outcomes. Our results revealed that: 1) Compared to non-ESM participants, the ESM group has significantly fewer men and had significantly higher perceptions of instructor support, 2) Average anxiety levels measured via ESM were lower and more variable than those measured via pre-post surveys, and 3) Post-survey measures of anxiety and average ESM measures of anxiety significantly predicted students’ final grade. We discuss the implications of these results for future applications of ESM and pre-post survey methods; specifically, we propose that ESM methods may be more advantageous than pre-post surveys in cases where researchers aim to understand intra-individual processes, like emotions.
Model-Based Assessment of Photoplethysmogram Signal Quality in Real-Life Environments
Authors: Su Yan-Wei , Hao Chia-Cheng , Liu Gi-Ren , Sheu Yuan-Chung , Wu Hau-Tieng
Published: June 2024

Abstract

Assessing signal quality is crucial for photoplethysmogram analysis, yet a precise mathematical model for defining signal quality is often lacking, posing challenges in the quantitative analysis. To tackle this problem, we propose a Signal Quality Index (SQI) based on the adaptive non-harmonic model (ANHM) and a Signal Quality Assessment (SQA) model, which is trained using the boosting learning algorithm. The effectiveness of the proposed SQA model is tested on publicly available databases with experts’ annotations. Result: The DaLiA database [20] is used to train the SQA model, which achieves favorable accuracy and macro-F1 scores in other public databases (accuracy 0.83, 0.76 and 0.87 and macro-F1 0.81, 0.75 and 0.87 for DaLiA-testing dataset, TROIKA dataset [31], and WESAD dataset [23], respectively). This preliminary result shows that the ANHM model and the model-based SQI have potential for establishing an interpretable SQA system.
A Denoising Convolutional Autoencoder for SNR Enhancement in Chemical Exchange Saturation Transfer imaging: (DCAE-CEST)
Authors: Kurmi Yashwant , Viswanathan Malvika , Zu Zhongliang
Published: June 2024

Purpose

To develop a SNR enhancement method for chemical exchange saturation transfer (CEST) imaging using a denoising convolutional autoencoder (DCAE), and compare its performance with state-of-the-art denoising methods.

Method

The DCAE-CEST model encompasses an encoder and a decoder network. The encoder learns features from the input CEST Z-spectrum via a series of 1D convolutions, nonlinearity applications and pooling. Subsequently, the decoder reconstructs an output denoised Z-spectrum using a series of up-sampling and convolution layers. The DCAE-CEST model underwent multistage training in an environment constrained by Kullback–Leibler divergence, while ensuring data adaptability through context learning using Principal Component Analysis processed Z-spectrum as a reference. The model was trained using simulated Z-spectra, and its performance was evaluated using both simulated data and in-vivo data from an animal tumor model. Maps of amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) effects were quantified using the multiple-pool Lorentzian fit, along with an apparent exchange-dependent relaxation metric.

Results

In digital phantom experiments, the DCAE-CEST method exhibited superior performance, surpassing existing denoising techniques, as indicated by the peak SNR and Structural Similarity Index. Additionally, in vivo data further confirms the effectiveness of the DCAE-CEST in denoising the APT and NOE maps when compared to other methods. While no significant difference was observed in APT between tumors and normal tissues, there was a significant difference in NOE, consistent with previous findings.

Conclusion

The DCAE-CEST can learn the most important features of the CEST Z-spectrum and provide the most effective denoising solution compared to other methods.
Loss of ARID1A accelerates prostate tumourigenesis with a proliferative collagen-poor phenotype through co-operation with AP1 subunit cFos
Authors: Hartley Andrew , Galbraith Laura C.A. , Shaw Robin , Tibbo Amy , Veeratterapillay Rajan , Wilson Laura , Heer Rakesh , Blyth Karen , Leung Hing , Ahmad Imran
Published: June 2024

