bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating the Prevalence of Generative AI Use in Medical School Application Essays
Authors: Spies Nicholas C. , Ratts Valerie S. , Hagemann Ian S.
Published: October 2024

Background

Generative artificial intelligence (AI) tools became widely available to the public in November 2022. The extent to which these tools are being used by aspiring medical school applicants during the admissions process is unknown.

Methods

We retrospectively analyzed 6,000 essays submitted to a U.S. medical school in 2021– 2022 (baseline, before wide availability of AI) and in 2023–2024 (test year) to estimate the prevalence of AI use and its relation to other application data. We used GPTZero, a commercially available detection tool, to generate a metric for the likelihood that each essay was human-generated, Phuman, ranging from 0 (entirely AI) to 1 (entirely human).

Results

Fully human-generated negative controls demonstrated a median Phumanof 0.93, while AI-generated positive controls demonstrated a median Phumanof 0.01. Personal Comments essays submitted in the ‘23–‘24 cycle had a median human-generated score of 0.77 (95% confidence interval 0.76–0.78), versus 0.83 (95% CI 0.82–0.85) during the ‘21–‘22 cycle. Approximately 12.3 and 2.7% of essays were evaluated as having Phuman< 0.5 in the test and baseline year, respectively. Secondary essays demonstrated lower Phumanthan Personal Comments essays, suggesting more AI use. In multivariate analysis, younger age, visa requirement, and higher GPA were significantly associated with lower Phuman. No differences were observed in gender, MCAT score, undergraduate major, or socioeconomic status. Phumanwas not predictive of admissions outcomes in uni- or multivariate analyses.

Conclusions

An AI detection algorithm estimated significantly increased use of generative AI in 2023-2024 medical school admission applications, as compared to the 2021-2022 baseline. Estimated AI use demonstrated no significant differences in admissions decisions. While these results provide information about the applicant pool as a whole, AI detection is imperfect. We recommended exercising caution before deploying any AI detection tools on individual applications in live admissions cycles.

Description

Medical school applicants increased their use of generative AI to write application essays in the most recent admissions cycle, but this use did not confer an admissions advantage.
Genetic and other omics-based information in the most-cited recent clinical trials
Authors: Russo Luigi , Siena Leonardo M. , Farina Sara , Pastorino Roberta , Boccia Stefania , Ioannidis John P.A.
Published: October 2024

Importance

Genetics and other -omics’ technologies have long been proposed for medical research use.

Objective

To assess how genetics and other -omics information’ are used in the most cited recent clinical trials, and to evaluate industry involvement and transparency patterns.

Design, Setting, Participants

Meta-research evaluation using a previously constructed database of the 600 most cited clinical trials published from 2019 to 2022.

Main Outcome(s) and Measure(s)

Utilization of genetic or other -omics information in the trial design, analysis, and results; industry involvement and transparency.

Results

132 (22%) trials used genetic or other -omics information, predominantly for detection of cancer mutations (n=101). Utilization included eligibility criteria (n=59), subgroup analysis (n=82), and stratification factor in randomization (n=14). Authors addressed the relevance in the conclusions in 82 studies (62%). 102 studies (77%) provided data availability statements and 6 had data already available. Most studies had industry funding (n=111 [84.0%]). Oncology trials were more likely to be industry-funded (90.1% vs 64.5%, p=0.001), to have industry-affiliated analysts (43.6% vs 22.6%, p=0.036) and to favor industry-sponsored interventions (83.2% vs 58.1% p=0.004). When compared to other trials, genetic and other -omics trials were more likely to be funded by industry (84% vs 63.9%, p<0.001) and tended to be less likely to have full protocols (p=0.018) and statistical plans (p=0.04) available.

Conclusions and Relevance

Our study highlights the current underutilization of genetic and other-omics technologies beyond testing for cancer mutations. Industry involvement in these trials appears to be more substantial and transparency is more limited, raising concerns about potential bias.

Key Points

Question

How are genetics and other -omics information used in highly impactful clinical trials, and what is the involvement of the industry in their development?

Findings

22% of the trials employed genetic or -omics information, with the vast majority being oncology-related and focusing on testing for mutations. Industry was more heavily involved in the funding and in the design of these trials, in particular for oncology trials.

Meaning

The use of genetics and -omics is limited and needs to become more common in non-oncology trials. Industry involvement is intense in this context, highlighting the need for improvements in transparency and independence.
ToxoplasmaInfection and Its Sequential Impact on Physical Health, Stress, and Anxiety: A Large Cross-Sectional Study Testing the Stress-Coping Hypothesis
Authors: Flegr Jaroslav , Latifi Ashkan , Kaňková Šárka
Published: October 2024

Introduction

Latent toxoplasmosis, affecting approximately one-third of people worldwide, was once thought to be asymptomatic. However, studies in the last three decades have revealed that it can cause significant psychological and behavioral changes in humans. The observation that the behavioral impacts of toxoplasmosis manifest in opposite directions in men and women has led to the development of the Stress-Coping Hypothesis. This hypothesis posits that health degradation from toxoplasmosis results in chronic stress, with gender-specific coping strategies explaining the divergent behavioral responses observed between men and women.

