bluuebunny/crossref_metadata_2025_split huggingface dataset:
AML/T cell interactomics uncover correlates of patient outcomes and the key role of ICAM1 in T cell killing of AML
Authors: Sayitoglu Ece Canan , Luca Bogdan A. , Boss Allison P. , Thomas Benjamin Craig , Freeborn Robert Arthur , Uyeda Molly J. , Chen Pauline P. , Nakauchi Yusuke , Waichler Colin , Lacayo Norman , Bacchetta Rosa , Majeti Ravindra , Gentles Andrew J. , Cepika Alma-Martina , Roncarolo Maria Grazia 
Published: September 2023

ABSTRACTT cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human engineered cytotoxic CD4+T cells. Single-cell RNA-seq of primary AML samples and CD4+T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4+T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cellsin vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulatedICAM1, a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing to primaryex vivo-isolated CD8+T cellsin vitro, and engineered CD4+T cellsin vitroandin vivo. Thus, ICAM1 on AML acts as an immune trigger, allowing T cell killing, and could affect AML patient survivalin vivo.SIGNIFICANCEAML is a common leukemia with sub-optimal outcomes. We show that AML transcriptional programs correlate with susceptibility to T cell killing. Killing resistance-associated AML programs are enriched in patients with poor survival. Killing-sensitive, but not resistant AML activate T cells and upregulateICAM1that binds to LFA-1 on T cells, allowing immune synapse formation which is critical for AML elimination.GRAPHICAL ABSTRACT
Continuous motor skills as flexible control policies: a video game study
Authors: Huberdeau David M. , Haith Adrian M. , Krakauer John W. 
Published: September 2023

AbstractMany motor skills consist of continuous sequential actions, such as a tennis serve. It is currently unclear how these surprisingly understudied behaviors are learned, with the leading hypothesis being that sequences of single actions become “chunked” into larger single executable units. Under this hypothesis, continuous sequential actions should become more task-specific and less generalizable with practice. To test this, we developed a video game that requires participants to hold a tablet with both hands and steer a virtual car (the “ant car”) along a curving track. We tested participants’ ability to generalize their skill to a probe track that required a different sequence of turns. Across days of practice, task success increased, and movement variability decreased. On the probe track, movement quality at the level of kinematics fully generalized but performance at the level of task success showed a consistent decrement. To address this apparent paradox, we empirically derived the control policy participants used at their maximal skill level on the training track. Notably, this policy was fully transferred to the probe track, but there were more instances of momentary deviations from it (lapses), which explains the worse performance despite equivalent skill. We conclude that continuous motor skills are acquired through learning of a flexible control policy that maps states onto actions and not through chunking or automatizing of a specific sequence of actions.
Automated customization of large-scale spiking network models to neuronal population activity
Authors: Wu Shenghao , Huang Chengcheng , Snyder Adam , Smith Matthew , Doiron Brent , Yu Byron 
Published: September 2023

AbstractUnderstanding brain function is facilitated by constructing computational models that accurately reproduce aspects of brain activity. Networks of spiking neurons capture the underlying biophysics of neuronal circuits, yet the dependence of their activity on model parameters is notoriously complex. As a result, heuristic methods have been used to configure spiking network models, which can lead to an inability to discover activity regimes complex enough to match large-scale neuronal recordings. Here we propose an automatic procedure, Spiking Network Optimization using Population Statistics (SNOPS), to customize spiking network models that reproduce the population-wide covariability of large-scale neuronal recordings. We first confirmed that SNOPS accurately recovers simulated neural activity statistics. Then, we applied SNOPS to recordings in macaque visual and prefrontal cortices and discovered previously unknown limitations of spiking network models. Taken together, SNOPS can guide the development of network models and thereby enable deeper insight into how networks of neurons give rise to brain function.
Multiscale effective connectivity analysis of brain activity using neural ordinary differential equations
Authors: Chang Yin-Jui , Chen Yuan-I , Stealey Hannah M. , Zhao Yi , Lu Hung-Yun , Contreras-Hernandez Enrique , Baker Megan N. , Yeh Hsin-Chih , Santacruz Samantha R. 
Published: September 2023

