bluuebunny/crossref_metadata_2025_split huggingface dataset:
The novel role of Kallistatin in linking metabolic syndromes and cognitive memory deterioration by inducing amyloid-β plaques accumulation and tau protein hyperphosphorylation
Authors: Qi Weiwei , Long Yanlan , Li Ziming , Zhao Zhen , Shi Jinhui , Xie Wanting , Wang Laijian , Tan Yandan , Zhou Ti , Jiang Ping , Jiang Bin , Yang Xia , Gao Guoquan 
Published: May 2024

AbstractAccumulation of amyloid β (Aβ) peptides and hyperphosphorylated tau proteins in the hippocampus triggers cognitive memory decline in Alzheimer’s disease (AD). The incidence and mortality of sporadic AD were tightly associated with diabetes and hyperlipidemia, while the exact linked molecular is uncertain. Here, we reported that serum Kallistatin concentrations were meaningfully higher in AD patients, with a higher concentration of fasting blood glucose and triglyceride. In addition, the constructed Kallistatin-transgenic (KAL-TG) mice defined its cognitive memory impairment phenotype and lower LTP in hippocampal CA1 neurons accompanied by increased Aβ deposition and tau phosphorylation. Mechanistically, Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling, resulting in Aβ cleavage and production. Besides, Kallistatin could promote the phosphorylation of tau by activating GSK-3β. Fenofibrate, a hypolipidemic drug, could alleviate cognitive memory impairment by down-regulating Aβ and tau phosphorylation of KAL-TG mice. Collectively, our data clarified a novel mechanism for Aβ accumulation and tau protein hyperphosphorylation regulation by Kallistatin, which might play a crucial role in linking metabolic syndromes and cognitive memory deterioration, and suggested that fenofibrate might have the potential for treating metabolism-related AD.HighlightsKallistatin-transgenic(KAL-TG) mice defined its cognitive memory impairment phenotype accompanied by increased Aβ deposition and tau phosphorylation.Kallistatin could directly bind to the Notch1 receptor and thereby upregulate BACE1 expression by inhibiting PPARγ signaling.Fenofibrate could alleviate cognitive memory impairment and down-regulate the serum Kallistatin level.
Accurate Conformation Sampling via Protein Structural Diffusion
Authors: Fan Jiahao , Li Ziyao , Alcaide Eric , Ke Guolin , Huang Huaqing , Weinan E 
Published: May 2024

AbstractAccurately sampling of protein conformations is pivotal for advances in biology and medicine. Although there have been tremendous progress in protein structure prediction in recent years due to deep learning, models that can predict the different stable conformations of proteins with high accuracy and structural validity are still lacking. Here, we introduce UFConf, a cutting-edge approach designed for robust sampling of diverse protein conformations based solely on amino acid sequences. This method transforms AlphaFold2 into a diffusion model by implementing a conformation-based diffusion process and adapting the architecture to process diffused inputs effectively. To counteract the inherent conformational bias in the Protein Data Bank, we developed a novel hierarchical reweighting protocol based on structural clustering. Our evaluations demonstrate that UFConf out-performs existing methods in terms of successful sampling and structural validity. The comparisons with long time molecular dynamics show that UFConf can overcome the energy barrier existing in molecular dynamics simulations and perform more efficient sampling. Furthermore, We showcase UFConf’s utility in drug discovery through its application in neural protein-ligand docking. In a blind test, it accurately predicted a novel protein-ligand complex, underscoring its potential to impact real-world biological research. Additionally, we present other modes of sampling using UFConf, including partial sampling with fixed motif, langevin dynamics and structural interpolation.
rpfFis not required forX. translucenspv. undulosa pathogenesis
Authors: Heiden Nathaniel , Butchacas Jules , Klass Taylor , Cohen Stephen P. , Roman-Reyna Veronica , Merfa Marcus V. , Valero David Guillermo E. , Vargas-Garcia Christian , Olmos Cristian , Vélez-Negrón Yesenia , Lewandowski Monica M. , Jacobs Jonathan M. 
Published: May 2024

