julilili42/papers huggingface dataset:
Center-surround interactions underlie bipolar cell motion sensitivity in the mouse retina
2022-09-26

Abstract Motion sensing is a critical aspect of vision. We studied the representation of motion in mouse retinal bipolar cells and found that some bipolar cells are radially direction selective, preferring the origin of small object motion trajectories. Using a glutamate sensor, we directly observed bipolar cells synaptic output and found that there are radial direction selective and non-selective bipolar cell types, the majority being selective, and that radial direction selectivity relies on properties of the center-surround receptive field. We used these bipolar cell receptive fields along with connectomics to design biophysical models of downstream cells. The models and additional experiments demonstrated that bipolar cells pass radial direction selective excitation to starburst amacrine cells, which contributes to their directional tuning. As bipolar cells provide excitation to most amacrine and ganglion cells, their radial direction selectivity may contribute to motion processing throughout the visual system.
Adenosine A2a Receptor Antagonism Restores Additive Cytotoxicity by Cytotoxic T Cells in Metabolically Perturbed Tumors
2022-09-26

Abstract Cytotoxic T lymphocytes (CTL) are antigen-specific effector cells with the ability to eradicate cancer cells in a contact-dependent manner. Metabolic perturbation compromises the CTL effector response in tumor subregions, resulting in failed cancer cell elimination despite the infiltration of tumor-specific CTLs. Restoring the functionality of these tumor-infiltrating CTLs is key to improve immunotherapy. Extracellular adenosine is an immunosuppressive metabolite produced within the tumor microenvironment. Here, by applying single-cell reporter strategies in 3D collagen cocultures in vitro and progressing tumors in vivo, we show that adenosine weakens one-to-one pairing of activated effector CTLs with target cells, thereby dampening serial cytotoxic hit delivery and cumulative death induction. Adenosine also severely compromised CTL effector restimulation and expansion. Antagonization of adenosine A2a receptor (ADORA2a) signaling stabilized and prolonged CTL–target cell conjugation and accelerated lethal hit delivery by both individual contacts and CTL swarms. Because adenosine signaling is a near-constitutive confounding parameter in metabolically perturbed tumors, ADORA2a targeting represents an orthogonal adjuvant strategy to enhance immunotherapy efficacy.
Recent findings on the role of wild-type and mutant p53 in cancer development and therapy
2022-09-26

The p53 protein is a tumor suppressor encoded by the TP53 gene and consists of 393 amino acids with four main functional domains. This protein responds to various cellular stresses to regulate the expression of target genes, thereby causing DNA repair, cell cycle arrest, apoptosis, metabolic changes, and aging. Mutations in the TP53 gene and the functions of the wild-type p53 protein (wtp53) have been linked to various human cancers. Eight TP53 gene mutations are located in codons, constituting 28% of all p53 mutations. The p53 can be used as a biomarker for tumor progression and an excellent target for designing cancer treatment strategies. In wild-type p53-carrying cancers, abnormal signaling of the p53 pathway usually occurs due to other unusual settings, such as high MDM2 expression. These differences between cancer cell p53 and normal cells have made p53 one of the most important targets for cancer treatment. In this review, we have dealt with various issues, such as the relative contribution of wild-type p53 loss of function, including transactivation-dependent and transactivation-independent activities in oncogenic processes and their role in cancer development. We also discuss the role of p53 in the process of ferroptosis and its targeting in cancer treatment. Finally, we focus on p53-related drug delivery systems and investigate the challenges and solutions.
Archaeological adhesives made from Podocarpus document innovative potential in the African Middle Stone Age
2022-09-26

Studying the earliest archaeological adhesives has implications for our understanding of human cognition. In southern Africa, the oldest adhesives were made by Homo sapiens in the Middle Stone Age. Chemical studies have shown that these adhesives were made from a local conifer of the Podocarpaceae family. However, Podocarpus does not exude resin, nor any other substance that could have been recognized as having adhesive properties. Therefore, it remains unknown how these adhesives were made. This study investigates how Podocarpus adhesives can be made, comparing their mechanical properties with other naturally available adhesives. We found that Podocarpus tar can only be made by dry distillation of leaves, requiring innovative potential, skill, and knowledge. This contrasts with our finding that the Middle Stone Age environment was rich in substances that can be used as adhesives without such transformation. The apparent preference for Podocarpus tar may be explained by its mechanical properties. We found it to be superior to all other substances in terms of its adhesive properties. In addition, the condensation method that allows producing it can be recognized accidentally, as the processes take place above ground and can be triggered accidentally. Our findings have implications for establishing a link between technology and cognition in the Middle Stone Age.
Combining CRISPR-Cas9 and brain imaging to study the link from genes to molecules to networks
2022-09-26

