Biology subjects

Beck, J.

Publications and source records attributed to Beck, J..

35 records · Page 2Linked to original sources

bioRxiv2023

Memory systems integration in sleep complements rapid systems consolidation in wakefulness

Sleep benefits memory performance by fostering systems consolidation, a process that embeds memories into neocortical networks and renders them independent of the hippocampus. Recent evidence shows that memory rehearsal during wakefulness likewise initiates systems consolidation and rapidly engenders neocortical engrams. Here, we investigate the effect of sleep-dependent consolidation for memories that have undergone rapid systems consolidation during wakefulness. After sleep compared to wakefulness, we find better memory retention and higher functional brain activity during memory retrieval in the medial parietal cortex, which hosts memory representations after rehearsal, and in the striatum and thalamus. Increased striatal and thalamic contributions were correlated with higher retrieval performance. Furthermore, all three regions decreased their functional connectivity to the hippocampus specifically after sleep. These findings show that besides continuing of systems consolidation initiated during wakefulness, sleep also acts to integrate different memory systems. Thus, rehearsal-induced and sleep-dependent consolidation seem to be complementary in nature.

neuroscience↗

bioRxiv2023

Combined statistical-mechanistic modeling links ionchannel genes to physiology of cortical neuron types

Neural cell types have classically been characterized by their anatomy and electrophysiology. More recently, single-cell transcriptomics has enabled an increasingly fine genetically defined taxonomy of cortical cell types, but the link between the gene expression of individual cell types and their physiological and anatomical properties remains poorly understood. Here, we develop a hybrid modeling approach to bridge this gap. Our approach combines statistical and mechanistic models to predict cells electrophysiological activity from their gene expression pattern. To this end, we fit biophysical Hodgkin-Huxley-based models for a wide variety of cortical cell types using simulation-based inference, while overcoming the challenge posed by the mismatch between the mathematical model and the data. Using multimodal Patch-seq data, we link the estimated model parameters to gene expression using an interpretable sparse linear regression model. Our approach recovers specific ion channel gene expressions as predictive of biophysical model parameters including ion channel densities, directly implicating their mechanistic role in determining neural firing.

neuroscience↗

bioRxiv2023

Changes in biodiversity impact atmospheric chemistry through plant volatiles and particles

Climate extremes in tandem with biodiversity change affect emissions of biogenic volatile organic compounds (BVOCs) from plants and, as a result, the formation of biogenic secondary organic aerosols (BSOA). The resulting BSOA can have a wide variety of impacts, such as on Earths radiative balance or cloud- and precipitation formation. However, at present, it is unclear how changing biodiversity will lead to changes in BVOC emissions, BSOA formation and their corresponding effects. We present a conceptual framework of the relationships between biodiversity and BVOC emissions based on our current mechanistic understanding and combining knowledge from the fields of biology and atmospheric chemistry. Parts of this framework are tested in a case study using a tree diversity experiment with adjunct BVOC and BSOA characterisation. The relative differences in tree monocultures and mixtures show that the overall concentration of BVOCs decreases with increasing biodiversity (p < 0.01), but results for BSOA compounds are mixed and overall non-significant (p = 0.40). We suggest future studies should follow a multidisciplinary approach where the fields of biology, atmospheric chemistry and climate research interact.

ecology↗

bioRxiv2022

Phase 1 of the NIH Preprint Pilot: Testing the viability of making preprints discoverable in PubMed Central and PubMed

IntroductionThe National Library of Medicine (NLM) launched a Pilot in June 2020 to: 1) explore the feasibility and utility of adding preprints to PubMed Central (PMC) and making them discoverable in PubMed, and 2) to support accelerated discoverability of National Institutes of Health (NIH)-supported research without compromising user trust in NLMs widely used literature services. MethodsThe first phase of the Pilot focused on archiving preprints reporting NIH-supported SARS-CoV-2 virus and COVID-19 research. To launch Phase 1, NLM identified eligible preprint servers and developed processes for identifying NIH-supported preprints within scope in these servers. Processes were also developed for the ingest and conversion of preprints in PMC and to send corresponding records to PubMed. User interfaces were modified for display of preprint records. NLM collected data on the preprints ingested and discovery of preprint records in PMC and PubMed and engaged users through focus groups and a survey to obtain direct feedback on the Pilot and perceptions of preprints. ResultsBetween June 2020 and June 2022, NLM added more than 3,300 preprint records to PMC (viewed 4 million times) and PubMed (viewed 3 million times) Nearly one-quarter of preprints in the Pilot were not associated with a peer-reviewed published journal article. User feedback revealed that the inclusion of preprints did not have a notable impact on trust in PMC or PubMed. DiscussionNIH-supported preprints can be identified and added to PMC and PubMed without disrupting existing operations processes. Additionally, inclusion of preprints in PMC and PubMed accelerates discovery of NIH research without reducing trust in NLM literature services. Phase 1 of the Pilot provided a useful testbed for studying NIH investigator preprint posting practices, as well as knowledge gaps among user groups, during the COVID-19 public health emergency, an unusual time with heightened interest in immediate access to research results.

