bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlated signatures of social behavior in cerebellum and anterior cingulate cortex
Authors: Hur Sung Won , Safaryan Karen , Yang Long , Blair Hugh T , Masmanidis Sotiris C , Mathews Paul J , Aharoni Daniel , Golshani Peyman 
Published: April 2023

AbstractThe cerebellum has been implicated in the regulation of social behavior. Its influence is thought to arise from communication, via the thalamus, to forebrain regions integral in the expression of social interactions, including the anterior cingulate cortex (ACC). However, the signals encoded or the nature of the communication between the cerebellum and these brain regions is poorly understood. Here, we describe an approach that overcomes technical challenges in exploring the coordination of distant brain regions at high temporal and spatial resolution during social behavior. We developed the E-Scope, an electrophysiology-integrated miniature microscope, to synchronously measure extracellular electrical activity in the cerebellum along with calcium imaging of the ACC. This single coaxial cable device combined these data streams to provide a powerful tool to monitor the activity of distant brain regions in freely behaving animals. During social behavior, we recorded the spike timing of multiple single units in cerebellar right Crus I (RCrus I) Purkinje cells (PCs) or dentate nucleus (DN) neurons while synchronously imaging calcium transients in contralateral ACC neurons. We found that during social interactions a significant subpopulation of cerebellar PCs were robustly inhibited, while most modulated neurons in the DN were activated, and their activity was correlated with positively modulated ACC neurons. These distinctions largely disappeared when only non-social epochs were analyzed suggesting that cerebellar-cortical interactions were behaviorally specific. Our work provides new insights into the complexity of cerebellar activation and co-modulation of the ACC during social behavior and a valuable open-source tool for simultaneous, multimodal recordings in freely behaving mice.
Ziqi Dihuang decoction ameliorates thrombosis in septic rats by inhitbiting plasminogen activator inhibitor-1
Authors: Geng YanXia , Fei ShuYe , Pei YingHao , Chen QiuHua , Wang Jian , Jiang Hua 
Published: April 2023

AbstractBackground and AimSepsis is now a global medical burden with high morbility and mortality. The focus of this study was to observe and elaborate the effect of Ziqi Dihuang (ZQDH) decoction on inflammatory and thrombosis-related parameters in septic rats.Experimental procedureA rat model of sepsis was established by cecal ligation and puncture (CLP). 24 male Sprague-Dawley (SD) rats were randomly divided into Sham group, CLP group, ZQDH-1ow group (0.735g/kg) and ZQDH-high group (1.47g/kg). Rats in ZQDH groups were given ZQDH decoction by gavage for 7 days before CLP, while rats in Sham and CLP groups were given the same amount of normal saline. Leukocytes and percentage of neutrophils (N %) in blood, and inflammatory cell infiltration of liver, kidney and lung were used to assess systemic inflammatory response. Coagulation and fibrinolytic indexes included platelet count, coagulation function, fibrin deposition, and levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in serum, liver, kidney and lung.ResultsZQDH decoctioninhibited N% growth in blood and inflammatory cell infiltration in the lung of CLP rats. Moreover, ZQDH decoctionalso ameliorated thrombocytopenia and prothrombin time, alleviated renal fibrin deposition, and improved tPA and PAI-1 levels in kidney.ConclusionThese results suggest that ZQDH decoction can dose-dependently relieve systemic inflammatory injury and regulate coagulation-fibrinolysis system in septic rats, which may be mediated by PAI-1.Highlights of the findings and noveltiesZQDH decoction relieves systemic inflammatory injury in sepsis;ZQDH decoction regulates coagulation-fibrinolysis system in sepsis;ZQDH decoction inhibits fibrinolysis by reducing inhibitor-1 (PAI-1) level in sepsis.
Metagenome mining and functional analysis reveal oxidized guanine DNA repair at the Lost City Hydrothermal Field
Authors: Utzman Payton H. , Mays Vincent P. , Miller Briggs C. , Fairbanks Mary C. , Brazelton William J. , Horvath Martin P. 
Published: April 2023

