bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic integration of cortical activity in the deep layer of the anterolateral superior colliculus
Authors: Sugino Hikaru , Tanno Sho , Yoshida Tatsumi , Isomura Yoshikazu , Hira Riichiro
Published: July 2024

The superior colliculus (SC) receives inputs from various brain regions in a layer- and radial location-specific manner, but whether the SC exhibits location-specific dynamics remains unclear. To address this issue, we recorded the spiking activity of single SC neurons while photoactivating cortical areas in awake head-fixed Thy1-ChR2 rats. We classified 309 neurons that responded significantly into 8 clusters according to the response dynamics. Among them, neurons with monophasic excitatory responses (7–12 ms latency) that returned to baseline within 20 ms were commonly observed in the optic and intermediate gray layers of centromedial and centrolateral SC. In contrast, neurons with complex polyphasic responses were commonly observed in the deep layers of the anterolateral SC. Cross-correlation analysis suggested that the complex pattern could be only partly explained by an internal circuit of the deep gray layer. Our results indicate that medial to centrolateral SC neurons simply relay cortical activity, whereas neurons in the deep layers of the anterolateral SC dynamically integrate inputs from the cortex, SNr, CN, and local circuits. These findings suggest a spatial gradient in SC integration, with a division of labor between simple relay circuits and those integrating complex dynamics.
AI-assisted In-silico Trial for the Optimization of Osmotherapy following Ischaemic Stroke
Authors: Chen Xi , Lu Lei , Józsa Tamás I. , Clifton David A. , Payne Stephen J.
Published: July 2024

Over the past few decades, osmotherapy has commonly been employed to reduce intracranial pressure in post-stroke oedema. However, evaluating the effectiveness of osmotherapy has been challenging due to the difficulties in clinical intracranial pressure measurement. As a result, there are no established guidelines regarding the selection of administration protocol parameters. Considering that the infusion of osmotic agents can also give rise to various side effects, the effectiveness of osmotherapy has remained a subject of debate. In previous studies, we proposed the first mathematical model for the investigation of osmotherapy and validated the model with clinical intracranial pressure data. The physiological parameters vary among patients and such variations can result in the failure of osmotherapy. Here, we propose an AI-assisted in-silico trial for further investigation of the optimisation of administration protocols. The proposed deep neural network predicts intracranial pressure evolution over osmotherapy episodes. The effects of the parameters and the choice of dose of osmotic agents are investigated using the model. In addition, clinical stratifications of patients are related to a brain model for the first time for the optimisation of treatment of different patient groups. This provides an alternative approach to tackle clinical challenges with in-silico trials supported by both mathematical/physical laws and patient-specific biomedical information.
Cannabidiol reverses fentanyl-induced addiction and modulates neuroinflammation
Authors: Bhandari Bidhan , Shimaoka Chagas Henrique Izumi , Naeini Sahar Emami , Chagas Pablo Shimaoka , Rogers Hannah M , Gouron Jules , Khan Aruba , Maciel Lívia Maria , Seyyedi Mohammad , MacKinnon Neil J , Khodadadi Hesam , Salles Évila Lopes , Hess David C , Morgan John C , Yu Jack C , Wang Lei P , Baban Babak
Published: July 2024

Introduction

Fentanyl and non-pharmaceutical fentanyl use have been the leading causes of opioid-induced death worldwide. Being 50 times stronger than heroin and 100 times stronger than morphine, fentanyl is a potent opioid with overdoses causing over 250,000 deaths since 2018 in the US alone. The treatment of fentanyl addiction is a complex process and a clinical challenge. There is a dire need to find other innovative and alternative modalities in the fight against fentanyl crisis.

Increasing evidence suggests a correlation between neuroinflammation and symptoms of drug abuse, opening up the possibility of immunoregulatory agents as therapy for fentanyl addiction as well as a other opioid-induced addiction.

Cannabidiol (CBD) is a non-opioid, relatively safe, non-psychoactive phyto-cannabinoid produced by cannabis plants. Importantly, recent reports have documented benefits of CBD in the treatment and management of complications related to opioid withdrawal.

We investigated if inhaled CBD could reverse the fentanyl addiction and whether the CBD treatment could ameliorate the addiction symptoms by regulating neuroinflammatory signals and re-establishing the homeostasis in CNS.

Method

We used a fentanyl-induced conditioned place preference (CPP) model in mouse to test whether inhaled CBD could reverse the fentanyl addiction and ameliorate the adversarial symptoms. By employing a combination of flow cytometry as well as behavioral tests, we further assessed the impact of fentanyl addiction on cells and neuroinflammatory signals in CNS and we measured the effects of CBD in the treatment of addiction symptoms and inflammatory signals.

Results

Our findings suggest that CBD inhalation could be used effectively in the treatment of fentanyl addiction. CBD mitigated the excessive fentanyl-induced neuroinflammatory responses and decreased cellular stress and senescence.