Receptors, transporters, and ion channels are important targets for therapy development in neurological diseases, but their mechanistic role in pathogenesis is often poorly understood. Gene editing and in vivo imaging approaches will help to identify the molecular and functional role of these targets and the consequence of their regional dysfunction on the whole-brain level. We combine CRISPR-Cas9 gene editing with in vivo positron emission tomography (PET) and functional MRI (fMRI) to investigate the direct link between genes, molecules, and the brain connectome. The extensive knowledge of the Slc18a2 gene encoding the vesicular monoamine transporter (VMAT2), involved in the storage and release of dopamine, makes it an excellent target for studying the gene network relationships while structurally preserving neuronal integrity and function. We edited the Slc18a2 in the substantia nigra pars compacta of adult rats and used in vivo molecular imaging besides behavioral, histological, and biochemical assessments to characterize the CRISPR-Cas9–mediated VMAT2 knockdown. Simultaneous PET/fMRI was performed to investigate molecular and functional brain alterations. We found that stage-specific adaptations of brain functional connectivity follow the selective impairment of presynaptic dopamine storage and release. Our study reveals that recruiting different brain networks is an early response to the dopaminergic dysfunction preceding neuronal cell loss. Our combinatorial approach is a tool to investigate the impact of specific genes on brain molecular and functional dynamics, which will help to develop tailored therapies for normalizing brain function.
Divisive normalization is an efficient code for multivariate Pareto-distributed environments
2022-09-26

Divisive normalization is a canonical computation in the brain, observed across neural systems, that is often considered to be an implementation of the efficient coding principle. We provide a theoretical result that makes the conditions under which divisive normalization is an efficient code analytically precise: We show that, in a low-noise regime, encoding an n -dimensional stimulus via divisive normalization is efficient if and only if its prevalence in the environment is described by a multivariate Pareto distribution. We generalize this multivariate analog of histogram equalization to allow for arbitrary metabolic costs of the representation, and show how different assumptions on costs are associated with different shapes of the distributions that divisive normalization efficiently encodes. Our result suggests that divisive normalization may have evolved to efficiently represent stimuli with Pareto distributions. We demonstrate that this efficiently encoded distribution is consistent with stylized features of naturalistic stimulus distributions such as their characteristic conditional variance dependence, and we provide empirical evidence suggesting that it may capture the statistics of filter responses to naturalistic images. Our theoretical finding also yields empirically testable predictions across sensory domains on how the divisive normalization parameters should be tuned to features of the input distribution.
Transforming Governance of German Higher Education Institutions
2022-09-26

Since the implementation of the Excellence Initiative and the Excellence Strategy, German higher education institutions have been restructuring university governance, especially those selected as Universities of Excellence. This study uses a holistic and mission-related integrated governance approach to conduct a qualitative analysis of the governance transformation of German Universities of Excellence, aiming to provoke discussion on transforming governance to optimize organizational effectiveness and sustainable development of German higher education institutions. Transforming governance of German Universities of Excellence involves mission statements, strategic goals, institutional strategies, research, teaching, the third mission, internationalization, global engagement, governance relationships and structures, institutional leadership, funding, autonomy, innovation, digital transformation, quality assurance, and sustainable development, aiming to enhance accountability, performativity, transparency, openness and organizational effectiveness with efficient administrative management in alignment with institutional missions, vision, core values, and strategic goals.
Engagement, not Dependence: Ethically Designing Assistive Systems for Users with Cognitive Impairments
2022-09-26

Assistive systems supporting users with cognitive impairments are commonplace in sheltered living facilities. Assistive systems may collect data or analyze user behavior to tailor services for the users' type and level of impairment. However, ways to integrate ethical standards into the design and deployment of assistive systems for users with cognitive impairments are not yet established. We conducted a qualitative inquiry inspired by literature in ethics to address this. We interviewed caretakers and tenants with cognitive impairments in a sheltered living facility. We present four themes that describe the lived practice of ethics when using assistive systems: Autonomy &amp;amp; Independence, Confidence in Technology, Motivation, and Communal Living. Combining the themes with ethics theory, we derived five design implications for the ethical design of assistive systems. Our work proposes boundaries in which new assistive systems can be designed ethically and guide future assistive systems for marginalized populations.
Investigation of urinary metabolomics in a phase I hookworm vaccine trial in Gabon
2022-09-26

Metabolomics provides a powerful tool to study physiological changes in response to various perturbations such as vaccination. We explored whether metabolomic changes could be seen after vaccination in a phase I trial where Gabonese adults living either in rural or semi-urban areas received the subunit hookworm vaccine candidates ( Na -GST-1 and Na -APR-1 (M74) adjuvanted with Alhydrogel plus GLA-AF (n = 24) or the hepatitis B vaccine (n = 8) as control. Urine samples were collected and assayed using targeted 1 H NMR spectroscopy. At baseline, a set of metabolites significantly distinguished rural from semi-urban individuals. The pre- and post-vaccination comparisons indicated significant changes in few metabolites but only one day after the first vaccination. There was no relationship with immunogenicity. In conclusion, in a small phase 1 trial, urinary metabolomics could distinguish volunteers with different environmental exposures and reflected the safety of the vaccines but did not show a relationship to immunogenicity.
FIONA1-mediated methylation of the 3’UTR of FLC affects FLC transcript levels and flowering in Arabidopsis
2022-09-27