AbstractThe GO DNA repair system protects against GC → TA mutations by finding and removing oxidized guanine. The system is mechanistically well understood but its origins are unknown. We searched metagenomes and abundantly found the genes encoding GO DNA repair at the Lost City Hydrothermal Field (LCHF). We recombinantly expressed the final enzyme in the system to show MutY homologs function to suppress mutations. Microbes at the LCHF thrive without sunlight, fueled by the products of geochemical transformations of seafloor rocks, under conditions believed to resemble a young Earth. High levels of the reductant H2and low levels of O2in this environment raise the question, why are resident microbes equipped to repair damage caused by oxidative stress? MutY genes could be assigned to metagenome assembled genomes (MAGs), and thereby associate GO DNA repair with metabolic pathways that generate reactive oxygen, nitrogen and sulfur species. Our results indicate that cell-based life was under evolutionary pressure to cope with oxidized guanine well before O2levels rose following the great oxidation event.
Control of working memory maintenance by theta-gamma phase amplitude coupling of human hippocampal neurons
Authors: Daume Jonathan , Kaminski Jan , Schjetnan Andrea G. P. , Salimpour Yousef , Khan Umais , Reed Chrystal , Anderson William , Valiante Taufik A. , Mamelak Adam N. , Rutishauser Ueli 
Published: April 2023

AbstractRetaining information in working memory (WM) is a demanding process that relies on cognitive control to protect memoranda-specific persistent activity from interference. How cognitive control regulates WM storage, however, remains unknown. We hypothesized that interactions of frontal control and hippocampal persistent activity are coordinated by theta-gamma phase amplitude coupling (TG-PAC). We recorded single neurons in the human medial temporal and frontal lobe while patients maintained multiple items in WM. In the hippocampus, TG-PAC was indicative of WM load and quality. We identified cells that selectively spiked during nonlinear interactions of theta phase and gamma amplitude. These PAC neurons were more strongly coordinated with frontal theta activity when cognitive control demand was high, and they introduced information-enhancing and behaviorally relevant noise correlations with persistently active neurons in the hippocampus. We show that TG-PAC integrates cognitive control and WM storage to improve the fidelity of WM representations and facilitate behavior.
Applications of Boolean modeling to study the dynamics of a complex disease and therapeutics responses
Authors: Hemedan Ahmed Abdelmonem , Schneider Reinhard , Ostaszewski Marek 
Published: April 2023

ABSTRACTComputational modeling has emerged as a critical tool in investigating the complex molecular processes involved in biological systems and diseases. In this study, we apply Boolean modeling to uncover the molecular mechanisms underlying Parkinson’s disease (PD), one of the most prevalent neurodegenerative disorders. Our approach is based on the PD-map, a comprehensive molecular interaction diagram that captures the key mechanisms involved in the initiation and progression of PD. Using Boolean modeling, we aim to gain a deeper understanding of the disease dynamics, identify potential drug targets, and simulate the response to treatments. Our analysis demonstrates the effectiveness of this approach in uncovering the intricacies of PD. Our results confirm existing knowledge about the disease and provide valuable insights into the underlying mechanisms, ultimately suggesting potential targets for therapeutic intervention. Moreover, our approach allows us to parametrize the models based on omics data for further disease stratification. Our study highlight the value of computational modeling in advancing our understanding of complex biological systems and diseases, emphasizing the importance of continued research in this field. Furthermore, our findings have potential implications for the development of novel therapies for PD, which is a pressing public health concern. Overall, this study represents a significant step forward in the application of computational modeling to the investigation of neurodegenerative diseases, and underscores the power of interdisciplinary approaches in tackling challenging biomedical problems.
Development of subunit selective substrates forTrichomonas vaginalisproteasome
Authors: Fajtova Pavla , Hurysz Brianna M , Miyamoto Yukiko , Serafim Mateus , Jiang Zhenze , Trujillo Diego F. , Liu Lawrence , Somani Urvashi , Almaliti Jehad , Myers Samuel A. , Caffrey Conor R. , Gerwick William H. , Kirk Christopher J , Boura Evzen , Eckmann Lars , O’Donoghue Anthony J 
Published: April 2023

