bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co-aggregation with Apolipoprotein E modulates the function of Amyloid-β in Alzheimer’s disease
Authors: Xia Zengjie , Prescott Emily E. , Wareing Hollie E , Matuszyk Martyna M , Dakin Helen , Dimou Eleni , Zuo Eric , Zhang Yu P. , Lam Jeff Y.L. , Danial John S. H. , Leah Tom , Barnes Katy A. , Strickland Michael , Jiang Hong , Thornton Peter , Crowther Damian C. , Holtzman David M. , Bell Simon M. , Higginbottom Adrian , Ferraiuolo Laura , Mortiboys Heather , Wharton Stephen B. , Ranasinghe Rohan T. , Klenerman David , De Suman 
Published: July 2021

AbstractWhich isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer’s Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-β (Aβ) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aβ in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aβ co-aggregates account for ∼50% of the mass of soluble Aβ aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aβ. Selectively removing non-lipidated apoE4-Aβ co-aggregates enhances clearance of toxic Aβ by glial cells, and reduces inflammation and membrane damage, demonstrating a clear path to AD therapeutics.
Caveolin-1 temporal modulation enhances trastuzumab and trastuzumab-drug conjugate efficacy in heterogeneous gastric cancer
Authors: Pereira Patrícia M. R. , Mandleywala Komal , Monette Sébastien , Lumish Melissa , Tully Kathryn M. , Cornejo Mike , Mauguen Audrey , Ragupathi Ashwin , Mattar Marissa , Janjigian Yelena Y. , Lewis Jason S. 
Published: July 2021

ABSTRACTResistance mechanisms and heterogeneity in HER2-positive gastric cancers (GC) limit trastuzumab benefit in 32% of patients, and other targeted therapies have failed in clinical trials. Using genomic data from patient tissue, patient-derived xenografts (PDXs), partially humanized biological models, and HER2-targeted imaging we identified caveolin-1 (CAV1) as a complementary biomarker in GC selection for trastuzumab therapy. In retrospective analyses of samples from patients enrolled on trastuzumab trials, the CAV1-high profile was associated with low membrane HER2 density and reduced patient survival. We found a negative correlation between CAV1 tumoral protein levels – a major protein of cholesterol-rich membrane domains – and trastuzumab-drug conjugate TDM1 tumor uptake. Finally, CAV1 depletion using knockdown or pharmacologic approaches was shown to increase HER2-directed immunoPET uptake and TDM1 efficacy in GC with incomplete HER2 membranous reactivity. In support of these findings, background statin use in patients is associated with enhanced antibody efficacy. Together, this work provides mechanistic justification and clinical evidence that require prospective investigation of HER2-targeted therapies combined with statins to delay drug resistance in GC.SIGNIFICANCEThis study identifies how CAV1 protein expression and statin use relate to GC response in HER2-targeted imaging and therapeutic approaches. In addition, to support the synergy of CAV1 depletion with TDM1 observed in mouse models, we demonstrate that statin users had better clinical responses to antibody-based therapies in HER2+ GC.
Mapping the subcortical connectivity of the human default mode network
Authors: Li Jian , Curley William H. , Guerin Bastien , Dougherty Darin D. , Dalca Adrian V. , Fischl Bruce , Horn Andreas , Edlow Brian L. 
Published: July 2021

