bluuebunny/crossref_metadata_2025_split huggingface dataset:
Precuneus activity during retrieval is positively associated with amyloid burden in cognitively normal olderAPOE4carriers
Authors: Fischer Larissa , Molloy Eóin N. , Binette Alexa Pichet , Vockert Niklas , Marquardt Jonas , Pilar Andrea Pacha , Kreissl Michael C. , Remz Jordana , Poirier Judes , Rajah M. Natasha , Villeneuve Sylvia ,   PREVENT-AD Research Group, Maass Anne 
Published: July 2024

AbstractThe precuneus is an early site of amyloid-beta (Aβ) accumulation. Previous cross-sectional studies reported increased precuneus fMRI activity in older adults with mild cognitive deficits or elevated Aβ. However, longitudinal studies in early Alzheimer’s disease (AD) risk stages are lacking and the interaction with Apolipoprotein-E (APOE) genotype is unclear. In the PREVENT-AD cohort, we assessed how precuneus activity during successful memory retrieval at baseline and over time relates to future Aβ and tau burden and to change in memory performance. We further studied the moderation byAPOE4genotype. We included 165 older adults (age: 62.8±4.4 years; 113 female; 66APOE4carriers) who were cognitively normal at baseline and had a family history of AD. All participants performed task-fMRI at baseline and underwent18F-flortaucipir-PET and18F-NAV4694-Aβ-PET on average 5 years later. We found that higher baseline activity and greater longitudinal change in activity in precuneus were associated with higher subsequent Aβ inAPOE4 carriers but not non-carriers. There were no effects of precuneus activity on tau burden. Finally,APOE4non-carriers with low baseline activity in the precuneus exhibited better longitudinal performance in an independent memory test compared toAPOE4non-carriers with high baseline activity andAPOE4carriers. Our findings suggest that higher task-related precuneus activity at baseline and over time are associated with subsequent Aβ burden in cognitively normalAPOE4carriers. Our results further indicate that the absence of hyperactivation and the absence of theAPOE4allele is related with the best future cognitive outcome in cognitively normal older adults at risk for AD.Significance StatementThe precuneus is a brain region involved in episodic memory function and is an early site of amyloid-beta (Aβ) accumulation. Alterations in task-related activity occur in the precuneus with ageing as well as with Alzheimer’s disease (AD) pathology even in the absence of cognitive symptoms; however, their course and implications are not well understood. We demonstrate that higher precuneus activity at baseline and its change over time during successful memory retrieval is associated with higher Aβ burden on average 5 years after baseline in Apolipoprotein-E4 (APOE4)carriers. Lower precuneus baseline activation was related to better memory performance over time inAPOE4non-carriers. Our findings provide novel longitudinal evidence that increased activity in posterior midline regions is linked to early AD pathology in dependence ofAPOE4genotype.
NLRP1B allele 2 does not respond to Val-boro-Pro (VbP) in the intestinal epithelium
Authors: Mazzone Ryan J. , Winsor Nathaniel J. , Li Lu Yi , Barry Kristian T. , Ranger Adrienne , Goyal Shawn , Meade Justin J. , Bruce Jessica , Philpott Dana J. , Mogridge Jeremy , Girardin Stephen E. 
Published: July 2024

