bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cell-autonomous GP130 activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment
Authors: Sternberg Christina , Limberger Tanja , Raigel Martin , Trachtová Karolína , Schlederer Michaela , Lindner Desiree , Kodajova Petra , Yang Jiaye , Ziegler Roman , Neubauer Heidi A. , Dey Saptaswa , Redmer Torben , Stoiber Stefan , Hejret Václav , Tichy Boris , Tomberger Martina , Harbusch Nora S. , Tangermann Simone , Oberhuber Monika , Bystry Vojtech , Persson Jenny L. , Pospisilova Sarka , Wolf Peter , Sternberg Felix , Högler Sandra , Lagger Sabine , Rose-John Stefan , Kenner Lukas 
Published: February 2024

AbstractProstate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles GP130-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. Here, we find that genetic cell-autonomous activation of the GP130 receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growthin vivo. Mechanistically, genetic activation of GP130 signaling mediates senescence via the STAT3/ARF/p53 axis and anti-tumor immunity via recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, highGP130mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. Our findings reveal a context-dependent role of GP130/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development. We challenge the prevailing concept of blocking GP130/STAT3 signaling as functional prostate cancer treatment and instead propose cell-autonomous GP130 activation as a novel therapeutic strategy.
Scalable nonparametric clustering with unified marker gene selection for single-cell RNA-seq data
Authors: Nwizu Chibuikem , Hughes Madeline , Ramseier Michelle L. , Navia Andrew W. , Shalek Alex K. , Fusi Nicolo , Raghavan Srivatsan , Winter Peter S. , Amini Ava P. , Crawford Lorin 
Published: February 2024

AbstractClustering is commonly used in single-cell RNA-sequencing (scRNA-seq) pipelines to characterize cellular heterogeneity. However, current methods face two main limitations. First, they require user-specified heuristics which add time and complexity to bioinformatic workflows; second, they rely on post-selective differential expression analyses to identify marker genes driving cluster differences, which has been shown to be subject to inflated false discovery rates. We address these challenges by introducing nonparametric clustering of single-cell populations (NCLUSION): an infinite mixture model that leverages Bayesian sparse priors to identify marker genes while simultaneously performing clustering on single-cell expression data. NCLUSION uses a scalable variational inference algorithm to perform these analyses on datasets with up to millions of cells. By analyzing publicly available scRNA-seq studies, we demonstrate that NCLUSION (i) matches the performance of other state-of-the-art clustering techniques with significantly reduced runtime and (ii) provides statistically robust and biologically relevant transcriptomic signatures for each of the clusters it identifies. Overall, NCLUSION represents a reliable hypothesis-generating tool for understanding patterns of expression variation present in single-cell populations.
Hemilineage-specific expression of the RHG genesGrimandReapersculpt neural network composition duringDrosophilaneurogenesis
Authors: Sproston Connor J , Rak Julia E , Kondo Shu , Williams Darren W 
Published: February 2024

AbstractDuring development, nervous systems generate an incredible diversity of different cell types. One mechanism that appears critical for controlling whether a specific subtype is present or absent, and ensuring that neuronal numbers are appropriate for specific regions, is programmed cell death.Here we show that the precisely patterned hemilineage-based cell death found in the ventral nerve cord ofDrosophila melanogasteris controlled by the transcription of the pro-apoptotic RHG genesreaperandgrim.Using smFISH we show thatreaperandgrim, but nothid, are expressed in postembryonic lineages during neurogenesis. By generating novel T2A-GAL4 knock-in tools we have been able to mapreaperandgrimexpression on a lineage-by-lineage basis and show diverse expression patterns within different hemilineage populations. Analysis of null mutants for both genes reveal a ‘division of labour’ with distinct combinations being important in sculpting the nervous system.Investigation of a specific sexually dimorphic lineage reveals temporal patterning of hemilineage-specific programmed cell death through Grim and Reaper function underpins the development of sex-specific circuitry in the VNC.Our findings suggest that the precisely patterned expression of these pro-apoptotic genes is a critical fate determinant that generates segmental-specific circuity and instructs the appropriate assembly of sexually dimorphic neural circuits in the VNC.
Single-cell and Spatial Transcriptomics Identified Fatty Acid-binding Proteins Controlling Endothelial Glycolytic and Arterial Programming in Pulmonary Hypertension
Authors: Liu Bin , Yi Dan , Li Shuai , Ramirez Karina , Xia Xiaomei , Cao Yanhong , Zhao Hanqiu , Tripathi Ankit , Qiu Shenfeng , Kala Mrinalini , Rafikov Ruslan , Gu Haiwei , Perez Vinicio de jesus , Lemay Sarah-Eve , Glembotski Christopher C. , Knox Kenneth S , Bonnet Sebastien , Kalinichenko Vladimir V. , Zhao You-Yang , Fallon Michael B. , Boucherat Olivier , Dai Zhiyu 
Published: February 2024

AbstractPulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Single-cell RNA sequencing (scRNAseq) analysis found that both FABP4 and FABP5 were highly induced in endothelial cells (ECs) ofEgln1Tie2Cre(CKO) mice, which was also observed in pulmonary arterial ECs (PAECs) from idiopathic PAH (IPAH) patients, and in whole lungs of pulmonary hypertension (PH) rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters using plasma proteome analysis. Genetic deletion of bothFabp4and 5 in CKO mice (Egln1Tie2Cre/Fabp4-5-/-, TKO) caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure assessed by echocardiography, hemodynamic and histological analysis. Employing bulk RNA-seq and scRNA-seq, and spatial transcriptomic analysis, we showed thatFabp4/5deletion also inhibited EC glycolysis and distal arterial programming, reduced ROS and HIF-2α expression in PH lungs. Thus, PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.
SLC-25A46 Regulates Mitochondrial Fusion through FZO-1/Mitofusin and is Essential for Maintaining Neuronal Morphology
Authors: Obinata Hiroyuki , Takahashi Hironori , Shimo Satoshi , Oda Toshiyuki , Sugimoto Asako , Niwa Shinsuke 
Published: February 2024

AbstractMitochondria are dynamic organelles shaped by sequential fission and fusion events. The mitochondrial protein SLC25A46 has been identified as a causative gene for mitochondrial neuropathies. However, the function of SLC25A46 in mitochondrial morphogenesis remains controversial, with several reports suggesting it acts as a mitochondrial fission factor, while others propose it as a fusion factor. In this study, employing forward genetics, we identifiedslc-25A46, aCaenorhabditis elegansorthologue of human SLC25A46, as an essential factor for mitochondrial fusion. Suppressor mutagenesis screening revealed loss-of-function mutations indrp-1, a mitochondrial fission factor, as suppressors ofslc-25A46. The phenotype ofslc-25A46mutants is similar to those offzo-1mutants, wherein the mitochondrial fusion factor Mitofusin is disrupted. Overexpressing FZO-1/Mitofusin mitigated mitochondrial defects inslc-25a46mutants, indicating SLC-25A46 promotes fusion through FZO-1/Mitofusin. Disease model worms carrying mutations associated with SLC25A46 exhibited mitochondrial fragmentation and accelerated neurodegeneration, suggestingslc-25A46maintains neuronal morphology through mitochondrial fusion regulation.
Oncogenic STIL-mediated loss of BRCA1 functionality causes DNA damage and centrosome amplification
Authors: Sanghi Srishti , Singh Priyanka 
Published: February 2024

ABSTRACTDNA damages increase centrosome number, a typical phenotype in many cancers. However, the molecular linkers between the two pathways remain elusive. STIL (SCL/TAL1 Interrupting locus) is a core centrosome-organizing protein overexpressed in different cancer types. This work shows that STIL forms a complex with the DNA damage response protein, BRCA1, and is required for regulating its protein stability. Subsequently, STIL depletion resulting in BRCA1 loss from the nucleus causes centrosome amplification and DNA damage. We also identified a heterozygous missense mutation (S76L) in STIL from the pan-cancer datasets, which does not affect total BRCA1 protein levels. However, it reduces BRCA1 nuclear localization with enhanced centrosome recruitment simultaneously at the S-phase. The enhanced BRCA1 at centrosome causes an increase in Aurora-A kinase levels at centrosomes, thus culminating in DNA damage and centrosome amplification. The expression of exogenous BRCA1 can push back this imbalance of the STIL-BRCA1 axis in oncogenic conditions. The amplified centrosomes in oncogenic STIL condition cluster in the M phase and cause pseudo-bipolar spindle organization. We could decluster them by the HSET(KIFC1)-specific inhibitor, CW069, suggesting a promising target for anti-cancer treatment.
Supramodal neural information supports stimulus-driven attention across cortical levels
Authors: Niedernhuber Maria , Fardo Francesca , Allen Micah , Bekinschtein Tristan 
Published: February 2024