scientific communication and education↗

bioRxiv2022

Combination therapy of glycation lowering compounds reduces caloric intake, improves insulin sensitivity and extends lifespan.

Non-enzymatic reactions in glycolysis lead to the accumulation of methylglyoxal (MGO), a reactive precursor to advanced glycation end-products (AGEs), which has been hypothesized to drive obesity, diabetes and aging-associated pathologies. A combination of nicotinamide, -lipoic acid, thiamine, pyridoxamine, and piperine (Gly-Low) lowered deleterious effects of glycation by reducing MGO and MGO-derived AGE, MG-H1, in mice. Gly-Low supplementation in the diet reduced food consumption, decreased body weight, improved insulin sensitivity, and increased survival in leptin receptor-deficient (Leprdb) and wild-type C57B6/J mice. Transcriptional, protein, and functional analyses demonstrated that Gly-Low inhibited appetite-stimulating ghrelin signaling and enhanced the appetite-satiating mTOR pathways within the hypothalamus. Consistent with these molecular findings, Gly-Low inhibited ghrelin-mediated hunger responses. When administered as a late-life intervention, Gly-Low slowed hypothalamic aging signatures, improved glucose homeostasis and motor coordination, and increased lifespan, suggesting its potential benefits in ameliorating age-associated decline. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/503411v3_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1beedc4org.highwire.dtl.DTLVardef@1ec1933org.highwire.dtl.DTLVardef@16a7ad2org.highwire.dtl.DTLVardef@1a5a608_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

Effects of microplastics mixed with natural particles on Daphnia magna populations

The toxicity of microplastics on Daphnia magna as a key model for freshwater zooplankton is well described. While several studies predict population-level effects based on short-term, individual-level responses, only very few have validated these predictions experimentally. Thus, we exposed D. magna populations to irregular polystyrene microplastics and diatomite as natural particle (both [≤] 63 m) over 50 days. We used mixtures of both particle types at fixed particle concentrations (50,000 particles mL-1) and recorded the effects on overall population size and structure, the size of the individual animals, and resting egg production. Particle exposure adversely affected the population size and structure and induced resting egg production. The terminal population size was 28-42% lower in exposed compared to control populations. Interestingly, mixtures containing diatomite induced stronger effects than microplastics alone, highlighting that natural particles are not per se less toxic than microplastics. Our results demonstrate that an exposure to synthetic and natural particles has negative population-level effects on zooplankton. Understanding the mixture toxicity of microplastics and natural particles is important given that aquatic organisms will experience exposure to both. Just as for chemical pollutants, better knowledge of such joint effects is essential to fully understand the environmental impacts of complex particle mixtures. Environmental ImplicationsWhile microplastics are commonly considered hazardous based on individual-level effects, there is a dearth of information on how they affect populations. Since the latter is key for understanding the environmental impacts of microplastics, we investigated how particle exposures affect the population size and structure of Daphnia magna. In addition, we used mixtures of microplastics and natural particles because neither occurs alone in nature and joint effects can be expected in an environmentally realistic scenario. We show that such mixtures adversely affect daphnid populations and highlight that population-level and mixture-toxicity designs are one important step towards more environmental realism in microplastics research. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/490562v3_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@11a9358org.highwire.dtl.DTLVardef@1bfa315org.highwire.dtl.DTLVardef@6bc0cdorg.highwire.dtl.DTLVardef@3ef1b8_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDaphnia populations exposed to mixtures of microplastics and diatomite C_LIO_LIEffects on population size, structure, and resting egg production C_LIO_LIDiatomite as natural particle more toxic than microplastics C_LIO_LIParticle mixtures induce negative population-level effects C_LIO_LIParticle mixtures represent more realistic exposure scenario C_LI

ecology↗

bioRxiv2021

Effects of co-incubation of LPS-stimulated RAW 264.7 macrophages on leptin production by 3T3-L1 adipocytes: A method for co-incubating distinct adipose tissue cell lines.

