bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cameroonian blackflies (Diptera: Simuliidae) harbour a plethora of (RNA) viruses
Authors: De Coninck Lander , Hadermann Amber , Ingletto Ludovica , Colebunders Robert , Njamnshi Kongnyu Gamnsi , Njamnshi Alfred Kongnyu , Mokili John L , Siewe Fodjo Joseph Nelson , Matthijnssens Jelle 
Published: April 2024

AbstractStrong epidemiological evidence suggests that onchocerciasis may be associated with epilepsy – hence the name onchocerciasis-associated epilepsy (OAE). However, the pathogenesis of OAE still needs to be elucidated, as recent studies failed to detectOnchocerca volvulusin the central nervous system of persons with OAE. Therefore, it was suggested that a potentially neurotropic virus transmitted by blackflies could play a role in triggering OAE. To investigate this hypothesis, adult blackflies were collected in an onchocerciasis-endemic area with a high OAE prevalence in the Ntui Health District, Cameroon. A whole-genome shotgun sequencing approach was used to detect viral sequences in fifty-five pools of ten blackflies. A very high abundance of viral reads was detected across multiple (novel) viral families, including viral families associated with human disease. Although, no genomes closely related to known neurotropic viruses were found in the blackfly virome, the plethora of novel viruses representing novel species, genera and even families, warrant further exploration for their potential to infect vertebrates. These results could serve as a first step for studying the viruses associated with the hematophagous blackfly, which also could be present in their nematode hostO. volvulus. Exploring the diversity of viruses in blackflies should be included in the active surveillance of zoonotic diseases.
Genome mining leads to the identification of a stable and promiscuous Baeyer-Villiger monooxygenase from a thermophilic microorganism
Authors: Bunyat-zada Amir R. , Ducharme Stephan E. , Cleveland Maria E. , Hoffman Esther R. , Howe Graeme W. 
Published: April 2024

AbstractBaeyer-Villiger monooxygenases are NAD(P)H-dependent flavoproteins that catalyze oxygen insertion reactions which convert ketones to valuable esters and lactones. While these enzymes offer an appealing alternative to traditional Baeyer-Villiger oxidations, these proteins tend to be either too unstable or exhibit too narrow of a substrate scope for implementation as industrial biocatalysts. Here, sequence similarity networks were used to search for novel Baeyer-Villiger monooxygenases that are both stable and substrate promiscuous. Our genome mining efforts led to the identification of an enzyme fromChloroflexotabacterium (strain G233) dubbedssnBVMO that exhibits i) the highest melting temperature recorded to date for a naturally sourced Baeyer-Villiger monooxygenase, ii) a remarkable kinetic stability across a wide range of conditions, and iii) a broad substrate scope that includes linear aliphatic, aromatic, and sterically bulky ketones. Kinetic characterization of this enzyme was undertaken to identify the optimal conditions forssnBVMO catalysis, and a subsequent quantitative assay using propiophenone as a substrate afforded more than 95% conversion. To spur the implementation of this enzyme as an oxidative biocatalyst, several fusion proteins were constructed that linkedssnBVMO to a thermostable phosphite dehydrogenase. These self-sufficient enzymes can recycle NADPH and permit oxidations to be run with sub-stoichiometric quantities of this expensive cofactor. Extensive characterization of these fusion enzymes permitted identification of PTDH-L1-ssnBVMO as the most promising oxidative biocatalyst. Results described herein demonstrate that this new monooxygenase has significant potential as a useful industrial biocatalyst for Baeyer-Villiger oxidations.
MtrAB two-component system is crucial for the intrinsic resistance and virulence ofMycobacterium abscessus
Authors: Zhang Jingran , Ju Yanan , Li Lijie , Hameed Adnan , Yusuf Buhari , Gao Yamin , Fang Cuiting , Tian Xirong , Ding Jie , Ma Wanli , Chen Xinwen , Wang Shuai , Zhang Tianyu 
Published: April 2024