ABSTRACTThe intestinal mucosa must balance tolerance to commensal microbes and luminal antigens with rapid detection of enteric pathogens in order to maintain homeostasis. This balance is facilitated through the regulation of epithelial layer integrity by innate immune receptors. Certain NOD-like receptors (NLRs) expressed in intestinal epithelial cells, including NLRC4 and NLRP9B, form inflammasomes that protect against pathogens by activating caspase-1 to cause extrusion of infected cells. NLRP1B is a murine NLR encoded by five alleles of a highly polymorphic gene homologous to human NLRP1. NLRP1B forms inflammasomes in response to a variety of pathogens that cause intestinal infections, but it has almost exclusively been studied in immune cells and has not been characterized in cells of the intestinal epithelium. Here, we show thatNlrp1bis expressed in ileal and colonic organoids derived for C57BL/6J mice.Nlrp1bwas upregulated by interleukin-13 in organoids and by the protozoanTritrichomonas murisin vivo, suggesting that NLRP1B may be involved in defense against enteric parasites. Surprisingly, while Val-boro-Pro (VbP) activated NLRP1B in bone marrow-derived macrophages, it did not activate NLRP1B in organoids. We furthermore did not detectNlrp1bin organoids derived from Balb/cJ mice, which express a different allele than the one expressed in C57BL/6J mice. Together, our results suggest that NLRP1B may have an allele-dependent function in murine IECs whose regulation is distinct from that of macrophages.
ARGX-119, a therapeutic agonist antibody targeting MuSK
Authors: Vanhauwaert Roeland , Oury Julien , Vankerckhoven Bernhardt , Steyaert Christophe , Jensen Stine Marie , Vergoossen Dana L.E. , Kneip Christa , Santana Leah , Lim Jamie L. , Plomp Jaap J. , Augustinus Roy , Koide Shohei , Blanchetot Christophe , Ulrichts Peter , Huijbers Maartje G. , Silence Karen , Burden Steven J. 
Published: July 2024

AbstractARGX-119 is a novel, humanized, agonist monoclonal SIMPLE Antibody™ specific for muscle-specific kinase (MuSK) that is being developed for treatment of patients with neuromuscular diseases. ARGX-119 is the first monoclonal antibody (mAb) that binds with high affinity to the Frizzled-like domain of human, non-human primate, rat and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc-region, ARGX-119 harbors L234A, L235A mutations to diminish potential immune-activating effector functions. Its mode-of-action is to activate MuSK without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors (AChRs) in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model forDOK7congenital myasthenia (CM), ARGX-119 prevented early postnatal lethality and reversed disease relapse by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic (PK) studies in non-human primates, rats and mice revealed non-linear PK behavior of ARGX-119, indicative of target-mediated-drug disposition (TMDD) andin vivotarget engagement. Instability of neuromuscular synapses contributes to symptoms in many neuromuscular diseases for example congenital myasthenia (CM), amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). ARGX-119 is a novel, first-in-class MuSK agonist mAb in clinical development. Based on this proof-of-concept study, it has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function.One sentence summaryARGX-119 is a novel first-in-class MuSK agonist monoclonal antibody in clinical development for treatment of neuromuscular diseases.
Gencube: Efficient retrieval, download, and unification of genomic data from leading biodiversity databases
Authors: Son Keun Hong , Cho Je-Yoel 
Published: July 2024

AbstractMotivationWith the daily submission of numerous new genome assemblies, associated annotations, and experimental sequencing data to genome archives for various species, the volume of genomic data is growing at an unprecedented rate. Major genomic databases are establishing new hierarchical structures to manage this data influx. However, there is a significant need for tools that can efficiently access, download, and integrate genomic data from these diverse repositories, making it challenging for researchers to keep pace.ResultsWe have developedGencube, a command-line tool with two primary functions. First, it facilitates the utility of genome assemblies, related annotations, gene set sequences, and cross-species data from various leading biodiversity databases. Second, it helps researchers intuitively explore experimental sequencing data that meets their needs and consolidates the metadata of the retrieved outputs.Availability and implementationGencubeis a free and open-source tool, with its code available on GitHub:https://github.com/snu-cdrc/gencube.
Exploring the Mechanism of Gentiana in Treating Pancreatic Cancer Based on Network Pharmacology and Molecular Docking Techniques
Authors: Qian Yuanyuan , Wang Zhaojunli , Ji Jiancheng 
Published: July 2024