Prostate cancer (PC) is the most common male visceral cancer, and second leading cause of cancer mortality in men in the Western world. Using a forward-mutagenesis Sleeping Beauty (SB) transposon-based screen in a Probasin Cre-Recombinase (Pb-Cre)Pten-deficient mouse model of PC, we identifiedArid1aloss as a driver in the development of metastatic disease. The insertion of transposon in theArid1agene resulted in a 60% reduction ofArid1aexpression, and reduced tumour free survival (SB:Ptenfl/flArid1aINTmedian 226 days vsSB:Ptenfl/flArid1aWT293 days, p=0.02),with elevated rates of metastasis (SB:Ptenfl/flArid1aINT75% lung metastasis rate vs 17%SB:Ptenfl/flArid1aWT,p<0.001 ). We further generated aPb-Cre Pten- andArid1a-deficient mouse model, in which loss ofArid1ademonstrated a profound acceleration in tumorigenesis inPtenfl/flmice compared toPtenloss alone (Pb-Cre Ptenfl/flArid1a+/+median survival of 267 days vs Pb-CrePtenfl/flArid1afl/fl103 days, p<0.0001). Our data revealed homozygousArid1aloss is required to dramatically accelerate prostate tumourigenesis, resulting in tumours with a less differentiated phenotype and a disorganised stroma. Furthermore,Arid1aloss mediated tumour formation in the mouse involved both the anterior and dorsolateral lobes, a unique feature fromPten-loss and other reported PC GEMM where tumour formation tends to be limited to the anterior lobes. Analysis of RNA and ChIP -Sequencing data suggestsArid1aloss enhanced the function of AP-1 subunit cFos. In clinical PC cohort, ARID1A and cFos levels stratified an aggressive subset of PC with a poor survival outcome with a median of only 30 months.
The Untapped Potential of Tree Size in Reconstructing Evolutionary and Epidemiological Dynamics
Authors: MacPherson Ailene , Pennell Matt
Published: June 2024

A phylogenetic tree has three types of attributes: size, shape (topology), and branch lengths. Phylody-namic studies are often motivated by questions regarding the size of clades, nevertheless, nearly all of the inference methods only make use of the other two attributes. In this paper, we ask whether there is additional information if we consider tree size more explicitly in phylodynamic inference methods. To address this question, we first needed to be able to compute the expected tree size distribution under a specified phylodynamic model; perhaps surprisingly, there is not a general method for doing so — it is known what this is under a Yule or constant rate birth-death model but not for the more complicated scenarios researchers are often interested in. We present three different solutions to this problem: using i) the deterministic limit; ii) master equations; and iii) an ensemble moment approximation. Using simulations, we evaluate the accuracy of these three approaches under a variety of scenarios and alternative measures of tree size (i.e., sampling through time or only at the present; sampling ancestors or not). We then use the most accurate measures for the situation, to investigate the added informational content of tree size. We find that for two critical phylodynamic questions — i) is diversification diversity dependent? and, ii) can we distinguish between alternative diversification scenarios? — knowing the expected tree size distribution under the specified scenario provides insights that could not be gleaned from considering the expected shape and branch lengths alone. The contribution of this paper is both a novel set of methods for computing tree size distributions and a path forward for richer phylodynamic inference into the evolutionary and epidemiological processes that shape lineage trees.
Contingencies in biofilm adaptation ofMycobacterium tuberculosis
Authors: Kernien John F. , Youngblom Madison A. , Smith Tracy M. , Fry Sydney S. , Mohamed Mohamed A. , Murray Holly J. , Lawrence Kadee N. , Pepperell Caitlin S.
Published: June 2024

Biofilms are structured microbial communities that offer protection from a range of environmental stressors. Studies of experimental evolution within biofilms have yielded important insights into mechanisms of biofilm formation, as well as fundamental principles governing bacterial adaptation within these structured communities. Building on research using tractable species, our lab created a model for studying biofilm adaptation inMycobacterium tuberculosis (M. tb),a fastidious, slow growing and lethal pathogen of humans. Here, we evolved eighteenM. tbpopulations arising from six parental genetic backgrounds under biofilm selection to investigate diversity in mechanisms ofM. tbbiofilm adaptation. We found that fine-scale differences among strains at the initiation of the experiment influenced the degree of replicability in their evolution. Adaptive paths were highly parallel for some strains, whereas others evolved distinct mutations across iterations of the experiment. Our data suggest that differences in replicability arise from mutational biases and variable fitness impacts of mutations across genetic backgrounds. Comparison of our results with genomic data fromM. tbpopulations within hosts with tuberculosis (TB) revealed that several mutations associated with biofilm selection are also among the most common to emerge during natural infection. These biofilm-associated variants are not maintained in naturalM. tbpopulations, suggesting that biofilm selection in our model mimics selection pressures that are transiently encountered byM. tbduring specific phases of infection. Overall, these results support development of biofilm directed therapies for TB and demonstrate the importance of subtle genetic variation in shapingM. tbresponses to changing selection pressures.