ABSTRACTMycobacterium abscessus(Mab) poses serious therapeutic challenges, principally due to its intrinsic resistance to a wide array of antibiotics. The pressing issue of drug resistance has spurred an urgent need to explore novel targets and develop new therapeutic agents against Mab. The MtrAB two-component system, conserved among Actinobacteria, is pivotal for regulating various metabolic processes. Nevertheless, the role of MtrAB in Mab remains elusive.In this study, we uncovered that Mab strains with disruptedmtrA, mtrBor both exhibited heightened susceptibility to a variety of antibiotics with diverse mechanisms of action, in contrast to the wild-type strain. In a murine model, rifabutin, bedaquiline, and amikacin, which were inactive against the wild-type Mab strain, demonstrated efficacy against all themtrA, mtrBandmtrABknockout strains, significantly reducing pulmonary bacterial burdens compared to vehicle controls after ten days of treatment. Notably, the virulence of all themtrA, mtrB, andmtrABknockout strains was highly diminished in the murine model, as evidenced by a substantial decrease in bacterial load in the lungs of mice after 16 days. We observed that all three knockout strains exhibited a significantly reduced growth rate compared to the wild-type strain.We discovered that cells lackingmtrA, mtrBor both exhibited an elongated cell length and had multiple septa, suggesting that both MtrA and MtrB regulate cell division of Mab. Subsequently, an ethidium bromide accumulation assay disclosed that the absence of eithermtrAormtrBor both significantly increased cell envelope permeability.In summary, this study suggests thatmtrAandmtrBplay an important role in the intrinsic resistance and virulence of Mab by affecting cell division and altering cell permeability. Consequently, MtrA and MtrB represent promising targets for the discovery of anti-Mab drugs.HIGHLIGHTSKnockout ofmtrA, mtrBormtrABleads to increased sensitivity ofM. abscessus in vitroandin vivo.ThemtrA, mtrBormtrABknockoutM. abscessusstrains exhibit highly reduced virulence.MtrA and MtrB are potential targets for anti-M. abscessusdrug discovery.Knockout ofmtrA, mtrBormtrABresults in defective cell division inM. abscessus.
An optical aptamer-based cytokine nanosensor detects macrophage activation by bacterial toxins
Authors: Ryan Amelia K. , Rahman Syeda , Williams Ryan M. 
Published: April 2024

AbstractOveractive or dysregulated cytokine expression is hallmark of many acute and chronic inflammatory diseases. This is true for acute or chronic infection, neurodegenerative diseases, autoimmune diseases, cardiovascular disease, cancer, and others. Cytokines such as interleukin-6 (IL-6) are known therapeutic targets and biomarkers for such inflammatory diseases. Platforms for cytokine detection are therefore desirable tools for both research and clinical applications. Single-walled carbon nanotubes (SWCNT) are versatile nanomaterials with near-infrared fluorescence that can serve as transducers for optical sensors. When functionalized with an analyte-specific recognition element, SWCNT emission may become sensitive and selective towards the desired target. SWCNT-aptamer sensors are easily assembled, inexpensive, and biocompatible. In this work, we introduced a nanosensor design based on SWCNT and a DNA aptamer specific to IL-6. We first evaluated several SWCNT-aptamer constructs based on this simple direct complexation method, wherein the aptamer both solubilizes the SWCNT and confers sensitivity to IL-6. The sensor limit of detection, 105 ng/mL, lies in the relevant range for pathological IL-6 levels. Upon investigation of sensor kinetics, we found rapid response within seconds of antigen addition which continued over the course of three hours. We found that this sensor construct is stable, and the aptamer is not displaced from the nanotube surface during IL-6 detection. Finally, we investigated the ability of this sensor construct to detect macrophage activation caused by bacterial lipopolysaccharides (LPS) in an in vitro model of disease, finding rapid and sensitive detection of macrophage-expressed IL-6. We are confident further development of this sensor will have novel implications for diagnosis of acute and chronic inflammatory diseases, in addition to contributing to the understanding of the role of cytokines in these diseases.
The RNA landscape of the human commensalSegatella coprireveals a small RNA essential for gut colonization
Authors: El Mouali Youssef , Tawk Caroline , Huang Kun D. , Amend Lena , Lesker Till Robin , Ponath Falk , Vogel Jörg , Strowig Till 
Published: April 2024