AbstractNeural mechanisms and underlying directionality of signaling among brain regions depend on neural dynamics spanning multiple spatiotemporal scales of population activity. Despite recent advances in multimodal measurements of brain activity, there is no broadly accepted multiscale dynamical models for the collective activity represented in neural signals. Here we introduce a neurobiological-driven deep learning model, termedmultiscale neuraldynamicsneuralordinarydifferentialequation (msDyNODE), to describe multiscale brain communications governing cognition and behavior. We demonstrate that msDyNODE successfully captures multiscale activity using both simulations and electrophysiological experiments. The msDyNODE-derived causal interactions between recording locations and scales not only aligned well with the abstraction of the hierarchical neuroanatomy of the mammalian central nervous system but also exhibited behavioral dependences. This work offers a new approach for mechanistic multiscale studies of neural processes.Author SummaryMulti-modal measurements have become an emerging trend in recent years due to the capability of studying brain dynamics at disparate scales. However, an integrative framework to systematically capture the multi-scale nonlinear dynamics in brain networks is lacking. A major challenge for creating a cohesive model is a mismatch in the timescale and subsequent sampling rate of the dynamics for disparate modalities. In this work, we introduce a deep learning-based approach to characterize brain communications between regions and scales. By modeling the continuous dynamics of hidden states using the neural network-based ordinary differential equations, the requirement of downsampling the faster sampling signals is discarded, thus preventing from losing dynamics information. Another advantageous feature of the proposed method is flexibility. An adaptable framework to bridge the gap between scales is necessary. Depending on the neural recording modalities utilized in the experiment, any suitable pair of well-established models can be plugged into the proposed multi-scale modeling framework. Thus, this method can provide insight into the brain computations of multi-scale brain activity.
The social determinants associated with decreased rate of breast cancer screening, delayed presentation, and advanced stage diagnosis of breast cancer: A systematic review
Authors: Fekry Madonna A. , Yang Justin C. 
Published: September 2023

AbstractBackgroundThere are many barriers that hinder breast cancer (BC) early detection such as social, demographic, and economic factors. We examined the barriers to early detection.MethodsPubMed, Scopus, and Web of Science databases were chosen to conduct a comprehensive literature search. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) was used to select the relevant studies on decreased rate of BC screening, delayed presentation of BC, and advanced stage diagnosis of BC.ResultsThe literature demonstrates that several determinants had a significant impact on the delay in seeking medical help, rate of performing breast cancer screening (BCS), and stage at diagnosis of BC. Younger age, rural residence, being non-white, being single, low socioeconomic status, absence of medical insurance, having no paid job, low educational level, positive family history of BC, and having TNBC or HER2E BC subtypes were significantly associated with presenting at advanced stages, decreased rate of BCS, and delayed presentation. Meanwhile, the associations between BC and BMI, parity, religion, and menopausal status were underexamined in the literature.ConclusionPromoting early detection of BC should be taking the sociodemographic disparities into consideration. To address these disparities, raising public awareness, implementing universal health coverage (UHC), and increasing government expenditure on health and education are needed, especially among vulnerable societies.
Genetic synergy inAcinetobacter baumanniiundecaprenyl biosynthesis and maintenance of lipid asymmetry impacts outer membrane and antimicrobial resistance
Authors: Noel Hannah R. , Keerthi Sowmya , Ren Xiaomei , Winkelman Jonathan D. , Troutman Jerry M. , Palmer Lauren D. 
Published: September 2023

AbstractAcinetobacter baumanniiis a Gram-negative healthcare-associated pathogen that poses a major health concern due to increasing multidrug resistance. The Gram-negative cell envelope is a key barrier to antimicrobial entry and includes an inner and outer membrane. The outer membrane has an asymmetric composition that is important for structural integrity and barrier to the environment. Therefore, Gram-negative bacteria have mechanisms to uphold this asymmetry such as the maintenance of lipid asymmetry system (Mla), which removes glycerophospholipids from the outer leaflet of the outer membrane and transports them to the inner membrane. Loss of this system inA. baumanniiresults in attenuated virulence and increased susceptibility to membrane stressors and some antibiotics. We recently reported two strain variants of theA. baumanniitype strain ATCC 17978, 17978VU and 17978UN. We show here that ΔmlaFmutants in the two strains display different phenotypes for membrane stress resistance, antibiotic resistance, and pathogenicity in a murine pneumonia model. We used comparative genetics to identify interactions between ATCC 17978 strain alleles andmlaFto uncover the cause behind the phenotypic differences. Although allele differences inobgEwere previously reported to synergize with ΔmlaFto affect growth and stringent response, we show thatobgEalleles do not affect membrane stress resistance. Instead, a single nucleotide polymorphism (SNP) in the essential gene encoding undecaprenyl pyrophosphate (Und-PP) synthase,uppS, synergizes with ΔmlaFto increase susceptibility to membrane stress and antibiotics, and reduce persistence in a mouse lung infection. Und-P is a lipid glycan carrier known to be required for biosynthesis ofA. baumanniicapsule, cell wall, and glycoproteins. Our data suggest that in the absence of the Mla system, the cellular level of Und-P is critical for envelope integrity, antibiotic resistance, and lipooligosaccharide abundance. These findings uncover synergy between Und-P and the Mla system in maintaining theA. baumanniiouter membrane and stress resistance.
Natural selection drives emergent genetic homogeneity in a century-scale experiment with barley
Authors: Landis Jacob B , Guercio Angelica M , Brown Keely E , Fiscus Christopher J , Morrell Peter L , Koenig Daniel 
Published: September 2023