Significance

Mycobacterium tuberculosis (M. tb),the causative agent of tuberculosis (TB), a difficult-to-treat, persistent infection with high mortality. One cause of this persistence is the ability ofM. tbto form biofilms, aggregated structures capable of resisting antibiotics and host defenses. Here, we used an evolutionary model to investigate mechanisms ofM. tbbiofilm formation. We found adaptation to biofilm growth to be affected by mutational biases and interactions among mutations. Our simple in vitro model appears to mimic aspects of natural infection, as identical mutations emerge in the laboratory under biofilm selection and within hosts with TB. These results expand our knowledge ofM. tbbiofilm development and inform our understanding of how this bacterium responds to novel selection pressures.
Lower-limb coordination changes following a six-week training intervention that elicited enhancements to maximum velocity sprint performance
Authors: Lenthall Daniel , Brazil Adam , Castaño-Zambudio Adrián , Lightfoot Harry , Mendiguchia Jurdan , Jiménez-Reyes Pedro , Colyer Steffi L.
Published: June 2024

Alterations to intra- and inter-limb coordination with improved maximal velocity performance remain largely unexplored. This study quantified within-day variability in lower-limb segmental coordination profiles during maximal velocity sprinting and investigated the modifications to coordination strategies in 15 recreationally active males following a six-week period comprised of a multimodal training programme (intervention group (INT); n = 7) or continued participation in sports (control group; n = 8). The INT demonstrated a large decline (effect size = -1.54) in within-day coordination profile variability, suggesting potential skill development. Thigh-thigh coordination modifications for the INT were characterised by an earlier onset of trail thigh reversal in early swing (26 vs. 28% stride) and lead thigh reversal in late swing (76 vs. 79% stride), rather than increases in overall time spent in anti-phase. Moreover, an increase in backwards thigh-dominant, thigh-shank (effect size, 95% CIs: 0.75, 0.17 to 1.33) and shank-dominant, shank-foot (0.76, -0.17 to 1.68) rotations during late swing likely facilitated more aggressive acceleration of the foot prior to touchdown, contributing to reduced touchdown distance and more favourable lower-limb configuration at initial ground contact. These novel findings provide empirical support for the role of longitudinal coordination modifications in improving maximal velocity performance.

SUMMARY STATEMENT

Coordination during the swing phase was more modifiable than during stance, with earlier reversal of antiphase thigh-thigh and backwards thigh-shank and shank-foot rotations in late swing observed with improved performance.
Chemoresistance ofTP53mutant AML requires the mevalonate byproduct, GGPP, for regulation of ROS and induction of a mitochondria stress response
Authors: Skuli Sarah J. , Bakayoko A’Ishah , Kruidenier Marisa , Manning Bryan , Pammer Paige , Salimov Akmal , Riley Owen , Brake-Sillá Gisela , Bowman Michael , Martinez-Gutierrez Leslie N. , Buono Roberta , Paul Madhuri , Saland Estelle , Wong Sarah , Xu Jimmy , Nee Eva , Hausler Ryan , Anderson Colin , Reisz Julie A. , D’Alessandro Angelo , Lai Catherine , Maxwell Kara N. , Sarry Jean-Emmanuel , Fruman David A. , Mesaros Clementina , Keith Brian , Simon M. Celeste , Sung Pamela J. , Wertheim Gerald , Skuli Nicolas , Bowman Robert L. , Matthews Andrew , Carroll Martin
Published: June 2024

Acute myeloid leukemia (AML) with mutations in the tumor suppressor gene,TP53(TP53mutAML), is fatal with a median survival of only 6 months. RNA sequencing on purified AML patient samples showTP53mutAML has higher expression of mevalonate pathway genes. We retrospectively identified a survival benefit inTP53mutAML patients who received chemotherapy concurrently with a statin, which inhibits the mevalonate pathway. Mechanistically,TP53mutAML resistance to standard AML chemotherapy, cytarabine (AraC), correlates with increased mevalonate pathway activity and a mitochondria stress response with increased mitochondria mass and oxidative phosphorylation. Pretreatment with a statin reverses these effects and chemosensitizesTP53mutAML cell lines and primary samplesin vitroandin vivo. Mitochondria-dependent chemoresistance requires the geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway and novel GGPP-dependent synthesis of glutathione to manage AraC-induced reactive oxygen species (ROS). Overall, we show that the mevalonate pathway is a novel therapeutic target inTP53mutAML.

