bluuebunny/crossref_metadata_2025_split huggingface dataset:
From Eggs to Guts: Symbiotic Association ofSodalis nezaraesp. nov. with the Southern Green Shield BugNezara viridula
Authors: Rogowska-van der Molen Magda A. , Manzano-Marín Alejandro , Postma Jelle L. , Coolen Silvia , van Alen Theo , Jansen Robert S. , Welte Cornelia U. 
Published: October 2024

AbstractPhytophagous insects engage in symbiotic relationships with bacteria that contribute to digestion, nutrient supplementation, and development of the host. The analysis of shield bug microbiomes has been mainly focused on the gut intestinal tract predominantly colonized byPantoeasymbionts, and other microbial community members in the gut or other organs have hardly been investigated. In this study, we reveal that the Southern green shield bugNezara viridulaharbours aSodalissymbiont in several organs, with a notable prevalence in salivary glands, and anterior regions of the midgut. Removing external egg microbiota via sterilization profoundly impacted insect viability but did not disrupt the vertical transmission ofSodalisandPantoeasymbionts. Based on the dominance ofSodalisin testes, we deduce thatN. viridulamales could be involved in symbiont vertical transmission. Genomic analyses comparingSodalisspecies revealed thatSodalissp. Nvir shares characteristics with both free- living and obligate insect-associatedSodalisspp.Sodalissp. Nvir also displays genome instability typical of endosymbiont lineages, which suggests ongoing speciation to an obligate endosymbiont. Together, our study reveals that shield bugs harbour unrecognized symbionts that might be paternally transmitted.
ACSS2 regulates ferroptosis in an E2F1-dependent manner in breast cancer brain metastatic cells
Authors: Esquea Emily M. , Young Riley G. , Ciraku Lorela , Merzy Jessica , Ahmed Nusaiba N. , Talarico Alexandra N. , Karuppiah Mangalam , Gocal Wiktoria , Simone Nicole L. , Dick Alexej , Reginato Mauricio J. 
Published: October 2024

ABSTRACTBrain metastasis diagnosis in breast cancer patients is considered an end-stage event. The median survival after diagnosis is measured in months, thus there is an urgent need to develop novel treatment strategies. Breast cancers that metastasize to the brain must adapt to the unique brain environment and are highly dependent on acetate metabolism for growth and survival. However, the signaling pathways that regulate survival in breast cancer brain metastatic (BCBM) tumors are not known. Primary brain tumor cells can convert acetate to acetyl-CoA via phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by the cyclin-dependent kinase-5 (CDK5) regulated by the nutrient sensor O-GlcNAc transferase (OGT). Here, we show that breast cancer cells selected to metastasize to the brain contain increased levels of O-GlcNAc, OGT and ACSS2-Ser267 phosphorylation compared to parental breast cancer cells. Moreover, OGT and CDK5 are required for breast cancer cell growth in the brain parenchymain vivo.Importantly, ACSS2 and ACSS2-S267D phospho-mimetic mutant are critical forin vivobreast cancer growth in the brain but not in the mammary fat pad. Mechanistically, we show that ACSS2 regulates BCBM cell survival by suppressing ferroptosis via regulation of E2F1-mediated expression of anti-ferroptotic proteins SLC7A11 and GPX4. Lastly, we show treatment with a novel brain-permeable small molecule ACSS2 inhibitor induced ferroptosis and reduced BCBM growthex vivoandin vivo. These results suggest a crucial role for ACSS2 in protecting from ferroptosis in breast cancer brain metastatic cells and suggests that breast cancer brain metastatic cells may be susceptible to ferroptotic inducers.
NUDIX Hydrolases Target Specific Inositol Pyrophosphates and Regulate Phosphate and Iron Homeostasis, and the Expression of Defense Genes in Arabidopsis
Authors: Schneider Robin , Lami Klea , Prucker Isabel , Stolze Sara Christina , Strauß Annett , Langenbach Kevin , Kamleitner Marília , Belay Yemisrach Zewdu , Ritter Kevin , Furkert David , Gaugler Philipp , Lange Esther , Faiß Natalie , Schmidt Julie Marie , Harings Michael , Krusenbaum Lukas , Wege Stefanie , Kriescher Simon ,   The Jeremy, Schoof Heiko , Fiedler Dorothea , Nakagami Hirofumi , Giehl Ricardo F. H. , Lahaye Thomas , Jessen Henning J. , Gaugler Verena , Schaaf Gabriel 
Published: October 2024