Methods

This study, conducted on 1,768 individuals who had previously been tested for toxoplasmosis or borreliosis, sought to examine this hypothesis through a survey that included the Perceived Stress Scale and the State-Trait Anxiety Inventory.

Results

Confirmed poorer health, higher stress, and anxiety levels amongToxoplasma-infected participants. Path analysis showed that toxoplasmosis directly negatively impacts physical health, which in turn directly increases stress and anxiety among infected individuals, thereby negatively affecting cognitive performance. This pattern was not seen with borreliosis, serving as a negative control, underscoring the unique impact of toxoplasmosis on human physical health, well-being, and cognition.

Conclusions

Our findings strongly suggest that the cognitive impairments associated with toxoplasmosis are primarily side effects of chronic stress resulting from the compromised health of infected individuals.

Key Points

Chronic stress mediates the negative effects of toxoplasmosis on cognition, stemming from the impaired health of infected individuals.

This effect was not observed with the negative control, borreliosis.

Our results support the side effects hypothesis and contradict the parasite manipulation hypothesis.
Change in Acetylcholinesterase Activity from Childhood to Young Adulthood
Authors: Suarez-Lopez Jose R. , Gould Carlos F. , Vashishtha Devesh , Bradman Asa , Suarez-Torres Jose , Lopez-Paredes Dolores , Martinez Danilo , Moore Raeanne M.
Published: October 2024

Objective

Acetylcholinesterase (AChE) is an enzyme that metabolizes acetylcholine, an essential neurotransmitter, and is frequently used to monitor adult agricultural workers for exposure to cholinesterase inhibitor pesticides. Yet, there are no clear standards for AChE activity in children and adolescents, which prohibits evaluations of dangerous pesticide exposures in younger populations.

Methods

We measured AChE activity from a single finger stick blood sample data from 746 participants ages 4 to 26 years across 3,100 observations who resided in an agricultural county in Ecuador. We used generalized estimating equations to predict AChE activity levels in one year age increments from 5 to 25 years, accounting for nonlinear aging patterns and survey wave specific effects. We also decomposed variation in observed AChE activity levels into aging effects, differences in our recruited participants, and participant-specific aging patterns.

Results

Average AChE activity levels across all observations were 3.88 U/mL (standard deviation [sd] = 0.67). AChE activity levels increased nonlinearly as participants aged. We found that males had higher AChE activity levels than females and that those levels established themselves later in age than females. AChE activity levels increased essentially linearly from ages 5 to 12 or 18 years, depending on sex, at which point levels did not meaningfully change with age. Most variation observed in AChE activity levels were due to aging effects.

Conclusion

Our findings provide reference levels for AChE activity across childhood, adolescence, and into early adulthood that can be used by clinicians and researchers in the context of assessing neurodevelopment and potential exposure to neurotoxicants.
Virus testing optimisation using Hadamard pooling
Authors: Beddard Godfrey S. , Yorke Briony A.
Published: October 2024

Pooled testing is an established strategy for efficient surveillance testing of infectious diseases with low prevalence. Pooled testing works by combining clinical samples from multiple individuals into one test, where a negative result indicates the whole pool is disease free and a positive result indicates that individual testing is needed. Here we present a straightforward and simple method for pooled testing that uses the properties of Hadamard matrices to design optimal pooling strategies. We show that this method can be used to efficiently identify positive specimens in large sample sizes by simple pattern matching, without the requirement of complex algorithms.
Community-based interventions to address depression in older adults: a systematic scoping review
Authors: Restrepo-Escudero Laura , Jaimes Maria Alejandra , Arango Isabela , Santos Sofia , Ramírez Valentina , Uribe Daniel , Muñoz Jenny , Ballesteros Lina Maria González
Published: October 2024

Depression is a prevalent psychiatric disorder among adults aged 65 and older, significantly impacting their well-being. With an aging global population, effective community-based interventions are vital to combat this issue. This review provides an overview of the characteristics of community-based interventions addressing depression in the elderly, identifying knowledge gaps by synthesizing current data. The search strategy entails a systematic database search. Results show that interventions have been effective in reducing depressive symptoms and enhancing social interaction, mainly those that include physical activity, social engagement, or mental health education. Success depends on factors such as participant engagement, adherence, and the sociocultural environment. Addressing these barriers requires a comprehensive understanding of local contexts and innovative service delivery approaches. Improving recruitment by overcoming cultural and logistical challenges could expand the reach and accessibility of these programs, thereby increasing their overall impact on older adults mental health and quality of life.
N-Palmitoyl glycine activates transient receptor potential channel 5 and increases the risk of Brugada syndrome
Authors: Xu Hongxuan , Li Bingxun , Chen Ying , Lin Yanyun , Zhang An , Wu Lin
Published: October 2024

Background

Brugada syndrome (BrS) is an arrhythmic disorder associated with an increased risk of sudden cardiac death; however, current treatment options are limited due to their side effects and variable efficacy.

Methods

In this study, we first employed Mendelian randomization analysis utilizing proteomic, transcriptomic, and metabolomic data to identify potential therapeutic targets for BrS. Ex vivo perfused heart models were used to assess the effects of the potential targets on action potentials and QT intervals. Calcium indicators were employed to evaluate calcium homeostasis in primary cardiomyocytes, and patch-clamp techniques were used to investigate the impact on Nav1.5 and TRPC5 channels.