AbstractSensory systems utilise stimulus-driven attention to survey the environment for significant features. The question arises: are the cortical networks that influence stimulus-driven attention supramodal or specific to each sensory modality? Here we employed a hierarchical target detection task (n=30), examining cortical responses linked to the detection of salient targets in the somatosensory and auditory modality. In a temporal decoding analysis, we reveal a transient early supramodal process activated by target detection. We also demonstrate that both common and unique modulations of salience-related cortical responses to somatosensory and auditory targets involve modality-specific and frontal regions using Parametric Empirical Bayes. Specifically, we found that the inferior frontal gyri share information across both sensory modalities, while recurrent information transfer between ipsilateral inferior frontal gyri and associative regions was modality-specific. Finally, we showed both supramodal and modality-specific attentional modulations of effective connectivity linking regions across hierarchical levels in the cortex. Our results provide evidence for an attention network which integrates information across inferior frontal cortices to detect salient targets irrespective of their specific sensory modality. Beyond the notion of a supramodal attention system, our findings support the role of modality-specific cortices in processing inputs from other sensory modalities, highlighting that attention can bias these processes at multiple stages of the cortical hierarchy.Author summaryA key task of the brain is to deploy attention to detect important sensory events in its environment. How does the brain coordinate information from different senses when a sensory event pops out from the environment? Here we designed a nested oddball paradigm in which expectations about somatosensory and auditory stimuli are violated while high-density EEG is recorded. We also varied the extent to which the odd stimulus pops out from its sensory environment. Using temporal decoding, we reveal a supramodal short-lived cortical process when salient targets are detected. In an effective connectivity analysis, we also show that the detection of salient targets relies on a common interhemispheric inhibition between inferior frontal gyri. Beyond that, there are supramodal and modality-specific changes in effective connectivity linking associative and modality-specific regions in the cortex. Our results support a rapid and short-lived supramodal process in a distributed saliency detection system extending across the cortical hierarchy.
Intercalated amygdala dysfunction drives extinction deficits in theSapap3mouse model of obsessive-compulsive disorder
Authors: St. Laurent Robyn , Kusche Kelly M , Kreitzer Anatol C , Malenka Robert C 
Published: February 2024

ABSTRACTBackgroundThe avoidance of aversive stimuli due to negative reinforcement learning is critical for survival in real-world environments, which demand dynamic responding to both positive and negative stimuli that often conflict with each other. Individuals with obsessive-compulsive disorder (OCD) commonly exhibit impaired negative reinforcement and extinction, perhaps involving deficits in amygdala functioning. An amygdala subregion of particular interest is the intercalated nuclei of the amygdala (ITC) which has been linked to negative reinforcement and extinction, with distinct clusters mediating separate aspects of behavior. This study focuses on the dorsal ITC cluster (ITCd) and its role in negative reinforcement during a complex behavior that models real-world dynamic decision making.MethodsWe investigated the impact of ITCdfunction on negative reinforcement and extinction by applying fiber photometry measurement of GCamp6f signals and optogenetic manipulations during a platform-mediated avoidance task in a mouse model of OCD-like behavior: theSapap3-null mouse.ResultsWe find impaired neural activity in the ITCdof male and femaleSapap3-null mice to the encoding of negative stimuli during platform-mediated avoidance.Sapap3-null mice also exhibit deficits in extinction of avoidant behavior, which is modulated by ITCdneural activity.ConclusionsSapap3-null mice fail to extinguish avoidant behavior in platform-mediated avoidance, due to heightened ITCdactivity. This deficit can be rescued by optogenetically inhibiting ITCdduring extinction. Together, our results provide insight into the neural mechanisms underpinning negative reinforcement deficits in the context of OCD, emphasizing the necessity of ITCdin responding to negative stimuli in complex environments.
Streptavidin-drug conjugates streamline optimization of antibody-based conditioning for hematopoietic stem cell transplantation
Authors: Yelamali Aditya R. , Chendamarai Ezhilarasi , Ritchey Julie K. , Rettig Michael P. , DiPersio John F. , Persaud Stephen P. 
Published: February 2024

