bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Silico Identification of Potential Inhibitors of Mycobacterium tuberculosis DNA Gyrase from Phytoconstituents of Indian Medicinal Plants
Authors: Rout Janmejaya , Das Sayani , Kaledhonkar Sandip 
Published: June 2024

AbstractDNA gyrase, the sole type-II topoisomerase inMycobacterium tuberculosis, plays a significant role in the bacteria’s survival by catalyzing the DNA topology change and is considered a crucial drug target. The emergence of drug resistance inMycobacterium tuberculosisspecifically against the second line of drugs; fluoroquinolones, targeting DNA gyrase, demands new potential compounds that would efficiently interact with it. To find a common suitable inhibitor for the apo and mutated forms of DNA gyrase, in this study, the compounds from an Indian medicinal plant database were screened for selecting potential drug-like molecules and two compounds IM5 and IM7 were selected after successful virtual screening and hit optimization with ADMET predictions, and chosen for MD simulation. The MMPBSA analysis of binding free energy validates the docking results of the two molecules. The principal component analysis also supported the stability of the complexes and thus, these two molecules have turned out to be promising candidates againstMycobacterium tuberculosis. Overall, this work sheds light on the potential of DNA gyrase inhibitors as therapeutic agents forMycobacterium tuberculosistreatment, and IM5 and IM7 showed promise as future research compounds.
LRRK2G2019S variant is associated with transcriptional changes in Parkinson’s disease human myeloid cells under proinflammatory environment
Authors: Navarro Elisa , Efthymiou Anastasia G. , Parks Madison , Riboldi Giulietta M , Vialle Ricardo A. , Udine Evan , Muller Benjamin Z. , Humphrey Jack , Allan Amanda , Argyrou Charlie Charalambos , Lopes Katia de Paiva , Münch Alexandra , Raymond Deborah , Sachdev Rivka , Shanker Vicki L. , Miravite Joan , Katsnelson Viktoryia , Leaver Katherine , Frucht Steve , Bressman Susan B , Marcora Edoardo , Saunders-Pullman Rachel , Goate Alison , Raj Towfique 
Published: June 2024

AbstractThe G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is a major risk factor for the development of Parkinson’s disease (PD). LRRK2, although ubiquitously expressed, is highly abundant in cells of the innate immune system. Given the importance of central and peripheral immune cells in the development of PD, we sought to investigate the consequences of the G2019S mutation on microglial and monocyte transcriptome and function. We have generated large-scale transcriptomic profiles of isogenic human induced microglial cells (iMGLs) and patient derived monocytes carrying the G2019S mutation under baseline culture conditions and following exposure to the proinflammatory factors IFNγ and LPS. We demonstrate that the G2019S mutation exerts a profound impact on the transcriptomic profile of these myeloid cells, and describe corresponding functional differences in iMGLs. The G2019S mutation led to an upregulation in lipid metabolism and phagolysosomal pathway genes in untreated and LPS/IFNγ stimulated iMGLs, which was accompanied by an increased phagocytic capacity of myelin debris. We also identified dysregulation of cell cycle genes, with a downregulation of the E2F4 regulon. Transcriptomic characterization of human-derived monocytes carrying the G2019S mutation confirmed alteration in lipid metabolism associated genes. Altogether, these findings reveal the influence of G2019S on the dysregulation of the myeloid cell transcriptome under proinflammatory conditions.
Evidence for domain-general arousal from semantic and neuroimaging meta-analyses reconciles opposing views on arousal
Authors: Sabat Magdalena , de Dampierre Charles , Tallon-Baudry Catherine 
Published: June 2024