AbstractInositol pyrophosphates (PP-InsPs) are important signaling molecules that regulate diverse cellular processes in eukaryotes, including energy homeostasis and phosphate (Pi) signaling. However, the enzymes responsible for their turnover in plants remain largely unknown. Using a non-hydrolysable PP-InsP analog in a pull-down approach, we identified a family of Arabidopsis Nudix hydrolases (NUDTs) that group into two closely related subclades. Throughin vitroassays, heterologous expression systems, and higher-order gene-edited mutants, we explored the substrate specificities and physiological roles of these hydrolases. Using a combination of strong anion exchange (SAX)-HPLC, PAGE, and capillary electrophoresis electrospray ionization mass spectrometry (CE-ESI-MS), we found that their PP-InsP pyrophosphatase activity is enantiomer-selective and Mg2+-dependent. Specifically, subclade I NUDTs preferentially hydrolyze 4-InsP7, while subclade II NUDTs target 3-InsP7, with minor activity against other PP-InsPs, including 5-InsP7. In higher-order mutants of subclade II NUDTs, we observed defects in both Piand iron homeostasis, accompanied by increased levels of 1/3-InsP7and 5-InsP7, with a markedly larger increase in 1/3-InsP7. Furthermore, ectopic expression of NUDTs from both subclades induced local Pistarvation responses (PSRs). However, RNA-seq analysis of WT andnudt12/13/16plants suggests that these NUDTs have PSR-independent roles, potentially involving 1/3-InsP7in the regulation of plant defense. Expanding beyond subclade II NUDTs, we demonstrated susceptibility of the 3PP-position of PP-InsPs to enzymatic activities unrelated to NUDTs, and found that such activities are conserved across plants and humans. Additionally, we found that NUDT effectors from pathogenic ascomycete fungi exhibit a substrate specificity similar to subclade I NUDTs. Collectively, our study provides new insights into the roles of NUDTs in regulating PP-InsP signaling pathways in plants and highlights cross-kingdom conservation of enzymes involved in PP-InsP metabolism.
Conserved principles of spatial biology define tumor heterogeneity and response to immunotherapy
Authors: Behera Vivek , Giba Hannah , Pen Ue-Yu , Di Lello Anna , Doran Benjamin A. , Esposito Alessandra , Pezeshk Apameh , Bestvina Christine M. , Kline Justin , Garassino Marina C. , Raman Arjun S. 
Published: October 2024

AbstractThe tumor microenvironment (TME) is an immensely complex ecosystem1,2. This complexity underlies difficulties in elucidating principles of spatial organization and using molecular profiling of the TME for clinical use3. Through statistical analysis of 96 spatial transcriptomic (ST-seq) datasets spanning twelve diverse tumor types, we found a conserved distribution of multicellular, transcriptionally covarying units termed ‘Spatial Groups’ (SGs). SGs were either dependent on a hierarchical local spatial context – enriched for cell-extrinsic processes such as immune regulation and signal transduction – or independent from local spatial context – enriched for cell-intrinsic processes such as protein and RNA metabolism, DNA repair, and cell cycle regulation. We used SGs to define a measure of gene spatial heterogeneity – ‘spatial lability’ – and categorized all 96 tumors by their TME spatial lability profiles. The resulting classification captured spatial variation in cell-extrinsic versus cell-intrinsic biology and motivated class-specific strategies for therapeutic intervention. Using this classification to characterize pre-treatment biopsy samples of 16 non-small cell lung cancer (NSCLC) patients outside our database distinguished responders and non-responders to immune checkpoint blockade while programmed death-ligand 1 (PD-L1) status and spatially unaware bulk transcriptional markers did not. Our findings show conserved principles of TME spatial biology that are both biologically and clinically significant.
Computational design of bifaceted protein nanomaterials
Authors: Rankovic Sanela , Carr Kenneth D. , Decarreau Justin , Skotheim Rebecca , Kibler Ryan D. , Ols Sebastian , Lee Sangmin , Chun Jung-Ho , Tooley Marti R. , Dauparas Justas , Eisenach Helen E. , Glögl Matthias , Weidle Connor , Borst Andrew J. , Baker David , King Neil P. 
Published: October 2024