AbstractDirect observation is central to our understanding of the process of adaptation, but evolution is rarely documented in a large, multicellular organism for more than a few generations. Here, we observe genetic and phenotypic evolution across a century-scale competition experiment, barley composite cross II (CCII). CCII was founded in 1929 with tens of thousands of unique genotypes and has been adapted to local conditions in Davis, CA, USA for 58 generations. We find that natural selection has massively reduced genetic diversity leading to a single clonal lineage constituting most of the population by generation F50. Selection favored alleles originating from similar climates to that of Davis, and targeted genes regulating reproductive development, including some of the most well-characterized barley diversification loci,Vrs1,HvCEN, andPpd-H1. We chronicle the dynamic evolution of reproductive timing in the population and uncover how parallel molecular pathways are targeted by stabilizing selection to optimize this trait. Our findings point to selection as the predominant force shaping genomic variation in one of the world’s oldest ongoing biological experiments.One-Sentence SummaryWholesale genetic restructuring of an experimental population is a consequence of rapid environmental adaptation.
Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease
Authors: Flønes Irene H , Toker Lilah , Sandnes Dagny Ann , Castelli Martina , Mostafavi Sepideh , Lura Njål , Shadad Omnia , Fernandez-Vizarra Erika , Painous Cèlia , Pérez-Soriano Alexandra , Compta Yaroslau , Molina-Porcel Laura , Alves Guido , Tysnes Ole-Bjørn , Dölle Christian , Nido Gonzalo S , Tzoulis Charalampos 
Published: September 2023

AbstractIdiopathic Parkinson’s disease (iPD) is believed to have a heterogeneous pathophysiology, but molecular disease subtypes have not been identified. Here, we show that iPD can be stratified according to the severity of neuronal respiratory complex I (CI) deficiency, and identify two emerging disease subtypes with distinct molecular and clinical profiles. The CI deficient (CI-PD) subtype accounts for approximately a fourth of all cases, and is characterized by anatomically widespread neuronal CI deficiency, a distinct cell type-specific gene expression profile, increased load of neuronal mtDNA deletions, and a predilection for non-tremor dominant motor phenotypes. In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype. These findings constitute a step towards resolving the biological heterogeneity of iPD with implications for both mechanistic understanding and treatment strategies.
Cryo-EM structure of Alzheimer’s disease tau filaments with PET ligand MK-6240
Authors: Kunach Peter , Vaquer-Alicea Jaime , Smith Matthew S. , Hopewell Robert , Monistrol Jim , Moquin Luc , Therriault Joseph , Tissot Cecile , Rahmouni Nesrine , Massarweh Gassan , Soucy Jean-Paul , Guiot Marie-Christine , Shoichet Brian K. , Rosa-Neto Pedro , Diamond Marc I. , Shahmoradian Sarah H. 
Published: September 2023

AbstractPositron Emission Tomography (PET) ligands have advanced Alzheimer’s disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identified AD brain tissue with elevated tau burden, purified filaments, and determined the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine K353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.
A history of avoidance does not impact extinction learning in male rats
Authors: López-Moraga Alba , Luyten Laura , Beckers Tom 
Published: September 2023

AbstractPervasive avoidance is one of the central symptoms of all anxiety-related disorders. In treatment, avoidance behaviors are typically discouraged because they are assumed to maintain anxiety. Yet, it is not clear that engaging in avoidance is always detrimental. In this study, we used a platform-mediated avoidance task to investigate the influence of avoidance history on extinction learning in male rats. Our results show that having the opportunity to avoid during fear acquisition training has no marked effect on the extinction of auditory cued fear in a platform-mediated avoidance procedure that constitutes a realistic approach/avoidance conflict in male rats, regardless of whether avoidance was possible during extinction or not. This suggests that imposing a realistic cost on avoidance behavior prevents the adverse effects that avoidance has been claimed to have on extinction, but even then, avoidance does not appear to have clear positive effects on extinction learning nor on retention either.
When the whole is only the parts: non-holistic object parts predominate face-cell responses to illusory faces
Authors: Sharma Saloni , Vinken Kasper , Livingstone Margaret S. 
Published: September 2023