Conclusion

inhaled CBD could alleviate the fentanyl addiction and regulate neuroinflammatory responses. This novel approach is non-invasive, accessible, effective, and warrants further, translational and research.
Correlation between religiosity and family functioning among secondary school students in high-risk residing areas and factors associated with substance use
Authors: Aziz Noor Adnin binti Ab , Wahab Suzaily , Sutan Rosnah binti , Baharom Muhammad Adib , Azmi Amirul Danial , Asmai Siti Azirah binti
Published: July 2024

Introduction

Substance use in adolescents poses a complex societal challenge that undermines nation-building and socioeconomic growth. Religiosity refers to a person’s religious beliefs, habits, and involvement in religious activities. Family functioning refers to the overall health and operation of a family unit, which includes communication, emotional bonding, support, roles, and behavioral control. Both aspects play a significant impact in determining substance use in adolescents. This study is to assess the correlation between religiosity, and family functioning, and to determine factors associated with substance use among adolescents in secondary schools in high-risk areas.

Methods

A cross-sectional study was conducted among 312 adolescents from selected secondary schools in substance use hotspot areas in Northern Malaysia. Alcohol, Smoking, and Substance Involvement Screening Tool-Lite (ASSIST-Lite), Family Adaptation and Cohesion Scale version IV (FACES-IV), and Hatta Islamic Religiosity Scale (HIRS) were used as instruments.

Results

The prevalence of substance use among adolescents was 9.6%(n=30). Most of the users used a single substance (76.7%; n=23) and only (23.3%; n=7) used multiple substances. The mean age was 14.13 years (SD:0.67), and the majority were Malays (99.0%; n=309) with a background in Muslim religion. Adolescent substance use was significantly associated with gender (16.3% in males and 6.3% in females) and having a recent family history of substance use (16.8%). A negative correlation was found between substance use and family functioning; balanced flexibility (rs=-0.12; P=<0.05), family communication (rs=-0.12; P=<0.05), and family satisfaction (rs=-0.15; P=<0.01). There was a positive correlation between substance use and chaotic family (rs=0.12; P=<0.05). Regression analysis reveals that only male adolescents and a recent family history of substance use were significant predictors of substance use. Family satisfaction was the only significant protective factor. There was no significant association between substance use and religiosity (rs=-0.01; P= 0.83).

Conclusions

These findings can assist policymakers, healthcare professionals and schools develop interventions to reduce substance use, especially in high-risk communities, and increase adolescents’ well-being in general.
MegaMASLD: An interactive platform for exploring stratified transcriptomic signatures in MASLD progression
Authors: Cheng Hong Sheng , Chua Damien , Chan Sook Teng , Yew Kuo Chao , Wong Sunny Hei , Tan Nguan Soon
Published: July 2024

Liver transcriptomic data from patients with metabolic dysfunction-associated steatotic liver disease (MASLD) offers valuable resource for deciphering pathogenic molecular drivers. Here, we performed a Mega-analysis of MASLD Liver Transcriptomes (MegaMASLD) which reanalysed raw RNAseq data of over 800 livers in a standardized and integrative manner, aiming to unravel druggable molecular events in MASLD. Our analysis revealed a progressive transcriptomic shift predominantly associated with immunopathologies during MASLD progression. The differential transcriptomes produced a MASLD gene signature useful for quantitative assessment of MASLD severity but failed to faithfully recapitulate the exact histological staging. Instead, a histologic-independent unsupervised clustering analysis predicted a high-risk group prone to develop metabolic dysfunction-associated steatohepatitis (MASH), characterized by aberrant changes in humoral immune response and antibody repertoires. These findings were supported by another histologic-independent pseudotime analysis, which also identified several potentially targetable molecular switches, including FGFR, PDGFR, PAK, PRKG1 and CAMK kinase families, activated at various transitory phases of MASLD. The robust analysis has enabled risk stratification and deepened our understanding of the dynamic molecular events driving MASLD, thereby offering new options to enhance precision medicine of MASLD. An online web tool featuring MegaMASLD is available athttps://bioanalytics-hs.shinyapps.io/MegaMASLD/.
Conserved signals orchestrate self-organization and symmetry breaking of bi-layered epithelia during development and regeneration
Authors: Journot Robin P. , Huyghe Mathilde , Barthelemy Alexandre , Couto-Moreira Hugo , Sumbal Jakub , Faraldo Marisa M. , Dubail Maxime , Fouillade Charles , Fre Silvia
Published: July 2024

Organ development relies on complex molecular mechanisms that guide initially homogeneous populations of stem cells to differentiate into specialized cell types within defined spatial patterns. While stable during homeostasis, the proper spatial organization of cell types must be re-established in case of tissue injury for successful regeneration of organ shape and function. How cells commit to a differentiation path is a central question in stem cell research; however, the coordination between tissue geometry and cell fate specification remains enigmatic. To elucidate the molecular mechanisms instructing self-organization and symmetry breaking of epithelial stem cells, we developed a multi-faceted approach combiningin vitroorganoids,ex vivoembryonic tissue explants, and single-cell quantitative imaging to investigate the dynamic acquisition of cell fate in four bi-layered epithelia, during embryonic development but also in regeneration. Our findings indicate that tissue architecture is the primary determinant of cell fate decisions in these tissues. Upon the initial cell internalization event, the homogeneous population of stem cell break symmetry. Through genetic and pharmacological perturbations, we have demonstrated that a tightly coordinated interplay between Hippo/YAP and Notch signaling is essential for conveying information from tissue architecture to functional cell differentiation and stem cell potency restriction. Globally, this study uncovers the inherent capacity of stem cells to self-organize into multicellular structures, where the precise position of each differentiated cell is critical to instruct their differentiation choices during embryonic development and regeneration.
Bacillus toyonensisbiovar Thuringiensis: an overlooked entomopathogen?
Authors: Sauka Diego Herman , Del Valle Eleodoro E. , Palma Leopoldo
Published: July 2024