Adenosine bases of RNA can be transiently modified by the deposition of a methyl-group to form N 6 -methyladenosine (m 6 A). This adenosine-methylation is an ancient process and the enzymes involved are evolutionary highly conserved. A genetic screen designed to identify suppressors of late flowering transgenic Arabidopsis plants overexpressing the miP1a microProtein yielded a new allele of the FIONA1 (FIO1) m 6 A-methyltransferase. To characterize the early flowering phenotype of fio1 mutant plants we employed an integrative approach of mRNA-seq, Nanopore direct RNA-sequencing and meRIP-seq to identify differentially expressed transcripts as well as differentially methylated RNAs. We provide evidence that FIO1 is the elusive methyltransferase responsible for the 3’-end methylation of the FLOWERING LOCUS C ( FLC ) transcript. Furthermore, our genetic and biochemical data suggest that 3’-methylation stabilizes FLC mRNAs and non-methylated FLC is a target for rapid degradation.
Assessing effective connectivity of the cerebellum with cerebral cortex using TMS-EEG
2022-09-27

The EEG responses observed in this highly controlled experimental design may cautiously be attributed to reflect specific signatures of the activation of the cerebello-dentato-thalamo-cortical pathway by cbTMS. Therefore, these responses may provide biomarkers for assessing the integrity of this pathway, a proposition that will need further testing in clinical populations.
The evolutionary conservation of eukaryotic membrane-bound adenylyl cyclase isoforms
2022-09-27

The nine membrane-delimited eukaryotic adenylyl cyclases are pseudoheterodimers with an identical domain order of seven (nine) distinct subdomains. Bioinformatics show that the protein evolved from a monomeric bacterial progenitor by gene duplication and fusion probably in a primordial eukaryotic cell around 1.5 billion years ago. Over a timespan of about 1 billion years, the first fusion product diverged into nine highly distinct pseudoheterodimeric isoforms. The evolutionary diversification ended approximately 0.5 billion years ago because the present isoforms are found in the living fossil coelacanth, a fish. Except for the two catalytic domains, C1 and C2, the mAC isoforms are fully diverged. Yet, within each isoform a high extent of conservation of respective subdomains is found. This applies to the C- and N-termini, a long linker region between the protein halves (C1b), two short cyclase-transducing-elements (CTE) and notably to the two hexahelical membrane domains TM1 and TM2. Except for the membrane anchor all subdomains were previously implicated in regulatory modalities. The bioinformatic results unequivocally indicate that the membrane anchors must possess an important regulatory function specifically tailored for each mAC isoform.
Phase of firing does not reflect temporal order in sequence memory of humans and recurrent neural networks
2022-09-27

Abstract A prominent theory proposes that the temporal order of a sequence of items held in memory is reflected in ordered firing of neurons at different phases of theta oscillations 1 . We probe this theory by directly measuring single neuron activity (1420 neurons) and local field potentials (LFP, 921 channels) in the medial temporal lobe of 16 epilepsy patients performing a working memory task for temporal order. We observe theta oscillations and preferential firing of single neurons at theta phase during memory maintenance. We find that - depending on memory performance - phase of firing is related to item position within a sequence. However, in contrast to the theory, phase order did not match item order. To investigate underlying mechanisms, we subsequently trained recurrent neural networks (RNNs) to perform an analogous task. Similar to recorded neural activity, we show that RNNs generate theta oscillations during memory maintenance. Importantly, model neurons exhibit theta phase-dependent firing related to item position, where phase of firing again did not match item order. Instead, we observed a mechanistic link between phase order, stimulus timing and oscillation frequency - a relationship we subsequently confirmed in our neural recordings. Taken together, in both biological and artificial neural networks we provide validating evidence for the role of phase-of-firing in memory processing while at the same time challenging a long-held theory about the functional role of spiking and oscillations in sequence memory.
Comprehensive Multi-compartment Sampling for Quantification of Long-Term Accumulation of PAHs in Soils
2022-09-27

