bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tbx1 haploinsufficiency causes brain metabolic and behavioral anomalies in adult mice which are corrected by vitamin B12 treatment
Authors: Caterino Marianna , Paris Debora , Torromino Giulia , Costanzo Michele , Flore Gemma , Tramice Annabella , Golini Elisabetta , Mandillo Silvia , Cavezza Diletta , Angelini Claudia , Ruoppolo Margherita , Motta Andrea , Leonibus Elvira De , Baldini Antonio , Illingworth Elizabeth , Lania Gabriella 
Published: February 2024

AbstractIntroductionThe brain-related phenotypes observed in 22q11.2 deletion syndrome (22q11.2DS) are highly variable and their origin is poorly understood. Changes in brain metabolism may cause or contribute to the phenotypes, given that many of the deleted genes (approx. 10%) are implicated in metabolic processes, but this is currently unknown. It is clearly important to address this knowledge gap, but in humans, the primary material required for studying brain metabolism is inaccessible. For this reason, we sought to address the issue using two mouse models of 22q11.2DS.MethodsWe used three independent approaches to investigate brain metabolism in young adult mice, namely, mass spectrometry, nuclear magnetic resonance spectroscopy and transcriptomics. We selected to study primarilyTbx1single gene mutants because it is the primary candidate disease gene. We then confirmed key findings in the multi-gene deletion mutantDf1/+.ResultsWe found thatTbx1mutants have alterations of specific brain metabolites, including methylmalonic acid, which is highly brain-toxic, as well as a more general metabolomic imbalance. We provide transcriptomic evidence of an interaction genotype-vB12 treatment, and behavioural evidence of a response to vB12 treatment, which rescued some of the behavioural anomaly observed inTbx1mutants. We conclude thatTbx1haploinsufficiency causes extensive brain metabolic anomalies, which are partially responsive to vB12 treatment. We suggest that alterations of glutamine-glutamate metabolism and fatty acid metabolism are key components of the metabolic phenotype in these mutants.
The role of NMDA receptors in memory and prediction in cultured neural networks
Authors: Lamberti Martina , van Putten Michel J.A.M. , Marzen Sarah , le Feber Joost 
Published: February 2024

AbstractMemory has been extensively studied at the behavioural as well as the cellular level. Spike timing dependent plasticity (STDP) is associated with N-methyl-D-aspartate (NMDA) receptor activation and is widely accepted to be essential for long-term memory. However, experimental evidence remains sparse, probably due to the required complex combination of cellular and functional readouts. Recent work showed that in-vitro cortical networks memorize and predict inputs. The initial dependency of prediction on short-term memory decreased during the formation of long-term memory traces. Here, we stimulated in-vitro networks to investigate memory and prediction under control conditions, or under NMDA block. The NMDA anatagonist 2-amino-5-phosphonovaleric acid (APV) at a concentration that did not significantly reduce network excitability, but did impede long-term memory trace formation. In APV-treated cultures short-term memory of stimuli persisted, and they were still able to predict. In contrast to control cultures, prediction remained fully dependent on short-term memory. This confirms that NMDA receptor activation is essential for the formation of long-term memory traces and supports the notion that, as control cultures learn to memorize the stimulus, long-term memory starts to contribute to their predictive capability.
DNA-Diffusion: Leveraging Generative Models for Controlling Chromatin Accessibility and Gene Expression via Synthetic Regulatory Elements
Authors: DaSilva Lucas Ferreira , Senan Simon , Patel Zain Munir , Reddy Aniketh Janardhan , Gabbita Sameer , Nussbaum Zach , Córdova César Miguel Valdez , Wenteler Aaron , Weber Noah , Tunjic Tin M. , Khan Talha Ahmad , Li Zelun , Smith Cameron , Bejan Matei , Louis Lithin Karmel , Cornejo Paola , Connell Will , Wong Emily S. , Meuleman Wouter , Pinello Luca 
Published: February 2024