Horizontal gene transfer (HGT) significantly influences prokaryotic genome evolution.Bacillus cereusandBacillus thuringiensisare nearly identical genetically, except forB. thuringiensisproducing parasporal crystals. The genes for these crystal proteins (e.g.,cry1A), along with other encoded insecticidal proteins (e.g.,vip3A), are located on megaplasmids and can be horizontally transferred. Recently, Sauka et al. (2022) reported aBacillus toyonensisstrain that produces parasporal crystals with dual insecticidal activity. This strain was classified asBacillus toyonensisbiovar Thuringiensis (NCBI: txid2923195) following Carroll et al.’s (2020) nomenclature. MisclassifiedB. toyonensisstrains, previously identified asB. thuringiensis(e.g., strain MC28), encodecryandcytgenes toxic to lepidopterous and dipterous insects. Advances in genome sequencing and bioinformatics tools now reduce misidentifications, enabling accurate reclassification in databases like GenBank.
Relative fire-proneness of land cover types in the Brazilian Atlantic Forest
Authors: Adorno Bruno FCB , Piratelli Augusto AJ , Hasui Erica , Ribeiro Milton C , Vaz Pedro G
Published: July 2024

Fires are increasingly affecting tropical biomes, where landscape-fire interactions remain understudied. We investigate the fire-proneness (the likelihood of a land use or land cover (LULC) type burning more or less than expected based on availability) in the Brazilian Atlantic Forest (AF). This biodiversity hotspot is increasingly affected by fires due to human activities and climate change. Using a selection ratio-based approach, we analyzed fire-LULC interactions in 40,128 fires over a 35-year period (1987-2022) across various ecoregions in the AF. Our findings revealed that secondary forests, forest areas that have regrown after major disturbances, burned 61% more than expected by chance, whereas old-growth forests, native forests that have developed over very long periods, burned 57% less than expected, highlighting a nearly inverse relationship in their fire-proneness. Interestingly, our data indicate that pastures in the AF are less prone to fire than expected, despite being considered among the land uses that burn the most in Brazil. Other LULCs showed variable fire-proneness, with some differences between ecoregions. Over time, the fire-proneness of secondary forests decreased, likely due to forest aging and changes in land management practices. We emphasize the necessity for tailored fire management strategies that address the unique vulnerabilities of secondary forests, particularly in the context of ongoing restoration efforts aimed at increasing native forests. Effective measures, including the implementation of 'fire-smart management' practices and enhancing the perceived value of secondary forests among local communities, are crucial for mitigating fire risks. Integrating these strategies with incentive-based approaches can bolster fire prevention, ensuring the long-term success of restoration programs. Our study provides a framework for understanding fire-landscape dynamics in tropical forests and offers actionable insights for practitioners working to safeguard these biomes from the escalating threat of wildfires.
Queen number shapes worker longevity, fecundity and gene expression in the invasive, highly polygynous antTapinoma magnum
Authors: Lenhart Anna , Majoe Megha , Selvi Sibel , Colgan Thomas J. , Libbrecht Romain , Foitzik Susanne
Published: July 2024

In social animals, reproductive activity and ageing patterns are influenced by group composition. A well-documented phenomenon in monogynous (one-queen) insect societies is that queen presence affects worker fecundity and longevity. Little is known about whether and how workers respond to queen number variation in polygynous (multi-queen) species and how their queens age. We created queenless, one-queen, and two-queen colonies of the invasive, polygynous antTapinoma magnumto examine worker survival, fecundity, oxidative stress resistance, and fat body gene expression. Additionally, we compared fecundity and brain and fat body transcriptomes of young and old queens. Queenless workers experienced the highest mortality, contrasting with monogynous species where queen removal typically extends lifespan. Workers in single-queen colonies lived longer and were more fertile than in two-queen colonies. Queen number did not directly affect oxidative stress resistance or fat body transcription, though the latter depended on an interaction with worker task. Furthermore, younger nurses demonstrated higher fecundity, oxidative stress resistance and upregulated antioxidant genes compared to older foragers. Absent or minor shifts in fecundity and transcription with queen age, respectively, indicated physiological stability with age. Our research highlights distinct caste- and tissue-specific ageing patterns in this supercolonial species, deviating from typical monogynous ants.
Click-chemistry-aided quantitation and sequencing of oxidized guanines and apurinic sites uncovers their transcription-linked strand bias in human cells
Authors: Takhaveev Vakil , Püllen Nikolai J.L. , Singh Navnit K. , Huber Sabrina M. , Schauer Stefan , Gahlon Hailey L. , Poetsch Anna R. , Sturla Shana J.
Published: July 2024