AbstractThe default mode network (DMN) mediates self-awareness and introspection, core components of human consciousness. Therapies to restore consciousness in patients with severe brain injuries have historically targeted subcortical sites in the brainstem, thalamus, hypothalamus, basal forebrain, and basal ganglia, with the goal of reactivating cortical DMN nodes. However, the subcortical connectivity of the DMN has not been fully mapped and optimal subcortical targets for therapeutic neuromodulation of consciousness have not been identified. In this work, we created a comprehensive map of DMN subcortical connectivity by combining high-resolution functional and structural datasets with advanced signal processing methods. We analyzed 7 Tesla resting-state functional MRI (rs-fMRI) data from 168 healthy volunteers acquired in the Human Connectome Project. The rs-fMRI blood-oxygen-level-dependent (BOLD) data were temporally synchronized across subjects using the BrainSync algorithm. Cortical and subcortical DMN nodes were jointly analyzed and identified at the group level by applying a novel Nadam-Accelerated SCAlable and Robust (NASCAR) tensor decomposition method to the synchronized dataset. The subcortical connectivity map was then overlaid on a 7 Tesla 100 micron ex vivo MRI dataset for neuroanatomic analysis using automated segmentation of nuclei within the brainstem, thalamus, hypothalamus, basal forebrain, and basal ganglia. We further compared the NASCAR subcortical connectivity map with its counterpart generated from canonical seed-based correlation analyses. The NASCAR method revealed that BOLD signal in the central lateral nucleus of the thalamus and ventral tegmental area of the midbrain is strongly correlated with that of the DMN. In an exploratory analysis, additional subcortical sites in the median and dorsal raphe, lateral hypothalamus, and caudate nuclei were correlated with the cortical DMN. We also found that the putamen and globus pallidus are negatively correlated (i.e., anti-correlated) with the DMN, providing rs-fMRI evidence for the mesocircuit hypothesis of human consciousness, whereby a striatopallidal feedback system modulates anterior forebrain function via disinhibition of the central thalamus. Seed-based analyses yielded similar subcortical DMN connectivity, but the NASCAR result showed stronger contrast and better spatial alignment with dopamine immunostaining data. The DMN subcortical connectivity map identified here advances understanding of the subcortical regions that contribute to human consciousness and can be used to inform the selection of therapeutic targets in clinical trials for patients with disorders of consciousness.
Learning spatio-temporal properties of hippocampal place cells
Authors: Lian Yanbo , Burkitt Anthony N. 
Published: July 2021

AbstractHippocampal place cells have spatio-temporal properties: they generally respond to a single spatial location of a small environment; in addition, they also display the temporal response property of theta phase precession, namely that the phase of spiking relative to the theta wave shifts from the late phase to early phase as the animal crosses the place field. Grid cells in layer II of the medial entorhinal cortex (MEC) also have spatio-temporal properties similar to hippocampal place cells, except that grid cells respond to multiple spatial locations that form a hexagonal pattern. Other non-grid spatial cells are also abundant in the entorhinal cortex (EC). Because the EC is the upstream area that projects strongly to the hippocampus, a number of EC-hippocampus models have been proposed to explain how the spatial receptive field properties of place cells emerge. However, none of these learning models have explained how the temporal response properties of hippocampal place cells emerge as a result of the EC input. A learning model is presented here based on non-negative sparse coding in which we show that the spatial and temporal properties of hippocampal place cells can be simultaneously learnt from EC input: both MEC grid cells and other EC spatial cells contribute to the spatial properties of hippocampal place cells while MEC grid cells predominantly determine the temporal response properties of hippocampal place cells.
Metabolic endotoxemia is dictated by the type of lipopolysaccharide
Authors: Anhê Fernando F. , Barra Nicole G. , Cavallari Joseph F. , Henriksbo Brandyn D. , Schertzer Jonathan D. 
Published: July 2021

AbstractLipopolysaccharides (LPS) can promote metabolic endotoxemia, which is considered inflammatory and metabolically detrimental based on Toll-like receptor (TLR)4 agonists such as Escherichia coli-derived LPS. LPS from certain bacteria antagonize TLR4 yet contribute to endotoxemia measured by Endotoxin Units (EU). We found that E. coli LPS impaired gut barrier function and worsened glycemic control in mice, but equal doses of LPS from other bacteria did not. Matching the LPS dose from R. sphaeroides and E. coli by EU revealed that only E. coli LPS promoted dysglycemia, adipose inflammation, delayed intestinal glucose absorption, and augmented insulin and GLP-1 secretion. Metabolically beneficial endotoxemia promoted by R. sphaeroides LPS counteracted dysglycemia caused by an equal dose of E. coli LPS and promoted insulin sensitivity in obese mice. The concept of metabolic endotoxemia should be expanded beyond LPS load (EU) to include LPS characteristics, where the balance of deleterious and beneficial endotoxemia regulates host metabolism.HighlightsType of LPS dictates gut barrier function, inflammation, insulin, GLP-1, intestinal glucose absorption and blood glucoseEndotoxin Units (EU) do not reflect how LPS influences blood glucose or hormonesLPS derived from certain types of bacteria are insulin sensitizersR. sphaeroides LPS promotes metabolically beneficial endotoxemiaLPS characteristics dictate metabolically beneficial versus deleterious endotoxemia
ATP-Independent Nucleosome Unfolding by FACT: Electron Microscopy Analysis
Authors: Sivkina Anastasiia L. , Karlova Maria G. , Valieva Maria E. , McCullough Laura L. , Formosa Timothy , Shaytan Alexey K. , Feofanov Alexey V. , Kirpichnikov Mikhail P. , Sokolova Olga S. , Studitsky Vasily M. 
Published: July 2021