ABSTRACTThe protozoan parasite,Trichomonas vaginalis(Tv) causes trichomoniasis, the most common, non-viral, sexually transmitted infection in the world. Only two closely related drugs are approved for its treatment. The accelerating emergence of resistance to these drugs and lack of alternative treatment options poses an increasing threat to public health. There is an urgent need for novel effective anti-parasitic compounds. The proteasome is a critical enzyme forT. vaginalissurvival and was validated as a drug target to treat trichomoniasis. However, to develop potent inhibitors of theT. vaginalisproteasome, it is essential that we understand which subunits should be targeted. Previously, we identified two fluorogenic substrates that were cleaved byT. vaginalisproteasome, however after isolating the enzyme complex and performing an in-depth substrate specificity study, we have now designed three fluorogenic reporter substrates that are each specific for one catalytic subunit. We screened a library of peptide epoxyketone inhibitors against the live parasite and evaluated which subunits are targeted by the top hits. Together we show that targeting of the β5 subunit ofT. vaginalisis sufficient to kill the parasite, however, targeting of β5 plus either β1 or β2 results in improved potency.
Methionine aminopeptidase 2 and its autoproteolysis product have different binding sites on the ribosome
Authors: Klein Marius A. , Wild Klemens , Kišonaitė Miglė , Sinning Irmgard 
Published: April 2023

AbstractExcision of the initiator methionine is among the first co-translational processes that occur at the ribosome. While this crucial step in protein maturation is executed by two types of methionine aminopeptidases in eukaryotes (MAP1 and MAP2), additional roles in disease and translational regulation have drawn more attention to MAP2. Here, we report several cryo-EM structures of MAP2 at the 80S-ribosome. The MAP2 interaction is highly robust but can be perturbed by emerging nascent chains, which induce an adaptive tilting of the enzyme. In rotation, the MAP2-specific N-terminal extension engages in stabilizing interactions with the long rRNA expansion segment ES27L. Loss of this extension by autoproteolytic cleavage impedes the tunnel interaction, while promoting MAP2 to enter the ribosomal A-site, where it engages with crucial functional centers of translation. These findings reveal that proteolytic remodeling of MAP2 severely affects ribosome binding, and set the stage for targeted functional studies.
The bloodstream form ofTrypanosoma bruceidisplays non-canonical gluconeogenesis
Authors: Kovářová Julie , Moos Martin , Barrett Michael P. , Horn David , Zíková Alena 
Published: April 2023

AbstractTrypanosoma bruceiis a causative agent of the Human and Animal African Trypanosomiases. The mammalian stage parasites infect various tissues and organs including the bloodstream, central nervous system, skin, adipose tissue and lungs. They rely on ATP produced in glycolysis, consuming large amounts of glucose, which is readily available in the mammalian host. In addition to glucose, glycerol can also be used as a source of carbon and ATP and as a substrate for gluconeogenesis. However, the physiological relevance of glycerol-fed gluconeogenesis for the mammalian-infective life cycle forms remains elusive. To demonstrate its (in)dispensability, first we must identify the enzyme(s) of the pathway. Loss of the canonical gluconeogenic enzyme, fructose-1,6-bisphosphatase, does not abolish the process hence at least one other enzyme must participate in gluconeogenesis in trypanosomes. Using a combination of CRISPR/Cas9 gene editing and RNA interference, we generated mutants for four enzymes potentially capable of contributing to gluconeogenesis: fructose-1,6-bisphoshatase, sedoheptulose-1,7-bisphosphatase, phosphofructokinase and transaldolase, alone or in various combinations. Metabolomic analyses revealed that flux through gluconeogenesis was maintained irrespective of which of these genes were lost. Our data render unlikely a previously hypothesised role of a reverse phosphofructokinase reaction in gluconeogenesis and preclude the participation of a novel biochemical pathway involving transaldolase in the process. The sustained metabolic flux in gluconeogenesis in our mutants, including a triple-null strain, indicates the presence of a unique enzyme participating in gluconeogenesis. Additionally, the data provide new insights into gluconeogenesis and the pentose phosphate pathway, and improve the current understanding of carbon metabolism of the mammalian-infective stages ofT. brucei.Author SummaryTrypanosoma bruceiis a unicellular parasite causing sleeping sickness in humans and nagana disease in cattle. The parasite invades the bloodstream and cerebrospinal fluid and only recently, it has been shown to infect additional tissues such as skin, adipose tissue, or lungs. While the glucose-based metabolism of the bloodstream form is well understood, the parasite’s metabolism in these secondary tissues has not been sufficiently explored, despite its importance for drug development. One possibility is the use of gluconeogenesis since the mammalian-infective stages can use glycerol as a carbon and ATP source. First, enzymes involved in gluconeogenesis have to be identified, then it can be tested if the pathway is advantageous for the survival of the parasite. We generated mutants in four different enzymes potentially involved in this metabolic pathway. Surprisingly, the flux in gluconeogenesis was maintained in all cell lines tested, implying that another non-canonical enzyme participates in the production of glucose from glycerol in these parasites.
Fitness cost associated with cell phenotypic switching drives population diversification dynamics and controllability
Authors: Henrion Lucas , Martinez Juan Andres , Vandenbroucke Vincent , Delvenne Mathéo , Telek Samuel , Zicler Andrew , Grünberger Alexander , Delvigne Frank 
Published: April 2023

