bluuebunny/crossref_metadata_2025_split huggingface dataset:
Astrocytes control UP state and slow oscillation periodicity in human cortical networks
Authors: Crowe James A , Bazzari Amjad H , Nagel David A , Sokolovski Sergei G , Rafailov Edik U , Hill Eric J , Parri Rhein H 
Published: November 2024

AbstractAstrocytes are well known for homeostatic roles in energy maintenance, neurotransmitter recovery and immunoreactivity, however their contributing role in active modulation of neuronal activity remains controversial. Recent evidence highlights astrocytes as a potential signalling partner in ongoing high-order neuronal activity, and a modulator of baseline activity.Here we utilise an iPSC-derived in vitro cortical network model to describe a slow-wave oscillation and examine the contributions of astrocytes to development of this oscillatory activity, dependant upon generation of UP/DOWN state phenomena. To examine the role of astrocytes we invoke an acetylcholinergic oscillation in the neuronal population by addition of carbachol, which proved to be a robust mechanism for eliciting prolonged and synchronised network bursting. Pharmalogical interrogation determined oscillatory maintenance was dependent on both glutamatergic and purinergic signalling pathways. Upon further interrogation, we determined that astrocytic calcium signalling was essential to timing of the oscillatory signal. By utilising chemogenetic actuators we showed that whilst neurons are essential and sufficient for instigating the oscillatory signal, astrocytes played a key role in timing.This previously unreported mechanism may contribute to initial development of brain activity, and may underlie a basal activity present later during adulthood. In collaboration with recent results highlighting the role of active gliotransmission, this highlights astrocytes as an important research target for understanding brain activity alterations during development and disease.
The role of the LysR-type transcription factor PacR in regulating nitrogen metabolism inAnabaenasp. PCC7120
Authors: Werner E. , Huokko T. , Santana-Sanchez A. , Picossi S. , Nikkanen L. , Herrero A. , Allahverdiyeva Y. 
Published: November 2024

AbstractIn the filamentous model cyanobacteriumAnabaenasp. PCC 7120 heterocyst formation is triggered by changes in the C/N-ratio and relies on transcriptional reprogramming in cells. The transcription factor PacR is thought to serve as a global regulator of carbon assimilation under photoautotrophic conditions. In response to Ci-availability, PacR may modulate the carbon concentrating mechanism and photosynthesis, balancing reducing power generation while protecting the photosynthetic apparatus from oxidative damage. However, PacR also binds to promoters of genes associated with heterocyst formation, although the underlying mechanisms remain unclear. To explore this, we studied a response of a PacR-deletion mutant to a nitrogen source shift from ammonium to nitrate. The absence of PacR led to the heterocyst formation in nitrate containing media, as well as reduced growth and chlorophyll-content. We observed impaired nitrate uptake and disrupted ammonium assimilation via the GOGAT-cycle. This phenotype may be exacerbated by reduced PSI-yield and reduced expression of ferredoxin, which may lead to less reducing equivalents for nitrogen assimilation.Our results provide insights into the regulation of heterocyst-formation inAnabaena, potentially advancing its use in biotechnological applications that utilize heterocyst as microoxic cell factories for N2-fixation and hydrogen production.
Acute and early stress axis modulation in joint disease permanently reduces pain and emotional comorbidities
Authors: Hestehave Sara , Florea Roxana , Singleton Samuel , Fedorec Alexander J.H. , Caxaria Sara , Morgan Oakley , Kopp Katharina Tatjana , Brown Laurence A. , Heymann Tim , Sikandar Shafaq , Hausch Felix , Peirson Stuart N. , Géranton Sandrine M. 
Published: November 2024