Results

Our findings indicate that N-palmitoyl glycine (PalGly) is linked to an increased risk of BrS and interacts with BrS-associated proteins, demonstrating moderate binding affinities for DCC, CR1, CTSB, NAAA, DEFB1, EPHA1, IGF1/IGFBP3/ALS, and LTA. Electrophysiological experiments showed that although PalGly does not interact with Nav1.5, it enhances calcium sparks in ventricular cardiomyocytes. We determined that the calcium-modulating effect of PalGly is mediated by its binding to and activation of the transient receptor potential channel 5 (TRPC5) channel. Furthermore, PalGly was found to shorten the QT interval and action potential duration in Langendorff-perfused rabbit hearts and isolated rabbit cardiomyocytes. Transcriptomic and lipidomic analyses of PalGly-treated neonatal rat cardiomyocytes revealed significant negative modulation of immune pathways, akin to the effects observed with agonizing TRPC5.

Conclusion

Our study underscores the involvement of PalGly, TRPC5, and inflammation-related proteins in the pathophysiology of BrS.
Engineering Resilient Gene Drives Towards Sustainable Malaria Control: Predicting, Testing and Overcoming Target Site Resistance
Authors: Morianou Ioanna , Phillimore Lee , Khatri Bhavin S. , Marston Louise , Gribble Matthew , Burt Austin , Bernardini Federica , Hammond Andrew M. , Nolan Tony , Crisanti Andrea
Published: October 2024

CRISPR-based gene drives are selfish genetic elements with the potential to spread through entire insect populations for sustainable vector control. Gene drives designed to disrupt the reproductive capacity of females can suppress laboratory populations of the malaria mosquito. However, any suppressive intervention will inevitably exert an evolutionary pressure for resistance. Here, we present a pipeline for the accelerated discovery, engineering, and testing of both natural and drive-induced variants that could reverse gene drive spread. We applied our method to stress-test a highly effective gene drive that has evaded resistance in all laboratory-contained releases to date, known as Ag(QFS)1. We showed that previously undetected resistant alleles can arise at low frequency, and discovered novel, partially resistant alleles that can perturb drive-invasion dynamics. We then engineered next-generation gene drives that can actively remove resistant alleles by targeting several highly conserved and non-overlapping sites in the female-specific exon of thedoublesexgene. Our models predict that such gene drive designs could suppress large, natural populations of the malaria mosquito in the field.
Differential enrichment of retinal ganglion cells underlies proposed core neurodegenerative transcription programs
Authors: Watkins Trent A.
Published: October 2024

In a published Correction1, a revised analysis updated two “core transcription programs” proposed to underlie axon injury-induced retinal ganglion cell (RGC) neurodegeneration. Though extensive, the Correction purported to leave the two principal conclusions of its parent study2unaltered. The first of those findings was that a core program mediated by the Activating Transcription Factor-4 (ATF4) and its likely heterodimeric partner does not include numerous canonical ATF4 target genes stimulated by RGC axon injury. The second was that the Activating Transcription Factor-3 (ATF3) and C/EBP Homologous Protein (CHOP) function with unprecedented coordination in a parallel program regulating innate immunity pathways. Here those unexpected findings are revealed to instead reflect insufficient knockout coupled with differences in RGC enrichment across conditions. This analysis expands on the published Correction’s redefinition of the purported transcription programs to raise foundational questions about the proposed functions and relationships of these transcription factors in neurodegeneration.
COmapper: High-resolution mapping of meiotic crossovers by long-read sequencing inArabidopsis
Authors: Byun Dohwan , Son Namil , Kim Heejin , Kim Jaeil , Park Jihye , Park Sang-jun , Kim Hyein , Kim Jaebeom , Kim Juhyun , Lee Seula , Hyun Youbong , Ziolkowski Piotr A. , Henderson Ian R. , Choi Kyuha
Published: October 2024

Meiotic crossovers rearrange existing genetic variation between homologous chromosomes, profoundly affecting genomic diversity. Crossovers are typically constrained to 1–3 events per chromosome pair, and their distribution is shaped by chromatin accessibility and DNA polymorphisms. Genome-wide crossover maps can be generated in plants by high-throughput short-read sequencing or linked-read sequencing. Here, we use long-read nanopore sequencing technology to develop a crossover mapping pipeline, COmapper, for high-resolution mapping of genome-wide crossovers from pooled DNA of F1hybrid pollen and F2recombinant seedlings derived from a cross betweenArabidopsis thalianaaccessions Col and Ler. We validate the high accuracy of COmapper by applying nanopore long-read sequencing to pooled DNA ofArabidopsisF2individuals with crossovers mapped by short-read sequencing. Using the COmapper, we constructed high-resolution genomic maps of crossovers using F1hybrid pollen and F2seedlings in wild type and crossover-elevatedrecq4a recq4bmutant, showing results comparable to short-read sequencing. Crossovers were enriched at gene-proximal promoters in wild type and increased but reshaped by high polymorphism density inrecq4a recq4b. We propose that COmapper will be widely applicable for exploring the effects of genetic, epigenetic and environmental changes on the crossover patterns across diverse plant species.
A surface lipoprotein onPasteurella multocidabinds complement factor I to promote immune evasion
Authors: Nguyen Quynh Huong , Lai Chun Heng Royce , Norris Michael J. , Ng Dixon , Shah Megha , Lai Christine Chieh-Lin , Isenman David E. , Moraes Trevor F.
Published: October 2024

