Biology subjects

Stahl, A.

Publications and source records attributed to Stahl, A..

18 recordsLinked to original sources

bioRxiv2026

Browning Lipid Nanoparticles Deliver Metabolic Benefits via Transient Conversion of White Adipose Tissue

Therapeutic strategies based on increasing uncoupled respiration (browning) in white adipose tissue (WAT) have great potential for treating obesity-related disorders such as diabetes and steatotic liver disease, but have not had a clinical impact because safe and efficient methods for browning WAT have not been developed. Lipid nanoparticles (LNPs) offer a promising platform for adipose-directed siRNA delivery; however, conventional formulations often exhibit limited activity in adipocytes and can induce inflammatory responses that may restrict repeated administration. Here we demonstrate that LNPs that contain ionizable lipids with three lipid tails and siRNAs targeting TLE3 and ZFP423 can efficiently transfect mature adipocytes and induce browning of WAT in vitro and in vivo while providing the biocompatibility needed for repeated subcutaneous injections. Repeated local administration of BLNPs in diet-induced obese mice resulted in sustained target gene silencing, increased expression of thermogenic markers, altered energy metabolism, and decreased hepatic lipid accumulation despite minimal effects on body weight relative to scramble siRNA controls. Collectively, these findings establish BLNPs as a promising platform for adipose-directed RNA delivery and targeted modulation of thermogenic pathways, providing a strategy for investigating how localized adipose tissue remodeling influences metabolic physiology.

bioengineering↗

bioRxiv2026

High-throughput stomatal phenotyping provides selection targets for stress-resilient wheat

Phenotyping stomatal traits and their developmental plasticity is time-consuming but holds potential to improve water use efficiency and photosynthesis for designing stress-tolerant crops under climate change. Here, we develop a robust, high-throughput pipeline for phenotyping 14 stomatal traits in winter wheat related to size, variation, maximum conductance, and spatial patterning. We (1) analyze over 25,000 images from 60 wheat cultivars grown in growth chamber, greenhouse, and field conditions; (2) investigate the impact of light, temperature, and reduced water and nitrogen supply on stomatal traits and their developmental plasticity across adaxial and abaxial surfaces; and (3) evaluate genetic diversity and breeding progress of stomatal traits. Stomatal traits were highly broad-sense heritable, were largely plastic in response to environmental conditions, and showed genotype-specific responses. Stomatal traits of third leaves under controlled environments with stable light and temperature conditions reliably captured the genetic variance of flag leaves under field conditions. Our data suggests that the upper leaf surface contributed more to transpiration and cooling through consistently higher stomatal density, area, and maximum conductance, while the lower surface facilitated CO2 diffusion via systematic proper patterning and spacing. Breeding maintains the genetic diversity of stomatal traits, and our pipeline facilitates breeders to target them to enhance water use efficiency in high-yielding modern cultivars.

plant biology↗

bioRxiv2026

Progeny differentiation in faba bean using hyperspectral images and machine learning

Though currently a minor crop, faba bean is a promising source of plant-based protein as global diets shift towards more plant-based nutrition. To realise this potential, advances in breeding and cultivation are crucial. To exploit heterosis, faba bean breeding frequently utilises synthetic cultivars, which involves open pollination of inbred lines to produce a mixture of F1 hybrid seeds and self-pollinated offspring. Pure F1 hybrid cultivars are currently unavailable due to unstable cytoplasmic male sterility (CMS) systems. An ability to distinguish F1 seeds from their parental inbreds via characteristics associated with xenia effects could change this. The xenia effect refers to the influence of paternal pollen on seed traits, for example seed weight and cotyledon cells in faba bean. In this study, we exploited the xenia effect captured in hyperspectral imaging data to develop machine learning scenarios for discriminating between parental and F1 seeds of open pollinated synthetic combinations (Syn-1). The hyperspectral data were pre-processed using Savitzky-Golay filtering to reduce noise and smooth the spectra. Various machine learning algorithms were applied, incorporating Bayesian hyperparameter optimisation. The scenarios achieved up to 98.9 % accuracy in separating parental components of Syn-1. When including all seeds, the model achieved 40.7 %, indicating moderate detection and classification performance. As the harmonic mean of precision and recall, the F1 score accounts for both the correctness of F1 seed detections and the completeness with which F1 seeds were detected. While this approach does not yet enable the development of full hybrid cultivars, it paves the way for hybrid-enriched cultivars. These could help to streamline breeding for synthetic cultivars and potentially increase yields, for example by increasing the proportion of F1 hybrid seeds in synthetic cultivars. This study extends knowledge of the xenia effect in faba bean and provides a basis for further research aimed at enhancing breeding methods and productivity.