SummaryThe bacteriumSegatella copriis a prevalent member of the human gut microbiota associated with both health and disease states, but intrinsic factors that determine its ability to effectively colonize the gut are not understood. By extensive transcriptome mapping ofS. copriand examining human-derived samples, we discover a previously unknown small RNA named hereSegatellaRNA colonization factor (SrcF). We show that SrcF is essential forS. coprigut colonization in a gnotobiotic mouse model. SrcF regulates genes involved in nutrient acquisition, and its own expression is controlled by complex carbohydrates, particularly fructans. Furthermore, SrcF expression is strongly influenced by human microbiome composition and by the breakdown of fructans by cohabitating commensals, suggesting that the breakdown of complex carbohydrates mediates inter-species signaling among commensals beyond its established function in generating energy. Together, this study highlights the contribution of a small RNA as a key regulator in gut colonization.
A tunable and versatile chemogenetic near infrared fluorescent reporter
Authors: Hajji Lina El , Bunel Benjamin , Joliot Octave , Li Chenge , Tebo Alison G. , Rampon Christine , Volovitch Michel , Fischer Evelyne , Pietrancosta Nicolas , Perez Franck , Morin Xavier , Vriz Sophie , Gautier Arnaud 
Published: April 2024

ABSTRACTNear-infrared (NIR) fluorescent reporters provide additional colors for highly multiplexed imaging of cells and organisms, and enable imaging with less toxic light and higher contrast and depth. Here, we present the engineering of nirFAST, a small tunable chemogenetic NIR fluorescent reporter that is brighter than top-performing NIR fluorescent proteins in cultured mammalian cells. nirFAST is a small genetically encoded protein of 14 kDa that binds and stabilizes the fluorescent state of synthetic, highly cell-permeant, fluorogenic chromophores (so-called fluorogens) that are otherwise dark when free. Engineered to emit NIR light, nirFAST can also emit far-red or red lights through change of chromophore. nirFAST allows the imaging of proteins in live cultured mammalian cells, chicken embryo tissues and zebrafish larvae. Its near infrared fluorescence provides an additional color for high spectral multiplexing. We showed that nirFAST is well-suited for stimulated emission depletion (STED) nanoscopy, allowing the efficient imaging of proteins with subdiffraction resolution in live cells. nirFAST enabled the design of a chemogenetic green-NIR fluorescent ubiquitination-based cell cycle indicator (FUCCI) for the monitoring of the different phases of the cell cycle. Finally, bisection of nirFAST allowed the design of a fluorogenic chemically induced dimerization technology with NIR fluorescence readout, enabling the control and visualization of protein proximity.
Adolescent Seizure Impacts Oligodendrocyte Development, Neuronal-Glial Circuit Formation, and Myelination
Authors: Foutch Kylie , Tilton Iris , Cooney Aundrea , Brock Robert , Gupta Raghav , Bender Cole , Franzia Chloe , Garcia Mary Francis , Deneen Jeni , Baldemor Megan , Reyes Christopher Arellano , Moura Daniela , Noguchi Hirofumi , Cocas Laura 
Published: April 2024