Long-term accumulation in the soils of ubiquitous organic pollutants such as many polycyclic aromatic hydrocarbons (PAHs) depends on deposition from the atmosphere, revolatilization, leaching, and degradation processes such as photolysis and biodegradation. Quantifying the phase distribution and fluxes of these compounds across environmental compartments is thus crucial to understand the long-term contaminant fate. The gas-phase exchange between soil and atmosphere follows chemical fugacity gradients that can be approximated by gas-phase concentrations, yet which are difficult to measure directly. Thus, passive sampling, measured sorption isotherms, or empirical relationships to estimate sorption distribution have been combined in this study to determine aqueous (or gas) phase concentrations from measured bulk concentrations in soil solids. All these methods have their strengths and weaknesses but agree within 1 order of magnitude except for <i>ex situ</i> passive samplers employed in soil slurries, which estimated much lower concentrations in soil water and gas likely due to experimental artifacts. In field measurements, PAH concentrations determined in the atmosphere show a pronounced seasonality with some revolatilization during summer and gaseous deposition during winter, but overall dry deposition dominates annual mean fluxes. The characteristic patterns of PAHs in the different phases (gas phase, atmospheric passive samplers, bulk deposition, and soil solids) confirm the expected compound-specific distribution pattern and behavior. Since revolatilization fluxes in summer are only minor and wet and dry deposition is ongoing, our results clearly show that the PAH loads in topsoils will continue to increase.
Validation of an SH-SY5Y Cell–Based Acetylcholinesterase Inhibition Assay for Water Quality Assessment
2022-09-27

Abstract The acetylcholinesterase (AChE) inhibition assay has been frequently applied for environmental monitoring to capture insecticides such as organothiophosphates (OTPs) and carbamates. However, natural organic matter such as dissolved organic carbon (DOC) co-extracted with solid-phase extraction from environmental samples can produce false-negative AChE inhibition in free enzyme-based AChE assays. We evaluated whether disturbance by DOC can be alleviated in a cell-based AChE assay using differentiated human neuroblastoma SH-SY5Y cells. The exposure duration was set at an optimum of 3 h considering the effects of OTPs and carbamates. Because loss to the airspace was expected for the more volatile OTPs (chlorpyrifos, diazinon, and parathion), the chemical loss in this bioassay setup was investigated using solid-phase microextraction followed by chemical analysis. The three OTPs were relatively well retained (loss &amp;lt;34%) during 3 h of exposure in the 384-well plate, but higher losses occurred on prolonged exposure, accompanied by slight cross-contamination of adjacent wells. Inhibition of AChE by paraoxon-ethyl was not altered in the presence of up to 68 mgc/L Aldrich humic acid used as surrogate for DOC. Binary mixtures of paraoxon-ethyl and water extracts showed concentration-additive effects. These experiments confirmed that the matrix in water extracts does not disturb the assay, unlike purified enzyme-based AChE assays. The cell-based AChE assay proved to be suitable for testing water samples with effect concentrations causing 50% inhibition of AChE at relative enrichments of 0.5–10 in river water samples, which were distinctly lower than corresponding cytotoxicity, confirming the high sensitivity of the cell-based AChE inhibition assay and its relevance for water quality monitoring. Environ Toxicol Chem 2022;41:3046–3057. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. Abstract Pesticides in the environment can inhibit acetylcholinesterase (AChE). However, natural organic matter such as dissolved organic carbon (DOC) can be co-extracted from the environmental samples and can interfere with the AChE inhibition assays that use purified enzymes. We confirmed that there was no bias by DOC in our cell-based AChE inhibition assay. In addition, loss of well-known AChE inhibitors to the airspace was evaluated, and it was shown that the 3-h AChE inhibition assay can be run without substantial loss of chemicals.
Platelets and the Cybernetic Regulation of Ischemic Inflammatory Responses through PNC Formation Regulated by Extracellular Nucleotide Metabolism and Signaling
2022-09-27

Ischemic events are associated with severe inflammation and are here referred to as ischemic inflammatory response (IIR). Recent studies identified the formation of platelet–neutrophil complexes (PNC) as key players in IIR. We investigated the role of extracellular platelet nucleotide signaling in the context of IIR and defined a cybernetic circle, including description of feedback loops. Cybernetic circles seek to integrate different levels of information to understand how biological systems function. Our study specifies the components of the cybernetic system of platelets in IIR and describes the theoretical progression of IIR passing the cybernetic cycle with positive and negative feedback loops based on nucleotide-dependent signaling and functional regulation. The cybernetic components and feedback loops were explored by cytometry, immunohistological staining, functional blocking antibodies, and ADP/ATP measurements. Using several ex vivo and in vivo approaches we confirmed cybernetic parameters, such as controller, sensor, and effector (VASP phosphorylation, P2Y12, ADORAs and GPIIb/IIIa activity), as well as set points (ADP, adenosine) and interfering control and disturbance variables (ischemia). We demonstrate the impact of the regulated platelet–neutrophil complex (PNC) formation in blood and the resulting damage to the affected inflamed tissue. Taken together, extracellular nucleotide signaling, PNC formation, and tissue damage in IIR can be integrated in a controlled cybernetic circle of platelet function, as introduced through this study.