Pasteurella multocidais the leading cause of wound infections in humans following animals’ bites or scratches. This bacterium is also commonly found in the respiratory tract of many mammals and can cause serious diseases resulting in the brutal rapid death of infected animals, especially cattle. To prevent these infections in cattle, a subunit-based vaccine utilizing the surface lipoprotein PmSLP was developed and showed remarkable protection with a single dose administration. Here, we report that PmSLP binds host complement factor I (FI) and facilitates cleavage of complement components C3b and C4b independently of any cofactors (e.g FH, C4BP), thereby allowing the pathogen to evade host defence. Cryo-EM structure of PmSLP bound to FI reveals that PmSLP stimulates FI enzymatic activity by stabilizing the catalytic domain. This is the first time that a bacterial protein has been shown to directly activate FI independent of complement cofactors and target all arms of the complement cascade.
Extending sampling approaches for great crested newt (Triturus cristatus) eDNA monitoring
Authors: Harper Lynsey R. , Harper Kirsten J. , Platts Suzie , Irwin Rebecca , Bennett Michael , Jones Ben , Taylor Oliver , Plant Laura , Eccleshall Danielle , Briscoe Andrew , Gorman Luke , Stanhope Kat , Egeter Bastian
Published: October 2024

Environmental DNA (eDNA) monitoring has been used for great crested newt (Triturus cristatus, GCN) survey in the UK since the publication of a Defra-funded trial in 2014. Surveys can only be performed during a 76-day survey window (15 April – 30 June), and only if approved methods for collection of 6 x 15 mL subsamples for ethanol precipitation are used. However, filtration may be a more effective and sustainable method of eDNA capture than ethanol precipitation, and detection may be possible outside of the current survey window.

We investigated whether the GCN eDNA survey season could be extended and filtration could be used for GCN eDNA capture by reviewing the available evidence and conducting a field study from April to October 2022. Paired water samples for ethanol precipitation and filtration were collected from ponds once a month, resulting in 124 ethanol precipitation kits and 124 filtration kits from 25 ponds. All samples were analysed with the approved quantitative PCR assay for GCN.

Our results indicate that GCN can be reliably detected using both eDNA capture methods from April to August, with detection rates decreasing in September and October. GCN eDNA detection was comparable or higher with filtration than ethanol precipitation, thus filtration could be a reliable and more sustainable means for assessing GCN presence.

Inclusion of filtration as an accepted eDNA capture method for GCN eDNA surveys would allow more water to be processed for robust and reliable estimates of GCN presence. Extending the GCN eDNA survey season to August would allow more waterbodies to be surveyed and identification of sites that provide important habitat for GCN outside of the breeding season. This would also remove logistical challenges and costs associated with completing GCN surveys and laboratory analysis within 10 weeks, improving performance of surveyors and laboratories as well as quality of results. Furthermore, GCN eDNA surveys could be carried out alongside monitoring for other species, which would enable infrastructure projects to develop more effective mitigation measures as well as reduce time required from surveyors and survey costs.
Fusarium graminearumcopper amine-oxidases redundantly increase virulence by converting tryptamine from hydrolyzed plant defense compounds into auxin
Authors: Svoboda Thomas , Ceranic Asja , Spörhase Pia , Bartholomäus Anika , Wiesenberger Gerlinde , Fruhmann Philipp , Beltran Eduardo , Berthiller Franz , Krska Rudolf , Schuhmacher Rainer , Adam Gerhard
Published: October 2024

Plant pathogenic fungi have evolved different strategies to interfere with plant defense mechanisms. The well described fungal plant pathogenFusarium graminearumis not only able to produce trichothecene toxins like deoxynivalenol, but also the plant hormone auxin. Highly elevated levels of auxin and auxin derivatives such as IAA-glucoside or IAA amino-acid conjugates were observed in wheat cultivar Apogee infected withF. graminearum. We report thatF. graminearumis able to cleave tryptamine-derived hydroxycinnamic acid amides, e.g. the defense compound coumaroyl-tryptamine. In this study we investigated copper amine-oxidases, candidate genes for auxin biosynthesis converting tryptamine into the IAA precursor indole-3-acetyldehyde. After consecutive knock outs of all seven copper amine oxidases the resulting septuple knock out strain had strongly reduced ability to produce auxin. Virulence of the septuple mutant was significantly impaired while DON productionin plantawas comparable to the wild type. We conclude thatF. graminearum, often presumed to be a simple nectrotroph, has a biotrophic phase and is able to employ plant defense compounds by converting them into defense suppressing auxin.
Loss of O-specific antigen shapesPseudomonas aeruginosapopulation microbiogeography in murine preclinical pulmonary infection model
Authors: Fraser H. , Moustafa D. A. , Goldberg J. B. , Azimi S.
Published: October 2024