AbstractThe term arousal is very often used, but classical textbooks from different domains of neuroscience and psychology offer surprisingly different views on what arousal is. The huge number of scientific articles with the term arousal (∼50.000) highlights the importance of the concept but also explains why such a vast literature has never been systematically reviewed so far. Here, we leverage the tools of natural language processing to probe the nature of arousal in a data-driven, comprehensive manner. We show that arousal comes in seven varieties: cognitive, emotional, physiological, sexual, related to stress disorders, to sleep, or to sleep disorders. We then ask whether domain-general arousal exists, and run meta-analyses of the brain imaging literature to reveal that all varieties of arousal, except arousal in sleep disorders for lack of data, converge onto a cortical arousal network composed of the pre-supplementary motor area and the left and right dorsal anterior insula. More precisely, we find that activity in dysgranular insular area 7, the region with the highest convergence across varieties of arousal is also specific to arousal. Our results show that arousal corresponds to a construct at least partially shared across different domains of neuroscience and identify the domain-general cortical arousal network. Novel taxonomies of arousal reconciling seemingly opposing views on what arousal is should thus include domain-general arousal as a central component.Significance statementThe term arousal has been used in almost 50.000 scientific papers, but it is only loosely defined. The few attempts at defining arousal in neuroscience and psychology resulted in divergent views: arousal as a multi-dimensional construct or arousal as a global state. Is arousal an abstraction of the scientists’ mind reflecting a myriad of distinct processes, or is there some common neuronal feature? We used large-scale semi-automatic text mining methods and neuroimaging meta-analyses to review this vast and heterogeneous literature. Our results reveal the existence of domain-general arousal, a process shared by situations as different as a cognitive task, an emotional context, and the transition to wakefulness or sexual behavior. Domain-general arousal reconciles the concepts of general and multi-dimensional arousal.
Development and assessment of a new multichannel electrocutaneous device for non-invasive somatosensory stimulation for magnetic resonance applications
Authors: Travassos Carolina , Sayal Alexandre , Fonte Paulo , Carolino Nuno , Direito Bruno , Lopes Luis , Afonso Sonia , Lopes Tania , Sousa Teresa , Castelo-Branco Miguel 
Published: June 2024

AbstractElectrocutaneous stimulation (ES) relies on the application of an electrical current flowing through the surface of the skin, eliciting a tactile percept. It can be applied for somatosensory mapping approaches at functional magnetic resonance imaging (fMRI) to obtain somatotopic maps illustrating the spatial patterns reflecting the functional organization of the primary somatosensory cortex (S1). However, its accessibility remains constrained, particularly in applications requiring multiple stimulation channels. Furthermore, the magnetic resonance (MR) environment poses several limitations in this regard. This study presents a prototype of a multichannel electrocutaneous stimulation device designed for somatosensory stimulation of the upper limbs of human participants in an MR environment in an inexpensive, safe, customizable, controlled, reproducible, and automated way. Our current-controlled, voltage-limited, stimulation device comprises 20 stimulation channels that can be individually configured to deliver various non-simultaneous combinations of personalized electrical pulses, depending on the subject, stimulation site, and stimulation paradigm. It can deliver a predefined electrical stimulus during fMRI acquisition, synchronized with the stimulation task design and triggered upon initiation of the acquisition sequence. Regarding device assessment, we conducted tests using an electrical circuit equivalent to the impedance of the human body and the electrode-skin interface to validate its feasibility. Then, we evaluated user acceptability by testing the device in human participants. Considering the stringent conditions of the MR environment, we performed a comprehensive set of safety and compatibility evaluations using a phantom. Lastly, we acquired structural and functional MR data from a participant during a somatosensory stimulation experiment to validate brain activity elicited by electric stimulation with our device. These assessments confirmed the device’s safety in fMRI studies and its ability to elicit brain activity in the expected brain areas. The scope of application of our device includes fMRI studies focused on somatosensory mapping and brain-computer interfaces related to somatosensory feedback.
Vascular regional analysis unveils differential responses to anti-angiogenic therapy in pancreatic xenografts through macroscopic photoacoustic imaging
Authors: Sweeney Allison , Xavierselvan Marvin , Langley Andrew , Solomon Patrick , Arora Aayush , Mallidi Srivalleesha 
Published: June 2024