genetics↗

bioRxiv2026

A Liver-Targeted Copper Supplement Reduces Metabolic Dysfunction-Associated Liver Steatosis by Increasing Lipolysis and Fatty Acid Oxidation

Metabolic-associated steatotic liver disease (MASLD) is a prevalent liver disease driven by complex dysregulation of hepatic lipid metabolism. Here we show that copper deficiency is a nutrient vulnerability in steatotic liver disease and that selective liver-targeted copper supplementation can reduce excess lipid accumulation. Analysis of steatotic patient and mouse tissues identify widespread alterations in hepatic copper homeostasis markers. Integrated multi-omics analyses reveal that copper induces lipolysis of PLIN2-containing lipid droplets while lipid importer CD36 is downregulated. We show that copper inhibits cAMP hydrolase activity of PDE3B, thus activating PKA-mediated HSL and AMPK activation upstream of lipolysis. Fatty acids liberated through lipolysis are subsequently degraded via enhanced mitochondrial fatty acid oxidation, supported by energetic rewiring toward oxidative phosphorylation (OXPHOS) with increased copper-dependent complex IV and SOD1 activity. Our findings establish a multi-pronged mechanism by which hepatic copper supplementation coordinately regulates lipid metabolism in response to steatosis and unveils a therapeutic metallomedicine strategy to rewire lipid regulation. SummaryLiver-targeted copper supplementation reduces diet-induced liver steatosis by dual activation of lipolysis and fatty acid degradation pathways. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/725917v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@982970org.highwire.dtl.DTLVardef@1c8adb5org.highwire.dtl.DTLVardef@4762dorg.highwire.dtl.DTLVardef@ea95cd_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2026

Chiral methionine oxidation reagents reveal stereospecific proteome modifications

Life is predicated on chirality, a molecular asymmetry akin to the left and right versions of human hands. Here we show that privileged protein residues are predisposed for chiral regulation. We developed enantiomeric oxaziridine reagents that systematically identify pro-(S) and pro-(R) methionine oxidation sites across proteomes that can be erased by stereospecific methionine sulfoxide reductase enzymes A and B, respectively. These probes reveal that chiral regulation of methionine oxidation-reduction processes can allosterically regulate protein function, as shown in cell and murine models of oxidative stress where selective (R)-methionine sulfoxide formation on M69 of biphenyl hydrolase-like protein leads to hydrolase inhibition and amplification of proteome N-homocysteinylation modifications. This work introduces a platform for characterizing sites of asymmetric methionine oxidation and the functional consequences concomitant with an individual chiral single-atom modification.