AbstractMyelin sheaths, formed by oligodendrocyte cells in the CNS, are vital for rapid conduction of electrical signals down neuronal axons. Oligodendrocyte progenitors differentiate and myelinate axons during development and following demyelinating injury. However, the mechanisms that drive the timing and specificity of developmental myelination are not well understood. It is known that oligodendrocyte progenitors receive synapses from neurons, providing a potential mechanism for neuronal-glial communication. We have previously shown that changing neuronal activity affects the proliferation of oligodendrocyte cells and neuron to OPC connections. We hypothesized that OPC proliferation and differentiation would be affected by pathological neuronal activity during adolescent development, when developmental myelination is occurring, and that this would also impact neuron to OPC connectivity and myelination. We used kainic acid to induce a seizure, then analyzed changes in the rate of OPC proliferation and differentiation five days later in the cerebral cortex, corpus callosum, and hippocampus. We found that OPC proliferation increased, the overall numbers of OPCs increased, and the number of mature oligodendrocytes decreased. We measured changes in the myelination to determine whether seizure activity directly affected myelination rate in adolescent development, and found decreased myelin in the cerebral cortex, corpus callosum, and hippocampus. We used viral monosynaptic circuit tracing to determine whether connections between neurons and OPCs were affected by seizure activity, and found a decrease in neuron to OPC connections in seizure mice compared to controls. Finally, we measured changes in the presence of kir4.1 potassium channels in OPCs, an important regulator of OPC membrane potential as well as an ion channel important for myelination, and found that there was a decrease in the number of potassium channels on OPCs after adolescent seizure. These findings provide insight into the response of the adolescent brain to seizure activity, as well as how seizures affect neuronal glial connections, OPC development and myelin formation, with the goal of understanding how these mechanisms may be important for treatment of demyelination after seizure and in epilepsy.
Integrating HiTOP and RDoC Frameworks Part I: Genetic Architecture of Externalizing and Internalizing Psychopathology
Authors: Davis Christal N. , Khan Yousef , Toikumo Sylvanus , Jinwala Zeal , Boomsma Dorret I. , Levey Daniel F. , Gelernter Joel , Kember Rachel L. , Kranzler Henry R. 
Published: April 2024

AbstractBackgroundThere is considerable comorbidity between externalizing (EXT) and internalizing (INT) psychopathology. Understanding the shared genetic underpinnings of these spectra is crucial for advancing knowledge of their biological bases and informing empirical models like the Research Domain Criteria (RDoC) and Hierarchical Taxonomy of Psychopathology (HiTOP).MethodsWe applied genomic structural equation modeling to summary statistics from 16 EXT and INT traits in European-ancestry individuals (n = 16,400 to 1,074,629). Traits included clinical (e.g., major depressive disorder, alcohol use disorder) and subclinical measures (e.g., risk tolerance, irritability). We tested five confirmatory factor models to identify the best fitting and most parsimonious genetic architecture and then conducted multivariate genome-wide association studies (GWAS) of the resulting latent factors.ResultsA two-factor correlated model, representing EXT and INT spectra, provided the best fit to the data. There was a moderate genetic correlation between EXT and INT (r = 0.37, SE = 0.02), with bivariate causal mixture models showing extensive overlap in causal variants across the two spectra (94.64%, SE = 3.27). Multivariate GWAS identified 409 lead genetic variants for EXT, 85 for INT, and 256 for the shared traits.ConclusionsThe shared genetic liabilities for EXT and INT identified here help to characterize the genetic architecture underlying these frequently comorbid forms of psychopathology. The findings provide a framework for future research aimed at understanding the shared and distinct biological mechanisms underlying psychopathology, which will help to refine psychiatric classification systems and potentially inform treatment approaches.
The Burr distribution as a model for the delay between key events in an individual’s infection history
Authors: Jamieson Nyall , Charalambous Christiana , Schultz David M. , Hall Ian 
Published: April 2024

