bluuebunny/crossref_metadata_2025_split huggingface dataset:
Psilocybin biphasically modulates cortical and behavioral activity in mice
Authors: Brockett Adam T. , Francis Nikolas A. 
Published: January 2024

SUMMARYPsilocybin is a serotonergic psychedelic believed to have therapeutic potential for neuropsychiatric conditions. Despite well-documented prevalence of perceptual alterations, hallucinations, and synesthesia associated with psychedelic experiences, little is known about how psilocybin affects sensory cortex or alters the activity of neurons in awake animals. To investigate, we conducted 2-photon imaging experiments in auditory cortex of awake mice and video analysis of mouse behavior, both at baseline and during psilocybin treatment. We found biphasic effects of psilocybin on behavioral and cortical activity. A 2 mg/kg dose of psilocybin initially increased behavioral activity and neural responses to sound. 30 minutes post-dose, mice became behaviorally hypoactive and cortical responses to sound decreased, while neural response variance and noise correlations increased. In contrast, neuronal selectivity for auditory stimuli remained stable during psilocybin treatment. Our results suggest that psilocybin modulates the role of intrinsic versus stimulus-driven activity in sensory cortex, while preserving fundamental sensory processing.Graphical Abstract.Summary of psilocybin’s effect on auditory cortical responses to sound in mice.30 minutes after injecting the inert vehicle saline, typical auditory responses occur within a relatively narrow range of possible amplitudes, i.e., each neuron’s response variance is weakly correlated with a neighboring neuron’s response variance. In contrast, 30 minutes after injecting 2 mg/kg of psilocybin, population response variance becomes more correlated between individual neurons, and the range of response amplitudes increases. These findings suggest that psilocybin modulates the role of intrinsic versus stimulus-driven neural activity in sensory perception, which may serve as a basis for auditory hallucination at the level of neuronal micro-circuits.
Engineering CRBN for rapid identification of next generation binders
Authors: Bailey Henry J. , Eisert Jonathan , Vollrath Joshua , Leibrock Eva-Maria , Kondratov Ivan , Matviyuk Tetiana , Tolmachova Nataliya , Langer Julian D. , Wegener Ansgar A. , Sorrell Fiona J. , Dikic Ivan 
Published: January 2024

AbstractThe majority of clinical degrader candidates utilize an immunomodulatory imide drug (IMiD)-based derivative, that directs their target substrate to the E3 ligase receptor Cereblon (CRBN), however, concomitant neo-substrate degradation by IMiDs often results in severe off-target effects. Further biophysical screening is needed to discover CRBN binders that might overcome these safety concerns, but the previously reported CRBN protein constructs suffer significant limitations that reduce their applicability as tools for biophysical assays making large-scale screening efforts a costly endeavor. This is due to the requirement of CRBN co-expression with DDB1 in insect cells to produce soluble protein that contains all the reported structural features necessary for proper compound interaction. Here, a near full-length human CRBN construct was designed that retains these required features, but for the first time allows the generation of highly homogenous and cost-efficient expression inE.coli, eliminating the need for DDB1 co-expression. We have extensively profiled the new construct against the existing CRBN constructs in binary and ternary degrader complexes, showing it to be the “best of both worlds” in terms of binding characteristics and ease of protein production. We then designed the Enamine CRBN focused IMiD library of 4480-compounds and demonstrated applicability of the new construct to high throughput screening by identifying novel CRBN binders with high potency and ligand efficiency. The new methods described here should serve as valuable tools for the development of the next generation IMiD-based degraders.
Structural features of heteromeric channels composed of CALHM2 and CALHM4 paralogs
Authors: Drożdżyk Katarzyna , Peter Martina , Dutzler Raimund 
Published: January 2024