AbstractObjectiveThis study aims to investigate the mechanism of Gentiana in treating pancreatic cancer using network pharmacology and molecular docking techniques.MethodsActive compounds of Gentiana were screened from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The 3D structures of the active compounds were downloaded from the PubChem database. Reverse docking was performed using the PharmMapper database to identify potential target proteins. Differential gene expression data related to colorectal cancer were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes were selected. Venn diagram analysis was employed to identify common genes between the protein targets and differentially expressed genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool. Molecular docking was performed using ChemDraw 20.0, AutoDock, and PyMOL.ResultsA total of 72 common genes and 15 signaling pathways were identified from the reverse docking data of Gentiana and the pancreatic cancer dataset (GSE196009). Molecular docking results demonstrated favorable binding energies between the active compounds of Gentiana and proteins 1og5, 1pq2, 2bxr, 2bk3, 1u3w, 1wma, 1wuu, 1tdi, 1mlw, 1egc, 1s1p, 1f12, 1m51, 1kqu, 1ls6, 1ry0, 1nhx, and 1db4.ConclusionGentiana may exert its therapeutic effects on pancreatic cancer through a multi-component, multi-target, and multi-pathway mechanism.
CytoNormPy enables a fast and scalable removal of batch effects in cytometry datasets
Authors: Exner Tarik , Hackert Nicolaj , Leomazzi Luca , Van Gassen Sofie , Saeys Yvan , Lorenz Hanns-Martin , Grieshaber-Bouyer Ricardo 
Published: July 2024

AbstractMotivationWe present a python implementation of the widely used CytoNorm algorithm for the removal of batch effects.ResultsOur implementation ran up to 85% faster than its R counterpart, while being fully compatible with common single-cell data structures and -frameworks of python. We extend the previous functionality by adding common clustering algorithms and provide key visualizations of the algorithm and its evaluation.Availability and implementationThe CytoNormPy implementation is freely available on GitHub:https://github.com/TarikExner/CytoNormPy.
PLAbDab-nano: a database of camelid and shark nanobodies from patents and literature
Authors: Gordon Gemma L. , Greenshields-Watson Alexander , Agarwal Parth , Wong Ashley , Boyles Fergus , Hummer Alissa , Lujan Hernandez Ana G. , Deane Charlotte M. 
Published: July 2024

Nanobodies are essential proteins of the adaptive immune systems of camelid and shark species, complementing conventional antibodies. Properties such as their relatively small size, solubility and high thermostability make VHH and VNAR modalities a promising therapeutic format and a valuable resource for a wide range of biological applications. The volume of academic literature and patents related to nanobodies has risen significantly over the past decade. Here, we present PLAbDab-nano, a nanobody complement to the Patent and Literature Antibody Database (PLAbDab). PLAbDab-nano is a selfupdating, searchable repository containing approximately 5000 annotated VHH and VNAR sequences. We describe the methods used to curate the entries in PLAbDab-nano, and highlight how PLAbDab-nano could be used to design diverse libraries, as well as find sequences similar to known patented or therapeutic entries. PLAbDab-nano is freely available as a searchable web server (opig.stats.ox.ac.uk/webapps/plabdab-nano/).Graphical Abstract
Glutamine-addiction in cisplatin resistant cancer cells is mediated by SLC7A11 and can be targeted with asparaginase therapy
Authors: Wang Jiantao , Strauss Robert , Bartek Jiri , Rudd Sean G 
Published: July 2024

AbstractLinking disease phenotypes with molecular targets is key to the rational design of treatment interventions. Resistance to the chemotherapeutic cisplatin is one of the major factors limiting the clinical utility of this therapy, which is central to the treatment of a variety of solid malignancies. In this study, we couple the upregulation of a chemoresistant factor, the glutamate-cystine antiporter SLC7A11, with the addiction of cisplatin-resistant cancer cells to extracellular glutamine. In doing so, we thus provide a putative biomarker for this acquired metabolic dependency of chemoresistance. Subsequently, we evaluate various therapeutic strategies to selectively kill SLC7A11highcisplatin-resistant cancer cells, identifying cross-resistance to ferroptosis-inducing compounds and hypersensitivity to glutaminase inhibitor CB-839. We identify enzymatic depletion of extracellular glutamine using the long-standing anti-leukemic therapy asparaginase (ASNase), which possesses glutaminase activity, as a potential approach, and show this can be successfully combined with cisplatin in cell models. In summary, this study mechanistically links an acquired metabolic dependency of chemoresistant cancer cells with a putative biomarker and provides a potentially actionable strategy to target these drug resistant cells warranting further investigation.
Extending the Acute Skin Response Spectrum to Include the Far-UVC
Authors: Gutierrez-Bayona Natalia E. , Petersen Camryn , Hashmi Raabia H. , Buonanno Manuela , Shuryak Igor , Ponnaiya Brian , Kleiman Norman J. , Brenner David J. , Welch David 
Published: July 2024