Significance

Chemotherapy-persistingTP53mutAML cells induce a mitochondria stress response that requires mevalonate byproduct, GGPP, through its novel role in glutathione synthesis and regulation of mitochondria metabolism. We provide insight into prior failures of the statin family of mevalonate pathway inhibitors in AML. We identify clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need ofTP53mutAML.
Polymeric Micellar Nanoparticles Enable Image-guided Drug Delivery in Solid Tumors
Authors: Uddin Jashim , Lo Justin Han-Je , Gupta Mukesh K. , Werfel Thomas A. , Asaduzzaman Abu , Oltman Connor G. , Gbur Eva F. , Mohyuddin Mohammed T. , Nazmin Farhana , Rahman Saidur , Jashim Ahan , Crews Brenda C. , Kingsley Philip J. , Marnett Lawrence J. , Duvall Craig L. , Cook Rebecca S.
Published: June 2024

We report the development of a nanotechnology to co-deliver chemocoxib A with a reactive oxygen species (ROS)-activatable and COX-2 targeted pro-fluorescent probe, fluorocoxib Q (FQ) enabling real time visualization of COX-2 and CA drug delivery into solid cancers, using a di-block PPS135-b-POEGA17copolymer, selected for its intrinsic responsiveness to elevated reactive oxygen species (ROS), a key trait of the tumor microenvironment. FQ and CA were synthesized independently, then co-encapsulated within micellar PPS135-b-POEGA17co-polymeric nanoparticles (FQ-CA-NPs), and were assessed for cargo concentration, hydrodynamic diameter, zeta potential, and ROS-dependent cargo release. The uptake of FQ-CA-NPs in mouse mammary cancer cells and cargo release was assessed by fluorescence microscopy. Intravenous delivery of FQ-CA-NPs to mice harboring orthotopic mammary tumors, followed by vital optimal imaging, was used to assess delivery to tumorsin vivo. The CA-FQ-NPs exhibited a hydrodynamic diameter of 109.2 ± 4.1 nm and a zeta potential (ζ) of –1.59 ± 0.3 mV. Fluorescence microscopy showed ROS-dependent cargo release by FQ-CA-NPs in 4T1 cells, decreasing growth of 4T1 breast cancer cells, but not affecting growth of primary human mammary epithelial cells (HMECs). NP-derived fluorescence was detected in mammary tumors, but not in healthy organs. Tumor LC-MS/MS analysis identified both CA (2.38 nmol/g tumor tissue) and FQ (0.115 nmol/g tumor tissue), confirming the FQ-mediated image guidance of CA delivery in solid tumors. Thus, co-encapsulation of FQ and CA into micellar nanoparticles (FQ-CA-NPs) enabled ROS-sensitive drug release and COX-2-targeted visualization of solid tumors.
Akt2 deficiency impairs Th17 differentiation, augments Th2 differentiation, and alters the peripheral response to immunization
Authors: Banks Lauren B. , Sklarz Tammarah , Gohil Mercy , O’Leary Claire , Behrens Edward M. , Sun Hong , Chen Youhai H. , Koretzky Gary A. , Jordan Martha S.
Published: June 2024

Akt1 and Akt2, isoforms of the serine threonine kinase Akt, are essential for T cell development. However, their role in peripheral T cell differentiation remains undefined. Using mice with germline deletions of either Akt1 or Akt2, we found that both isoforms are important for Th17 differentiation, although Akt2 loss had a greater impact than loss of Akt1. In contrast to defective IL-17 production, Akt2−/−T cells exhibited enhanced IL-4 productionin vitrounder Th2 polarizing conditions.In vivo, Akt2−/−mice displayed significantly diminished IL-17A and GM-CSF production following immunization with myelin oligodendrocyte glycoprotein (MOG). This dampened response was associated with further alterations in Th cell differentiation including decreased IFNγ production but preserved IL-4 production, and preferential expansion of regulatory T cells compared to non-regulatory CD4 T cells. Taken together, we identify Akt2 as an important signaling molecule in regulating peripheral CD4 T cell responses.
Learning context-aware, distributed gene representations in spatial transcriptomics with SpaCEX
Authors: Sun Xiaobo , Xu Yucheng , Li Wenlin , Huang Mengqian , Wang Ziyi , Chen Jing , Wu Hao
Published: June 2024