biochemistry↗

bioRxiv2026

NOHIC: A PIPELINE FOR PLANT CONTIG SCAFFOLDING USING PERSONALIZED REFERENCES FROM PANGENOME GRAPHS

Hi-C data is commonly used for reference-free de novo scaffolding. However, with the rapid increase in high-quality reference genomes, reference-guided workflows are now more practical for assembling large numbers of target genomes without relying on costly and labor-intensive Hi-C sequencing. Recently, a pangenome graph-based haplotype sampling algorithm was introduced to generate personalized graphs for target genomes. Such graphs have strong potential as references for reference-guided contig scaffolding. Here, we present noHiC, a reference-guided scaffolding pipeline supporting key steps of plant contig scaffolding. A distinctive feature of noHiC is the nohic-refpick script, generating a best-fit synthetic reference (synref) from a pangenome graph that is genetically close to the target contigs. This enables the integration of genetic information from many references (up to 48 in our tests) without using them separately during scaffolding. Synrefs showed advantages over highly contiguous conventional references in reducing false contig breaking during reference-based correction. Additionally, nohic-refpick can be combined with fast scaffolders (ntJoin) to rapidly produce highly contiguous assemblies using synrefs derived from pangenome graphs. The noHiC pipeline, used alone or in combination with ntJoin, can generally produce assemblies that are structurally consistent with public Hi-C-based or manually curated genomes. The pipeline is publicly available at https://github.com/andyngh/noHiC. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/712436v1_ufig1.gif" ALT="Figure 1"> View larger version (9K): org.highwire.dtl.DTLVardef@40bd8forg.highwire.dtl.DTLVardef@5d2bbborg.highwire.dtl.DTLVardef@e214a3org.highwire.dtl.DTLVardef@b90b06_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Bioenergetic responses to β-adrenergic stimulation in beige adipocyte depend on actomyosin driven forces

Beige (BeAT) and white adipoctyes (WAT) reside within the same fat depots but differ in their responses to {beta}-adrenergic stimulation. While both activate classical PKA-mediated pathways, only beige adipocytes show induction of UCP1 expression and enhanced mitochondrial respiration, suggesting additional mechanisms that distinguish their responses. Here we uncover a parallel, non-canonical biomechanical pathway specific to beige adipocytes that is essential for thermogenic activation. Mechanistically, {beta}-AR stimulation induces a rapid Myh9-mediated actomyosin contraction and stiffening in beige, but not white, adipocytes that activates focal adhesion kinase (FAK), which we show to be critical for the expression of oxidative and thermogenic genes including UCP1 and PLIN5. These findings reveal a new biomechanical Myh9-FAK signaling arm downstream of b-adrenergic activation that differentiates thermogenic from white adipocytes.

cell biology↗

bioRxiv2024

Neurofibromin deficiency alters the patterning and prioritization of motor behaviors in a state-dependent manner

Genetic disorders such as neurofibromatosis type 1 increase vulnerability to cognitive and behavioral disorders, such as autism spectrum disorder and attention-deficit/hyperactivity disorder. Neurofibromatosis type 1 results from loss-of-function mutations in the neurofibromin gene and subsequent reduction in the neurofibromin protein (Nf1). While the mechanisms have yet to be fully elucidated, loss of Nf1 may alter neuronal circuit activity leading to changes in behavior and susceptibility to cognitive and behavioral comorbidities. Here we show that mutations decreasing Nf1 expression alter motor behaviors, impacting the patterning, prioritization, and behavioral state dependence in a Drosophila model of neurofibromatosis type 1. Loss of Nf1 increases spontaneous grooming in a nonlinear spatial and temporal pattern, differentially increasing grooming of certain body parts, including the abdomen, head, and wings. This increase in grooming could be overridden by hunger in food-deprived foraging animals, demonstrating that the Nf1 effect is plastic and internal state-dependent. Stimulus-evoked grooming patterns were altered as well, with nf1 mutants exhibiting reductions in wing grooming when coated with dust, suggesting that hierarchical recruitment of grooming command circuits was altered. Yet loss of Nf1 in sensory neurons and/or grooming command neurons did not alter grooming frequency, suggesting that Nf1 affects grooming via higher-order circuit alterations. Changes in grooming coincided with alterations in walking. Flies lacking Nf1 walked with increased forward velocity on a spherical treadmill, yet there was no detectable change in leg kinematics or gait. Thus, loss of Nf1 alters motor function without affecting overall motor coordination, in contrast to other genetic disorders that impair coordination. Overall, these results demonstrate that loss of Nf1 alters the patterning and prioritization of repetitive behaviors, in a state-dependent manner, without affecting motor coordination.

neuroscience↗

bioRxiv2024

Viscoelastic high-molecular-weight hyaluronic acid hydrogels support rapid glioblastoma cell invasion with leader-follower dynamics