ABSTRACTGuidance on maximal limits for ultraviolet (UV) exposure has been developed by national and international organizations to protect against adverse effects on human skin and eyes. These guidelines consider the risk of both acute effects (i.e. erythema and photokeratitis) and delayed effects (e.g., skin and ocular cancers) when determining exposure limits, and specify the dose a person can safely receive during an 8-hour period without harmful effects. The determination of these exposure limits relies on the action spectra of photobiological responses triggered by UV radiation that quantify the effectiveness of each wavelength at eliciting each of these effects. With growing interest in using far-UVC (200-235 nm) radiation to control the spread of airborne pathogens, recent arguments have emerged about revisiting exposure limits for UV wavelengths. However, the standard erythema action spectra, which provides some of the quantitative basis for these limits, has not been extended below 240 nm. This study assists to expand the erythema action spectrum to far-UVC wavelengths using a hairless albino mice model. We estimate that inducing acute effects on mouse skin with 222 nm radiation requires a dose of 1,162 mJ/cm2, well above the current ACGIH skin exposure limit of 480 mJ/cm2.
A distinct Down state assembly in retrosplenial cortex during slow-wave sleep
Authors: Opalka Ashley N , Dougherty Kimberly J , Wang Dong V 
Published: July 2024

ABSTRACTUnderstanding the intricate mechanisms underlying slow-wave sleep (SWS) is crucial for deciphering the brain’s role in memory consolidation and cognitive functions. It is well-established that cortical delta oscillations (0.5–4 Hz) coordinate communications among various cortical, hippocampal, and thalamic regions during SWS. These delta oscillations have periods of Up and Down states, with the latter previously thought to represent complete cortical silence; however, new evidence suggests that Down states serve important functions for information exchange during memory consolidation. The retrosplenial cortex (RSC) stands out for its pivotal role in memory consolidation due to its extensive connectivity with memory-associated regions, although it remains unclear how RSC neurons engage in delta-associated consolidation processes. Here, we employed multi-channelin vivoelectrophysiology to study RSC neuronal activity in freely behaving mice during natural SWS. We discovered that the RSC contains a discrete assembly of putative excitatory neurons (∼20%) that initiated firing at SWS Down states and reached maximal firing at the Down-to-Up transitions. Therefore, we termed these RSC neurons the Down state assembly (DSA), and the remaining RSC excitatory neurons as non-DSA. Compared to non-DSA, DSA neurons exhibit a higher firing rate, larger cell body size, and no connectivity with nearby RSC neurons. Subsequently, we investigated RSC neuronal activity during a contextual fear conditioning paradigm and found that both DSA and non-DSA neurons exhibited increased firing activity during post-training sleep compared to pre-training sleep, indicating their roles in memory consolidation. Lastly, optogenetics combined with electrophysiology revealed that memory-associated inputs differentially innervated RSC excitatory neurons. Collectively, these findings provide insight on distinct RSC neuronal subpopulation activity in sleep and memory consolidation.
Long-lived adult-born hippocampal neurons promote successful cognitive aging
Authors: Blin Nicolas , Charrier Vanessa , Farrugia Fanny , Cartier Estelle , Pacary Emilie , Koehl Muriel , Lois Carlos , Lie Dieter Chichung , Masachs Nuria , Abrous Djoher Nora 
Published: July 2024

AbstractAging is commonly associated with a decline in memory abilities, yet some individuals remain resilient with preserved memory abilities. Memory processing is critically dependent on adult neurogenesis, a unique form of plasticity in the hippocampus. However, it remains unknown if cognitive aging influences the integration and role of adult-born hippocampal neurons (ABNs) generated early in adult life. Here, we investigated the role of long-lived ABNs in rats characterized as either resilient or vulnerable to cognitive aging using a peudo-longitudinal approach. Our findings reveal that long-lived ABNs support successful cognitive aging by preserving their synaptic inputs onto the proximal segments of their dendrites, and that these proximal synaptic sites also demonstrate a maintenance of their mitochondrial homeostasis. Furthermore, by-passing the reduced inputs of ABNs in vulnerable rats through direct optogenetic stimulation successfully improved their memory abilities. Overall, our data indicate that the maintenance of long-lived ABNs integration within the neuronal network is essential for successful cognitive aging, highlighting their potential as a therapeutic target for restoring cognitive functions in old age.Graphical abstract
Mitochondria affect photosynthesis through altered tissue levels of oxygen
Authors: Punkkinen Matleena , Blokhina Olga , Peralta Ogorek Lucas León , Kim Minsoo , Fagerstedt Kurt , Vierling Elizabeth , Pedersen Ole , Shapiguzov Alexey 
Published: July 2024