ChronicPseudomonas aeruginosainfections are the hallmark of late-stage lung disease in individuals with cystic fibrosis. During chronic infectionP. aeruginosabecomes the dominant bacteria in the airway. Within-host adaptation ofP. aeruginosaleads to vast phenotypic and genetic population heterogeneity.In vitrostudies show mutations in lipopolysaccharide (LPS) O-specific antigen changes the aggregate formation inP. aeruginosa, however role of these changes in aggregate assemblyin vivois not understood. Using a synthetic CF sputum media and a preclinical murine infection model we assessed how the PAO1 wildtype and O-specific antigen mutants interact with each other, and ifP. aeruginosapopulation heterogeneity affects the colonization of the murine lungs. Our findings suggest that the presence of variants lacking O-specific antigen does not impact the population fitness and size in bothin vitroandin vivo, however it can influence the aggregate volumein vivo.
Aerial root formation in Oaxacan maize (Zea mays) landraces persists into the adult phase and is minimally affected by soil nitrogen and ambient humidity
Authors: Wilker Jennifer , Venado Rafael E. , Infante Valentina , McLimans Caitlin , Robbins Fletcher , Phillips Courtney , Calderón Claudia Irene , Wallace Jason , Ané Jean-Michel
Published: October 2024

Maize (Zea mays) is the most widely produced crop in the world, and conventional production requires significant amounts of synthetic nitrogen fertilizer, which has negative economic and environmental consequences. Maize landraces from Oaxaca, Mexico, can acquire nitrogen from nitrogen-fixing bacteria that live in a mucilage secreted by aerial nodal roots. The development of these nodal roots is a characteristic traditionally associated with the juvenile vegetative stage of maize plants. However, mature Oaxacan landraces develop many more nodes with aerial roots than commercial maize varieties. Our study shows that Oaxacan landraces develop aerial roots during both the juvenile and adult vegetative phases and even during early flowering under greenhouse and field conditions. Surprisingly, the development of these roots was only minimally affected by soil nitrogen and ambient humidity. These findings are an important first step in developing maize varieties that can reduce fertilizer needs in maize production across different environmental conditions.
Expansion, restructuring and characterization of theLegionellaceaefamily
Authors: Gabrielli Marco , Cavallaro Alessio , Hammes Frederik
Published: October 2024

Legionellaceaeare a large and widespread family of facultative intracellular bacteria with high clinical relevance. WhileLegionella pneumophila, the most clinically relevant species, is relatively well studied, very limited information is available regarding the other species belonging to this family. Here, we analyzed all publicly-availableLegionellaceaegenomes and metagenome-assembled genomes, nearly doubling the number of recognized species and highlighting the need to restructure the family’s taxonomy to include multiple genera that present distinct clinical relevance. We found that secretion systems and traits linked to host invasion vary significant across genus clusters and species, likely influencing their survival in their environment. While genus clusters presented different metabolic capabilities, species closely related toL. pneumophilawere characterized by a more complete metabolism with fewer auxotrophies. Finally, we showed that while species have distinct environmental distributions, niche overlap increases at higher metabolic similarity. Together, our results shed light on the ecology of these microorganisms, highlight the diversity of traits that can occur in closely related facultative intracellular bacteria, and call for the restructuring of this clade to align with genomic information and clinical relevance to aid the management ofLegionellaceaebacteria.

Significance Statement

Legionellaceaebacteria are responsible for Legionnaires’ disease, the leading waterborne disease in many industrialized countries. Historically, attention was focused onLegionella pneumophilaand the ecology of other species remained largely unknown and unexplored. However, several water safety regulations cover the entireLegionellagenus, currently the only recognized within this large family, including microorganisms with unknown health relevance. Using a comparative genomics approach and leveraging public genomes and amplicon data, we shed light on the scale, diversity and ecology of this family, finding a surprisingly diversity of the traits linked to host invasion and metabolism, likely driving the species’ environmental distributions. This study proposes to restructure the familyLegionellaceaein multiple genera to align with known clinical associations and predicted phenotypes.
A circuit involving the lncRNA MB3 and the driver genes MYC and OTX2 inhibits apoptosis in Group 3 Medulloblastoma by regulating the TGF-β pathway via HMGN5
Authors: Alessia Grandioso , Paolo Tollis , Romana Pellegrini Francesca , Elisabetta Falvo , Alessandro Palma , Francesco Migliaccio , Alessandro Belvedere , Jessica Rea , Giada Tisci , Annamaria Carissimo , Irene Bozzoni , Daniela Trisciuoglio , Monica Ballarino , Pierpaolo Ceci , Pietro Laneve
Published: October 2024

Background

Group 3 (G3) is one of the most common, aggressive and fatal subtypes of the paediatric cerebellar tumour Medulloblastoma (MB), primarily driven by the MYC oncogene. Targeting MYC has long been challenging and this, combined with our incomplete understanding of G3 MB molecular bases, has hindered the development of effective targeted therapies. Long noncoding RNAs (lncRNAs), with their extensive oncogenic roles, cancer-specific expression, and connection to MYC biology, offer opportunities for unravelling this complexity and providing new insights and therapeutic targets.