AbstractThe CALHM proteins constitute a family of large pore channels that contains six closely related paralogs in human. Two family members, CALHM1 and 3, have been associated with the release of ATP during taste sensation. Both proteins form heteromeric channels that activate at positive potential and decreased extracellular Ca2+concentration. Although the structures of several family members displayed large oligomeric organizations of different size, their function has in most cases remained elusive. Our previous study has identified the paralogs CALHM2, 4 and 6 to be highly expressed in the placenta and defined their structural properties as membrane proteins exhibiting features of large pore channels with unknown activation properties (Drozdzyk et al., 2020). Here we investigated whether these placental paralogs would form heteromers and characterized heteromeric complexes consisting of CALHM2 and CALHM4 subunits using specific binders as fiducial markers. Both proteins assemble with different stoichiometries with the largest population containing CALHM2 as predominant component. In these oligomers, the subunits segregate and reside in their preferred conformation found in homomeric channels. Our study has thus revealed the properties that govern the formation of CALHM heteromers in a process of potential relevance in a cellular context.
Alteration of long and short-term hematopoietic stem cell ratio causes myeloid-biased hematopoiesis
Authors: Nishi Katsuyuki , Sakamaki Taro , Nagasaka Akiomi , Kao Kevin S. , Sadaoka Kay , Asano Masahide , Yamamoto Nobuyuki , Takaori-Kondo Akifumi , Miyanishi Masanori 
Published: January 2024

AbstractMyeloid-biased hematopoiesis is a well-known age-related alteration. Several possibilities, including myeloid-biased hematopoietic stem cell (HSC) clones, may explain this. However, the precise mechanisms remain controversial.Utilizing the Hoxb5 reporter system to prospectively isolate long-term HSCs (LT-HSCs) and short-term HSCs (ST-HSCs), we found that young and aged LT-HSCs co-transplanted into the same recipients demonstrated nearly equivalent myeloid lineage output, contrary to the theory of myeloid-biased HSC clones. Transcriptomics indicated no significant myeloid gene enrichment in aged LT-HSCs compared to their young counterparts. Instead, transplanting reconstituted young HSCs with the ratio of LT/ST-HSCs seen in aged mice can significantly skew the lineage output to myeloid cells. In addition, while the niche environment in the bone marrow minimally affects myeloid-biased hematopoiesis, aged thymi and spleens substantially hinder lymphoid hematopoiesis, resulting in further myeloid-domination. Thus, we demonstrate that myeloid-biased hematopoiesis in aged organisms originates due to alteration of the ratio between LT-HSCs and ST-HSCs rather than in heterogeneous HSC clones with various cell fates.
Binding profiles for 954 Drosophila andC. eleganstranscription factors reveal tissue specific regulatory relationships
Authors: Kudron Michelle , Gevirtzman Louis , Victorsen Alec , Lear Bridget C. , Gao Jiahao , Xu Jinrui , Samanta Swapna , Frink Emily , Tran-Pearson Adri , Huynh Chau , Vafeados Dionne , Hammonds Ann , Fisher William , Wall Martha , Wesseling Greg , Hernandez Vanessa , Lin Zhichun , Kasparian Mary , White Kevin , Allada Ravi , Gerstein Mark , Hillier LaDeana , Celniker Susan E. , Reinke Valerie , Waterston Robert H. 
Published: January 2024

SUMMARYA catalog of transcription factor (TF) binding sites in the genome is critical for deciphering regulatory relationships. Here we present the culmination of the modERN (model organism Encyclopedia of Regulatory Networks) consortium that systematically assayed TF binding events in vivo in two major model organisms,Drosophila melanogaster(fly) andCaenorhabditis elegans(worm). We describe key features of these datasets, comprising 604 TFs identifying 3.6M sites in the fly and 350 TFs identifying 0.9 M sites in the worm. Applying a machine learning model to these data identifies sets of TFs with a prominent role in promoting target gene expression in specific cell types. TF binding data are available through the ENCODE Data Coordinating Center and athttps://epic.gs.washington.edu/modERNresource, which provides access to processed and summary data, as well as widgets to probe cell type-specific TF-target relationships. These data are a rich resource that should fuel investigations into TF function during development.
Layered entrenchment maintains essentiality in protein-protein interactions
Authors: Schulz Luca , Zarzycki Jan , Steinchen Wieland , Hochberg Georg K. A. , Erb Tobias J. 
Published: January 2024