AbstractUnderstanding the temporal relationship between key events in an individual’s infection history is crucial for disease control. Delay data between events, such as infection and symptom onset times, is doubly censored because the exact time at which these key events occur is generally unknown. Current mathematical models for delay distributions rely solely on heuristic justifications for their applicability. Here, we derive a new model for delay distributions, specifically for incubation periods, motivated by bacterial-growth dynamics that lead to the Burr family of distributions being a valid modelling choice. We also incorporate methods within these models to account for the doubly censored data. Our approach provides biological justification in the derivation of our delay distribution model, the results of fitting to data highlighting the superiority of the Burr model compared to currently used models in the literature. Our results indicate that the derived Burr distribution is 13 times more likely to be a better-performing model to incubation-period data than currently used methods. Further, we show that incorporating methods for handling the censoring issue results in the mean of the underlying continuous incubation-period model being reduced by a whole day, compared to the mean obtained under alternative modelling techniques in the literature.Author summaryIn public health, it is important to know key temporal properties of diseases (such as how long someone is ill for or infectious for). Mathematical characterisation of properties requires information about patients’ infection histories, such as the number of days between infection and symptom onset, for example. These methods provide useful insights, such as how their infectiousness varies over time since they were infected. However, two key issues arise with these approaches. First, these methods do not have strong arguments for the validity of their usage. Second, the data typically used is provided as a rounded number of days between key events, as opposed to the exact period of time. We address both these issues by developing a new mathematical model to describe the important properties of the infection process of various diseases based on strong biological justification, and further incorporating methods within the mathematical model which consider infection and symptom onset to occur at any point within an interval, as opposed to an exact time. Our approach provides more preferable results, based on AIC, than existing approaches, enhancing the understanding of properties of diseases such as Legionnaires’ disease.
Topology changes of the regeneratingHydradefine actin nematic defects as mechanical organizers of morphogenesis
Authors: Ravichandran Yamini , Vogg Matthias , Kruse Karsten , Pearce Daniel JG , Roux Aurélien 
Published: April 2024

AbstractHydrais named after the mythological animal for its regenerative capabilities, but contrary to its mythological counterpart, it only regenerates one head when cut. Here we show that soft compression of head regenerating tissues induces the regeneration of viable, two headed animals. Topological defects in the supracellular nematic organization of actin were previously correlated with the new head regeneration site1. Soft compression creates new topological defects associated with additional heads. To test the necessity of topological defects in head regeneration, we changed the topology of the tissue. By compressing the head regenerating tissues along their body axis, topological defects of the foot and of the regenerating head fused together, forming a toroid with no defects. Perfectly ordered toroids did not regenerate over eight days and eventually disintegrated. Spheroids made from excised body column tissue partially lose their actin order during regeneration. Compression of spheroids generated toroids with actin defects. These tissues regenerated into toroidal animals with functional head and foot, and a bifurcated body. Our results show that topological defects in the actin order are necessary to shape the head of the regeneratingHydra,supporting the notion that actin topological defects are mechanical organizers of morphogenesis.
Maternal and Infant Research Electronic Data Analysis (MIREDA): A protocol for creating a common data model for federated analysis of UK birth cohorts and the life course
Authors: Seaborne MJ , Jones HE , Cockburn N , Durbaba S , Giles TC , González-Izquierdo A , Hough A , Mason D , Mendez-Villalon A , Sanchez-Soriano C. , Orton C. , Ford D , Quinlan P , Nirantharakumar K , Poston L. , Reynolds RM , Santorelli G , Brophy S 
Published: April 2024

AbstractIntroductionBirth cohorts are valuable resources for studying early life, the determinants of health, disease, and development. They are essential for studying life course. Electronic cohorts are live, dynamic longitudinal cohorts using anonymised, routinely collected data. There is no selection bias through direct recruitment, but they are limited to health and administrative system data and may lack contextual information.The MIREDA (Maternal and Infant Research Electronic Data Analysis) partnership creates a UK-wide birth cohort by aligning existing electronic birth cohorts to have the same structure, content, and vocabularies, enabling UK-wide federated analyses.ObjectivesCreate a core dynamic, live UK-wide electronic birth cohort with approximately 100,000 new births per year using a common data model (CDM).Provide data linkage and automation for long-term follow up of births from MuM-PreDiCT and the ‘Born in’ initiatives of Bradford, Wales, Scotland, and South London for comparable analyses.MethodsWe will establish core data content and collate linkable data. Use a suite of extraction, transformation, and load (ETL) tools will be used to transform the data for each birth cohort into the CDM. Transformed datasets will remain within each cohort’s trusted research environment (TRE). Metadata will be uploaded for the public to theHealth Data Research (HDRUK) Innovation Gateway. We will develop a single online data access request for researchers. A cohort profile will be developed for researchers to reference the resource.EthicsEach cohort has approval from their TRE through compliance with their project application processes and information governance.DisseminationWe will engage with researchers in the field to promote our resource through partnership networking, publication, research collaborations, conferences, social media, and marketing communications strategies.