AbstractRecent advances in computational methods have led to considerable progress in the design of self-assembling protein nanoparticles. However, nearly all nanoparticles designed to date exhibit strict point group symmetry, with each subunit occupying an identical, symmetrically related environment. This limits the structural diversity that can be achieved and precludes anisotropic functionalization. Here, we describe a general computational strategy for designing multi-component bifaceted protein nanomaterials with two distinctly addressable sides. The method centers on docking pseudosymmetric heterooligomeric building blocks in architectures with dihedral symmetry and designing an asymmetric protein-protein interface between them. We used this approach to obtain an initial 30-subunit assembly with pseudo-D5 symmetry, and then generated an additional 15 variants in which we controllably altered the size and morphology of the bifaceted nanoparticles by designingde novoextensions to one of the subunits. Functionalization of the two distinct faces of the nanoparticles withde novoprotein minibinders enabled specific colocalization of two populations of polystyrene microparticles coated with target protein receptors. The ability to accurately design anisotropic protein nanomaterials with precisely tunable structures and functions could be broadly useful in applications that require colocalizing two or more distinct target moieties.
Rapid Hippocampal Synaptic Potentiation Induced by Ketamine Metabolite (2R,6R)-Hydroxynorketamine Persistently Primes Synaptic Plasticity
Authors: Brown Kyle A. , Ajibola Musa I. , Gould Todd D. 
Published: October 2024

ABSTRACTThe pharmacologically active (R,S)-ketamine (ketamine) metabolite (2R,6R)-hydroxynorketamine (HNK) maintains ketamine’s preclinical antidepressant profile without adverse effects. While hypotheses have been proposed to explain how ketamine and its metabolites initiate their antidepressant-relevant effects, it remains unclear how sustained therapeutic actions arise following drug elimination. To distinguish the physiological mechanisms involved in the rapid from sustained actions of HNK, we utilized extracellular electrophysiology combined with pharmacology to develop anin vitrohippocampal slice incubation model that exhibited pharmacological fidelity to the 1) rapid synaptic potentiation induced by HNK at the Schaffer collateral-CA1 (SC-CA1) synapse during bath-application to slices collected from mice, and 2) maintenance of metaplastic (priming) activity that lowered the threshold forN-methyl-D-aspartate receptor (NMDAR) activation-dependent long-term potentiation (LTP) hours afterin vivodosing. We then used this model to reveal novel druggable mechanisms engaged in HNK’s temporally-sensitive antidepressant synaptic actions, finding that the induction of synaptic potentiation by HNK did not require NMDAR activity, but NMDAR activity was necessary to maintain synaptic priming. HNK required protein kinase A (PKA) activity to rapidly potentiate SC-CA1 neurotransmission to facilitate synaptic priming that persistently promoted LTP formation. HNK’s rapid actions were blocked by inhibitors of adenylyl cyclase 1 (AC1), but not an AC5 inhibitor. We conclude that HNK rapidly potentiates SC-CA1 synaptic efficacy, which then stimulates priming mechanisms that persistently favor antidepressant-relevant plasticity. Targeting such priming mechanisms may be an effective antidepressant strategy, and using approaches such as our incubation model may aid in revealing novel pharmacological targets.
Mitochondrial small RNA alterations associated with increased lysosome activity in an Alzheimer’s Disease Mouse Model uncovered by PANDORA-seq
Authors: Zhang Xudong , Shi Junchao , Thakore Pratish , Gonzales Albert L. , Earley Scott , Chen Qi , Zhou Tong , Earley Yumei Feng 
Published: October 2024

AbstractEmerging small noncoding RNAs (sncRNAs), including tRNA-derived small RNAs (tsRNAs) and rRNA-derived small RNAs (rsRNAs), are critical in various biological processes, such as neurological diseases. Traditional sncRNA-sequencing (seq) protocols often miss these sncRNAs due to their modifications, such as internal and terminal modifications, that can interfere with sequencing. We recently developed panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq), a method enabling comprehensive detection of modified sncRNAs by overcoming the RNA modifications. Using PANDORA-seq, we revealed a novel sncRNA profile enriched by tsRNAs/rsRNAs in the mouse prefrontal cortex and found a significant downregulation of mitochondrial tsRNAs and rsRNAs in an Alzheimer’s disease (AD) mouse model compared to wild-type controls, while this pattern is not present in the genomic tsRNAs and rsRNAs. Moreover, our integrated analysis of gene expression and sncRNA profiles reveals that those downregulated mitochondrial sncRNAs negatively correlate with enhanced lysosomal activity, suggesting a crucial interplay between mitochondrial RNA dynamics and lysosomal function in AD. Given the versatile tsRNA/tsRNA molecular actions in cellular regulation, our data provide insights for future mechanistic study of AD with potential therapeutic strategies.Graphical Abstract
Early life factors and dementia risk: A study of adverse childhood experiences and later-life cognition and behaviour
Authors: Mudalige Dinithi , Guan Dylan X. , Ballard Clive , Creese Byron , Corbett Anne , Pickering Ellie , Hampshire Adam , Roach Pamela , Smith Eric E. , Ismail Zahinoor 
Published: October 2024