AbstractFACT is a histone chaperone that unfolds nucleosomes without ATP hydrolysis. We used electron microscopy to study FACT and FACT:nucleosome complexes, and found that both adopt broad ranges of configurations, indicating high flexibility. We found unexpectedly that the DNA binding protein Nhp6 also binds to the C-terminal tails of FACT subunits, inducing more open geometries of FACT even in the absence of nucleosomes. Nhp6 therefore supports nucleosome unfolding by altering both FACT structure and nucleosome properties. Complexes formed with FACT, Nhp6, and nucleosomes also produced a broad range of structures, revealing a large number of potential intermediates along a proposed unfolding pathway. The data suggest that Nhp6 has multiple roles before and during nucleosome unfolding by FACT, and that the process proceeds through a series of energetically similar intermediate structures, ultimately leading to an extensively unfolded form.One Sentence SummaryElectron microscopy reveals the pathway of ATP-Independent nucleosome unfolding by histone chaperone FACT.
Synergistic interactions between Stachybotrys chartarum and other indoor fungal species in moisture-damaged houses
Authors: Chakravarty Paris 
Published: July 2021

ABSTRACTThe interactions between six commonly occurring fungal species in damp or water-damaged houses in southern California were studied. These fungal species were Alternaria alternata, Aspergillus niger, Chaetomium globosum, Cladosporium herbarum, Penicillium chrysogenum and Stachybotrys chartarum. In the damp building materials, S. chartarum was found to be associated with A. niger, C. globosum, and P. chrysogenum but not with A. alternata and C. herbarum. Stachybotrys chartarum showed strong antagonistic effect against A. alternata and C. herbarum and significantly inhibited in vitro growth of A. alternata and C. herbarum but had no effect on A. niger, C. globosum, and P. chrysogenum. Two trichothecenes, produced by S. chartarum, trichodermin and trichodermol, significantly inhibited spore germination and in vitro growth of A. alternata and C. herbarum but had no effect on A. niger, C. globosum, P. chrysogenum and S. chartarum. In the damp building materials (drywall, ceiling tile, and oak woods), S. chartarum significantly inhibited the growth of A. alternata and C. herbarum and had no effect on the growth and colonization of A. niger, C. globosum, P. chrysogenum in these substrata.
Candida auris is rendered non-viable by medium-chain fatty acids
Authors: Green Kalynne R. , De Jesus Magdia , Gunsalus Kearney T. W. 
Published: July 2021

AbstractThe medium-chain fatty acids, octanoic and decanoic acid, found in coconut oil, were fungistatic and decanoic acid was fungicidal against a panel of Candida auris strains, during both planktonic and biofilm growth. The strains were from all four major geographic clades, and some were resistant to several classes of antifungal drugs. These compounds are safe, natural products and could provide a new strategy for skin decolonization and environmental decontamination.
Assessment of the evolutionary consequence of putative driver mutations in colorectal cancer with spatial multiomic data
Authors: Heide Timon , Househam Jacob , Cresswell George D , Spiteri Inmaculada , Lynn Claire , Kimberley Chris , Mossner Max , Zapata Luis , Gabbutt Calum , Ramazzotti Daniele , Chen Bingjie , Fernandez-Mateos Javier , James Chela , Vinceti Alessandro , Berner Alison , Schmidt Melissa , Lakatos Eszter , Baker Ann-Marie , Nichol Daniel , Costa Helena , Mitchinson Miriam , Werner Benjamin , Iorio Francesco , Jansen Marnix , Barnes Christopher , Caravagna Giulio , Shibata Darryl , Bridgewater John , Rodriguez-Justo Manuel , Magnani Luca , Graham Trevor A , Sottoriva Andrea 
Published: July 2021