DNA modifications drive aging, neurodegeneration, carcinogenesis, and chemotherapy drug action. To understand the functional genomic roles of DNA modifications, it is critical to accurately map their diverse chemical forms with single-nucleotide precision in complex genomes, but it remains challenging. Click-code-seq is a click-chemistry-aided single-nucleotide-resolution strategy for guanine-oxidation mapping, used in yeast DNA but having poor applicability to human genomes. Here, we upgraded click-code-seq to enable its first application for sequencing DNA oxidation and depurination in human genomes. For this, we developed a companion fluorescence assay, click-fluoro-quant, to rapidly quantify different common DNA modifications, and devised novel adapters to minimize false modification detection and assess modification frequency in cell populations. We uncovered that endogenous DNA oxidation in a human cell line has a highly similar pattern to cancer mutational signatures associated with reactive oxygen species. We established that the DNA-alkylating chemotherapy drug irofulven preferentially induces depurination in ApA dimers and promoter regions. Intriguingly, we revealed that oxidized guanines and apurinic sites, both irofulven-induced and endogenous, are depleted in gene transcribed strands, and the strand bias widens with increasing gene expression. This work substantially advances click-code-seq for deciphering the impacts of key modifications in human DNA on cellular physiology and toxicological responses.
FEHAT: Efficient, Large scale and Automated Heartbeat Detection in Medaka Fish Embryos
Authors: Ferreira Marcio Soares , Stricker Sebastian , Fitzgerald Tomas , Monahan Jack , Defranoux Fanny , Watson Philip , Welz Bettina , Hammouda Omar , Wittbrodt Joachim , Birney Ewan
Published: July 2024

High resolution imaging of model organisms allows the quantification of important physiological measurements. In the case of fish with transparent embryos, these videos can visualise key physiological processes, such as heartbeat. High throughput systems can provide enough measurements for the robust investigation of developmental processes as well as the impact of system perturbations on physiological state. However, few analytical schemes have been designed to handle thousands of high-resolution videos without the need for some level of human intervention. We developed a software package, named FEHAT, to provide a fully automated solution for the analytics of large numbers of heart rate imaging datasets obtained from developing Medaka fish embryos in 96 well plate format imaged on an Acquifer machine. FEHAT uses image segmentation to define regions of the embryo showing changes in pixel intensity over time, followed by the classification of the most likely position of the heart and Fourier Transformations to estimate the heart rate. Here we describe some important features of the FEHAT software, showcasing its performance across a large set of medaka fish embryos and compare its performance to established, less automated solutions. FEHAT provides reliable heart rate estimates across a range of temperature-based perturbations and can be applied to tens of thousands of embryos without the need for any human intervention.
Feature Importance in Predicting Clinical Outcome: Statistics vs. Explainable Artificial Intelligence
Authors: Amin Parisa
Published: July 2024

At the time of diagnosis for cancer patients, a wide array of data can be gathered, ranging from clinical information to multiple layers of omics data. Determining which of these data are most informative is crucial, not only for advancing biological understanding but also for clinical and economic considerations. This process facilitates the selection of the most significant markers, enhancing patient stratification and informing treatment recommendations. In this paper, we start with 89 features extracted from multiomics and clinical data and aim to identify the most important ones in predicting response to neoadjuvant chemotherapy (NAC) using different explainable Artificial Intelligence (XAI) models and statistics. Our results show that XAI methods consistently recover important features that are missed by statistics and vice versa, hinting towards the need for complementary implementation of these methods. Furthermore, we find that a myriad of features, from mutations to immune infiltration, affect the response to NAC in breast tumors.
Is there a negative trend in abundance of the weedy seadragon (Phyllopteryx taeniolatus) discernible in survey data summarised in Edgar et al. (2023)?
Authors: Schlögl Erik , Booth David J.
Published: July 2024

Decadal changes in abundance of marine organisms along the Australian coastline were reported in a recentNaturepaper by Edgar et al. (2023). We reexamine the data used in that paper, and show that the conclusion of a 59% decline in weedy seadragons (Phyllopteryx taeniolatus) cannot be justified based on these data. The data are too sparse, especially for the final survey years of 2020 and 2021, and it is this sparsity in combination with particular modelling choices made by Edgar et al. (2023) that drives their results. While not specifically considered here, it is likely that these issues also affect the results on numerous other species reported in Edgar et al. (2023).
DriverOmicsNet: An Integrated Graph Convolutional Network for Multi-Omics Exploration of Cancer Driver Genes
Authors: Dai Yang-Hong , Chang Chia-Jun , Shen Po-Chien , Jheng Wun-Long , Chen Yu-Guang
Published: July 2024

Background

Cancer is a complex and heterogeneous group of diseases driven by genetic mutations and molecular changes. Identifying and characterizing cancer driver genes (CDgs) is crucial for understanding cancer biology and guiding precision oncology. Integrating multi-omics data can reveal the intricate molecular interactions underlying cancer progression and treatment responses.

Methods

We developed a graph convolutional network (GCN) framework, DriverOmicsNet, that integrates multi-omics data using STRING protein-protein interaction (PPI) networks and correlation-based weighted correlation network analysis (WGCNA). We applied this framework to 15 cancer types, analyzing 5555 tumor samples to predict cancer-related features such as homologous recombination deficiency (HRD), cancer stemness, immune clusters, tumor stage, and survival outcomes.