AbstractProtein complexes composed of strictly essential subunits are abundant in nature and arise through the gradual complexification of ancestral precursor proteins followed by their co-evolution with the newly recruited components. Essentiality arises during co-evolution by the accumulation of changes that are tolerated in the complex state but would be deleterious for the standalone complex components. While this theoretical framework to explain how essentiality arises has been proposed long ago, it is unclear which factors cause essentiality to persist over evolutionary timescales. In this work we show that the central enzyme of photosynthesis, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), rapidly started to depend on a newly recruited interaction partner through multiple, genetically distinct mechanisms that affect stability, solubility, and catalysis. We further demonstrate that layering multiple mechanisms of essentiality can lead to the persistence of essentiality, even if any given mechanism reverts through chance or selection. More broadly, our work highlights that new interaction partners can drastically re-shape which substitutions are tolerated in the proteins they are recruited into. This can lead to the rapid evolution of multi-layered essentiality through the exploration of areas of sequence space that are only accessible in the complex state.
PINK1 knockout rats show premotor cognitive deficits measured through a complex maze
Authors: Soto Isabel , Nejtek Vicki A. , Siderovski David P. , Salvatore Michael F. 
Published: January 2024

AbstractCognitive decline in Parkinson’s disease (PD) emerges up to 10 years before clinical recognition. Neurobiological mechanisms underlying premotor cognitive impairment in PD can potentially be examined in the PINK1-/-rat, which exhibits a protracted motor onset. To enhance translation to human PD cognitive assessments, we tested a modified multiple T-maze, which measures cognitive flexibility similarly to the Trail-Making Test in humans. Like human PD outcomes, PINK1-/-rats made more errors and took longer to complete the maze than wild types. Thus, we have identified a potential tool for assessing cross-species translation of cognitive functioning in an established PD animal model.
Dermal wound healing contribution of aqueous extracts ofAcalypha indica, Calotropis gigantea, Bacopa monnieriand their combination
Authors: Tanimu Habibu , Zirmire K Ravindra , Jamora Colin , Karthik Parimala , Bindhu O.S 
Published: January 2024

ABSTRACTWound healing is a complex process that requires a well-orchestrated integration of an array of molecular events such as cell migration and proliferation, deposition and remodeling of extracellular matrix components for restoring the structural and functional integrity of the tissue injured. Ayurveda suggests wound healing herbs can achieve enhanced therapeutic effect with reduced toxicity when they are optimally combined in a specific ratio as polyherbal formulation (PHF). The present study was aimed to evaluate the combinatorial wound healing efficacy (in vivowound closure and histological changes) of aqueous extracts of three medicinal plants (Bacopa monnieri,Acalypha indicaandCalotropis gigantea). This study also explored how the combination influenced the overall quality of healed wound. Individual wound closure kinetic performance of aqueous plant extracts in C57B/6J mice was assessed using safe concentrations obtained from human adult dermal fibroblast viability assay. The aqueous plant extract combination optimized using response surface methodology was tested forin vivowound closure effectiveness. Quality of healed wound was assessed via Hematoxylin & Eosin and immunohistochemical staining of markers (K1, K5, Loricrin, Ki67, CD31 and collagen1). The combination treatment(B.monnieri-15μg/ml,A.indica-11.59μg/ml,C.gigantea-1μg/ml) contributed to faster wound closure (11 days), improved collagen type I remodeling and angiogenesis, complete re-epithelialization, similar epidermal differentiation pattern as that of individual and control treatments. Ki67 staining revealed no significant increase in cell proliferation in combination compared to individual and control. Findings from the study validates the polyherbal combination’s impressive capability to promote wound healing.
FAP20 is required for flagellum assembly inTrypanosoma brucei
Authors: Shimogawa Michelle M. , Jonnalagadda Keya , Hill Kent L. 
Published: January 2024