ABSTRACTPancreatic cancer (PC) is a highly lethal malignancy and the third leading cause of cancer deaths in the U.S. Despite major innovations in imaging technologies, there are limited surrogate radiographic indicators to aid in therapy planning and monitoring. Amongst the various imaging techniques Ultrasound-guided photoacoustic imaging (US-PAI) is a promising modality based on endogenous blood (hemoglobin) and blood oxygen saturation (StO2) contrast to monitor response to anti-angiogenic therapies. Adaptation of US-PAI to the clinical realm requires macroscopic configurations for adequate depth visualization, illuminating the need for surrogate radiographic markers, including the tumoral microvessel density (MVD). In this work, subcutaneous xenografts with PC cell lines AsPC-1 and MIA-PaCa-2 were used to investigate the effects of receptor tyrosine kinase inhibitor (sunitinib) treatment on MVD and StO2. Through histological correlation, we have shown that regions of high and low vascular density (HVD and LVD) can be identified through frequency domain filtering of macroscopic PA images which could not be garnered from purely global analysis. We utilized vascular regional analysis (VRA) of treatment-induced StO2and total hemoglobin (HbT) changes. VRA as a tool to monitor treatment response allowed us to identify potential timepoints of vascular remodeling, highlighting its ability to provide insights into the TME not only for sunitinib treatment but also other anti-angiogenic therapies.
Multi-omics profiling of mouse polycystic kidney disease progression at a single cell resolution
Authors: Muto Yoshiharu , Yoshimura Yasuhiro , Wu Haojia , Chang-Panesso Monica , Ledru Nicolas , Woodward Owen M. , Outeda Patricia , Cheng Tao , Mahjoub Moe R. , Watnick Terry J. , Humphreys Benjamin D. 
Published: June 2024

AbstractAutosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to end-stage kidney disease. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single nucleus multimodal atlas of an orthologous mouse PKD model at early, mid and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalogue differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses toPkd1deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution.
Structural determinants of protein kinase A essential for CFTR channel activation
Authors: Mihályi Csaba , Iordanov Iordan , Szöllősi András , Csanády László 
Published: June 2024

AbstractCFTR, the anion channel mutated in cystic fibrosis (CF) patients, is activated by the catalytic subunit of protein kinase A (PKA-C). PKA-C activates CFTR both reversibly, through binding, and irreversibly, through phosphorylation of multiple serines in CFTR’s regulatory (R) domain. Here we identify key molecular determinants of the CFTR/PKA-C interaction essential for these processes. By comparing CFTR current activation in the presence of ATP or an ATP analog unsuitable for phosphotransfer, as well as pseudosubstrate peptides of various lengths, we identify two distinct specific regions of the PKA-C surface which interact with CFTR to cause reversible and irreversible CFTR stimulation, respectively. Whereas the “substrate site” mediates CFTR phosphorylation, a distinct hydrophobic patch (the “docking site”) is responsible for reversible CFTR activation, achieved by stabilizing the R domain in a “released” conformation permissive to channel gating. Furthermore, by comparing PKA-C variants with different posttranslational modification patterns we find that direct membrane tethering of the kinase through its N-terminal myristoyl group is an unappreciated fundamental requirement for CFTR activation: PKA-C demyristoylation abolishes reversible, and profoundly slows irreversible, CFTR stimulation. For the F508del CFTR mutant, present in ∼90% of CF patients, maximal activation by de-myristoylated PKA-C is reduced by ∼10-fold compared to that by myristoylated PKA-C. Finally, in bacterial genera that contain common CF pathogens we identify virulence factors that demyristoylate PKA-Cin vitro, raising the possibility that during recurrent bacterial infections in CF patients PKA-C demyristoylation may contribute to the exacerbation of lung disease.Significance StatementCFTR is an anion channel crucial for salt-water transport across epithelia, and is activated by the catalytic subunit of protein kinase A (PKA-C). Reduced activity of mutant CFTR causes cystic fibrosis and CFTR hyperstimulation by sustained PKA-C activity causes diarrhea. PKA-C activates CFTR reversibly through simple binding, and irreversibly by phosphorylating the channel. We uncover here important structural requirements for these two processes. First, two distinct PKA-C surface areas mediate reversible and irreversible CFTR activation. Second, membrane anchoring of PKA-C through a covalently linked fatty (myristic) acid is required for both effects. Finally, we identify bacterial enzymes that cleave the myristic acid from PKA-C, thereby reducing activation of mutant CFTR channels, present in cystic fibrosis patients, by up to tenfold.
Cognitive reserves hold back age-related upregulation of neural activities in speech-in-noise perception
Authors: Zhang Lei , Ross Bernhard , Du Yi , Alain Claude 
Published: June 2024