AbstractBacterial cells self-coordinate via a mechanism called quorum sensing. InXanthomonasspecies the generpfFencodes the quorum sensing autoinducer synthase.Xanthomonasspecies are divided into two main phylogenetic groups called Clade I and Clade II. Therpfquorum sensing system has been well studied in multiple Clade IIXanthomonasspecies and deletion ofrpfFresulted in a major loss of virulence on susceptible hosts. However, the only Clade IXanthomonasspecies in which therpfFsystem was previously studied was in the sugarcane pathogenX. albilineans. InX. albilineanstherpfcluster plays a relatively small role in pathogenesis.Xanthomonas translucenspv. undulosa (Xtu) is a Clade IXanthomonasspecies that causes bacterial leaf streak (BLS) and black chaff of wheat and barley and has increased as a concern in recent decades. Neither major resistance nor chemical treatments are available to prevent disease caused by Xtu. Interference withrpfbacterial quorum sensing systems has demonstrated some success in other systems. It was unknown whether BLS caused by Xtu could be prevented via quorum sensing interference. We found that Xtu encodes anrpfFhomolog and we created anrpfFknockout mutant to study the role of therpfsystem in Xtu. We found that therpfFmutant was unaffected in its pathogenesis as it caused BLS symptoms and multiplied within wheat plants to the same levels as the wildtype strain. The XturpfFmutant grew normally in lag and log phasesin vitro, however it exhibited a shorter stationary phase and an early death phase in plant-derived media. The importance of RpfF in Xtu’s life cycle is unknown, though it appears to carry out a role in population stability. Our research determined thatrpfFis not a major Xtu pathogenicity factor. Therefore, we do not recommend the targeting of therpfquorum sensing system as a preventative treatment for BLS of wheat.
Projections from thalamic nucleus reuniens to medial septum enable extinction of remote fear memory
Authors: Tomaszewski Kamil F. , Ziółkowska Magdalena , Łukasiewicz Kacper , Cały Anna , Sotoudeh Narges , Puchalska Monika , Salamian Ahmad , Radwanska Kasia 
Published: May 2024

AbstractAversive experiences lead to the formation of long-lasting memories. Despite the need to better understand how enduring fear memories can be attenuated, the underlying brain circuits remain largely unknown. In this study, employing a combination of genetic manipulations, neuronal circuit mapping, and chemogenetics in mice, we identify a new projection from the thalamic nucleus reuniens (RE) to the medial septum (MS), and show that this circuit is involved in the extinction of remote (30-day old), but not recent (1-day old), fear memories. These findings provide the first functional description of the RE→MS circuit and highlight the significance of the thalamo-septal regions in memory organization as a function of memory age, a phenomenon known as systems consolidation.
Huntingtin loss-of-function contributes to transcriptional deregulation in Huntington’s disease
Authors: Emilia Kozłowska , Agata Ciołak , Grażyna Adamek , Julia Szcześniak , Agnieszka Fiszer 
Published: May 2024

AbstractHuntington’s disease (HD) is a fatal neurodegenerative disorder that is caused by the expansion of CAG repeats in theHTTgene, which results in a long polyglutamine (polyQ) tract in the huntingtin protein (HTT). In this study, we searched for networks of deregulated RNAs that contribute to initial transcriptional changes in HD neuronal cells and HTT-deficient cells.We used RNA-seq (including small RNA sequencing) to analyze a set of isogenic, human induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs); and we observed numerous changes in gene expression and substantial dysregulation of miRNA expression in HD andHTT-knockout (HTT-KO) cell lines. The gene set that was upregulated in both HD andHTT-KO cells was enriched in genes that are associated with DNA binding and regulation of transcription. For both of these models, we confirmed the substantial upregulation of the transcription factors (TFs)TWIST1, SIX1, TBX1, TBX15, MSX2, MEOX2andFOXD1in NSCs and medium spiny neuron (MSN)-like cells. Moreover, we identified miRNAs that were consistently deregulated in HD andHTT-KO NSCs and MSN-like cells, including miR-214, miR-199, and miR-9. We suggest that these miRNAs function in the network that regulatesTWIST1andHTTexpressionviaregulatory feed-forward loop (FFL) in HD. Additionally, we reported that the expression of selected TFs and miRNAs tended to progressively change during the neural differentiation of HD cells, what was not observed inHTT-KO model. Based on comparing the HD andHTT-KO cell lines, we propose that early transcriptional deregulation in HD is largely caused by loss of HTT function.
Conservation of the cooling agent binding pocket within the TRPM subfamily
Authors: Huffer Kate , Denley Matthew C.S. , Oskoui Elisabeth V. , Swartz Kenton J. 
Published: May 2024