AbstractInteractions between plant energy organelles, the chloroplasts and the mitochondria, are crucial for plant development and acclimation. These interactions occur at different levels including exchange of metabolites and reducing power, organelle signaling pathways and intracellular gas exchange. Mitochondrial retrograde stress signaling activates expression of nuclear genes encoding mitochondrial components, including alternative oxidases. High abundances of these respiratory enzymes coincide not only with the changes in plant respiration but also with alterations in the chloroplast. For example, plants that overexpress alternative oxidases are tolerant to methyl viologen, a redox-active compound that catalyzes transfer of electrons from Photosystem I to molecular oxygen. The mechanism of this inter-organelle interaction is unclear but could be related to diminished availability of tissue oxygen. Here we assessed respiration, photosynthesis andin vivolevels of oxygen in a set of Arabidopsis lines with perturbations in diverse mitochondrial functions, including defects in respiratory complex I, mitochondrial protein processing, transcription, nucleoid organization, altered fission and architecture or suppressed ATP synthase activity. In these lines, the increased abundance and activity of alternative oxidases strongly correlated with higher oxygen consumption in darkness, lower oxygen re-accumulation in light, and diminished effects of methyl viologen in chloroplasts. These results support the hypothesis that increased mitochondrial oxygen sink capacity affects photosynthesis by decreasing oxygen levels in tissues. This phenomenon can be one of the reasons for the impact that stressed mitochondria have on chloroplasts and photosynthesis. It contributes to our understanding of the mechanisms of hypoxia establishment and acclimation in plants.
A Ketogenic Diet Sensitizes Pancreatic Cancer to Inhibition of Glutamine Metabolism
Authors: Hajihassani Omid , Zarei Mehrdad , Roichman Asael , Loftus Alexander , Boutros Christina S. , Hue Jonathan , Naji Parnian , Boyer Jacob , Tahan Soubhi , Gallagher Peter , Beegan William , Choi James , Lei Shihong , Kim Christine , Rathore Moeez , Nakazzi Faith , Shah Ishan , Lebo Kevin , Cheng Helen , Mudigonda Anusha , Alibeckoff Sydney , Ji Karen , Graor Hallie , Miyagi Masaru , Vaziri-Gohar Ali , Brunengraber Henri , Wang Rui , Lund Peder J. , Rothermel Luke D. , Rabinowitz Joshua D. , Winter Jordan M. 
Published: July 2024

AbstractPancreatic cancer is the third leading cause of cancer death in the United States, and while conventional chemotherapy remains the standard treatment, responses are poor. Safe and alternative therapeutic strategies are urgently needed1. A ketogenic diet has been shown to have anti-tumor effects across diverse cancer types but will unlikely have a significant effect alone. However, the diet shifts metabolism in tumors to create new vulnerabilities that can be targeted (1). Modulators of glutamine metabolism have shown promise in pre-clinical models but have failed to have a marked impact against cancer in the clinic. We show that a ketogenic diet increases TCA and glutamine-associated metabolites in murine pancreatic cancer models and under metabolic conditions that simulate a ketogenic dietin vitro.The metabolic shift leads to increased reliance on glutamine-mediated anaplerosis to compensate for low glucose abundance associated with a ketogenic diet. As a result, glutamine metabolism inhibitors, such as DON and CB839 in combination with a ketogenic diet had robust anti-cancer effects. These findings provide rationale to study the use of a ketogenic diet with glutamine targeted therapies in a clinical context.Graphical AbstractGraphical Abstract Description:Mechanistic rationale for combining a ketogenic diet and glutamine metabolism inhibitors.The combination of low glucose from a ketogenic diet and pharmacologic glutamine inhibition impairs nutrient input to mitochondria, reducing cancer growth.