AbstractIsogenic cell populations can cope with stress conditions by switching to alternative phenotypes. Even if it can lead to increased fitness in a natural context, this feature is typically unwanted for a range of applications (e.g., bioproduction, synthetic biology, biomedicine…) where it tends to decrease the controllability of the cellular response. However, little is known about the diversification profiles that can be adopted by a cell population. We characterized the diversification dynamics for various systems (bacteria and yeast) and for different phenotypes (utilization of alternative carbon sources, general stress response and more complex development patterns). Interestingly, our results suggest that the diversification dynamics and the fitness cost associated with cell switching are coupled. For quantifying the contribution of the switching cost on population dynamics, we built a stochastic model that allowed us to reproduce the dynamics observed experimentally and identified three diversification regimes, i.e., constrained (at low switching cost), dispersed (at medium and high switching cost), and bursty (for very high switching cost). Furthermore, we used a cell-machine interface that we call the Segregostat to demonstrate that different levels of control can be applied to these diversification regimes, enabling applications involving more precise cellular responses.
Differential Regulation of Retinoic Acid Metabolism in Fanconi Anemia
Authors: Blaize Justin L. , Noori Bahaa M. , Hunter Kelsey P. , Henrikson Kathryn A. , Atoyan Janet A. , Ardito Alan A. , Donovan Frank X. , Chandrasekharappa Settara C. , Schindler Detlev , Howlett Niall G. 
Published: April 2023

ABSTRACTFanconi anemia (FA) is a rare genetic disease characterized by heterogeneous congenital abnormalities and increased risk for bone marrow failure and cancer. FA is caused by mutation of any one of 23 genes, the protein products of which function primarily in the maintenance of genome stability. An important role for the FA proteins in the repair of DNA interstrand crosslinks (ICLs) has been establishedin vitro. While the endogenous sources of ICLs relevant to the pathophysiology of FA have yet to be clearly determined, a role for the FA proteins in a two-tier system for the detoxification of reactive metabolic aldehydes has been established. To discover new metabolic pathways linked to FA, we performed RNA-seq analysis on non-transformed FA-D2 (FANCD2-/-) and FANCD2-complemented patient cells. Multiple genes associated with retinoic acid metabolism and signaling were differentially expressed in FA-D2 (FANCD2-/-) patient cells, includingALDH1A1andRDH10, which encode for retinaldehyde and retinol dehydrogenases, respectively. Increased levels of the ALDH1A1 and RDH10 proteins was confirmed by immunoblotting. FA-D2 (FANCD2-/-) patient cells displayed increased aldehyde dehydrogenase activity compared to the FANCD2-complemented cells. Upon exposure to retinaldehyde, FA-D2 (FANCD2-/-) cells exhibited increased DNA double-strand breaks and checkpoint activation indicative of a defect in the repair of retinaldehyde-induced DNA damage. Our findings describe a novel link between retinoic acid metabolism and FA and identify retinaldehyde as an additional reactive metabolic aldehyde relevant to the pathophysiology of FA.
An experimental comparison of the Digital Spatial Profiling and Visium spatial transcriptomics technologies for cancer research
Authors: Wang Taopeng , Harvey Kate , Reeves John , Roden Daniel L. , Bartonicek Nenad , Yang Jessica , Al-Eryani Ghamdan , Kaczorowski Dominik , Chan Chia-Ling , Powell Joseph , O’Toole Sandra , Lim Elgene , Swarbrick Alexander 
Published: April 2023