AbstractDuring cognitive tasks, increased frontoparietal neural activity and functional connectivity are commonly observed in older adults. Cognitive reserves accrued from positive life choices can provide additional neural resources to cope with aging. However, how cognitive reserves interact with upregulated neural activity in older adults is poorly understood. We measured brain activity with fMRI during a speech-in-noise task and assessed whether cognitive reserve accumulated from long-term musical training bolsters or holds back age-related upregulated activity. Older musicians exhibited less upregulation of task-induced functional connectivity than older non-musicians in auditory dorsal regions, which predicted better behavioral performance in older musicians. These results suggest that cognitive reserve may hold back neural recruitment. Besides functional connectivity strength, we also found that older musicians showed more youth-like fine spatial patterns of functional connectivity than older non-musicians. Our findings enlightened the intricate interplay between cognitive reserve and age-related upregulated activity during speech in noise perception.Significance StatementUnderstanding the interplay between cognitive reserve and age-related neural changes is vital for developing strategies to mitigate cognitive decline in older adults. This study reveals that long-term musical training, which provides cognitive reserve for speech perception, helps older musicians preserve youth-like levels of functional connectivity and fine-scale activity patterns in the auditory dorsal stream during speech-in-noise perception. Unlike older non-musicians, who exhibit age-related neural upregulation, older musicians maintain youth-like connectivity patterns akin to those of younger adults, resulting in superior speech-in-noise perception. These findings support the “Hold-back upregulation” hypothesis and suggest that musical training counteracts age-related declines by preserving youthful brain function. The results offer valuable insights for designing interventions to enhance aging populations’ cognitive function and communication abilities.
The 11β-hydroxysteroid dehydrogenase type 1 inhibitor SPI-62 prevents morbidity in a mouse model of Cushing’s syndrome
Authors: Pan Xingyu , Hou Qiongqiong , Su Jing , Xu Jiahui , Li Min , Li Jiawen , Shi Xuerou , Schmicker Caleb , Magers Tobias , Bracken William M , Katz David A. 
Published: June 2024

Abstract11β-hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitors represent a potential therapeutic approach for patients with Cushing’s syndrome, autonomous cortisol secretion (ACS), or iatrogenic glucocorticoid (GC) excess. We assessed whether the HSD-1 inhibitor SPI-62 prevents GC-associated morbidity in a mouse Cushing’s syndrome model. Corticosterone (CORT) was administered to mice for 5 weeks. Animals who received CORT were randomized between vehicle and 3 SPI-62 regimens. A control group received neither CORT nor SPI-62. Body weight was measured daily to enable weight-based SPI-62 administration. Food consumption by pair-housed animals was reported weekly. Insulin sensitivity was evaluated by fasting homeostatic model assessment of insulin resistance. Adiposity and skeletal myopathy were measured using magnetic resonance imaging and post-mortem weights of fat depots and skeletal muscles. Grip strength was measured with a digital meter. Ambulation behavior in an open field maze was assessed. Post-mortem dermal thickness was quantified. Skin structure was evaluated by histology. CORT was associated with decreased insulin sensitivity, increased adiposity, skeletal myoatrophy, reduced grip strength, decreased dermal thickness, and skin structural changes. A trend of increased food consumption and an unexpected biphasic weight change were observed with CORT. SPI-62 attenuated all observed adverse effects in a dose-dependent manner. In general, results for the high SPI-62 regimen were similar as those in animals who received no CORT, suggesting that full HSD-1 inhibition should be maintained throughout a dose interval to mitigate the effects of glucocorticoid excess.
It only takes seconds for a human monoclonal autoantibody to inhibit N-methyl-D-aspartate receptors
Authors: Yang Shang , Heckmann Johanna , Taha Abdulla , Gao Shiqiang , Steinke Stephan , Hust Michael , Prüß Harald , Furukawa Hiro , Geis Christian , Heckmann Manfred , Yu-Strzelczyk Jing 
Published: June 2024