ABSTRACTTransient Receptor Potential (TRP) channels are a large and diverse family of tetrameric cation selective channels that are activated by many different types of stimuli, including noxious heat or cold, organic ligands such as vanilloids or cooling agents, or intracellular Ca2+. Structures available for all subtypes of TRP channels reveal that the transmembrane domains are closely related despite their unique sensitivity to activating stimuli. Here we use computational and electrophysiological approaches to explore the conservation of the cooling agent binding pocket identified within the S1-S4 domain of the Melastatin subfamily member TRPM8, the mammalian sensor of noxious cold, with other TRPM channel subtypes. We find that a subset of TRPM channels, including TRPM2, TRPM4 and TRPM5, contain pockets very similar to the cooling agent binding pocket in TRPM8. We then show how the cooling agent icilin modulates activation of TRPM4 to intracellular Ca2+, enhancing the sensitivity of the channel to Ca2+and diminishing outward-rectification to promote opening at negative voltages. Mutations known to promote or diminish activation of TRPM8 by cooling agents similarly alter activation of TRPM4 by icilin, suggesting that icilin binds to the cooling agent binding pocket to promote opening of the channel. These findings demonstrate that TRPM4 and TRPM8 channels share related ligand binding pockets that are allosterically coupled to opening of the pore.
Validating an Immunoassay to Measure Fecal Glucocorticoid Metabolites in Yellow-Bellied Marmots
Authors: Ortiz-Ross Xochitl , Taha Hash Brown , Press Emily , Rhone Sarah , Blumstein Daniel T. 
Published: May 2024

ABSTRACTThe yellow-bellied marmot (Marmota flaviventer) study at the Rocky Mountain Biological Laboratory near Crested Butte, Colorado, USA is the world’s second longest study of free-living mammals. Quantifying physiological stress is essential for understanding their health, reproductive success, and survival in a variable environment. Historically, we used a validated radioimmunoassay (RIA) to measure fecal glucocorticoid metabolites (FGMs). Given the costs and risks of working with radioisotopes, we have shifted to a more sustainable method. Here we evaluate the suitability of two competitive enzyme-linked immunosorbent assays (ELISA) from Cayman Chemical Company (CCC) and Arbor Assays (AA) to measure corticosterone levels in FGMs. The findings revealed that the AA ELISA, unlike the CCC ELISA, consistently matched the RIA in terms of accuracy across high and low corticosterone concentrations, demonstrated superior assay parameters, showed the highest correlations with RIA results and effectively captured the annual variations in FGM concentrations, indicative of its reliability for use in longitudinal studies. We further analytically validated the usage of the AA ELISA for FGMs, confirming its efficacy without matrix effects, thus establishing its suitability for ongoing and future studies of FGMs in marmots. The transition to the AA ELISA from the RIA ensures continued data integrity while enhancing safety and environmental sustainability.
Modeling epithelial homeostasis and perturbation in three-dimensional human esophageal organoids
Authors: Shimonosono Masataka , Morimoto Masaki , Hirose Wataru , Tomita Yasuto , Matsuura Norihiro , Flashner Samuel , Ebadi Mesra S. , Okayasu Emilea H. , Lee Christian Y. , Britton William R. , Martin Cecilia , Wuertz Beverly R. , Parikh Anuraag S. , Sachdeva Uma M. , Ondrey Frank G. , Atigadda Venkatram R. , Elmets Craig A. , Abrams Julian A. , Muir Amanda B. , Klein-Szanto Andres J. , Weinberg Kenneth I. , Momen-Heravi Fatemeh , Nakagawa Hiroshi 
Published: May 2024

AbstractBackgroundEsophageal organoids from a variety of pathologies including cancer are grown in Advanced Dulbecco’s Modified Eagle Medium-Nutrient Mixture F12 (hereafter ADF). However, the currently available ADF-based formulations are suboptimal for normal human esophageal organoids, limiting the ability to compare normal esophageal organoids with those representing a given disease state.MethodsWe have utilized immortalized normal human esophageal epithelial cell (keratinocyte) lines EPC1 and EPC2 and endoscopic normal esophageal biopsies to generate three-dimensional (3D) organoids. To optimize ADF-based medium, we evaluated the requirement of exogenous epidermal growth factor (EGF) and inhibition of transforming growth factor-(TGF)-β receptor-mediated signaling, both key regulators of proliferation of human esophageal keratinocytes. We have modeled human esophageal epithelial pathology by stimulating esophageal 3D organoids with interleukin (IL)-13, an inflammatory cytokine, or UAB30, a novel pharmacological activator of retinoic acid signaling.ResultsThe formation of normal human esophageal 3D organoids was limited by excessive EGF and intrinsic TGFβ receptor-mediated signaling. In optimized HOME0, normal human esophageal organoid formation was improved, whereas IL-13 and UAB30 induced epithelial changes reminiscent of basal cell hyperplasia, a common histopathologic feature in broad esophageal disease conditions including eosinophilic esophagitis.Conclusions:HOME0 allows modeling of the homeostatic differentiation gradient and perturbation of the human esophageal epithelium while permitting a comparison of organoids from mice and other organs grown in ADF-based media.
Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging
Authors: Roy Ethan R. , Li Sanming , Wang Yanyu , Cao Wei 
Published: May 2024