SummaryHumans are inclined to perceive faces in everyday objects with a face-like configuration. This illusion, known as face pareidolia, is often attributed to a specialized network of ‘face cells’ in primates. We found that face cells in macaque inferotemporal cortex responded selectively to pareidolia images, but this selectivity did not require a holistic, face-like configuration, nor did it encode human faceness ratings. Instead, it was driven mostly by isolated object parts that are perceived as eyes only within a face-like context. These object parts lack usual characteristics of primate eyes, pointing to the role of lower-level features. Our results suggest that face-cell responses are dominated by local, generic features, unlike primate visual perception, which requires holistic information. These findings caution against interpreting neural activity through the lens of human perception. Doing so could impose human perceptual biases, like seeing faces where none exist, onto our understanding of neural activity.
Neural stem cells protect blood-brain barrier integrity via the p38, JNK, and ERK1/2 pathways following intracerebral hemorrhage in rats
Authors: Sun Jing , Yang Xiuli , Carmichael Austin , Kim Tae Jung , Kim Young-Ju , Wei Zhiliang , Han Ling , Stanciu Nicolas , Ko Sang-Bae , Nan Guangxian , Yoon Byung-Woo 
Published: September 2023

AbstractNeural stem cells (NSCs) have displayed great potential in ameliorating brain damage following intracerebral hemorrhage (ICH) via proliferation, differentiation, and immunomodulation. However, it remains unclear whether NSCs can improve microvascular function, e.g., blood-brain barrier (BBB) integrity, after ICH. In this study, we investigate the potential therapeutic benefit of NSCs on BBB integrity as well as the underlying mechanism. Adult male Sprague-Dawley rats were randomly divided into sham, ICH+PBS, and ICH+NSCs groups for comparisons. ICH was induced by intrastriatal injection of bacterial collagenase. An aliquot of NSCs or PBS was injected via the tail vein 2 h after ICH induction. The following multiparametric measurements were compared: brain edema, hematoma volume, behavior, BBB permeability, and mitogen-activated protein kinase (MAPK) signaling pathway activity. We found that NSCs treatment attenuates BBB permeability, reduces brain edema, and promotes brain function recovery after ICH by inhibiting ERK1/2, p38, and JNK signaling pathway activation. These findings provide novel insight for future therapies aiming to prevent BBB dysfunction and improve functional recovery in ICH patients.
Neuroimaging and plasma marker evidence for white matter macrostructure loss in Parkinson’s disease
Authors: Zarkali Angeliki , Hannaway Naomi , McColgan Peter , Heslegrave Amanda J , Veleva Elena , Laban Rhiannon , Zetterberg Henrik , Lees Andrew J , Fox Nick C. , Weil Rimona S 
Published: September 2023

AbstractParkinson’s disease (PD) is the second commonest neurodegenerative disorder and over half of patients progress to postural instability, dementia or death within 10 years of diagnosis.However, onset and rate of progression to poor outcomes is highly variable, underpinned by heterogeneity in the underlying pathological process. Improved biomarkers of poor outcomes would be helpful for targeted treatment, but most studies to-date have been limited to a single modality or the assessment of patients with established cognitive impairment. Here, we use multimodal neuroimaging and plasma biomarkers in 98 patients with PD and 28 age-matched controls followed-up over 3 years, including: gray matter (cortical thickness), white matter (macrostructure: fibre-cross section and microstructure: fibre density) at whole-brain and tract level, structural and functional connectivity and plasma levels of neurofilament light chain (NFL) and phosphorylated tau (p-tau) 181. We show extensive reductions in fibre cross-section and structural connectivity in PD with poor outcomes, with preserved gray matter and functional connectivity. NFL, but not p-tau181 levels was increased in PD with poor outcomes and correlated with white matter loss. These findings suggest that imaging sensitive to white matter macrostructure and plasma NFL may be useful biomarkers of poor outcomes in PD. As new targeted treatments are emerging, these biomarkers show important potential to aid patient selection for treatments and improve stratification to clinical trials.
Inhibition of mammalian mtDNA transcription paradoxically activates liver fatty acid oxidation to reverse diet-induced hepatosteatosis and obesity
Authors: Jiang Shan , Yuan Taolin , Kremer Laura S , Rosenberger Florian A , Hansen Fynn M , Borg Melissa , Rubalcava-Gracia Diana , Mennuni Mara , Filograna Roberta , Alsina David , Misic Jelena , Koolmeister Camilla , Ren Lipeng , Andersson Olov , Unger Anke , Bergbrede Tim , Lucrezia Raffaella Di , Wibom Rolf , Zierath Juleen R , Krook Anna , Giavalisco Patrick , Mann Matthias , Larsson Nils-Göran 
Published: September 2023

SummaryThe oxidative phosphorylation (OXPHOS) system in mammalian mitochondria plays a key role in harvesting energy from ingested nutrients1, 2. Mitochondrial metabolism is very dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states3, 4. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases5, 6and is also necessary to promote tumour growth7–11. Here, we demonstrate thatper oraltreatment with an inhibitor of mitochondrial transcription (IMT)11shifts whole animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of glucose tolerance in mice on high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of OXPHOS capacity concomitant with a marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and non-targeted metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase that feeds electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase (ETF-DH) and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a novel principle for drug treatment of obesity and obesity-related pathology.