AbstractTransfer of autoantibodies targeting ionotropic N-methyl-D-aspartate receptors in autoimmune encephalitis patients into mice leads to typical disease signs. Long-term effects of the pathogenic antibodies consist of immunoglobulin G-induced crosslinking and receptor internalization. We focused on the direct and immediate impact of a specific pathogenic patient-derived monoclonal autoantibody (immunoglobulin G #003-102) on receptor function.We performed cell-attached recordings in cells transfected with the GluN1 and GluN2A subunit of the N-methyl-D-aspartate receptor. Immunoglobulin G #003-102 binds to the amino-terminal domain of the glycine-binding GluN1 subunit. It reduced simultaneous receptor openings significantly compared to controls at both low and high glutamate and glycine concentrations. Closer examination of our data in 50-second to 2-second intervals revealed, that Immunoglobulin G #003-102 rapidly decreases the number of open receptors. However, antigen-binding fragments of immunoglobulin G #003-102 did not reduce the receptor openings.In conclusion, patient-derived immunoglobulin G #003-102 inhibits N-methyl-D-aspartate receptors rapidly and directly before receptor internalization occurs and the entire immunoglobulin G is necessary for this acute inhibitory effect. This suggests an application of the antigen-binding fragment-like constructs of #003-102 as a potential new treatment strategy for shielding the pathogenic epitopes on the N-methyl-D-aspartate receptors.
The correct temporal connectivity of the DG-CA3 circuits involved in declarative memory processes depends on Vangl2-dependent planar cell polarity signaling
Authors: Depret Noémie , Gleizes Marie , Moreau Maïté Marie , Poirault-Chassac Sonia , Quiedeville Anne , Dos Santos Carvalho Steve , Venugopal Vasika , Al Abed Alice Shaam , Barthet Gael , Mulle Christophe , Desmedt Aline , Marighetto Aline , Racca Claudia , Montcouquiol Mireille , Sans Nathalie 
Published: June 2024

SummaryIn the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal cells via their axons, the mossy fibers (Mf). The synaptic terminals of Mfs (Mf boutons, MfBs) form large and complex synapses with thorny excrescences (TE) on the proximal dendrites CA3 pyramidal cells (PCs). MfB/TE synapses have distinctive “detonator” properties due to low intitial release probability and large presynaptic facilitation. The molecular mechanisms shaping the morpho-functional properties of MfB/TE synapses are still poorly understood, though alterations in their morphology are associated with Down syndrome, intellectual disabilities, and Alzheimer’s disease. Here, we identify the core PCP geneVangl2as essential to the morphogenesis and function of MfB/TE synapses. Vangl2 colocalises with the presynaptic heparan sulfate proteoglycan glypican 4 (GPC4) to stabilise the postsynaptic orphan receptor GPR158. Embryonic loss of Vangl2 disrupts the morphology of MfBs and TEs, impairs ultrastructural and molecular organisation, resulting in defective synaptic transmission and plasticity. In adult, the early loss of Vangl2 results in a number of hippocampus-dependent memory deficits including characteristic flexibility of declarative memory, organisation and retention of working/ everyday-like memory. These deficits also lead to abnormal generalisation of memories to salient cues and diminished ability to form detailed contextual memories. Together, these results establish Vangl2 as a key regulator of DG-CA3 connectivity and functions.HighlightsVangl2 is a key regulator of MfB/TE synapses morphogenesis and plasticity in CA3Vangl2-mediated GPC4-GPR158 interaction maintains MfB-TE pre-synaptic morphology and functionVangl2deletion affects declarative memory in adult miceVangl2 function is necessary for contextual learning and its loss leads toa maladaptive fear memory for salient cues