Methodology

Using genome-wide, molecular and cellular assays, we characterised the activity of the MYC-dependent, anti-apoptotic lncRNAlncMB3in G3 MB cells.

Results

Through transcriptomic and interactomic analyses, we clarifiedlncMB3function and mode-of-action.LncMB3controls the TGF-β pathway, critically altered in G3 medulloblastomagenesis. This regulation occurs via the direct coding-noncoding RNA interaction betweenlncMB3and the mRNA for the epigenetic factor HMGN5, with both sharing targets in the TGF-β cascade. This axis converges on apoptosis through OTX2, another G3 MB driver gene, and photoreceptor lineage genes. Synergistic effects betweenlncMB3targeting and cisplatin treatment underscores the relevance of this regulatory networkin vitro. Finally, we propose novel ferritin-based nanocarriers as efficient delivery tools for antisense oligonucleotides targetinglncMB3.

Conclusions

LncMB3emerges as a central node linking MYC amplification to apoptosis inhibition through a circuit involving RNA-based mechanisms, G3 MB key drivers and underexplored factors. This integrated framework deepens our understanding of G3 MB molecular underpinnings and lay the foundation for translating lncRNA research into potential applications.
Unveiling the Gut Microbiome Network Fingerprint: A Deep Learning Approach to Predict Immunotherapy Response in Melanoma Patients
Authors: Sun Jie , Fan Zhenjiang , Sriram Aditya , Park Hyun Jung
Published: October 2024

Immune checkpoint inhibitors (ICI) are critical in cancer therapy, harnessing the immune system to fight tumors. The gut microbiome, a diverse ecosystem of trillions of microorganisms, has emerged as a key influencer of ICI efficacy. However, the specific gut bacteria linked to ICI response in melanoma patients remain unclear, with studies showing inconsistent findings across cohorts. Attributing the lack of consensus to multiple layers of non-linear interactions with host factors and within the microbial community, we developed DeepMicroNET, a novel deep neural network (DNN) model-driven network analysis method to identify and characterize the gut bacteria associated with treatment response. Utilizing data from five cohorts of advanced melanoma patients undergoing ICI therapies, we demonstrate how DeepMicroNET identifies gut bacteria consistently predicting immunotherapy responses (response-associated or RA bacteria). Further, DeepMicroNET revealed that these bacteria are associated with key immune pathways, such as antigen processing and presentation, offering novel insights into the molecular mechanisms that could be targeted to improve therapeutic outcomes. Altogether, by identifying gut bacteria robustly associated with immunotherapy response, DeepMicroNET opens the door to a new era of personalized medicine based on the gut microbiome profile.
Pseudomonas aeruginosasupports the survival ofPrevotella melaninogenicain a cystic fibrosis lung polymicrobial community through metabolic cross-feeding
Authors: El Hafi Bassam , Jean-Pierre Fabrice , O’Toole George A.
Published: October 2024

Cystic fibrosis (CF) is a multi-organ genetic disorder that affects more than 100,000 individuals worldwide. Chronic respiratory infections are among the hallmark complications associated with CF lung disease, and these infections are often due to polymicrobial communities that colonize the airways of persons with CF (pwCF). Such infections are a significant cause of morbidity and mortality, with studies indicating that pwCF who are co-infected with more than one organism experience more frequent pulmonary exacerbations, leading to a faster decline in lung function. Previous work established anin vitroCF-relevant polymicrobial community model composed ofP. aeruginosa,S. aureus,S. sanguinis, andP. melaninogenica.P. melaninogenicacannot survive in monoculture in this model. In this study, we leverage this model to investigate the interactions betweenP. aeruginosaandP. melaninogenica, allowing us to understand the mechanisms by which the two microbes interact to support the growth ofP. melaninogenicaspecifically in the context of the polymicrobial community. We demonstrate a cross-feeding mechanism wherebyP. melaninogenicametabolizes mucin into short-chain fatty acids that are in turn utilized byP. aeruginosaand converted into metabolites (succinate, acetate) that are cross-fed toP. melaninogenica, supporting the survival of this anaerobe in the CF lung-relevant model.

Importance

Polymicrobial interactions impact disease outcomes in pwCF who suffer from chronic respiratory infections. Previous work established a CF-relevant polymicrobial community model that allows experimental probing of these microbial interactions to achieve a better understanding of the factors that govern the mechanisms by which CF lung microbes influence each other. In this study, we investigate the interaction betweenP. aeruginosaandP. melaninogenica, which are two highly prevalent and abundant CF lung microbes. We uncover a cross-feeding mechanism that requires the metabolism of mucin byP. melaninogenicato generate short-chain fatty acids that are cross-fed toP. aeruginosa, and into metabolized into metabolites which are then cross-fed back toP. melaninogenicato support the growth of this anaerobe.
ARhodopseudomonasstrain with a substantially smaller genome retains the core metabolic versatility of its genus
Authors: Oda Yasuhiro , Nelson William C. , Alexander William G. , Nguyen Stella , Egbert Robert G. , Harwood Caroline S.
Published: October 2024