Findings

DriverOmicsNet demonstrated superior predictive accuracy and model performance metrics across all target labels when compared with GCN models based on STRING network alone. Gene expression emerged as the most significant feature, reflecting the dynamic and functional state of cancer cells. The combined use of STRING PPI and WGCNA networks enhanced the identification of key driver genes and their interactions.

Interpretation

Our study highlights the effectiveness of using GCNs to integrate multi-omics data for precision oncology. The integration of STRING PPI and WGCNA networks provides a comprehensive framework that improves predictive power and facilitates the understanding of cancer biology, paving the way for more tailored treatments.
Recent odor experience selectively modulates olfactory sensitivity across the glomerular output in the mouse olfactory bulb
Authors: Subramanian Narayan , Leong Lee Min , Salemi Mokri Boukani Paria , Storace Douglas A.
Published: July 2024

Although animals can reliably locate and recognize odorants embedded in complex environments, the neural circuits for accomplishing these tasks remain incompletely understood. Adaptation is likely to be important as it could allow neurons in a brain area to adjust to the broader sensory environment. Adaptive processes must be flexible enough to allow the brain to make dynamic adjustments, while maintaining sufficient stability so that organisms do not forget important olfactory associations. Processing within the mouse olfactory bulb is likely involved in generating adaptation, although there are conflicting models of how it transforms the glomerular output of the mouse olfactory bulb. Here we performed 2-photon Ca2+imaging from mitral/tufted glomeruli in awake mice to determine the time course of recovery from adaptation, and whether it acts broadly or selectively across the glomerular population. Individual glomerular responses, as well as the overall population odor representation was similar across imaging sessions. However, odor-concentration pairings presented with interstimulus intervals upwards of 30-s evoked heterogeneous adaptation that was concentration-dependent. We demonstrate that this form of adaptation is unrelated to variations in respiration, and olfactory receptor neuron glomerular measurements indicate that it is unlikely to be inherited from the periphery. Our results indicate that the olfactory bulb output can reliably transmit stable odor representations, but recent odor experiences can selectively shape neural responsiveness for upwards of 30 seconds. We propose that neural circuits that allow for non-uniform adaptation across mitral/tufted glomerular could be important for making dynamic adjustments in complex odor environments.
The Identification Markers of activated myofibroblast subsets in the Human Lung Fibrosis Ecosystem via integrated omics Analysis
Authors: Zheng Ying , Song Zhihong , Li Shifeng , Cao Bin , Wu Hongping
Published: July 2024

Background

The aberrant remodeling of the extracellular matrix (ECM) is closely associated with lung fibrosis. However, the mechanisms underlying ECM remodeling in pulmonary fibrosis (PF) remain unclear. The advent of single-cell RNA sequencing (scRNA-seq) has provided valuable insights into the diverse phenotypic and functional characteristics of human PF. Nevertheless, the dynamic of ECM remodeling in terms of ECM synthesizing and the potential activating markers of myofibroblasts in the human PF microenvironment still needs to be investigated.

Methods

We performed integrative scRNA-seq analyses on high-fidelity PF data from a public platform by filtering out the low-quality counts and doublets using two doublet prediction methods. Next, we investigated the dynamic of the ECM signature in diverse cells in PF and screened the potential markers of myofibroblasts via fitting a successful polynomial regression model. Finally, the markers of activated myofibroblasts were identified using bulk RNA-seq of pulmonary tissue.

Results

First, we depicted the pathogenic landscape and demonstrated the heterogeneity of ECM in PF by integratively analyzing single-cell RNA-seq data, and we hypothesized that myofibroblasts played a significant role in ECM formation. Second, our results successfully displayed the biological dynamic changes of ECM and investigated the 73 positive correlated genes of myofibroblasts in PF via a polynomial regression model. Then, the bulk RNA-seq results further identified eight new activating markers of myofibroblasts, such as MFAP2, MXRA5, and LRRC17 via transcriptomic signature, correlation and ROC scores. Finally, the results of cell-cell interaction indicated that myeloid cells may be involved in regulating ECM remodeling through proliferation mediated by myofibroblasts that secrete POSTN, suggesting that ECM remodeling in PF is a complex and multi-participated process.

Conclusions

In summary, we provided insights into the contributions of ECM in human PF by integrative analysis and highlighted potential clinical utilities of myofibroblast subsets as therapeutic targets.
Dual modes of DNA N6-methyladenine maintenance by distinct methyltransferase complexes
Authors: Wang Yuanyuan , Nan Bei , Ye Fei , Zhang Zhe , Yang Wentao , Pan Bo , Niu Junhua , Ju Aili , Liu Yongqiang , Zhang Wenxin , Liu Yifan , Gao Shan
Published: July 2024

Stable inheritance of DNA N6-methyladenine (6mA) is crucial for its biological functions in eukaryotes. Here, we identify two distinct methyltransferase (MTase) complexes, both sharing the catalytic subunit AMT1, but featuring AMT6 and AMT7 as their unique components, respectively. While the two complexes are jointly responsible for 6mA maintenance methylation, they exhibit distinct enzymology, DNA/chromatin affinity, genomic distribution, and knockout phenotypes. AMT7 complex, featuring high MTase activity and processivity, is connected to transcription-associated epigenetic marks, including H2A.Z and H3K4me3, and is required for the bulk of maintenance methylation. In contrast, AMT6 complex, with reduced activity and processivity, is recruited to initiate maintenance methylation immediately after DNA replication. These two complexes coordinate in maintenance methylation. By integrating signals from both replication and transcription, this mechanism ensures the faithful and efficient transmission of 6mA as an epigenetic mark in eukaryotes.