AbstractThe challenge of systematically modifying and optimizing regulatory elements for precise gene expression control is central to modern genomics and synthetic biology. Advancements in generative AI have paved the way for designing synthetic sequences with the aim of safely and accurately modulating gene expression. We leverage diffusion models to design context-specific DNA regulatory sequences, which hold significant potential toward enabling novel therapeutic applications requiring precise modulation of gene expression. Our framework uses a cell type-specific diffusion model to generate synthetic 200 bp regulatory elements based on chromatin accessibility across different cell types. We evaluate the generated sequences based on key metrics to ensure they retain properties of endogenous sequences: transcription factor binding site composition, potential for cell type-specific chromatin accessibility, and capacity for sequences generated by DNA diffusion to activate gene expression in different cell contexts using state-of-the-art prediction models. Our results demonstrate the ability to robustly generate DNA sequences with cell type-specific regulatory potential. DNA-Diffusion paves the way for revolutionizing a regulatory modulation approach to mammalian synthetic biology and precision gene therapy.
Mice born preterm develop gait dystonia and reduced cortical parvalbumin immunoreactivity
Authors: Gemperli Kat , Folorunso Femi , Norin Benjamin , Joshua Rebecca , Hill Clayton , Rykowski Rachel , Galindo Rafael , Aravamuthan Bhooma R. 
Published: February 2024

AbstractPreterm birth leading to cerebral palsy (CP) is the most common cause of childhood dystonia, a movement disorder that is debilitating and often treatment refractory. Dystonia has been typically associated with dysfunction of striatal cholinergic interneurons, but clinical imaging data suggests that cortical injury may best predict dystonia following preterm birth. Furthermore, abnormal sensorimotor cortex inhibition has been found in many studies of non-CP dystonias. To assess the potential for a cortical etiology of dystonia following preterm birth, we developed a new model of preterm birth in mice. Noting that term delivery in mice on a C57BL/6J background is embryonic day 19.1 (E19.1), we induced preterm birth at the limits of pup viability at embryonic day (E) 18.3, equivalent to human 22 weeks gestation. Mice born preterm demonstrate display clinically validated metrics of dystonia during gait (leg adduction amplitude and variability) and also demonstrate reduced parvalbumin immunoreactivity in the sensorimotor cortex, suggesting dysfunction of cortical parvalbumin-positive inhibitory interneurons. Notably, reduced parvalbumin immunoreactivity or changes in parvalbumin-positive neuronal number were not observed in the striatum. These data support the association between cortical dysfunction and dystonia following preterm birth. We propose that our mouse model of preterm birth can be used to study this association and potentially also study other sequelae of extreme prematurity.
Parallel evolution in mosquito vectors – a duplicated esterase locus is associated with resistance to pirimiphos-methyl inAn. gambiae
Authors: Nagi Sanjay C. , Lucas Eric R. , Egyir-Yawson Alexander , Essandoh John , Dadzie Samuel , Chabi Joseph , Djogbénou Luc S. , Medjigbodo Adandé A. , Edi Constant V. , Ketoh Guillaume K. , Koudou Benjamin G. , Ashraf Faisal , Clarkson Chris S. , Miles Alistair , Weetman David , Donnelly Martin J. 
Published: February 2024

AbstractThe primary control methods for the African malaria mosquito,Anopheles gambiae, are based on insecticidal interventions. Emerging resistance to these compounds is therefore of major concern to malaria control programmes. The organophosphate, pirimiphos-methyl, is a relatively new chemical in the vector control armoury but is now widely used in indoor residual spray campaigns. Whilst generally effective, phenotypic resistance has developed in some areas in malaria vectors. Here, we used a population genomic approach to identify novel mechanisms of resistance to pirimiphos-methyl inAnopheles gambiae s.lmosquitoes. In multiple populations, we found large and repeated signals of selection at a locus containing a cluster of detoxification enzymes, some of whose orthologs are known to confer resistance to organophosphates inCulex pipiens. Close examination revealed a pair of alpha-esterases,Coeae1fandCoeae2f, and a complex and diverse pattern of haplotypes under selection inAn. gambiae, An. coluzziiandAn. arabiensis. As inCx. pipiens, copy number variation seems to play a role in the evolution of insecticide resistance at this locus. We used diplotype clustering to examine whether these signals arise from parallel evolution or adaptive introgression. Using whole-genome sequenced phenotyped samples, we found that in West Africa, a copy number variant inAnopheles gambiaeis associated with resistance to pirimiphos-methyl. Overall, we demonstrate a striking example of contemporary parallel evolution which has important implications for malaria control programmes.
Towards understanding of allostery in MALT1: a possible role of interdomain motions as revealed by NMR and AlphaFold
Authors: Wallerstein Johan , Han Xiao , Levkovets Maria , Lesovoy Dmitry , Malmodin Daniel , Mirabello Claudio , Wallner Björn , Sun Renhua , Sandalova Tatyana , Agback Peter , Karlsson Göran , Achour Adnane , Agback Tatiana , Orekhov Vladislav 
Published: February 2024