Rhodopseudomonasare a group of phototrophic microbes with a marked metabolic versatility and flexibility that underpins their potential use in production of value-added products, bioremediation and plant growth promotion. Members of this group have an average genome size of about 5.5 Mb, but two closely related strains have genome sizes of about 4.0 Mb. To identify the types of genes missing in a reduced genome strain, we compared strain DSM127 with otherRhodopseudomonasisolates at the genomic and phenotypic levels. We found that DSM127 can grow as well as other members of theRhodopseudomonasgenus and retains most of their metabolic versatility, but it has many fewer genes associated with high affinity transport of nutrients, iron uptake, nitrogen metabolism and biodegradation of aromatic compounds. This analysis indicates genes that can be deleted in genome reduction campaigns and suggests that DSM127 could be a favorable choice for biotechnology applications usingRhodopseudomonasor as a strain that can be engineered further to reside in a specialized natural environment.

IMPORTANCE

Rhodopseudomonasare a cohort of phototrophic bacteria with broad metabolic versatility. Members of this group are present in diverse soil and water environments and some strains are found associated with plants and have plant growth promoting activity. Motivated by the idea that it may be possible to design bacteria with reduced genomes that can survive well only in a specific environment or that may be more metabolically efficient, we comparedRhodopseudomonasstrains with typical genome sizes of about 5.5 Mb to a strain with a reduced genome size of 4.0 Mb. From this we concluded that metabolic versatility is part of the identity of theRhodopseudomonasgroup, but high-affinity transport genes and genes of apparent redundant function can be dispensed with.
Stem and progenitor cell proliferation are independently regulated by cell type-specificcyclinDgenes
Authors: Lush Mark E. , Tsai Ya-Yin , Chen Shiyuan , Münch Daniela , Peloggia Julia , Sandler Jeremy E. , Piotrowski Tatjana
Published: October 2024

Regeneration and homeostatic turnover of solid tissues depend on the proliferation of symmetrically dividing adult stem cells, which either remain stem cells or differentiate based on their niche position. Here we demonstrate that in zebrafish lateral line sensory organs, stem and progenitor cell proliferation are independently regulated by twocyclinDgenes. Loss ofccnd2aimpairs stem cell proliferation during development, while loss ofccndxdisrupts hair cell progenitor proliferation but allows normal differentiation. Notably,ccnd2acan functionally replaceccndx, indicating that the respective effects of these Cyclins on proliferation are due to cell type-specific expression. However, even though hair cell progenitors differentiate normally inccndxmutants, they are mispolarized due tohes2and Emx2 downregulation. Thus, regulated proliferation ensures that equal numbers of hair cells are polarized in opposite directions. Our study reveals cell type-specific roles forcyclinDgenes in regulating the different populations of symmetrically dividing cells governing organ development and regeneration, with implications for regenerative medicine and disease.
Cluster Assembly Dynamics Drive Fidelity of Planar Cell Polarity Polarization
Authors: Nissen Silas Boye , Weiner Alexis T. , Suyama Kaye , Bosch Pablo Sanchez , Yu Maiya , Song Song , Gu Yuan , Dunn Alexander R. , Axelrod Jeffrey D.
Published: October 2024

In planar cell polarity (PCP) signaling, distinct molecular subcomplexes segregate to opposite sides of each cell, where they interact across intercellular junctions to form asymmetric clusters. Although proximal-distal asymmetry within PCP clusters is the defining feature of PCP signaling, the mechanism by which this asymmetry develops remains unclear. Here, we developed a method to count the number of monomers of core PCP proteins within individual clusters in live animals and used it to infer the underlying molecular dynamics of cluster assembly and polarization. Measurements over time and space in wild type and in strategically chosen mutants demonstrate that cluster assembly is required for polarization, and together with mathematical modeling provide evidence that clusters become increasingly asymmetric and correctly oriented as they increase in size. We propose that cluster assembly dynamics amplify weak and noisy inputs into a robust cellular output, in this case cell and tissue-level polarization.
Endothelial cell Nrf2 controls neuroinflammation following a systemic insult
Authors: Zou Haoyu , Huang Zhuochun , Leah Tom , He Xin , Dando Owen , Qiu Jing
Published: October 2024

Systemic inflammation can lead to neuroinflammation with acute consequences such as delirium and long-lasting deleterious effects including cognitive decline and the exacerbation of neurodegenerative disease progression. Here we show that the activation status of the transcription factor Nrf2 in endothelial cells is a critical regulator of this process. We found that peripheral inflammation caused infiltration of macrophages, microglial activation and inflammatory reactive astrogliosis, all of which could be prevented by RTA-404, an activator of the transcription factor Nrf2 and close structural relative of the recently FDA-approved Nrf2 activator RTA-408 (Omaveloxolone). To identify the key cellular mediator(s), we generated an endothelial cell-specific Nrf2 knockout mouse. Strikingly, the effects of RTA-404 on brain endothelial activation and downstream neuroinflammatory events was abolished by endothelial cell-specific Nrf2 deletion. This places endothelial cell Nrf2 as a peripherally accessible therapeutic target to reduce the CNS-adverse consequences of systemic inflammation.
Integrated local and systemic communication factors regulate nascent hematopoietic progenitor escape during developmental hematopoiesis
Authors: Shalaby Carson , Garifallou James , Thom Christopher S
Published: October 2024