AbstractBackgroundSpatial transcriptomic technologies are powerful tools for resolving the spatial heterogeneity of gene expression in tissue samples. However, little evidence exists on relative strengths and weaknesses of the various available technologies for profiling human tumour tissue. In this study, we aimed to provide an objective assessment of two common spatial transcriptomics platforms, 10X Genomics’ Visium and Nanostring’s GeoMx DSP.MethodThe abilities of the DSP and Visium platforms to profile transcriptomic features were compared using matching cell line and primary breast cancer tissue samples. A head-to-head comparison was conducted using data generated from matching samples and synthetic tissue references. Platform specific features were also assessed according to manufacturers’ recommendations to evaluate the optimal usage of the two technologies.ResultsWe identified substantial variations in assay design between the DSP and Visium assays such as transcriptomic coverage and composition of the transcripts detected. When the data was standardised according to manufacturers’ recommendations, the DSP platform was more sensitive in gene expression detection. However, its specificity was diminished by the presence of non-specific detection. Our results also confirmed the strength and weakness of each platform in characterising spatial transcriptomic features of tissue samples, in particular their application to hypothesis generation versus hypothesis testing.ConclusionIn this study, we share our experience on both DSP and Visium technologies as end users. We hope this can guide future users to choose the most suitable platform for their research. In addition, this dataset can be used as an important resource for the development of new analysis tools.
Heather pollen is not necessarily a healthy diet for bumble bees
Authors: Tourbez Clément , Semay Irène , Michel Apolline , Michez Denis , Gerbaux Pascal , Gekière Antoine , Vanderplanck Maryse 
Published: April 2023

ABSTRACTThere is evidence that specialised metabolites of flowering plants occur in both vegetative parts and floral resources (i.e., pollen and nectar), exposing pollinators to their biological activities. While such metabolites may be toxic to bees, it may also help them to deal with environmental stressors. One example is heather nectar which has been shown to limit bumble bee infection by a trypanosomatid parasite,Crithidiasp., because of callunene activity. Besides in nectar, heather harbours high content of specialised metabolites in pollen such as flavonoids but they have been poorly investigated. In this study, we aimed to assess the impact ofCrithidiasp., heather pollen and its flavonoids on bumble bees using non-parasitised and parasitised microcolonies fed either control pollen diet (i.e., willow pollen), heather pollen diet, or flavonoid-supplemented pollen diet. We found that heather pollen and its flavonoids significantly affected microcolonies by decreasing pollen collection as well as offspring production, and by increasing male fat body content while parasite exposure had no significant effect except for an increase in male fat body. We did not highlight any medicinal effect of heather pollen or its flavonoids on parasitised bumble bees. Our results provide insight into the impact of pollen specialised metabolites in heather-bumble bee-parasite interactions. They underline the contrasting roles for bumble bees of the two floral resources and highlight the importance of considering both nectar and pollen when addressing medicinal effects of a plant towards pollinators.
An improved mouse model of sepsis based on intraperitoneal injections of the enriched culture of cecum slurry
Authors: Atre Rajat , Sharma Rahul , Obukhov Alexander G , Saqib Uzma , Umar Sadiq , Darwhekar Gajanan N , Baig Mirza S 
Published: April 2023

AbstractSepsis is a life-threatening clinical syndrome comprising multiorgan dysfunction caused by a disproportionate body immune response to infection that can lead to septic shock and death. The current sepsis model has certain limitations. The gold standard Cecal Ligation and Puncture (CLP) model is known for its high variability owing to the undefined extent of cecum ligation, unstandardized cecal content, and degree of puncture that may vary in different laboratories. Here, we present an improved, efficient intraperitoneal (i.p) injection-based cecal slurry culture method of sepsis. Using this novel approach, we determined the optimal polymicrobial concentration that is sufficient to cause sepsis in mice. We also proposed the enrichment of bacterial culture, allowing the development of either gram-negative or gram-positive bacteria-induced sepsis models. Since those enriched bacterial cultures can be stored in glycerol at −80°C, it gives the ethical advantage of avoiding animal sacrifice for each experiment and experimental reproducibility.