Significance statement

DNA N6-methyladenine (6mA) has recently been recognized as an epigenetic mark in eukaryotes. The stable inheritance of 6mA is essential for its biological functions. However, the precise mechanisms by which 6mA patterns are faithfully and efficiently transmitted remain largely unknown. Here, we have identified two distinct 6mA methyltransferase (MTase) complexes and elucidated their coordinated role in maintenance methylation. This dual- complex mechanism ensures rapid and accurate methylation at newly replicated loci with proper transcription-associated epigenetic marks.
Reduced learning rate and E/I imbalance drive Peripersonal Space boundaries expansion in Schizophrenia
Authors: Paredes Renato , Grigoras Vlad , Ferroni Francesca , Ardizzi Martina , Ferri Francesca , Seriès Peggy
Published: July 2024

Background and Hypothesis

Abnormalities in the encoding of the space close to the body, named peripersonal space (PPS), is thought to play a crucial role in the disruption of the bodily self observed in schizophrenia (SCZ). Empirical evidence indicates a narrower extension of the PPS in SCZ compared to controls but preserved plasticity of the PPS. Computational studies suggest that increased excitation of sensory neurons could explain the smaller PPS observed in SCZ. However, it is unclear why SCZ patients preserve PPS plasticity and how such an excitation imbalance influences learning during the extension of the PPS boundaries.

Study Design

We hypothesise that Hebbian plasticity can account for PPS expansion after active tool use training, which occurs in spite of E/I imbalance and reduced synaptic density. Using simulations in a SCZ network model, we explored the effects of such impairments on PPS plasticity and fitted the model to behavioural data before and after a training routine.

Study Results

We found that increased excitation of sensory neurons does not impede the expansion of PPS and could explain a sharper demarcation of PPS boundaries after training. In addition, we found that a reduction in the learning rate is required to reproduce the post-training PPS representation of SCZ patients.

Conclusions

We discuss how the neural mechanisms behind the plasticity of PPS in the SCZ spectrum are related to the core pathophysiology of the disease.
Linalool fumigation improves mating competitiveness of males for population suppression of the global fruit pestCydia pomonella
Authors: Huang Sheng-Wang , Wang Peng-Cheng , Wang Yan , Wang Jie-Qiong , Gao Ping , Ji Qing-E , Yang Xue-Qing
Published: July 2024

BACKGROUND

The implementation of sterile insect technique (SIT) has proven effective in the area-wide suppression of several significant agricultural and sanitary pests by employing traditional cobalt-60 (60Co-γ) as a radiation source. Recently, X-ray has been validated as a feasible alternative to60Co-γ radiation sources. Nonetheless, higher doses of X-ray irradiation lead to insect sterility but diminish mating competitiveness, thereby impacting the effectiveness of SIT applications. Thus, it is crucial to ascertain the optimal irradiation dose and develop strategies to enhance the mating competitiveness of sterile insects to enhance SIT efficacy.

RESULTS

In this study, we determined the effect of various X-ray irradiation doses (ranging from 0 to 366 Gy) on the fecundity, fertility, and mating competitiveness ofCydia pomonella, a globally invasive fruit pest. Results demonstrated that the sterility rate of sterile males increased proportionally with irradiation dose up to 200 Gy, beyond which it plateaued. Notably, exposure to 200 Gy of irradiation notably decreased the mating competitiveness of male, as evidenced by a mating competitiveness index of 0.17 in laboratory and 0.096 in the orchard. This decline in mating competitiveness is likely linked to the down-regulation of genes associated with the recognition of sex pheromones, specificallyCpomOR3a,CpomOR3b, andCpomOR5, following X-ray irradiation. Fumigation of the plant volatile, linalool at varying concentrations (70, 83, and 96 μ L/m ³) resulted in differential enhancements in male mating competitiveness, with the moderate concentration significantly improving the competitiveness of sterilized males, possibly by restoring their ability to recognize sex pheromones. Implementation of repeated releases of sterilized males on a pilot scale led to a notable reduction in the population ofC. pomonellain the field.

CONCLUSION

These findings indicate that fumigation with plant volatiles has the potential to mitigate male sterility induced by X-ray irradiation, offering a promising approach to enhance the efficacy of SIT applications for the control ofC. pomonella.