Adipose tissue is a major endocrine organ capable of releasing inflammatory adipokines. Inflammatory adipokine release is linked to the changes occurring in adipose tissue in the overfed state, where tissue remodeling results in hypertrophic adipocytes that recruit monocytes to infiltrate the tissue and take on an inflammatory phenotype. As the proportion of inflammatory macrophages increases there is a concurrent increase in release of macrophage-specific inflammatory mediators, further contributing to the inflamed state and setting an inflammatory loop between the macrophages and adipocytes. Although most inflammatory adipokines are released by macrophages, adipocytes can also release immunomodulatory adipokines, such as leptin. The objective of this research was to determine if co-incubation of activated macrophages with mature adipocytes, using Transwell inserts, affected leptin release by mature adipocytes. We also examined if there were differences in the amount of cell-secreted products quantified in cell-conditioned media collected from macrophage-containing (Transwell insert) and adipocyte-containing (well) compartments. Mature adipocytes (differentiated 3T3-L1 murine fibroblasts) were co-incubated with control and lipopolysaccharide-stimulated (0.01 g/ml) murine macrophages (RAW264.7), and nitric oxide, interleukin-6, and leptin levels were quantified in the cell-conditioned media from the two compartments. Activation status of the macrophages did not affect leptin release by the adipocytes. We observed higher amounts of leptin in wells compared to Transwells. Nitric oxide and interleukin-6 levels were similar between Transwells and wells, suggesting that these adipokines are traveling through the Transwell inserts and reaching equilibrium between the two compartments. There was a weak negative relationship between nitric oxide release by macrophages and leptin release by adipocytes. Our results suggest that co-incubating activated macrophages and adipocytes using Transwell inserts can result in distinct microenvironments in the different cellular compartments and that separate sampling of these compartments is required to detect the subtle signaling dynamics that exist between these cells.

cell biology↗

bioRxiv2021

Impaired developmental microglial pruning of excitatory synapses on CRH-expressing hypothalamic neurons exacerbates stress responses throughout life

The developmental origins of stress-related mental illnesses are well-established, and early-life stress/adversity (ELA) is an important risk factor. However, it is unclear how ELA impacts the maturation of salient brain circuits, provoking enduring vulnerability to stress and stress-related disorders. Here we find that ELA increases the number and function of excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, and implicate disrupted synapse pruning by microglia as a key mechanism. Microglial process dynamics on live imaging, and engulfment of synaptic elements by microglia, were both attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor Mer. Accordingly, selective chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Selective early-life microglial activation also mitigated the adrenal hypertrophy and prolonged stress responses in adult ELA mice, establishing microglial actions during development as powerful contributors to experience-dependent sculpting of stress-related brain circuits.

neuroscience↗

bioRxiv2021

Spatiotemporal heterogeneity of glioblastoma is dictated by microenvironmental interference

Glioblastomas are highly malignant tumors of the central nervous system. Evidence suggests that these tumors display large intra- and inter-patient heterogeneity hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies1-3. However, the source for dynamic reorganization of cellular states within their spatial context remains elusive. Here, we in-depth characterized glioblastomas by spatially resolved transcriptomics, metabolomics and proteomics. By deciphering exclusive and shared transcriptional programs across patients, we inferred that glioblastomas develop along defined neural lineages and adapt to inflammatory or metabolic stimuli reminiscent of reactive transformation in mature astrocytes. Metabolic profiling and imaging mass cytometry supported the assumption that tumor heterogeneity is dictated by microenvironmental alterations. Analysis of copy number variation (CNV) revealed a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. Deconvolution of age-dependent transcriptional programs in malignant and non-malignant specimens identified the aging environment as the major driver of inflammatory transformation in GBM, suggesting that tumor cells adopt transcriptional programs similar to inflammatory transformation in astrocytes. Glioblastoma stem cells implanted into human neocortical slices of varying age levels, independently confirmed that the ageing environment dynamically shapes the intratumoral heterogeneity towards reactive transcriptional programs. Our findings provide insights into the spatial architecture of glioblastoma, suggesting that both locally inherent tumor as well as global alterations of the tumor microenvironment shape its transcriptional heterogeneity. Global age-related inflammation in the human brain is driving distinct transcriptional transformation in glioblastomas, which requires an adjustment of the currently prevailing glioma models.