ABSTRACTTrypanosoma bruceiis a human and animal pathogen that depends on flagellar motility for transmission and infection. The trypanosome flagellum is built around a canonical “9+2” axoneme, containing nine doublet microtubules (DMTs) surrounding two singlet microtubules. Each DMT contains a 13-protofilament A-tubule and a 10-protofilament B-tubule, connected to the A-tubule by a conserved, non-tubulin inner junction (IJ) filament made up of alternating PACRG and FAP20 subunits. Here we investigate FAP20 in procyclic formT. brucei. A FAP20-NeonGreen fusion protein localized to the axoneme as expected. Surprisingly, FAP20 knockdown led to a catastrophic failure in flagellum assembly and concomitant lethal cell division defect. This differs from other organisms, where FAP20 is required for normal flagellum motility, but generally dispensable for flagellum assembly and viability. Transmission electron microscopy demonstrates failed flagellum assembly in FAP20 mutants is associated with a range of DMT defects and defective assembly of the paraflagellar rod, a lineage-specific flagellum filament that attaches to DMT 4-7 in trypanosomes. Our studies reveal a lineage-specific requirement for FAP20 in trypanosomes, offering insight into adaptations for flagellum stability and motility in these parasites and highlighting pathogen versus host differences that might be considered for therapeutic intervention in trypanosome diseases.SIGNIFICANCE STATEMENTDiverse eukaryotic organisms rely on a generally conserved axoneme architecture and dynein-dependent beating mechanism to drive motility, but mechanisms conferring lineage-specific motility needs are largely unknown.FAP20 is a conserved flagellar protein that impacts flagellum motility in multiple organisms.The current work demonstrates FAP20 is particularly important in the pathogen,T. brucei, providing insight into pathogen adaptations for moving through host environments and illuminating targets to consider for therapeutic intervention in trypanosome diseases.
Sterol O-acyltransferase (SOAT/ACAT) activity is required to form cholesterol crystals in hepatocyte lipid droplets
Authors: Bairos Jordan A , Njoku Uche , Zafar Maria , Akl May G , Li Lei , Parlakgul Gunes , Arruda Ana Paula , Widenmaier Scott B 
Published: January 2024

ABSTRACTObjectiveExcess unesterified (free) cholesterol can induce formation of cholesterol crystals in hepatocyte lipid droplets. Presence of such crystal distinguishes metabolic dysfunction associated steatohepatitis (MASH) from simple steatosis and may underlie its pathogenesis by causing cell damage that triggers liver inflammation. The mechanism linking cholesterol excess to its crystallization in lipid droplets is unclear. As cholesteryl esters localize to and accumulate in lipid droplets much more readily than free cholesterol, we investigated whether cholesterol esterification by sterol O-acyltransferase (SOAT), also known as acyl co-A cholesterol acyltransferase (ACAT) is required for hepatocyte lipid droplet crystal formation.MethodCholesterol crystals were measured in cholesterol loaded Hep3B hepatocytes, RAW264.7 macrophages and mouse liver using polarizing light microscopy. We examined the effect of blocking SOAT activity on crystal formation and compared these results to cholesterol metabolism and the progression to intracellular crystal deposits.ResultsCholesterol loading of Hep3B cells caused robust levels of lipid droplet localized crystal formation in a dose- and time-dependent manner. Co-treatment with SOAT inhibitors and genetic ablation ofSOAT1blocked crystal formation. SOAT inhibitor also blocked crystal formation in low density lipoprotein (LDL) treated Hep3B cells, acetylated LDL treated RAW 264.7 macrophages, and in the liver of mice genetically predisposed to hepatic cholesterol overload and in mice fed a cholesterol enriched, MASH-promoting diet for 24 weeks.ConclusionSOAT1-mediated esterification may underlie cholesterol crystals associated with MASH by concentrating it in lipid droplets. These findings imply that inhibiting hepatocyte SOAT1 may alleviate cholesterol associated MASH. Moreover, that a lipid droplet localized cholesteryl ester hydrolase may be required for cholesterol crystal formation or, instead, that the crystals are composed of cholesteryl ester.Funding SourcesGrants supporting this research were awarded to SBW from the Natural Sciences and Engineering Research Council of Canada (NSERC). SBW was supported by a National New Investigator Award and McDonald Scholarship from the Heart and Stroke Foundation of Canada. UN and MA were supported by a James Regan Cardiology Research scholarship from University of Saskatchewan’s College of Medicine.
AXONAL distribution of mitochondria maintains neuronal autophagy during aging via eIF2β
Authors: Shinno Kanako , Miura Yuri , Iijima Koichi M. , Suzuki Emiko , Ando Kanae 
Published: January 2024

SummaryNeuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while cellular factors that trigger it are not identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. UsingDrosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found that eIF2β was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2α, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression ofeIF2βphenocopied the autophagic defects and neuronal dysfunctions, and loweringeIF2βexpression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2β axis maintains proteostasis in the axon, of which disruption may underly the onset and progression of age-related neurodegenerative diseases.HighlightsLoss of axonal mitochondria impairs autophagy and accumulates proteins in the axonLoss of axonal mitochondria increases eIF2β and decreases p-eIF2αNeuronal upregulation of eIF2β induces autophagic defects and locomotor dysfunctionLowering eIF2β rescues autophagic defects caused by loss of axonal mitochondria
Divergent opioid-mediated suppression of inhibition between hippocampus and neocortex across species and development
Authors: Caccavano Adam P. , Vlachos Anna , McLean Nadiya , Kimmel Sarah , Kim June Hoan , Vargish Geoffrey , Mahadevan Vivek , Hewitt Lauren , Rossi Anthony M. , Spineux Ilona , Wu Sherry Jingjing , Furlanis Elisabetta , Dai Min , Garcia Brenda Leyva , Wang Yating , Chittajallu Ramesh , London Edra , Yuan Xiaoqing , Hunt Steven , Abebe Daniel , Eldridge Mark A. G. , Cummins Alex C. , Hines Brendan E. , Plotnikova Anya , Mohanty Arya , Averbeck Bruno B. , Zaghloul Kareem , Dimidschstein Jordane , Fishell Gord , Pelkey Kenneth A. , McBain Chris J. 
Published: January 2024

SUMMARYWithin the adult rodent hippocampus, opioids suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting local micro-circuits. However, it is unknown if this disinhibitory motif is conserved in other cortical regions, species, or across development. We observed that PV-IN mediated inhibition is robustly suppressed by opioids in hippocampus proper but not primary neocortex in mice and nonhuman primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif was established in early development when PV-INs and opioids were found to regulate early population activity. Acute opioid-mediated modulation was partially occluded with morphine pretreatment, with implications for the effects of opioids on hippocampal network activity important for learning and memory. Together, these findings demonstrate that PV-INs exhibit a divergence in opioid sensitivity across brain regions that is remarkably conserved across evolution and highlights the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.
Effects of heater positions on magneto-hydrodynamic convection of CuO-water nanofluid flow in a grooved channel
Authors: Rahaman Md Motiur , Biswas Nirmalendu , Santra Apurba Kumar , Manna Nirmal K. 
Published: January 2024

Purpose
This study aims to delve into the coupled mixed convective heat transport process within a grooved channel cavity using CuO-water nanofluid and an inclined magnetic field. The cavity undergoes isothermal heating from the bottom, with variations in the positions of heated walls across the grooved channel. The aim is to assess the impact of heater positions on thermal performance and identify the most effective configuration.

Design/methodology/approach
Numerical solutions to the evolved transport equations are obtained using a finite volume method-based indigenous solver. The dimensionless parameters of Reynolds number (1 ≤ Re ≤ 500), Richardson number (0.1 ≤ Ri ≤ 100), Hartmann number (0 ≤ Ha ≤ 70) and magnetic field inclination angle (0° ≤ γ ≤ 180°) are considered. The solved variables generate both local and global variables after discretization using the semi-implicit method for pressure linked equations algorithm on nonuniform grids.

Findings
The study reveals that optimal heat transfer occurs when the heater is positioned at the right corner of the grooved cavity. Heat transfer augmentation ranges from 0.5% to 168.53% for Re = 50 to 300 compared to the bottom-heated case. The magnetic field’s orientation significantly influences the average heat transfer, initially rising and then declining with increasing inclination angle. Overall, this analysis underscores the effectiveness of heater positions in achieving superior thermal performance in a grooved channel cavity.

Research limitations/implications
This concept can be extended to explore enhanced thermal performance under various thermal boundary conditions, considering wall curvature effects, different geometry orientations and the presence of porous structures, either numerically or experimentally.

Practical implications
The findings are applicable across diverse fields, including biomedical systems, heat exchanging devices, electronic cooling systems, food processing, drying processes, crystallization, mixing processes and beyond.

Originality/value
This work provides a novel exploration of CuO-water nanofluid flow in mixed convection within a grooved channel cavity under the influence of an inclined magnetic field. The influence of different heater positions on thermomagnetic convection in such a cavity has not been extensively investigated before, contributing to the originality and value of this research.