Graphic Abstract

We determined the optimal X-ray irradiation dose and developed a linalool fumigation approach to improve the mating competitiveness of sterilized insects, thereby bolstering the efficacy of againstCydia pomonella.
Evaluating Inadequate Therapy Response in Ulcerative Colitis Adult Patients: A Retrospective Analysis of German Health Claims Data on Advanced Therapy Initiation
Authors: Dignass Axel , Blumenstein Irina , Schwedhelm Carolina , Strassen Katrin , Berger Leonie , Marquardt Sophie , Seiffert Anna , Kulchytska Nataliia , Hänsel Ivonne , Benson Alexa , Kisser Agnes
Published: July 2024

Background

The treatment landscape for active ulcerative colitis (UC) is rapidly evolving and current real-world evidence on response to advanced therapy is limited. This study aimed to determine indicators of inadequate therapeutic response among patients with UC in Germany initiating advanced therapy.

Methods

This retrospective analysis used German claims data (2015-2022) from adult patients (≥18 years). Prevalence and incidence of UC (ICD-10-GM: K51.X) were estimated. Inadequate response to therapy was evaluated in patients initiating advanced therapy based on eight predefined indicators observed for 12 months following index treatment prescription.

Results

Mean UC patient age in 2016-2022 ranged from 49.6 to 51.5 years, 47.6%-48.3% were female. Administrative prevalence ranged from 0.45% in 2016 to 0.53% in 2022. Number of patients initiating advanced treatment ranged from 157 to 347 across the study years (3.2%-4.9% of overall treated study population). On average from 2016-2021, 78.8% had inadequate response in the 12 months following index treatment. Common indicators included prolonged use of corticosteroids (46.2%) and augmentation with conventional therapies (43.9%).

Conclusions

Adult UC patients showed a high prevalence of inadequate response to advanced therapies. Our findings reveal a need for improved UC advanced therapy options, providing insight into inadequate response patterns. This may help identify patients who could benefit from a change in therapy to improve long-term outcomes.
Environment-Wide Association Study of Cognitive Function in U.S. Older Adults using the NHANES Data
Authors: Jang HyunA , Lee Jiyun , Nguyen Vy , Shin Hyeong-Moo
Published: July 2024

Neurodegenerative diseases pose increasing challenges to global aging populations. Cognitive decline in older adults is an initial indicator of neurodegenerative diseases, yet comprehensive research on environmental chemical exposures related to cognitive decline is limited. This study uses Environment-Wide Association Study (EWAS) framework to investigate associations of environmental chemicals with cognitive function in individuals aged ≥60 years. We used the Digit Symbol Substitution Test (DSST) scores (lower scores indicate cognitive decline) and chemical biomarker data of the U.S. National Health and Nutrition Examination Survey (NHANES) spanning four cycles (1999-2000, 2001-2002, 2011-2012, 2013-2014). We conducted multiple survey-weighted regression to identify biomarkers associated with DSST scores, penalized logit regression to estimate odds ratio (OR) of cognitive decline with identified biomarkers, and correlation network analyses to examine relationships among identified biomarkers and cognitive decline. After correction for multiple comparisons, 27 out of 173 biomarkers having a ≥10% detection rate were associated with DSST scores (q-value <0.05). Among them, increased odds of cognitive decline were associated with elevated levels of blood lead (Pb) (OR = 1.12, 95% CI: 1.01,1.42), blood 1,4-dichlorobenzene (1,4-DCB) (OR = 1.34, 95% CI: 1.17, 1.54), and urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) (OR = 1.34, 95% CI: 1.10, 1.62). Correlation network showed biomarkers that potentially impact cognitive decline upon related health conditions, such as stroke. In conclusion, leveraging the EWAS framework enables us to identify chemical biomarkers that were not previously discovered from traditional approaches of examining a small number of chemicals at a time. While our findings provide foundation for further research, longitudinal studies are warranted to elucidate causal relationships.
Isolation ofBorrelia puertoricensisfrom ticks collected in Merida, Yucatan, Mexico
Authors: Vázquez-Guerrero Edwin , Kneubehl Alexander R. , Reyes-Solís Guadalupe C. , Machain-Williams Carlos , Krishnavajhala Aparna , de los Santos Paulina Estrada , Lopez Job E. , Ibarra J. Antonio
Published: July 2024

Isolation of tick-borne relapsing fever (TBRF) spirochetes has proven to be a useful tool to understand their distribution by geographic areas where the tick vectors inhabit. However, their isolation and culture are not easy and in general an animal model is needed to achieve this task. Here, argasid ticks were collected from a neighborhood in Ciudad Caucel, Merida, Mexico, andBorrelia puertoricensiswas isolated with an immunosuppressed mouse model. By using this model, a higher number of spirochetes were observed in blood samples, and these were successfully cultivated in Barbour-Stoenner-Kelly (BSK)-IIB media. Genomic analyses confirmed that the isolate to beB. puertoricensis. The present report shows that this spirochete is present in argasid ticks in Ciudad Caucel and presents a potential medical and veterinary health risk.