AbstractAlthough aging significantly elevates the risk of developing neurodegenerative diseases, how age-related neuroinflammation preconditions the brain toward pathological progression is ill-understood. To comprehend the scope of type I interferon (IFN-I) activity in the aging brain, we surveyed IFN-I-responsive reporter mice and detected age-dependent signal escalation in multiple brain cell types from various regions. Selective ablation ofIfnar1from microglia in aged mice significantly reduced overall brain IFN-I signature, dampened microglial reactivity, lessened neuronal loss, and diminished the accumulation of lipofuscin, a core hallmark of cellular aging in the brain. Overall, our study demonstrates pervasive IFN-I activity during normal mouse brain aging and reveals a pathogenic role played by microglial IFN-I signaling in perpetuating neuroinflammation, neuronal dysfunction, and molecular aggregation. These findings extend the understanding of a principal axis of age-related inflammation in the brain, and provide a rationale to modulate aberrant immune activation to mitigate neurodegenerative process at all stages.
FDA-Approved MEK1/2 Inhibitor, Trametinib, Protects Mice from Cisplatin and Noise-Induced Hearing Loss
Authors: Lutze Richard D. , Ingersoll Matthew A. , Kelmann Regina G. , Teitz Tal 
Published: May 2024

AbstractHearing loss is one of the most common types of disability; however, there is only one FDA-approved drug to prevent any type of hearing loss. Treatment with the highly effective chemotherapy agent, cisplatin, and exposure to high decibel noises are two of the most common causes of hearing loss. The mitogen activated protein kinase (MAPK) pathway, a phosphorylation cascade consisting of RAF, MEK1/2, and ERK1/2, has been implicated in both types of hearing loss. Pharmacologically inhibiting BRAF or ERK1/2 is protective from noise and cisplatin-induced hearing loss in multiple mouse models. Trametinib, a MEK1/2 inhibitor, protects from cisplatin induced outer hair cell death in mouse cochlear explants; however, to the best of our knowledge, inhibiting MEK1/2 has not yet been shown to be protective from hearing lossin vivo. In this study, we demonstrate that trametinib protects from cisplatin-induced hearing loss in a translationally relevant mouse model and does not interfere with cisplatin’s tumor killing efficacy in cancer cell lines. Higher doses of trametinib were toxic to mice when combined with cisplatin but lower doses of the drug were protective from hearing loss without any known toxicity. Trametinib also protected mice from noise-induced hearing loss and synaptic damage. This study shows that MEK1/2 inhibition protects from both insults of hearing loss and that targeting all three kinases in the MAPK pathway protect from cisplatin and noise-induced hearing loss in mice.
A Single-Short Partial Reprogramming of the Endothelial Cells decreases Blood Pressure via attenuation of EndMT in Hypertensive Mice
Authors: Pernomian Laena , Waigi Emily W. , Nguyen Vi , Mohammed Ahmed D. , da Costa Tiago J. , Fontes Milene T. , Kubinak Jason L. , Aitken Andrew , Biancardi Vinicia Campana , Sinclair David A. , McCarthy Cameron G. , Wang Yunguan , Tan Wenbin , Wenceslau Camilla Ferreira 
Published: May 2024