ABSTRACTMucosa-associated lymphoid tissue lymphoma-translocation protein 1 (MALT1) has emerged as an attractive target for the development of modulatory compounds, particularly in the treatment of lymphoma and other cancers. While the three-dimensional structure of MALT1(PCASP-Ig3)339–719has been previously determined through X-ray analysis, its dynamic behaviour in solution has remained largely unexplored. We present here inaugural dynamic analyses of the apo MALT1(PCASP-Ig3)339–719form along with its mutated variant, E549A. This investigation harnessed an array of NMR relaxation techniques, including longitudinal and transverse15N auto-relaxation, heteronuclear NOE, transverse cross-correlated relaxation and NOE measurements between side-chain methyl groups. Our findings unequivocally confirm that MALT1(PCASP-Ig3)339–719exists solely as a monomer in solution, and demonstrate that the two domains display semi-independent movements in relation to each other. Our extensive dynamic study, covering a range of time scales, along with the assessment of diverse conformational populations for MALT1(PCASP-Ig3)339–719, by Molecular Dynamic simulations, Alpha Fold modelling and PCA analysis, shed light at potential mechanisms underlying the allosteric regulation of this enzyme, and the specific importance of interdomain motions.
A Multimodal Characterization of Low-Dimensional Thalamocortical Structural Connectivity Patterns
Authors: John Alexandra , Hettwer Meike D. , Schaare H. Lina , Saberi Amin , Bayrak Şeyma , Wan Bin , Royer Jessica , Bernhardt Boris C. , Valk Sofie L. 
Published: February 2024

AbstractThe human thalamus is a bilateral and heterogeneous grey matter structure that plays a crucial role in coordinating whole-brain activity. Investigations of its complex structural and functional internal organization revealed to a certain degree overlapping parcellations, however, a consensus on thalamic subnuclei boundaries remains absent. Recent work suggests that thalamic organization might additionally reflect continuous axes transcending nuclear boundaries. In this study, we used a multimodal approach to uncover how low-dimensional axes that describe thalamic connectivity patterns to the cortex are related to internal thalamic microstructural features, functional connectivity, and structural covariance. We computed a thalamocortical structural connectome via probabilistic tractography on diffusion MRI and derived two main axes of thalamic organization. The principal thalamic gradient, extending from medial to lateral and differentiating between transmodal and unimodal nuclei, was related to intrathalamic myelin profiles, and patterns of functional connectivity, while the secondary axis showed correspondence to core-matrix cell type distributions. Lastly, exploring multimodal thalamocortical associations on a global scale, we observed that the medial-to- lateral gradient consistently differentiated limbic, frontoparietal, and default mode network nodes from dorsal and ventral attention networks across modalities. However, the link with sensory modalities varied. In sum, we show the coherence between lower dimensional patterns of thalamocortical structural connectivity and various modalities, shedding light on multiscale thalamic organization.
Transcriptome analysis of the tardigradeHypsibius exemplarisexposed to the DNA-damaging agent bleomycin
Authors: Yoshida Yuki , Hirayama Akiyoshi , Arakawa Kazuharu 
Published: February 2024

AbstractTardigrades are microscopic animals that are renowned for their capabilities of tolerating near-complete desiccation by entering an ametabolic state called anhydrobiosis. However, many species also show high tolerance against radiation in the active state as well, suggesting cross-tolerance via the anhydrobiosis mechanism. Previous studies utilized indirect DNA damaging agents to identify core components of the cross-tolerance machinery; however, it was difficult to distinguish whether transcriptomic changes were the result of DNA damage or residual oxidative stress. To this end, we performed transcriptome analysis on bleomycin-exposedHypsibius exemplaris. We observed induction of several tardigrade-specific gene families that may be the core components of the cross-tolerance mechanism. We also identified an enrichment of the tryptophan metabolism pathway, which metabolomic analysis suggested the engagement of this pathway in stress tolerance. These results provide several candidates for the core component of the cross-tolerance, as well as possible anhydrobiosis machinery.
Decoding Huge Phage Diversity: A Taxonomic Classification of Lak Megaphages
Authors: Cook Ryan , Crisci Marco A. , Pye Hannah V. , Telatin Andrea , Adriaenssens Evelien M. , Santini Joanne M. 
Published: February 2024