AbstractCancer genomic medicine relies on targeting driver genes. However, current catalogues of cancer drivers are mostly based on indirect measurements of mutation frequencies, positions or types, rather than their effect on clonal expansionsin vivo. Moreover, non-genetic drivers are largely unknown, as are the epigenetic and transcriptomic effects of genetic drivers. Here we perform spatial computational inference on multiomic data with matched whole-genome sequencing, ATAC-seq and RNA-seq. Using 436 samples, we directly quantify the contribution, or lack thereof, of putative driver genes to subclonal expansionsin vivoin 30 colorectal carcinomas (4-33 samples per patient, median=15). Although subclonal neutral evolution was widespread (13/26 cases with sufficient data), there were cases with clear evidence of subclonal selection (6/26) in which we measured epigenetic and transcriptomic differences between subclonesin vivo. In 7/26 cases we could not distinguish between neutral or selective evolution with the available data. We identified expanding subclones that were not driven by known genetic alterations, and propose candidate epigenetic drivers. We identified the distinguishing patterns of genomic heterogeneity produced in fast, exponentially growing tumours (7/26) versus neoplasms growing only at the periphery (19/26), as well as identifying clonally intermixed (16/28 cases with sufficient data) versus segregated malignancies (10/28). Our model-based approach measures genetic and non-genetic subclonal selection, or lack thereof, in space and time and allowsin vivocomparisons of the emergent phenotypic properties of subclones within human tumours.
R-loop-induced p21 expression following CDC73, CTR9, and PAF1 loss protects cancer cells against replicative catastrophe following WEE1 inhibition
Authors: van Bijsterveldt Linda , Landsverk Helga B. , Nähse Viola , Durley Samuel C. , Sarkar Sovan S. , Syljuåsen Randi G. , Humphrey Timothy C. 
Published: July 2021

AbstractWEE1 inhibitors have now advanced into clinical studies as monotherapy or in combination with chemoradiotherapy in TP53, RAS, BRAF, and SETD2 mutation carriers across several tumour types, yet mechanisms of resistance are still poorly understood. Here, we further elucidate the mechanisms by which AZD1775, the most potent WEE1 inhibitor, kills cells and reveal additional genetic interactions that can result in resistance, but could be used to optimise its clinical utility.We identified RNA Polymerase II-associated factor 1 (PAF1) complex members, CDC73, CTR9, and PAF1 as major determinants of WEE1-inhibitor sensitivity in isogenic SETD2-positive and negative cell lines. PAF1-knockdown cells resist higher doses of the WEE1 inhibitor, which we show is due to reduced DNA damage induction (γH2AX) and delayed G1 checkpoint activation, ultimately protecting cells against replicative catastrophe. Investigations into the molecular mechanisms responsible for PAF1-mediated resistance identify involvement of R-loops and subsequent activation of the cyclin-dependent kinase inhibitor p21Cip1/Waf1, which in addition to causing prolonged G1 arrest in the following cell cycle, also regulates CDK activity, therefore limiting replication.These results provide evidence that the PAF1 complex and p21 are important regulators of proliferation under increased DNA replication stress and their expression levels might be useful biomarkers to predict clinical response to WEE1 inhibitors and other ribonucleotide reductase inhibitors.
Balanced release of neuropeptide FF and gonadotropin-releasing hormone 3 modulates male sexual behavior
Authors: Umatani Chie , Yoshida Nagisa , Yamamoto Eri , Akazome Yasuhisa , Mori Yasutaka , Kanda Shinji , Okubo Kataaki , Oka Yoshitaka 
Published: July 2021

AbstractAnimals properly perform sexual behaviors by using multiple sensory cues. However, neural mechanisms integrating multiple sensory cues and regulating motivation for sexual behaviors remain unclear. Here, we focused on peptidergic neurons, terminal nerve gonadotropin-releasing hormone (TN-GnRH) neurons, which receive inputs from various sensory systems and co-express neuropeptide FF (NPFF) in addition to GnRH. Our behavioral analyses using knockout medaka of GnRH (gnrh3) and/or NPFF (npff) demonstrated that some sexual behavioral repertories were ‘delayed’, not disrupted, in gnrh3-/- and npff-/- males, while the double knockout showed normal behaviors. We also found anatomical evidence to show that both neuropeptides modulate the sexual behavior-controlling brain areas. Furthermore, we demonstrated that NPFF activates neurons in the preoptic area via indirect pathway, which is considered to induce the increase in the motivation for male sexual behaviors. Considering these results, we propose a novel mechanism by which balanced release of co-existing peptides is important for the neuromodulatory function of TN-GnRH neurons in the control of behavioral motivation. Our results may go a long way toward understanding the functional significance of peptidergic neuromodulation in response to external environments.
Spike-based symbolic computations on bit strings and numbers
Authors: Kraišniković Ceca , Maass Wolfgang , Legenstein Robert 
Published: July 2021