Author Summary

Relapsing fever is a neglected disease caused by spirochetes bacteria of theBorreliaand genus that are different than those in the Lyme disease group. These bacteria are transmitted mostly byOrnithodoros(Alectorobious) soft ticks. In many countries, including Mexico,Ornithodorosspecies are understudied and often misidentified. In this report we obtained an isolate ofBorrelia puertoricensisfrom ticks captured in a small park in the city of Merida, Yucatan. These results emphasize the need for fine-scale vector surveillance in neighborhoods to determine the abundance ofBorreliaspecies, and to define their impact on humans and domestic and wild animals.
Operationalizing multimorbidity in relation to mortality and physical function: findings from a prospective longitudinal cohort study
Authors: Seo Han Sang , Davis Daniel , Khanolkar Amal R. , Hughes Alun , Patalay Praveetha
Published: July 2024

BACKGROUND AND OBJECTIVES

There is little consensus on how multimorbidity should be operationalized in life course research. We set out to derive better empirical definitions for multimorbidity by examining its different operationalizations and their associations with mortality, functional independence and physical capability in a longitudinal population-representative cohort.

RESEARCH DESIGN AND METHODS

We used data from 2653 (51.6% female) study members in the MRC National Survey of Health and Development (NSHD), a British cohort born in 1946. We examined predictive utility of five multimorbidity operationalizations by age 63 (binary multimorbidity, unweighted disease count, weighted disease count, clustered multimorbidity, cumulative multimorbidity) using 16 chronic disease, to predict 12-year mortality and age 69 functional independence and physical capability (grip strength, chair rise speed, balance).

RESULTS

The multimorbidity operationalizations ofunweighted disease count(16.3%) andweighted disease count(16.7%) explained the highest variation for mortality compared with other operationalizations. Similarly, explained variation forunweighted disease count(17.0%) andweighted disease count(16.4%) showed the highest prediction for functional independence and physical capability at age 69 years, with minor variations in physical performance measures where clustered multimorbidity also explained high variance (e.g. 8.6% for changes in chair rise speed). Binary multimorbidity, although frequently used in research was the least predictive of all outcomes.

DISCUSSION AND IMPLICATIONS

The associations between various multimorbidity measures and mortality and physical functioning lend support to important influence of multimorbidity on later-life health and functioning while highlighting the differences in variance prediction and point estimates when different approaches to operationalizing multimorbidity are used. An unweighted disease count approach might be suitable for many epidemiological research questions as it is simple to estimate while being as predictive as other more complex approaches such as weighted disease counts.

Translational Significance

Multimorbidity research urgently needs a standardized approach to its measurement and operationalization. This study simultaneously compares different strengths of association between multimorbidity definitions and mortality, functional independence and physical capability. This adds possibility by using the predictive utility for mortality, functional independence and physical capability as criteria for determining the usefulness of a given operationalization. Quantifying how these vary offers practical choices between methods of operationalizing multimorbidity for various purposes in research and clinical settings, for example, a targeted strategy aimed at understanding mortality, physical function and health care utilization.
Epigenetic Signatures of Asthma: A Comprehensive Study of DNA Methylation and Clinical Markers
Authors: Van Asselt Austin J. , Beck Jeffrey J. , Johnson Brandon N. , Finnicum Casey T. , Kallsen Noah , Viet Sarah , Huizenga Patricia , Ligthart Lannie , Hottenga Jouke-Jan , Pool René , Maitland-van der Zee A.H , Vijverberg S.J. , de Geus Eco , Boomsma Dorret I. , Ehli Erik A. , van Dongen Jenny
Published: July 2024

Background

Asthma, a complex respiratory disease, presents with inflammatory symptoms in the lungs, blood, and other tissues. We investigated the relationship between DNA methylation and 35 clinical markers of asthma. The Illumina Infinium EPIC v1 methylation array was used to evaluate 742,442 CpGs in whole blood samples from 319 participants. They were part of the Netherlands Twin Register from families with at least one member suffering from severe asthma. Repeat blood samples were taken after 10 years from 182 of these individuals. Principal component analysis (PCA) on the clinical markers yielded ten principal components (PCs) that explained 92.8% of the total variance. We performed epigenome-wide association studies (EWAS) for each of the ten PCs correcting for familial structure and other covariates.

Results

221 unique CpGs reached genome-wide significance at timepoint 1 (T1) after Bonferroni correction. PC7 accounted for the majority of associations (204), which correlated with loadings of eosinophil counts and immunoglobulin levels. Enrichment analysis via the EWAS Atlas identified 190 of these CpGs to be previously identified in EWASs of asthma and asthma-related traits. Proximity assessment to previously identified SNPs associated with asthma identified 17 unique SNPs within 1 MB of two of the 221 CpGs. EWAS in 182 individuals with epigenetic data at a second timepoint (T2) identified 49 significant CpGs. EWAS Atlas enrichment analysis indicated that 4 of the 49 were previously associated with asthma or asthma-related traits. Comparing the estimates of all the significant associations identified across the two time points (271 in total) yielded a correlation of 0.81.

Conclusion

We identified 270 unique CpGs that were associated with PC scores generated from 35 clinical markers of asthma, either cross-sectionally or 10 years later. A strong correlation was present between effect sizes at the 2 timepoints. Most associations were identified for PC7, which captured blood eosinophil counts and immunoglobulin levels and many of these CpGs have previous associations in earlier studies of asthma and asthma-related traits. The results point to using this robust DNA methylation profile as a new, stable biomarker for asthma.