AbstractChronic secondary musculoskeletal pain affects 20-30% of the population and includes sensory disturbances and emotional comorbidities, such as anxiety and depression, which reduce quality of life. We monitored a pre-clinical model of persistent joint pain for 6 months and found that sensory and functional changes were immediate while anxio-depressive comorbidities appeared from 3 months onwards. Modulating the stress axisviagenetic deletion or pharmacological blockade of the stress driver FKBP51 reduced both sensory and emotional symptoms, including injury-induced disruptions in sleep and activity patterns, and did not worsen joint damage. FKBP51 pharmacological blockade after the establishment of the hypersensitive state provided temporary relief while acute inhibition at disease onset, when sensory and affective responses were most severe, provided at least 6 months of pain relief and reduced or prevented late anxiety- and depressive-like behavior. RNA sequencing suggested that FKBP51 inhibition at disease onset downregulated theNaaagene in the superficial dorsal horn, a key regulator of the transition to chronic pain, and reorganized spinal cilia. Our findings suggest that acute and early, but not late, FKBP51 targeting can offer permanent relief from chronic pain and its emotional effects, highlighting the importance for fast therapeutic intervention.
Complex regulatory interactions atGDF5shape joint morphology and osteoarthritis disease risk
Authors: Coveney Clarissa R. , Maridas David , Chen Hao , Muthuirulan Pushpanathan , Liu Zun , Jagoda Evelyn , Yarlagadda Siddharth , Movahhedi Mohammadreza , Proffen Benedikt , Rosen Vicki , Kiapour Ata M. , Capellini Terence D. 
Published: November 2024

AbstractOur ability to pinpoint causal variants using GWAS is dependent on understanding the dynamic epigenomic and epistatic context of each associated locus. Being the best studied skeletal locus,GDF5associates with many diseases and has a complex cis-regulatory architecture. We interrogateGDF5regulatory interactions and model disease variantsin vitroandin vivo. For all regulatory regions we see that local epigenetic activation/repression impacts patterns of joint-specific expression and disease risk. By modeling the most cited risk variant in mice we found that it had no impact on expression, joint morphology, or disease. Yet, we identified significant epistatic expression interactions between this risk variant and others lying within regulatory regions subject to repression or activation. These findings are important lessons on how regulatory interactions and local epistasis work in the etiology of disease risk, and that assessment of individual variants of high GWAS significance need not alone be considered causal.TeaserGenetic interactions at the most studied skeletal disease locus reveal hidden complexities in pinpointing causal mutations.
Daily electric field treatment improves functional outcomes after thoracic contusion spinal cord injury in rats
Authors: Harland Bruce , Matter Lukas , Lopez Salvador , Fackelmeier Barbara , Hazelgrove Brittany , Meissner Svenja , O’Carroll Simon , Raos Brad , Asplund Maria , Svirskis Darren 
Published: November 2024

AbstractSpinal cord injury (SCI) can result in permanent loss of sensory, motor, and autonomic functions, with limited therapeutic options to recover the loss. Low-frequency electric fields with changing polarity have shown promise in promoting axon regeneration and improving outcomes. However, the metal electrodes used previously were prone to corrosion, and their epidural placement limited the penetration of the electric field into the spinal cord. Here, we demonstrate that a thin-film implant with supercapacitive electrodes placed under the dura mater can safely and effectively deliver electric field treatment in rats with thoracic SCI. Subdural stimulation enhanced hind limb function and touch sensitivity compared to controls, without inducing a neuroinflammatory response in the spinal cord. While axon density around the lesion site remained unchanged after 12 weeks,in vivomonitoring and electrochemical testing of electrodes indicated that treatment was administered throughout the study. These results highlight the promise of electric field treatment as a viable therapeutic strategy for achieving long-term functional recovery in SCI.
Molecular basis underlying specific interaction of mammalian melanopsins with an antagonist AA92593
Authors: Obayashi Kohei , Zou Ruisi , Mori Toshifumi , Tsukamoto Hisao 
Published: November 2024

AbstractMelanopsin functions in intrinsically photosensitive retinal ganglion cells of mammals to regulate circadian clock and pupil constriction. The opsinamide AA92593 has been reported to specifically inhibit mouse and human melanopsin functions as a competitive antagonist against retinal; however, the molecular mechanisms underlying its specificity have not been resolved. In this study, we attempted to identify amino acid residues responsible for the specific interaction of AA92593 with mammalian melanopsins. Our cell-based assays confirmed that AA92593 effectively inhibited the light-induced cellular responses of mammalian melanopsins, but not those of non-mammalian vertebrate and invertebrate melanopsins. These results suggest that amino acid residues specifically conserved among mammalian melanopsins are important for the antagonistic effect of AA92593, and we noticed Phe-94, Ser-188, and Ser-269 as candidate residues. Substitutions of these residues reduced the antagonistic effect of AA92593. We conducted docking and molecular dynamics simulations based on the AlphaFold-predicted melanopsin structure. The simulations indicated that Phe-94, Ser-188, and Ser-269 are located at the AA92593-binding site, and additionally identified Trp-189 and Leu-207 interacting with the antagonist. Substitutions of Trp-189 and Leu-207 affected the antagonistic effect of AA92593. Furthermore, substitutions of these amino acid residues converted AA92593-insensitive melanopsins susceptible to the antagonist. Based on experiments and molecular simulations, five amino acid residues, at positions 94, 188, 189, 207, and 269, were found to be responsible for the specific interaction with AA92593 in mammalian melanopsins.
The Testing of Copper Intrauterine Devices to Mitigate Uterine Infections in Mares: A Preliminary Study
Authors: Gradil Carlos , Jennette Amelia , Becker Klaus , Haire Teresa , Joone Carolynne , Leibstein Miranda , Minter Lisa 
Published: November 2024