AbstractThe brain uses recurrent spiking neural networks for higher cognitive functions such as symbolic computations, in particular, mathematical computations. We review the current state of research on spike-based symbolic computations of this type. In addition, we present new results which show that surprisingly small spiking neural networks can perform symbolic computations on bit sequences and numbers and even learn such computations using a biologically plausible learning rule. The resulting networks operate in a rather low firing rate regime, where they could not simply emulate artificial neural networks by encoding continuous values through firing rates. Thus, we propose here a new paradigm for symbolic computation in neural networks that provides concrete hypotheses about the organization of symbolic computations in the brain. The employed spike-based network models are the basis for drastically more energy-efficient computer hardware – neuromorphic hardware. Hence, our results can be seen as creating a bridge from symbolic artificial intelligence to energy-efficient implementation in spike-based neuromorphic hardware.
Human placental villi immune cells help maintain homeostasisin utero
Authors: Toothaker Jessica M , Olaloye Oluwabunmi , McCourt Blake T. , McCourt Collin C , Case Rebecca M , Liu Peng , Yimlamai Dean , Tseng George , Konnikova Liza 
Published: July 2021

AbstractMaintenance of healthy pregnancy is reliant on successful balance between the fetal and maternal immune systems. Although maternal mechanisms responsible have been well studied, those used by the fetal immune system remain poorly understood. Using suspension mass cytometry and various imaging modalities, we report a complex immune system within the mid-gestation (17-23 weeks) human placental villi (PV). Further, we identified immunosuppressive signatures in innate immune cells and antigen presenting cells that potentially maintain immune homeostasis in utero. Consistent with recent reports in other fetal organs, T cells with memory phenotypes were detected within the PV tissue and vasculature. Moreover, we determined PV T cells could be activated to upregulate CD69 and proliferate after T cell receptor (TCR) stimulation and when exposed to maternal uterine antigens. Finally, we report that cytokine production by PV T cells is sensitive to TCR stimulation and varies between mid-gestation, preterm (26-35 weeks) and term deliveries (37-40 weeks). Collectively, we elucidated the complexity and functional maturity of fetal immune cells within the PV and highlighted their immunosuppressive potential.
A time-varying grey Riccati model based on interval grey numbers for China's clean energy generation predicting
Authors: Guo Sandang , Jing Yaqian 
Published: July 2021

PurposeIn order to accurately predict the uncertain and nonlinear characteristics of China's three clean energy generation, this paper presents a novel time-varying grey Riccati model (TGRM(1,1)) based on interval grey number sequences.Design/methodology/approachBy combining grey Verhulst model and a special kind of Riccati equation and introducing a time-varying parameter and random disturbance term the authors advance a TGRM(1,1) based on interval grey number sequences. Additionally, interval grey number sequences are converted into middle value sequences and trapezoid area sequences by using geometric characteristics. Then the predicted formula is obtained by using differential equation principle. Finally, the proposed model's predictive effect is evaluated by three numerical examples of China's clean energy generation.FindingsBased on the interval grey number sequences, the TGRM(1,1) is applied to predict the development trend of China's wind power generation, China's hydropower generation and China's nuclear power generation, respectively, to verify the effectiveness of the novel model. The results show that the proposed model has better simulated and predicted performance than compared models.Practical implicationsDue to the uncertain information and continuous changing of clean energy generation in the past decade, interval grey number sequences are introduced to characterize full information of the annual clean energy generation data. And the novel TGRM(1,1) is applied to predict upper and lower bound values of China's clean energy generation, which is significant to give directions for energy policy improvements and modifications.Originality/valueThe main contribution of this paper is to propose a novel TGRM(1,1) based on interval grey number sequences, which considers the changes of parameters over time by introducing a time-varying parameter and random disturbance term. In addition, the model introduces the Riccati equation into classic Verhulst, which has higher practicability and prediction accuracy.