AbstractHigh-throughput sequencing for uncultivated viruses has accelerated the understanding of global viral diversity and uncovered viral genomes substantially larger than any that have so far been cultured. Notably, the Lak phages are an enigmatic group of viruses that present some of the largest known phage genomes identified in human and animal microbiomes, and are dissimilar to any cultivated viruses. Despite the wealth of viral diversity that exists within sequencing datasets, uncultivated viruses have rarely been used for taxonomic classification. We investigated the evolutionary relationships of 23 Lak phages and propose a taxonomy for their classification. Predicted protein analysis revealed the Lak phages formed a deeply branching monophyletic clade within the classCaudoviriceteswhich contained no other phage genomes. One of the interesting features of this clade is that all current members are characterised by an alternative genetic code. We propose the Lak phages belong to a new order, the “Grandevirales”. Protein and nucleotide-based analyses support the creation of two families, three sub-families, and four genera within the order “Grandevirales”. We anticipate that the proposed taxonomy of Lak megaphages will simplify the future classification of related viral genomes as they are uncovered. Continued efforts to classify divergent viruses are crucial to aid common analyses of viral genomes and metagenomes.
In vitroantimicrobial activity of non-aureus StaphylococciandMammaliicocciagainstStaphylococcus aureusandStreptococcus uberisand their relationship with the presence of intramammary infections in organic dairy cows
Authors: Peña-Mosca F. , Gaire T. N. , Dean C. , Manriquez D. , Pinedo P. , Noyes N. , Caixeta L. 
Published: February 2024

ABSTRACTThis study aimed to: (1) Assess thein vitroantimicrobial activity of non-aureus StaphylococciandMammaliicocci(NASM) isolates from organic cows teat apices with and without intramammary infections (IMI) byStaphylococcus aureus(SAU) orStreptococcusspp. andStreptococcus-like organisms (SSLO); (2) Investigate the relationship between IMI status and NASM counts on teat apex; (3) Explore the relationship between NASM species assigned taxonomy and the inhibitory activity against SAU andStreptococcus uberis(SUB). A total of 114 cows from 2 farms were sampled and followed from 8 weeks before to 5 weeks after calving. Weekly milk samples were cultured and used to design a case control study. Cases were defined as cows that had an IMI by SAU or SSLO, and controls were randomly chosen from cows without an IMI by these microorganisms. One teat apex sample from the week prior to IMI diagnosis was aerobically cultured. Taxonomy of recovered isolates was confirmed using mass spectrometry and whole genome sequencing. The inhibitory activity against SAU and SUB was investigated using agar dilution methods. Isolates were ranked based on in vitro inhibitory activity against SAU and SUB and categorized as “top 10” with the lowest minimum inhibitory concentration or not. The presence of NASM isolates classified as “top 10” against SAU was highest in controls (19.4%) compared to cases (5.8%). No difference in NASM counts on teat apex was observed between cases and controls. The inhibitory activity varied across NASM, withStaphylococcus succinusshowing the highest inhibitory activity against both SAU and SUB.
Synaptic plasticity in human thalamocortical assembloids
Authors: Patton Mary H. , Thomas Kristen T. , Bayazitov Ildar T. , Newman Kyle D. , Kurtz Nathaniel B. , Robinson Camenzind G. , Ramirez Cody A. , Trevisan Alexandra J. , Bikoff Jay B. , Peters Samuel T. , Pruett-Miller Shondra M. , Jiang Yanbo , Schild Andrew B. , Nityanandam Anjana , Zakharenko Stanislav S. 
Published: February 2024