Distributed gene representations are pivotal in data-driven genomic research, offering a structured way to understand the complexities of genomic data and providing foundation for various data analysis tasks. Current gene representation learning methods demand costly pretraining on heterogeneous transcriptomic corpora, making them less approachable and prone to over-generalization. For spatial transcriptomics (ST), there is a plethora of methods for learning spot embeddings but serious lacking method for generating gene embeddings from spatial gene profiles. In response, we present SpaCEX, a pioneer cost-effective self-supervised learning model that generates gene embeddings from ST data through exploiting spatial genomic “context” identified as spatially co-expressed gene groups. SpaCEX-generated gene embeddings (SGE) feature in context-awareness, rich semantics, and robustness to cross-sample technical artifacts. Extensive real data analyses reveal biological relevance of SpaCEX-identified genomic contexts and validate functional and relational semantics of SGEs. We further develop a suite of SGE-based computational methods for a range of key downstream objectives: identifying disease-associated genes and gene-gene interactions, pinpointing genes with designated spatial expression patterns, enhancing transcriptomic coverage of FISH-based ST, detecting spatially variable genes, and improving spatial clustering. Extensive real data results demonstrate these methods’ superior performance, thereby affirming the potential of SGEs in facilitating various analytical task.

Significance Statement

Spatial transcriptomics enables the identification of spatial gene relationships within tissues, providing semantically rich genomic “contexts” for understanding functional interconnections among genes. SpaCEX marks the first endeavor to effectively harnesses these contexts to yield biologically relevant distributed gene representations. These representations serve as a powerful tool to greatly facilitate the exploration of the genetic mechanisms behind phenotypes and diseases, as exemplified by their utility in key downstream analytical tasks in biomedical research, including identifying disease-associated genes and gene interactions,in silicoexpanding the transcriptomic coverage of low-throughput, high-resolution ST technologies, pinpointing diverse spatial gene expression patterns (co-expression, spatially variable pattern, and patterns with specific expression levels across tissue domains), and enhancing tissue domain discovery.
Genotyping-by-sequencing and DNA array for genomic prediction in soybean oil composition
Authors: Prado Melina , Priolli Regina Helena Geribello , Couto Evellyn Giselly De Oliveira , Sabadin Felipe , Dias Kaio Olimpio das Graças , Pinheiro José Baldin
Published: June 2024

Soybean oil is intended for various purposes, such as cooking oil and biodiesel. The oil composition changes the shelf life, palatability, and how healthy this oil is for the human diet. Genomic selection jointly uses these traits, phenotypes, and markers from one of the available genotyping platforms to increase genetic gain over time. This study aims to evaluate the impact of different genotyping platforms, DNA arrays, and Genotyping-by-Sequencing (GBS) on genomic selection in relation to the composition of fatty acids in soybean oil and total oil content. We used different quality control parameters, such as heterozygote rate, minor allele frequency, and missing data rate in ten combinations, and two prediction models, BayesB and BRR. To compare the impact of the genotyping approaches, we calculated the principal components analysis from the kinship matrices, the SNP density, and the traits prediction accuracies for each approach. Principal component analysis showed that the DNA array explained better the population genetic architecture.

On the other hand, prediction accuracies varied between the different genotyping platforms and only GBS was affected under different quality control parameters. Although the DNA array has important and well-studied polymorphisms for soybeans and is stable, it also has ascertainment bias. GBS, although not stable and requires more robust quality control, can discover alleles specific to the population under study. As soybean oil is used for different functions and the fatty acid profiles are different for each objective, the work constitutes a critical study and direction for improving the composition of soybean oil.
Calibrated prediction of scarce adverse drug reaction labels with conditional neural processes
Authors: Garcia-Ortegon Miguel , Seal Srijit , Singh Shantanu , Bender Andreas , Bacallado Sergio
Published: June 2024

Adverse drug reactions (ADRs) are a major source of concern in the development of novel pharmaceuticals. ADRs may be identified in the late stages of development or even after commercialization, which may lead to failure or discontinuation after spending enormous resources on candidate molecules. Thus, predicting ADRs early in the process could help reduce costs by avoiding future failures. However, due to the low number of drugs approved, the amount of historical datapoints on ADRs is limited, which makes their prediction challenging for traditional chemoinformatics methods. Interestingly, each approved drug may have been annotated for hundreds of ADRs, which opens the door to framing ADR prediction as a multi-task or meta-learning problem. In this work, we adopt a meta-learning approach to ADR prediction by applying conditional neural processes (CNPs) to the publicly available Side Effect Resource (SIDER). Our results suggest that CNPs are competitive against single-task baselines even when trained on sparse datasets with missing labels. Furthermore, we find that their predictions are well-calibrated. Finally, we evaluate their performance on ADRs associated to different physiological systems and confirm good predictions across organ classes. Our findings suggest that meta-learning strategies may be beneficial for data-limited clinical endpoints like ADRs.