Hyaluronic acid (HA), the primary component of brain extracellular matrix, is increasingly used to model neuropathological processes, including glioblastoma (GBM) tumor invasion. While elastic hydrogels based on crosslinked low-molecular-weight (LMW) HA are widely exploited for this purpose and have proven valuable for discovery and screening, brain tissue is both viscoelastic and rich in high-MW (HMW) HA, and it remains unclear how these differences influence invasion. To address this question, hydrogels comprised of either HMW (1.5 MDa) or LMW (60 kDa) HA are introduced, characterized, and applied in GBM invasion studies. Unlike LMW HA hydrogels, HMW HA hydrogels relax stresses quickly, to a similar extent as brain tissue, and to a greater extent than many conventional HA-based scaffolds. GBM cells implanted within HMW HA hydrogels invade much more rapidly than in their LMW HA counterparts and exhibit distinct leader-follower dynamics. Leader cells adopt dendritic morphologies, similar to invasive GBM cells observed in vivo. Transcriptomic, pharmacologic, and imaging studies suggest that leader cells exploit hyaluronidase, an enzyme strongly enriched in human GBMs, to prime a path for followers. This study offers new insight into how HA viscoelastic properties drive invasion and argues for the use of highly stress-relaxing materials to model GBM.

bioengineering↗

bioRxiv2023

Exploring the molecular makeup of support cells in insect camera eyes

Animals generally have either compound eyes, which have evolved repeatedly in different invertebrates, or camera eyes, which have evolved many times across the animal kingdom. Both eye types include two important kinds of cells: photoreceptor cells, which can be excited by light, and non-neuronal support cells (SupCs), which provide essential support to photoreceptors. Despite many examples of convergence in eye evolution, similarities in the gross developmental plan and molecular signatures have been discovered, even between phylogenetically distant and functionally different eye types. For this reason, a shared evolutionary origin has been considered for photoreceptors. In contrast, only a handful of studies, primarily on the compound eyes of Drosophila melanogaster, have demonstrated molecular similarities in SupCs. D. melanogaster SupCs (Semper cells and primary pigment cells) are specialized eye glia that share several molecular similarities with certain vertebrate eye glia, including Muller glia. This led us to speculate whether there are conserved molecular signatures of SupCs, even in functionally different eyes such as the image-forming larval camera eyes of the sunburst diving beetle Thermonectus marmoratus. To investigate this possibility, we used an in-depth comparative whole-tissue transcriptomics approach. Specifically, we dissected the larval principal camera eyes into SupC- and retina-containing regions and generated the respective transcriptomes. Our analysis revealed several conserved features of SupCs including enrichment of genes that are important for glial function (e.g. gap junction proteins such as innexin 3), glycogen production (glycogenin), and energy metabolism (glutamine synthetase 1 and 2). To evaluate the extent of conservation, we compared our transcriptomes with those of fly (Semper cells) and vertebrate (Muller glia) eye glia as well as respective retinas. T. marmoratus SupCs were found to have distinct genetic overlap with both fly and vertebrate eye glia. These results provide molecular evidence for the deep conservation of SupCs in addition to photoreceptor cells, raising essential questions about the evolutionary origin of eye-specific glia in animals.

neuroscience↗

bioRxiv2022

Protein profiling of breast carcinomas reveals expression of immune-suppressive factors and signatures relevant to patient outcome

BackgroundIn cancerous tissue, a complex interplay of tumour cells with different cell types from the tumour microenvironment is causing modulations in signalling processes. By directly assessing expression of a multitude of proteins and protein variants, extensive information on signalling pathways, their activation status and the effect of the immunological landscape can be obtained providing viable information for treatment response. MethodsProtein extracted from archived breast cancer tissue from patients without adjuvant therapy was subjected to high-throughput Western blotting using the DigiWest technology. Expression of 150 proteins and protein variants covering cell cycle control, apoptosis, Jak/Stat, MAPK-, Pi3K/Akt-, Wnt-, and, autophagic signalling as well as general tumour markers was monitored in a cohort of 84 patient samples. The degree of immune cell infiltration was investigated and set against treatment outcome by integrating patient specific follow-up data. ResultsCharacterization of the tumour microenvironment by monitoring CD8, CD11c, CD16 and CD68 expression revealed a strong correlation of event-free patient survival with immune cell infiltration. Furthermore, the presence of tumour infiltrating lymphocytes was linked to a pronounced activation of the Jak/Stat signalling pathway and apoptotic processes. Elevated phosphorylation of peroxisome proliferator-activated receptor gamma (PPAR{gamma}, pS112) in non-immune infiltrated tumour tissue suggests a novel immune evasion mechanism in breast cancer characterized by increased PPAR{gamma} activation. ConclusionMultiplexed immune cell marker assessment and protein profiling of tumour tissue provides functional signalling data facilitating breast cancer patient stratification.