ABSTRACTHematopoietic stem cell transplantation (HSCT) conditioning using antibody-drug conjugates (ADC) is a promising alternative to conventional chemotherapy- and irradiation-based conditioning regimens. The drug payload bound to an ADC is a key contributor to its efficacy and potential toxicities; however, a comparison of HSCT conditioning ADCs produced with different toxic payloads has not been performed. Indeed, ADC optimization studies in general are hampered by the inability to produce and screen multiple combinations of antibody and drug payload in a rapid, cost-effective manner. Herein, we used Click chemistry to covalently conjugate four different small molecule payloads to streptavidin; these streptavidin-drug conjugates can then be joined to any biotinylated antibody to produce stable, indirectly conjugated ADCs. Evaluating CD45-targeted ADCs produced with this system, we found the pyrrolobenzodiazepine (PBD) dimer SGD-1882 was the most effective payload for targeting mouse and human hematopoietic stem cells (HSCs) and acute myeloid leukemia cells. In murine syngeneic HSCT studies, a single dose of CD45-PBD enabled near-complete conversion to donor hematopoiesis. Finally, human CD45-PBD provided significant antitumor benefit in a patient-derived xenograft model of acute myeloid leukemia. As our streptavidin-drug conjugates were generated in-house with readily accessible equipment, reagents, and routine molecular biology techniques, we anticipate this flexible platform will facilitate the evaluation and optimization of ADCs for myriad targeting applications.
The metabolically protective energy expenditure increase ofPik3r1-related insulin resistance is not explained by Ucp1-mediated thermogenesis
Authors: Luijten Ineke , Onishi Ami , McKay Eleanor J. , Bengtsson Tore , Semple Robert K. 
Published: February 2024

AbstractHuman SHORT syndrome is caused by dominant negative humanPIK3R1mutations that impair insulin-stimulated phosphoinositide 3-kinase (PI3K) activity. This produces severe insulin resistance (IR) and often reduced adiposity, commonly described as lipodystrophy. However unlike human primary lipodystrophies, SHORT syndrome does not feature fatty liver or dyslipidaemia.Pik3r1Y657*/WT(Pik3r1Y657*) mice metabolically phenocopy humans, moreover exhibiting increased energy expenditure. We have hypothesised that this increased energy expenditure explains protection from lipotoxicity, and suggested that understanding its mechanism may offer novel approaches to mitigating the metabolic syndrome. We thus set out to determine whether increased Ucp1-dependent thermogenesis explains the increased energy expenditure inPik3r1-related IR. Male and female Pik3r1Y657*mice challenged with a 45% fat diet for 3 weeks at 21°C showed reduced metabolic efficiency not explained by changes in food intake or physical activity. No changes were seen in thermoregulation, assessed by thermal imaging and a modified Scholander protocol. Ucp1-dependent thermogenesis, assessed by norepinephrine-induced oxygen consumption, was also unaltered. Housing at 30°C did not alter the metabolic phenotype of male Pik3r1Y657*mice, but led to lowered physical activity in female Pik3r1Y657*mice compared to controls. Nevertheless these mice still exhibited increased energy expenditure. Ucp1-dependent thermogenic capacity at 30°C was similar in Pik3r1Y657*and WT mice. We conclude that the likely metabolically protective ‘energy leak’ in Pik3r1-related IR is not caused by Ucp1-mediated BAT hyperactivation, nor impaired thermal insulation. Further metabolic studies are required to seek alternative explanations such as non Ucp1-mediated futile cycling.New and NoteworthyUnderstanding how Pik3r1Y657*mice and humans are protected from lipotoxicity despite insulin resistance may suggest new ways to mitigate metabolic syndrome. We find reduced metabolic efficiency and increased energy expenditure in Pik3r1Y657*mice but no differences in locomotion, thermoregulation or Ucp1-dependent thermogenesis. Protective energy expenditure in Pik3r1-related insulin resistance has an alternative, likely metabolic, explanation
Chemogenetic activation of microglial Gi signaling decreases microglial surveillance and impairs neuronal synchronization
Authors: Zhao Shunyi , Wang Lingxiao , Liang Yue , Zheng Jiaying , Umpierre Anthony D. , Wu Long-Jun 
Published: February 2024