AbstractBackgroundSmall artery remodeling and endothelial dysfunction are hallmarks of hypertension. Growing evidence supports a likely causal association between cardiovascular diseases and the presence of endothelial-to-mesenchymal transition (EndMT), a cellular transdifferentiation process in which endothelial cells (ECs) partially lose their identity and acquire additional mesenchymal phenotypes. EC reprogramming represents an innovative strategy in regenerative medicine to prevent deleterious effects induced by cardiovascular diseases.MethodsUsing a partial reprogramming of ECs, via overexpression of Oct-3/4, Sox-2, and Klf-4 (OSK) transcription factors, we aimed to bring ECs back to a youthful phenotype in hypertensive mice. Primary ECs were infected with lentiviral vectors (LV) containing the specific EC marker cadherin 5 (Cdh5) and the fluorescent reporter enhanced green fluorescence protein (EGFP) with empty vector (LVCO) or with OSK (LV-OSK). Confocal microscopy and western blotting analysis were used to confirm the OSK overexpression. Cellular migration, senescence, and apoptosis were evaluated. Human aortic ECs (HAoECs) from male and female normotensive and hypertensive patients were analyzed after OSK or control treatments for their endothelial nitric oxide synthase (eNOS) levels, nitric oxide (NO), and genetic profile. Male and female normotensive (BPN/3J) and hypertensive (BPH/2J) mice were treated with an intravenous (i.v.) injection of LVCO or LV-OSK and evaluated 10 days post-infection. The blood pressure, cardiac function, vascular reactivity of small arteries,in vivoEGFP signal and EndMT inhibition were analyzed.ResultsOSK overexpression induced partial EC reprogrammingin vitro, and these cells showed endothelial progenitor cell (EPC)-like features with lower migratory capability. OSK treatment of hypertensive BPH/2J mice normalized blood pressure and resistance arteries hypercontractility, via the attenuation of EndMT and elastin breaks. EGFP signal was detectedin vivoin the prefrontal cortex of both BPN/3J and BPH/2J-treated mice, but OSK induced angiogenesis only in male BPN/3J mice. OSK-treated human ECs from hypertensive patients showed high eNOS activation and NO production, with low ROS formation. Single-cell RNA analysis showed that OSK alleviated EC senescence and EndMT, restoring their phenotypes in human ECs from hypertensive patients.ConclusionOverall, these data indicate that OSK treatment and EC reprogramming can decrease blood pressure and reverse hypertension-induced vascular damage.
Kinetochores promote timely spindle bipolarization to prevent microtubule attachment errors in oocytes
Authors: Yoshida Shuhei , Nakagawa Reiko , Kitajima Tomoya S. 
Published: May 2024

SummaryIncorrect kinetochore-microtubule attachment leads to chromosome segregation errors. The risk of incorrect attachments is particularly high in acentrosomal oocytes, where kinetochores are surrounded by randomly oriented microtubules until spindle bipolarization. How the timing of acentrosomal spindle bipolarization is coordinated with kinetochore-microtubule attachment is unknown. Here, we show that in mouse oocytes, kinetochores promote spindle bipolarization when microtubule attachment is unstable in early prometaphase. The kinetochore kinase MPS1 allows this function by regulating multiple pathways, including those mediated by the kinetochore proteins NDC80-NUF2 at their C-terminal domains and the antiparallel microtubule crosslinker PRC1. Inhibition of MPS1 delays spindle bipolarization to late prometaphase, thereby increasing incorrect kinetochore-microtubule attachments. Artificially accelerating spindle bipolarization by overexpressing KIFC1 prevents incorrect kinetochore-microtubule attachment in MPS1-inhibited oocytes. Thus, kinetochores autonomously promote timely acentrosomal spindle bipolarization prior to stabilizing microtubule attachment, thereby reducing the risk of egg aneuploidy.
Discriminating neural ensemble patterns through dendritic computations in randomly connected feedforward networks
Authors: Somashekar Bhanu Priya , Bhalla Upinder Singh 
Published: May 2024

AbstractCo-active or temporally ordered neural ensembles are a signature of salient sensory, motor, and cognitive events. Local convergence of such patterned activity as synaptic clusters on dendrites could help single neurons harness the potential of dendritic nonlinearities to decode neural activity patterns. We combined theory and simulations to assess the likelihood of whether projections from neural ensembles could converge onto synaptic clusters even in networks with random connectivity. Using rat hippocampal and cortical network statistics, we show that clustered convergence of axons from 3-4 different co-active ensembles is likely even in randomly connected networks, leading to representation of arbitrary input combinations in at least ten target neurons in a 100,000 population. In the presence of larger ensembles, spatiotemporally ordered convergence of 3-5 axons from temporally ordered ensembles is also likely. These active clusters result in higher neuronal activation in the presence of strong dendritic nonlinearities and low background activity. We mathematically and computationally demonstrate a tight interplay between network connectivity, spatiotemporal scales of subcellular electrical and chemical mechanisms, dendritic nonlinearities, and uncorrelated background activity. We suggest that dendritic clustered and sequence computation is pervasive, but its expression as somatic selectivity requires confluence of physiology, background activity, and connectomics.