cancer biology↗

bioRxiv2022

G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis

Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes (T2D). Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for T2D, but the mechanism behind this association has remained elusive. Here for the first time we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. Our findings establish a previously unknown role of Gpr151 in the liver and provides an explanation to the lowered T2D risk in individuals with nonsynonymous mutations in GPR151. This study highlights the therapeutic potential of targeting GPR151 for treatment of metabolic disease.

physiology↗

bioRxiv2022

Coenzyme Q regulates UCP1 expression and thermogenesis through the integrated stress responses

Coenzyme Q (CoQ) is an essential component of mitochondrial respiration1 and required for thermogenic activity in brown adipose tissues2 (BAT). CoQ deficiency leads to a wide range of pathological manifestations3 but mechanistic consequences of CoQ deficiency in specific tissues such as BAT remain poorly understood. Here we show that pharmacological or genetic CoQ deficiency (50-75% reduction) in BAT leads to accumulation of cytosolic mitochondrial RNAs (mtRNAs) and activation of the eIF2 kinase PKR resulting in the induction of the integrated stress response (ISR) and suppression of UCP1 expression in an ATF4-dependent fashion. Surprisingly, despite diminished UCP1 levels, BAT CoQ deficiency increases whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high fat diets (HFD). This mitohormesis like effect of BAT CoQ insufficiency is dependent on the ATF4-FGF21 axis in BAT revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.

cell biology↗

bioRxiv2021

Associative learning drives longitudinally-graded presynaptic plasticity of neurotransmitter release along axonal compartments

Anatomical and physiological compartmentalization of neurons is a mechanism to increase the computational capacity of a circuit, and a major question is what role axonal compartmentalization plays. Axonal compartmentalization may enable localized, presynaptic plasticity to alter neuronal output in a flexible, experience-dependent manner. Here we show that olfactory learning generates compartmentalized, bidirectional plasticity of acetylcholine release that varies across the longitudinal compartments of Drosophila mushroom body (MB) axons. The directionality of the learning-induced plasticity depends on the valence of the learning event (aversive vs. appetitive), varies linearly across proximal to distal compartments following appetitive conditioning, and correlates with learning-induced changes in downstream mushroom body output neurons (MBONs) that modulate behavioral action selection. Potentiation of acetylcholine release was dependent on the CaV2.1 calcium channel subunit cacophony. In addition, contrast between the positive conditioned stimulus and other odors required the inositol triphosphate receptor (IP3R), which was required to maintain responsivity to odors in untrained conditions. Downstream from the mushroom body, a set of MBONs that receive their input from the {gamma}3 MB compartment were required for normal appetitive learning, suggesting that they represent a key node through which discriminative effects influence appetitive memory and decision-making. These data demonstrate that learning drives valence-correlated, compartmentalized, bidirectional potentiation and depression of synaptic neurotransmitter release, which rely on distinct mechanisms and are distributed across axonal compartments in a learning circuit.

neuroscience↗

bioRxiv2020

Mitohormesis reprograms macrophage metabolism to enforce tolerance

Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, pharmacologically-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/347443v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@c5c03org.highwire.dtl.DTLVardef@16cd130org.highwire.dtl.DTLVardef@119b461org.highwire.dtl.DTLVardef@914ee4_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

4 β-hydroxycholesterol is a pro-lipogenic factor that promotes SREBP1c expression and activity through Liver X-receptor.