AbstractMicroglia actively survey the brain and dynamically interact with neurons to maintain brain homeostasis. Microglial Gi-protein coupled receptors (Gi-GPCRs) play a critical role in microglia-neuron communications. However, the impact of temporally activating microglial Gi signaling on microglial dynamics and neuronal activity in the homeostatic brain remains largely unknown. In this study, we employed Gi-based Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADD) to selectively and temporally modulate microglial Gi signaling pathway. By integrating this chemogenetic approach within vivotwo-photon imaging, we observed that exogenous activation of microglial Gi signaling transiently inhibited microglial process dynamics, reduced neuronal activity, and impaired neuronal synchronization. These altered neuronal functions were associated with a decrease in interactions between microglia and neuron somata. Altogether, this study demonstrates that acute, exogenous activation of microglial Gi signaling can regulate neuronal circuit function, offering a potential pharmacological target for neuromodulation through microglia.
ATP13A1 engages GET3 to facilitate substrate-specific translocation
Authors: Yang Xiaoyan , Li Tingting , Fang Zhiyu , Feng Zhigang , Zou Yan 
Published: February 2024

AbstractProper localization of proteins to their final destinations is crucial for preserving cellular structure and functions. The interpretation and sorting of highly variable targeting sequences in secreted and membrane proteins, however, pose a challenge in achieving precise localization within specific secretory apparatus. In this study, we demonstrate that atypical signal sequences characterized by high hydrophobicity and/or the absence of characteristic charges undergo targeting to the endoplasmic reticulum (ER) in a reverse orientation, followed by partial cleavage. The P5A- ATPase ATP13A1 recognizes the cleaved signal sequence and dislocates it to the targeting factor GET3, subsequently engaging SEC61 for further translocation. Our findings unveil a comprehensive translocation pathway that operates in a substrate- specific manner, ensuring both high efficiency and fidelity in the protein subcellular localization.
How to design optimal brain stimulation to modulate phase-amplitude coupling?
Authors: Duchet Benoit , Bogacz Rafal 
Published: February 2024

AbstractObjectivePhase-amplitude coupling (PAC), the coupling of the amplitude of a faster brain rhythm to the phase of a slower brain rhythm, plays a significant role in brain activity and has been implicated in various neurological disorders. For example, in Parkinson’s disease, PAC between the beta (13–30 Hz) and gamma (50–200 Hz) rhythms in the motor cortex is exaggerated, while in Alzheimer’s disease, PAC between the theta (4-8 Hz) and gamma rhythms is diminished. Modulating PAC (i.e. reducing or enhancing PAC) using brain stimulation could therefore open new therapeutic avenues. However, while it has been previously reported that phase-locked stimulation can increase PAC, it is unclear what the optimal stimulation strategy to modulate PAC might be. Here, we provide a theoretical framework to narrow down the experimental optimisation of stimulation aimed at modulating PAC, which would otherwise rely on trial and error.ApproachWe make analytical predictions using a Stuart-Landau model, and confirm these predictions in a more realistic model of coupled neural populations.Main resultsOur framework specifies the critical Fourier coefficients of the stimulation waveform which should be tuned to optimally modulate PAC. Depending on the characteristics of the amplitude response curve of the fast population, these components may include the slow frequency, the fast frequency, combinations of these, as well as their harmonics. We also show that the optimal balance of energy between these Fourier components depends on the relative strength of the endogenous slow and fast rhythms, and that the alignment of fast components with the fast rhythm should change throughout the slow cycle. Furthermore, we identify the conditions requiring to phase-lock stimulation to the fast and/or slow rhythms.SignificanceTogether, our theoretical framework lays the foundation for guiding the development of innovative and more effective brain stimulation aimed at modulating PAC for therapeutic benefit.