ABSTRACTIntroductionAdverse childhood experiences (ACEs) are associated with brain alterations and cognitive decline. In later life, cognitive impairment and mild behavioural impairment (MBI) are associated with greater dementia risk.Objective & Study DesignWe investigated whether more severe ACEs are cross-sectionally associated with worse later-life cognitive and behavioural symptoms.MethodData are from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN-PROTECT). Measures included the Childhood Trauma Screener (CTS-5), neuropsychological testing, Everyday Cognition (ECog)-II scale, and MBI Checklist (MBI-C). Linear regressions modelled associations between ACEs severity and neuropsychological test scores. Multivariable negative binomial regressions (zero-inflated, if appropriate) modelled associations between ACEs severity and ECog-II and MBI-C scores. All models controlled for age, sex, education, and ethnocultural origin. Clinical diagnoses of depression and/or anxiety were explored as covariates or mediators.ResultsIn adjusted analyses, higher ACEs scores were associated with worse performance on Trail-Making B (standardized b=0.10, q=0.003), Switching Stroop (b=-0.08, q=0.027), Paired Associates Learning (b=-0.08, q=0.049), and Digit Span (b=-0.08, q=0.029). Higher ACEs scores were also associated with higher ECog-II (b=1.08, q=0.029) and MBI-C (b=1.20, q<0.001) scores; these associations were neither mediated by affective symptoms (ECog p=0.16; MBI p=0.13) nor moderated by sex (ECog p=0.09; MBI p=0.46).ConclusionOlder adults with a history of more severe ACEs show greater cognitive and behavioural risk markers for dementia that cannot be explained by previous psychiatric history. Further research into ACEs as an early modifiable risk factor for dementia is warranted.
Psychological Variables Mediate Symptoms in Persistent Postural-Perceptual Dizziness (PPPD): A Cross-Sectional Self-Report Study
Authors: Sereda Ariel , Lam Ju Cheng , Hazar Ali-Mert , Ellmers Toby , Golding John , Kaski Diego 
Published: October 2024

AbstractBackgroundPersistent Postural-Perceptual Dizziness (PPPD) is a prevalent long-term functional neurological disorder characterised by non-spinning vertigo, perceived instability, and visual motion sensitivity. Current diagnostic criteria inadequately incorporate psychological variables widely associated with PPPD symptom onset and maintenance.ObjectivesThis study explored PPPD-specific psychological variables to differentiate PPPD patients from healthy controls and, exploratorily, from Bilateral Vestibulopathy (BVP) patients. We evaluated these variables as potential treatment targets through mediation analysis. Our aim was to inform more precise diagnostic criteria and guide targeted interventions for PPPD.MethodsWe conducted a cross-sectional study with 164 participants, including 59 diagnosed cases of PPPD, 16 cases of BVP, and 89 healthy controls. Participants completed a series of questionnaires assessing negative illness perception, balance vigilance, anxiety, visual sensitivity, dizziness and other related metrics.ResultsPsychological variables, particularly anxiety, cognitive fusion, and justice appraisal significantly mediated the relationship between key PPPD symptoms (dizziness, visual sensitivity, and balance vigilance) and PPPD diagnosis compared to healthy controls. Logistic regression suggested psychological differences between PPPD and BVP, but limited BVP sample size constrained generalisability. Between PPPD and healthy controls, psychological variables significantly improved classification accuracy compared to measures of dizziness alone.ConclusionIncorporating psychological variables in the diagnosis and management of PPPD could enhance the understanding of the disorder and may aid in developing better-targeted interventions. The study supports revising existing diagnostic criteria to include validated psychological assessments and highlights the potential of treatments addressing cognitive and emotional aspects of PPPD to improve patient outcomes.
Neural and behavioral reinstatement jointly reflect retrieval of narrative events
Authors: Nau Matthias , Greene Austin , Tarder-Stoll Hannah , Lossio-Ventura Juan Antonio , Pereira Francisco , Chen Janice , Baldassano Christopher , Baker Chris I. 
Published: October 2024