cancer biology↗

bioRxiv2020

Exposure to relaxing words during sleep promotes slow-wave sleep and subjective sleep quality

Our thoughts alter our sleep, but the underlying mechanisms are still unknown. We propose that mental processes are active to a greater or lesser extent during sleep and that this degree of activation affects our sleep depth. We examined this notion by activating the concept of "relaxation" during sleep using relaxation-related words in 50 healthy participants. In support of our hypothesis, playing relaxing words during non-rapid eye movement sleep extended the time spent in slow-wave sleep, increased power in the slow-wave activity band after the word cue, and abolished an asymmetrical sleep depth during the word presentation period. On the subjective level, participants reported a higher sleep quality and elevated alertness ratings. Our results support the notion that the activation of mental concepts during sleep can influence sleep depth and provide a basis for interventions using targeted activations to promote sleep depth and sleep quality to foster well-being and health.

neuroscience↗

bioRxiv2020

Inferring spatially transient gene expression pattern from spatial transcriptomic studies

Spatial transcriptomic is a technology to provide deep transcriptomic profiling by preserving the spatial organization. Here, we present a framework for SPAtial Transcriptomic Analysis (SPATA, https://themilolab.github.io/SPATA), to provide a comprehensive characterization of spatially resolved gene expression, regional adaptation of transcriptional programs and transient dynamics along spatial trajectories.

bioinformatics↗

bioRxiv2020

All-Trans Retinoic Acid induces synaptic plasticity in human cortical neurons

A defining feature of the brain is its ability to adapt structural and functional properties of synaptic contacts in an experience-dependent manner. In the human cortex direct experimental evidence for synaptic plasticity is currently missing. Here, we probed plasticity in human cortical slices using the vitamin A derivative all-trans retinoic acid, which has been suggested as medication for the treatment of neuropsychiatric disorders, e.g., Alzheimers disease. Our experiments demonstrate coordinated structural and functional changes of excitatory synapses of superficial (layer 2/3) pyramidal neurons in the presence of all-trans retinoic acid. This synaptic adaptation is accompanied by ultrastructural remodeling of the calcium-storing spine apparatus organelle and requires mRNA-translation. We conclude that all-trans retinoic acid is a potent mediator of synaptic plasticity in the adult human cortex.

neuroscience↗

bioRxiv2020

Lineage and Spatial Mapping of Glioblastoma-associated Immunity

The diversity of molecular states and cellular plasticity of immune cells in the glioblastoma environment is still poorly understood. Here, we performed scRNA sequencing of the immune compartment and mapped potential cellular interactions leading to an immunosuppressive microenvironment and dysfunction of T cells. Through inferring the dynamic adaptation during T cell activation, we identified three different terminal states with unique transcriptional programs. Modeling of driver genes for terminal T cell fate identified IL-10 signaling alterations in a subpopulation of HAVCR2(+) T cells. To explore in depth cellular interactions, we established an in-silico model by the integration of spatial transcriptomic and scRNA-sequencing, and identified a subset of HMOX1+ myeloid cells defined by IL10 release leading to T cell exhaustion. We found a spatial overlap between HMOX(+) myeloid and HAVCR2(+) T cells, suggesting that myeloid-lymphoid interaction causes immunosuppression present in tumor regions with enriched mesenchymal gene expression. Using human neocortical GBM model, coupled with patient-derived T cells, we confirmed that the functional interaction between myeloid and lymphoid cells, leads to a dysfunctional state of T cells. This IL-10 driven T cell exhaustion was found to be rescued by JAK/STAT inhibition. A comprehensive understanding of the cellular states and plasticity of lymphoid cells in GBM will aid towards successful immunotherapeutic approaches.

cancer biology↗

bioRxiv2018

A confirmation bias in perceptual decision-making due to hierarchical approximate inference