AbstractThis preliminary study evaluated the effectiveness of a novel hormone- and drug-free copper intrauterine device POD (CuiUPOD) with one to three copper-coated magnetic units in controllingStreptococcus equi subsp. zooepidemicusin seven intrauterine-inoculated mares. Initially, one unit was inserted into each mare and animals were followed weekly with trans-rectal ultrasonography, blood progesterone assay, uterine swabs for cytology and microbial culture, uterine specimens for biopsy, and trans-abdominal detection of the CuiUPOD using a handheld magnetic detector or a cell phone compass. Infection persisted after a CuiUPOD with one magnetic unit was inserted, but subsided shortly after two additional magnetic units were added. By day 60, at device removal, and after a 30-day exposure to copper, none of the mares presented with clinical signs of infection. On a scale of I-III (I, IIA, IIB, III), with I representing a healthy uterus, endometrial biopsies at the time of CuiUPOD removal, showed improved biopsy scores in two of seven mares (29%;p< 0.05). Thein vivoexperiments, complemented by anin vitroexperiment, demonstrated a time- (24-96 hours) and dose-dependent response to Cu: three CuiUPODs - OD readings = 0.538; two CuiUPODs - OD = 0.513; and one CuiUPOD - OD = 0.452. As the concentration of copper increased, so did the antimicrobial effect. These findings suggest a promising use for the one-time application of a CuiUPOD with two or three magnetic units to mitigate uterine infections in mares.Simple SummaryOnly a limited number of antimicrobials are effective against most resistant bacteria. Several studies have demonstrated the biocidal effect of copper on bacteria, fungi, and viruses. Copper-containing intrauterine devices provide a non-pharmacological solution to prevent and treat uterine infections in equids. This preliminary study provides evidence of the antimicrobial properties of copper both in vivo and in vitro and explores its possible application in mare reproductive practice. A 30-day intrauterine exposure to copper showed no clinical signs of infection with a common bacterium in horses -Streptococcus equi subsp. zooepidemicus- in intrauterine-inoculated mares. As the concentration of copper increased, so did the antimicrobial effect. Copper intrauterine devices show promise in mitigating uterine infections in mares.
Characterization of a NovelTequatrovirusPhage from Pristine Stretch of The Ganges River, India, in Reducing Bacterial Load from Sewage Water
Authors: Samson Rachel , Pawar Ameya , Khairnar Krishna , Dharne Mahesh 
Published: November 2024

AbstractEffective treatment of wastewater (WW) and its reuse is necessary to meet certain sustainable development goals and a circular economy.Escherichia coliis one of the primary contaminants in the WW, and its extra-intestinal occurrence poses a considerable threat under one health. This study is the first report of a novel broad-spectrum phage (фERS-1) isolated from a pristine stretch of the Ganges River in the biocontrol ofE. coli, resistant to 3rd-and 4thgeneration cephalosporins and aztreonam. This is the first report of a phage from theTequatrovirusgenus to infectP. aeruginosa. The фERS-1 could reduce the abundance ofE. colicells by 8.22 log10CFU/mL ≤24 hrs. Additionally, □ ERS-1 disrupted the biofilm ofE. coliwith a reduction of 3.88 log10CFU/mL. Further, □ ERS-1 could inhibit biofilm by multiple strains ofE. coliand multiple genera (E. coli, S. boydii,andP. aeruginosa). The phage □ ERS-1 reduced bacterial counts in raw WW by 2 log10CFU/mL and 4 log10CFU/mL reduction in coliform-enriched WW in ≤24 hours. Overall, this study suggests that □ ERS-1 could be used as an effective alternative to be combined with other treatments for improving the quality of WW disposal and environmental health by reducing the bacterial load.Graphical AbstractHighlightsIsolation of a novel phage from a pristine stretch of the Ganges RiverAntibiofilm activity againstE. coli>8 log10inhibition, >3 log10disruptionBiofilm inhibition of >50% againstP. aeruginosaandS. boydii2 log10and 4 log10reduction of bacterial counts in phage-treated raw sewage
RNA Binding Protein Khdrbs1 Regulates Hematopoietic Stem and Progenitor Cell Emergence via Splicing
Authors: Karp Ilana , Bowman Teresa V. 
Published: November 2024