AbstractWhen recalling past events, patterns of gaze position and neural activity resemble those observed during the original experience. We hypothesized that these two phenomena, known as gaze reinstatement and neural reactivation, are linked through a common process that underlies the reinstatement of past experiences during memory retrieval. Here, we tested this proposal based on the viewing and recall of a narrative movie, which we assessed through fMRI, deep learningbased gaze prediction, and language modeling of spoken recall. In line with key predictions, gaze behavior adhered to the same principles as neural activity; it was event-specific, robust across individuals, and generalized across viewing and recall. Additionally, gaze-dependent brain activity overlapped substantially across tasks. Collectively, these results suggest that retrieval engages mechanisms that direct our eyes during natural vision, reflecting common constraints within the functional organization of the nervous system. Moreover, they highlight the importance of considering behavioral and neural reinstatement together in our understanding of remembering.
Specialized cells and transporters mediate integument-absorption of environmental peptides in cichlids larvae
Authors: Con Pazit , Cnaani Avner 
Published: October 2024

AbstractNutrient absorption through the skin and gills into the organisms’ tissues has been documented in several aquatic invertebrates from different phyla. However, the actual absorption mechanism is still unknown. In teleost fish, as in all jawed vertebrates, intestinal absorption is considered as the sole source of nutrients. The proton-dependent peptide transporters (PepT) of theslc15agene family are the only known mechanism for cellular absorption of di- and tri-peptides within the animal kingdom. In this study, we explored the expression and localization of PepT2 in Mozambique tilapia (Oreochromis mossambicus) larvae. Transcript levels of PepT2 in dissected yolk-sacs from larvae showed significant expression during the larval developmental period. Immunofluorescence staining of PepT2 with Na/K-ATPase (NKA) and Na+/K+/2Cl-co-transporter (NKCC) on the yolk-sac membrane revealed co-staining with NKA and differential-staining with NKCC. While NKA staining was observed on the ionocytes’ basolateral membrane, PepT2 staining was restricted to the apical pit of the ionocytes, facing the surrounding water. In this study, we identified a nutrient transporter located on integument-specific cells, facing the outside aquatic environment. This is the first indication of environmental nutrients absorption in teleosts, and the first evidence of a possible absorption mechanism through PepT2, in specialized yolk-sac ionocytes.
Glutamine Transport via Neurotransmitter Transporter 4 (NTT4, SLC6A17) Maintains Presynaptic Glutamate Supply at Excitatory Synapses in the Central Nervous System
Authors: Nicoli Angela L. , Al Abed A. Shaam , Hulme Sarah R. , Das Abhijit , Gauthier-Coles Gregory , Bröer Angelika , Balkrishna Sarojini , Burgio Gaetan , Dehorter Nathalie , Rae Caroline D. , Bröer Stefan , Billups Brian 
Published: October 2024

AbstractThe glutamate-glutamine cycle is thought to be the principle metabolic pathway that recycles glutamate at excitatory synapses. In this cycle, synaptically released glutamate is sequestered by astrocytes and converted to glutamine before being returned to the presynaptic terminal for conversion back into glutamate to replenish the neurotransmitter pool. While many aspects of this cycle have been extensively studied, a key component remains unknown: the nature of the transporter responsible for the presynaptic uptake of glutamine. We hypothesise that neurotransmitter transporter 4 (NTT4/SLC6A17) plays this role. Accordingly, we generated NTT4 knockout mice to assess its contribution to presynaptic glutamine transport and synaptic glutamate supply. Using biochemical tracing of [1-13C] glucose and [1,2-13C] acetate in awake mice, we observe a reduction of neuronal glutamate supply when NTT4 is absent. In addition, direct electrical recording of hippocampal mossy fibre boutons reveals a presynaptic glutamine transport current that is entirely inhibited by genetic or pharmacological elimination of NTT4. The role of NTT4 in neurotransmission was demonstrated by electrophysiological recordings in acute hippocampal slices, which reveal that NTT4 is required to maintain vesicular glutamate content and to sustain adequate levels of glutamate supply during periods of high-frequency neuronal activity. Finally, behavioural studies in mice demonstrate a deficit in trace fear conditioning; a hippocampus-dependent memory paradigm, and abnormalities in nest building, anxiety behaviour, and social preference. These results demonstrate that NTT4 is a presynaptic glutamine transporter which is a central component of the glutamate-glutamine cycle. NTT4 and hence the glutamate-glutamine cycle maintain neuronal glutamate supply for excitatory neurotransmission during high-frequency synaptic activity, and are key regulators of memory retention and normal behaviour.