Making good decisions requires updating beliefs according to new evidence. This is a dynamical process that is prone to biases: in some cases, beliefs become entrenched and resistant to new evidence (leading to primacy effects), while in other cases, beliefs fade over time and rely primarily on later evidence (leading to recency effects). How and why either type of bias dominates in a given context is an important open question. Here, we study this question in classic perceptual decision-making tasks, where, puzzlingly, previous empirical studies differ in the kinds of biases they observe, ranging from primacy to recency, despite seemingly equivalent tasks. We present a new model, based on hierarchical approximate inference and derived from normative principles, that not only explains both primacy and recency effects in existing studies, but also predicts how the type of bias should depend on the statistics of stimuli in a given task. We verify this prediction in a novel visual discrimination task with human observers, finding that each observers temporal bias changed as the result of changing the key stimulus statistics identified by our model. By fitting an extended drift-diffusion model to our data we rule out an alternative explanation for primacy effects due to bounded integration. Taken together, our results resolve a major discrepancy among existing perceptual decision-making studies, and suggest that a key source of bias in human decision-making is approximate hierarchical inference.

animal behavior and cognition↗

bioRxiv2018

A conserved role of the insulin-like signaling pathway in uric acid pathologies revealed in Drosophila melanogaster

Elevated uric acid (UA) is a key factor for disorders, including gout or kidney stones and result from abrogated expression of Urate Oxidase (Uro) and diet. To understand the genetic pathways influencing UA metabolism we established a Drosophila melanogaster model with elevated UA using Uro knockdown. Reduced Uro expression resulted in the accumulation of UA concretions and diet-dependent shortening of lifespan. Inhibition of insulin-like signaling (ILS) pathway genes reduced UA and concretion load. In humans, SNPs in the ILS genes AKT2 and FOXO3 were associated with UA levels or gout, supporting a conserved role for ILS in modulating UA metabolism. Downstream of the ILS pathway UA pathogenicity was mediated partly by NADPH Oxidase, whose inhibition attenuated the reduced lifespan and concretion accumulation. Thus, genes in the ILS pathway represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones.\n\nHighlightsO_LIIn Drosophila high uric acid (UA) levels shorten lifespan and cause UA aggregation\nC_LIO_LIConserved in flies and humans, the ILS pathway associates with UA pathologies\nC_LIO_LIFoxO dampens concretion formation by reducing UA levels and ROS formation\nC_LIO_LIInhibition of NOX alleviates the lifespan attenuation and UA aggregation\nC_LI

pathology↗

bioRxiv2017

Striatal fast-spiking interneurons drive habitual behavior

Habit formation is a behavioral adaptation that automates routine actions. Habitual behavior correlates with broad reconfigurations of dorsolateral striatal (DLS) circuit properties that increase gain and shift pathway timing. The mechanism(s) for these circuit adaptations are unknown and could be responsible for habitual behavior. Here we find that a single class of interneuron, fast-spiking interneurons (FSIs), modulates all of these habit-predictive properties. Consistent with a role in habits, FSIs are more excitable in habitual mice compared to goal-directed and acute chemogenetic inhibition of FSIs in DLS prevents the expression of habitual lever pressing. In vivo recordings further reveal a previously unappreciated selective modulation of SPNs based on their firing patterns; FSIs inhibit most SPNs but paradoxically promote the activity of a subset displaying high fractions of gamma-frequency spiking. These results establish a microcircuit mechanism for habits and provide a new example of how interneurons mediate experience-dependent behavior.

neuroscience↗

bioRxiv2016

A Bayesian approach to inferring chemical signal timing and amplitude in a temporal logic gate using the cell population distributional response

1. Introduction 1. Introduction 2. The temporal logic... 3. Bayesian event detection... 4. Applying the Bayesian... 5. Conclusion References Stochastic gene expression poses an important challenge for engineering robust behaviors in a heterogeneous cell population [1]. Cells address this challenge using the distribution of cellular responses during some gene regulation and differentiation processes [2]. Similarly, the temporal logic gate design in Hsiao et al. [3] considers the distribution of responses across a cell population. The design employs integrases Bxb1 and TP901-1 [4] to engineer an E. coli strain with four DNA states that record the temporal order of two chemical signals. Hsiao et al. [3] also use the heter ...

synthetic biology↗