SUMMARYDefinitive hematopoietic stem and progenitor cells (HSPCs) arise through an endothelial-to-hematopoietic transition (EHT), whereby endothelial cells (ECs) acquire a hemogenic fate (HE) and convert to HSPCs. EHT regulators remain incompletely understood. Utilizing published RNA-seq data of ECs, HE/HSPCs, and HSPCs, we defined the alternative splicing landscape of zebrafish EHT and potential RNA binding proteins governing the process. Employing an F0 CRISPR-Cas9 mediated mutagenesis screen, we identified zebrafish homologs of KHDRBS1 as critical for embryonic HSPC formation. Mutagenesis ofkhdrbs1a/bled to diminished HSPCs and a profound lineage shift in differentiated cells, with the greatest decrease observed inrag+T-cells. Treatment of mutagenized embryos with the splicing modulator E7107 partially restored HSPCs to near wildtype levels indicating Khdrbs1 splicing regulation drives EHT. Consistently, Khdrbs1 binding motifs were the only ones enriched in EHT alternative splicing events. Identification of EHT-specific splicing regulation provides a deeper understanding of cell fate tuning by splicing.
Two methodologies and timescales show no promotion of antibiotic resistance from in-water coral disease treatments
Authors: Neely Karen L. , Kellogg Christina A. , Voelschow Julie J. , Cauvin Allison R. , Reed Sydney A. M. , Rubin Ewelina , Meyer Julie L. 
Published: November 2024

AbstractThe decimation of reefs caused by stony coral tissue loss disease prompted the use of a topical amoxicillin treatment to prevent coral mortality. Application of this treatment led to concerns about unintentional impacts such as potential alteration of the coral microbiome and possible spread of antibiotic resistance. We used two different methodologies – microbial RNA sequencing and microbial qPCR array – to assess these concerns. RNA sequencing was conducted on coral mucus samples collected before and 24 hours after amoxicillin application on wildMontastraea cavernosa. No differences in expression of antibiotic resistance genes (ARGs) were detected. Additionally, there were no notable changes in the microbial communities between the before and after samples. Microbial qPCR array was used to assess differences in ARGs over longer timescales in wildColpophylia natans, comparing never-treated corals with ones treated a single time seven months prior and with those treated multiple times seven months and more prior. No clinically relevant ARGs represented in the arrays were detected across any samples. A small number of above-detection reads (4 in the never-treated corals, 2 in the once-treated corals, and 0 in the multi-treated corals) may indicate weak amplification of similar environmental (non-anthropogenic) ARGs in the corals. Results indicate that the localized topical application of amoxicillin to prevent mortality of SCTLD-affected corals is neither disrupting the microbiome of treated corals nor driving the proliferation of antibiotic resistance.
Lateralized nodose ganglia gene expression implicates cholecystokinin receptors in interoceptive reward signaling
Authors: Welch Hailey F. , Sankaranarayanan Ishwarya , Hong Veronica M. , Mazhar Khadijah , Kolber Benedict J. , Price Theodore J. , Thorn Catherine A. 
Published: November 2024

SummaryThe vagus nerves are important carriers of sensory information from the viscera to the central nervous system. Emerging evidence suggests that sensory signaling through the right, but not the left, vagus nerve evokes striatal dopamine release and reinforces appetitive behaviors. However, the extent to which differential gene expression within vagal sensory neurons contributes to this asymmetric reward-related signaling remains unknown. Here, we use single-cell RNA sequencing to identify genes that are differentially expressed between the left and right nodose ganglia (NG) to identify candidate genes likely to contribute to vagus-mediated reward signaling. We find that a group of neurons expressingChrna3(nicotinic acetylcholine receptor subunit 3) andCckar(cholecystokinin A receptor) is preferentially expressed in the right NG of both rats and mice. This result suggests that differential expression of gut-innervating nutrient sensors in NG neurons may contribute to asymmetric encoding of interoceptive rewards by the vagus nerves.
Differential destinations, dynamics, and functions of high- and low-order features in the feedback signal during object processing
Authors: Hou Wenhao , He Sheng , Zhang Jiedong 
Published: November 2024