SUMMARYSynaptic plasticities, such as long-term potentiation (LTP) and depression (LTD), tune synaptic efficacy and are essential for learning and memory. Current studies of synaptic plasticity in humans are limited by a lack of adequate human models. Here, we modeled the thalamocortical system by fusing human induced pluripotent stem cell–derived thalamic and cortical organoids. Single-nucleus RNA-sequencing revealed that most cells in mature thalamic organoids were glutamatergic neurons. When fused to form thalamocortical assembloids, thalamic and cortical organoids formed reciprocal long-range axonal projections and reciprocal synapses detectable by light and electron microscopy, respectively. Using whole-cell patch-clamp electrophysiology and two-photon imaging, we characterized glutamatergic synaptic transmission. Thalamocortical and corticothalamic synapses displayed short-term plasticity analogous to that in animal models. LTP and LTD were reliably induced at both synapses; however, their mechanisms differed from those previously described in rodents. Thus, thalamocortical assembloids provide a model system for exploring synaptic plasticity in human circuits.HighlightsHuman thalamic organoids consist of mostly glutamatergic projection neurons.Thalamocortical assembloids form reciprocal glutamatergic synapses.Synapses are functional and undergo short-term plasticity resembling animal models.Long-term potentiation and depression reveal mechanisms distinct from rodents.eTOCHuman organoids are often used to model diseases with synaptic pathology; however, few studies have examined synaptic function via single-cell or single-synapse recordings. Patton et al. fused human thalamic and cortical organoids into assembloids to examine synaptic transmission and short- and long-term synaptic plasticity in human thalamocortical and corticothalamic circuits.GRAPHICAL ABSTRACT
Clostridioides difficile-mucus interactions encompass shifts in gene expression, metabolism, and biofilm formation
Authors: Furtado Kathleen L. , Plott Lucas , Markovetz Matthew , Powers Deborah , Wang Hao , Hill David B. , Papin Jason , Allbritton Nancy L. , Tamayo Rita 
Published: February 2024

ABSTRACTIn a healthy colon, the stratified mucus layer serves as a crucial innate immune barrier to protect the epithelium from microbes. Mucins are complex glycoproteins that serve as a nutrient source for resident microflora and can be exploited by pathogens. We aimed to understand how the intestinal pathogen,Clostridioides diffiicile, independently uses or manipulates mucus to its benefit, without contributions from members of the microbiota. Using a 2-D primary human intestinal epithelial cell model to generate physiologic mucus, we assessedC. difficile-mucus interactions through growth assays, RNA-Seq, biophysical characterization of mucus, and contextualized metabolic modeling. We found that host-derived mucus promotesC. difficilegrowth bothin vitroand in an infection model. RNA-Seq revealed significant upregulation of genes related to central metabolism in response to mucus, including genes involved in sugar uptake, the Wood-Ljungdahl pathway, and the glycine cleavage system. In addition, we identified differential expression of genes related to sensing and transcriptional control. Analysis of mutants with deletions in highly upregulated genes reflected the complexity ofC. difficile-mucus interactions, with potential interplay between sensing and growth. Mucus also stimulated biofilm formationin vitro, which may in turn alter viscoelastic properties of mucus. Context-specific metabolic modeling confirmed differential metabolism and predicted importance of enzymes related to serine and glycine catabolism with mucus. Subsequent growth experiments supported these findings, indicating mucus is an important source of serine. Our results better define responses ofC. difficileto human gastrointestinal mucus and highlight a flexibility in metabolism that may influence pathogenesis.IMPORTANCEClostridioides difficileresults in upwards of 250,000 infections and 12,000 deaths annually in the United States. Community-acquired infections continue to rise and recurrent disease is common, emphasizing a vital need to understandC. difficilepathogenesis.C. difficileundoubtedly interacts with colonic mucus, but the extent to which the pathogen can independently respond to and take advantage of this niche has not been explored extensively. Moreover, the metabolic complexity ofC. difficileremains poorly understood, but likely impacts its capacity to grow and persist in the host. Here, we demonstrate thatC. difficileuses native colonic mucus for growth, indicatingC. difficilepossesses mechanisms to exploit the mucosal niche. Furthermore, mucus induces metabolic shifts and biofilm formation inC. difficile, which has potential ramifications for intestinal colonization. Overall, our work is crucial to better understand dynamics ofC. difficile-mucus interactions in the context of the human gut.