Mammalian blood cells originate from specialized hemogenic endothelial (HE) cells in major arteries. During the endothelial-to-hematopoietic transition (EHT), nascent hematopoietic stem cells (HSCs) bud from the arterial endothelial wall and enter circulation, destined to colonize the fetal liver before ultimately migrating to the bone marrow. Mechanisms and processes that facilitate EHT and the release of nascent HSCs are incompletely understood, but may involve signaling from neighboring vascular endothelial cells, stromal support cells, circulating preformed hematopoietic cells, and/or systemic factors secreted by distal organs. In this study, we used single cell RNA sequencing analysis from human embryonic cells to identify relevant signaling pathways that support nascent HSC release. In addition to intercellular and secreted signaling modalities that have been previously functionally validated to support EHT and/or developmental hematopoiesis in model systems, we identify several novel modalities with plausible mechanisms to support EHT and HSC release. Our findings paint a portrait of the complex interregulated signals from the local niche, circulating hematopoietic/inflammatory cells, and distal fetal liver that support hematopoiesis.
Assessing microstructural damage in paediatric aortic coarctation tissue during benchtop balloon angioplasty and stenting
Authors: Linnane N. , Johnston R. D , Kenny D. , Lally C.
Published: October 2024

Endovascular stenting of native aortic coarctation has become standard treatment for children and young adults due to the shorter hospital stay and recovery time, lower procedural risk and less invasive nature. However, despite these advantages, neonatal coarctation remains a surgically treated lesion, owing to the challenges of vessel growth and stent design. Plain old balloon angioplasty (POBA) of neonatal coarctation has been used as a treatment modality in the past but concern around vessel damage and aneurysm formation limited its widespread adoption. To-date, stenting has often been preferred over POBA treatment to minimise tissue damage but very little evidence has been gathered to establish the degree of tissue damage during intravascular procedures in neonatal coarctation tissue.

The aim of this study was to perform balloon angioplasty and stenting on coarctation the aorta samples harvested at the time of surgery from neonatal patients and visualise the deformation under ultrasound guidance. From this, the novel collagen hybridizing peptide (CHP) was used to assess the level of collage denaturation and microstructural damage this tissue experienced when undergoing these procedures. The results demonstrate that balloon angioplasty singularly is not a viable treatment option at maintaining the lumen diameter unless higher levels of stretch are achieved to permanently deform the tissue. Five out of six neonatal coarctation samples were successfully stented with no stent failure, proving that stent insertion is a viable option to achieve the desired lumen diameter. In addition, for both procedures, increased collagen damage was observed with higher tissue strain. Overall, this work would suggest stent placement as the best option to achieve reliable lumen gain and to limit the level of the level of collagen damage when stretching the tissue to achieve the required lumen diameter.
Variation in Nutritional Composition of Anatomical Parts and Taxonomic Classes of Wild Animals: A Systematic Review Using Data Imputation with Artificial Intelligence
Authors: Medeiros Ana Luisa dos Santos , Oliveira Amanda Letícia Bezerra de , Medeiros Maria Fernanda Araújo de , Tregidgo Daniel , Giuntini Eliana Bistriche , de Menezes Neto Elias Jacob , Maia Juliana Kelly da Silva , Jacob Michelle Cristine Medeiros
Published: October 2024

Wildmeat is crucial for the food security of Indigenous Peoples and Local Communities, yet information about its nutritional profile remains scarce. This study systematically reviewed the impact of anatomical part and taxonomic class (mammals, birds, reptiles) on the nutritional composition of wildmeat. Using the PRISMA protocol, we selected articles from Web of Science, Scopus, and Medline/PubMed databases, with criteria including original articles on wild animal meat composition consumed by humans, excluding studies presenting secondary data or lacking detailed methodologies. We employed a quality questionnaire and concordance analysis (Fleiss’ Kappa = 1.00) for robustness. Artificial intelligence techniques (eg., K-Nearest Neighbors) estimated missing nutritional values in all 21 articles included in our study, covering 26 species and 10 nutrients. Results show statistically significant nutritional variations between anatomical parts and animal classes. Reptile viscera have over twice the fat content and triple the iron compared to muscles. Mammal viscera contain five times more omega-6 and selenium, four times more iron and manganese, and almost double the zinc compared to muscles. Among classes, bird muscles have over 90% higher fat content than mammal muscles and 20% higher than reptile muscles. Mammals have over 100% higher zinc levels than birds, and reptiles have over 400% more selenium than birds. No significant difference in iron content between mammals and birds was noted, likely due to bird slaughter methods. This study highlights the importance of wildmeat for food security. Importantly, we demonstrate an enormous variation in nutritional composition, underscoring how different anatomical parts and taxonomic classes can contribute to tackling different nutritional deficiencies. Additionally, it introduces a novel methodology for handling missing nutritional composition data, providing a comprehensive approach to understanding the nutritional value of wildmeat. Our findings can inform food security policies and wildlife management, balancing conservation and subsistence.