AbstractBrain is a hierarchical information processing system, in which the feedback signals from high-level to low-level regions are critical. The feedback signals may convey complex high-order features (e.g., category, identity) and simple low-order features (e.g., orientation, spatial frequency) to sensory cortex to interact with the feedforward information, but how these types of feedback information are represented and how they differ in facilitating visual processing is unclear. The current study used the peripheral object discrimination task, 7T fMRI, and MEG to isolate feedback from feedforward signals in human early visual cortex. The results showed that feedback signals conveyed both low-order features natively encoded in early visual cortex and high-order features generated in high-level regions, but with different spatial and temporal properties. The high-order feedback information targeted both superficial and deep layers, whereas the low-order feedback information reached only deep layers in V1. In addition, MEG results revealed that the feedback information from occipito-temporal to early visual cortex emerged around 200 ms after stimulus onset, and only the representational strength of high-order feedback information was significantly correlated with behavioral performance. These results indicate that the complex and simple components of feedback information play different roles in predictive processing mechanisms to facilitate sensory processing.
The presynaptic vesicle cluster transitions from a compact to loose organization during long-term potentiation
Authors: Garcia Guadalupe C. , Bartol Thomas M. , Kirk Lyndsey M. , Badala Priyal , Harris Kristen M. , Sejnowski Terrence J. 
Published: November 2024

AbstractFunctional and structural elements of synaptic plasticity are tightly coupled, as has been extensively shown for dendritic spines. Here, we interrogated structural features of presynaptic terminals in 3DEM reconstructions from CA1 hippocampal axons that had undergone control stimulation or theta-burst stimulation (TBS) to produce long-term potentiation (LTP). We reveal that after LTP induction, the synaptic vesicle (SV) cluster is less dense, and SVs are more dispersed. The distances between neighboring SVs are greater in less dense terminals and have more SV-associated volume. We characterized the changes to the SV cluster by measuring distances between neighboring SVs, distances to the active zone, and the dispersion of the SV cluster. Furthermore, we compared the distribution of SVs with randomized ones and provided evidence that SVs gained mobility after LTP induction. With a computational model, we can predict the increment of the diffusion coefficient of the SVs in the cluster. Moreover, using a machine learning approach, we identify presynaptic terminals that were potentiated after LTP induction. Lastly, we show that the local SV density is a volume-independent property under strong regulation. Altogether, these results provide evidence that the SV cluster is undergoing a transition during LTP.
The most significant differences between male and female rats regarding psychostimulant self-administration behavior are unrelated to biological sex
Authors: Showell Bryce H , Job Martin O 
Published: November 2024

AbstractBackgroundThe goals of this study were to 1) validate the MISSING (Mapping Intrinsic Sex Similarities as an Integral quality of Normalized Groups) model for psychostimulant self-administration (SA), and 2) utilize it to explain the inconsistencies in the observation of sex differences in psychostimulant SA.MethodsWe allowed male and female Long Evans rats (n = 40) to self-administer methamphetamine METH dose 0.1 mg/kg (male n = 9, female n = 18) and saline (male n = 3, female n = 10) via the intravenous route, FR1 schedule, 6 h per day, 5 days per week for 4 weeks. For the MISSING model, we identified behavioral clusters of males and females using normal mixtures clustering analysis of baseline intake, total intake and total intake normalized-to-baseline intake (NBI), followed by unpaired t-tests to compare clusters and Two-way ANOVA to determine if there were any SEX by cluster interactions. For the current model, we grouped our subjects according to biological sex and compared the above variables using unpaired t-tests. For both models, we employed Two-way repeated measures ANOVA and linear regression analysis to analyze SA time course.ResultsFor saline and METH SA, there were no sex differences when we compared males and females generally, with sex differences evident only when we compared sexes from distinct clusters. The current model could not explain the inconsistencies in the observability of sex differences in METH SA.ConclusionsWe validated the MISSING model -it can explain the inconsistencies around sex differences in METH SA.