Oxysterols are oxidized derivatives of cholesterol that play signaling roles in lipid biosynthesis and homeostasis. Here we show that 4{beta}-hydroxycholesterol (4{beta}-HC), a liver and serum abundant oxysterol of poorly defined function, is a potent and selective inducer of the master lipogenic transcription factor, Sterol Regulatory Element Binding Protein 1c (SREBP1c), but not the related steroidogenic transcription factor SREBP2. Mechanistically, 4{beta}-HC acts as a putative agonist for Liver X receptor (LXR), a sterol sensor and transcriptional regulator previously linked to SREBP1c activation. Unique among the oxysterol agonists of LXR, 4{beta}-HC induced expression of the lipogenic program downstream of SREBP1c, and triggered de novo lipogenesis both in primary hepatocytes and in mouse liver. 4{beta}-HC-acted in parallel to insulin-PI3K-dependent signaling to stimulate triglyceride synthesis and lipid droplet accumulation. Thus, 4{beta}-HC is an endogenous regulator of de novo lipogenesis through the LXR-SREBP1c axis.

biochemistry↗

bioRxiv2019

Electrophysiology and transcriptomics reveal two photoreceptor classes and complex visual integration in Hirudo verbana

Among animals with complex visual processing mechanisms, the leech Hirudo verbana is a rare example in which all neurons can be identified. However, little is known about its visual system, which is composed of several pigmented head eyes and photosensitive non-pigmented sensilla that are distributed across its entire body. Although several interneurons are known to respond to visual stimuli, their response properties are poorly understood. Among these, the S cell system is especially intriguing: It is multimodal, spans the entire body of the leech, and is thought to be involved in complex sensory integration. To improve our understanding of the role of this system, we tested its spectral sensitivity, spatial integration, and adaptation properties. The response of the S cell system to visual stimuli was found to be strongly dependent on the size of the area stimulated, and adaptation was local. Furthermore, a "bleaching experiment" demonstrated that at least two color channels contributed to the response, and that their contribution was dependent on the adaptation to the background. The existence of at least two color channels was further supported by transcriptomic evidence, which indicated the existence of at least two distinct groups of putative opsins for leeches. Taken together, our results show that the S cell system has highly sophisticated response properties, and could be involved in the processing of complex visual stimuli. We propose the leech as a novel system to understand visual processing mechanisms with many practical advantages. Summary statementDetailed quantitative analysis of light responses in the medicinal leech Hirudo verbana unequivocally demonstrates the existence of parallel visual pathways processing visual and UV stimuli. Responses to spatially complex stimuli indicate relatively sophisticated information processing.

neuroscience↗

bioRxiv2018

Metabolically-Driven Maturation of hiPSC-Cell Derived Heart-on-a-Chip

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) are a promising in vitro tool for drug development and disease modeling, but their immature electrophysiology limits diagnostic utility. Tissue engineering approaches involving aligned 3D cultures enhance hiPSC-CM structural maturation but are insufficient to induce mature electrophysiology. We hypothesized that mimicking post-natal switching of the hearts primary ATP source from glycolysis to fatty acid oxidation could enhance electrophysiological maturation of hiPSC-CM. We combined hiPSC-CM with microfabricated culture chambers to form 3D cardiac microphysiological systems (MPS) that enhanced immediate microtissue alignment and tissue specific extracellular matrix (ECM) production. Using Robust Experimental design, we identified a maturation media that improved calcium handling in MPS derived from two genetically distinct hiPSC sources. Although calcium handling and metabolic maturation were improved in both genotypes, there was a divergent effect on action potential duration (APD): MPS that started with abnormally prolonged APD exhibited shorter APD in response to maturation media, whereas the same media prolonged the APD in MPS that started with aberrantly short APD. Importantly, the APD of both genotypes was brought near the range of 270-300ms observed in human left ventricular cardiomyocytes. Mathematical modeling explained these divergent phenotypes, and further predicted the response of matured MPS to drugs with known pro-arrhythmic effects. These results suggest that systematic combination of biophysical stimuli and metabolic cues can enhance the electrophysiological maturation of hiPSC-derived cardiomyocytes. However, they also reveal that maturation-inducing cues can have differential effects on electrophysiology depending on the baseline phenotype of hiPSC-CM. In silico models provide a valuable tool for predicting how changes in cellular maturation will manifest in drug responsiveness.

bioengineering↗