Biology subjects

Jordan, J.

Publications and source records attributed to Jordan, J..

14 recordsLinked to original sources

bioRxiv2025

Spatiotemporal mapping of microscale stiffness during collagen polymerization and crosslinking by optical multifrequency time-harmonic elastography

Optical multifrequency time-harmonic elastography (OMTHE) was used for rapid mechanical characterization of extra-cellular matrix-derived collagen networks at micrometer resolution. OMTHE was optimized for point-wise shear wave excitation in small sample volumes and compared to tabletop magnetic resonance elastography (ttMRE) and optical intensity changes. Dynamic stiffening due to the fluid-gel transition during collagen polymerization and chemical crosslinking using glutaraldehyde was tracked by shear waves speed (SWS) at vibration frequencies between 3 and 10 kHz and frame rates up to 4 kHz. During collagen polymerization, after an initial lag phase, SWS increased on average 6 {+/-} 3 min earlier than optical density, suggesting that a load-bearing percolating fiber network was established before fibril thickening enhanced light scattering. In contrast, chemical crosslinking showed a lag-free, diffusion-driven SWS increase from 1.7 {+/-} 0.4 m/s to 2.5 {+/-} 0.5 m/s, matching the relative SWS change from ground-truth ttMRE. In conclusion, OMTHE provides a unique research tool that quantifies biomechanical property changes in small biological samples with spatiotemporal resolutions of micrometers and seconds. Key Results- Point-excitation OMTHE at microscopic resolution maps dynamic stiffness changes in collagen gels during polymerization and crosslinking at high frame rates. - Polymerization and crosslinking of collagen show distinct time courses with polymerization being in the order of minutes ahead of crosslinking. - Collagen stiffening due to polymerization precedes changes in optical density as seen by light microscopy.

biophysics↗

bioRxiv2025

Liver Viscosity Decreases Before the Onset of Fibrosis in Metabolic Dysfunction-Associated 1 Steatohepatitis (MASH)

Background and AimMetabolic dysfunction-associated steatohepatitis (MASH) is an increasingly prevalent condition worldwide, associated with biomechanical liver changes and detectable by magnetic resonance elastography (MRE). This study explored the pathophysiological features and their biomechanical manifestations at different stages of MASH in a mouse dietary model. MethodsUsing MRE on a clinical 3 Tesla MRI scanner, we measured liver stiffness, viscosity, fat fraction and water diffusion in 45 male mice. These values were correlated with histopathology and proteomics analyses to further characterize the liver microstructural and metabolic changes during MASH progression. ResultsWe found in a high-fat, low amino-acid model that early MASH was marked by fat accumulation and increasing inflammatory activity, while later stages showed a reduction in fat despite persistent inflammation. These changes in microstructure were associated with biomechanical adaptations, including a progressive decrease in hepatic viscosity and the water diffusion. Notably, viscosity was inversely correlated with lobular inflammation, cell adhesion, antioxidant activity, and metabolic adaptations such as enhanced ketone body synthesis. These findings, which precede the onset of fibrosis and tissue stiffening, show that tissue viscosity is highly sensitive to early microstructural and metabolic alterations in MASH. ConclusionSteatosis and inflammation significantly alter liver biophysical properties, particularly viscosity, in a mouse dietary model of MASH, even in the absence of fibrosis. These findings suggest that viscosity is a potential early and clinically translatable biomarker for the development and progression of MASH.

biophysics↗

bioRxiv2024

Increased perceptual reliability reduces membrane potential variability in cortical neurons

Uncertainty is omnipresent. While humans and other animals take uncertainty into account during decision making, it remains unclear how it is represented in cortex. To investigate the effect of stimulus reliability on uncertainty representation in cortical neurons, we analyzed single unit activity data recorded in mouse PPC, while animals performed a multisensory change detection task. We further used simulation-based inference (SBI) to infer membrane potential statistics underlying the spiking activity. Our analysis shows that stimulus changes increase spiking rate while decreasing its variability. The inferred membrane potential statistics suggest that PPC neurons decrease their membrane potential variability in response to task relevant stimuli. Furthermore, more perceptually reliable stimuli lead to a larger decrease in membrane potential variability than less reliable ones. These findings suggest that individual cortical neurons track uncertainty, providing Bayesian benefits for downstream computations.

neuroscience↗

bioRxiv2023

Submitochondrial Protein Translocation Upon Stress Inhibits Thermogenic Energy Expenditure

Mitochondria-rich brown adipocytes dissipate cellular energy as heat. Excessive nutrition or prolonged cold exposure suppress thermogenesis, but the mechanisms remain incompletely understood. Here we report that excessive cold or metabolic stress-induced proton leak into the matrix interface of mitochondrial innermembrane (IM) mobilizes 73 proteins from IM into matrix, which in turn alter mitochondrial bioenergetics. Interactome analysis indicates that key subunits of the electron transport chain and the mitochondrial calcium uniporter provide histidine-rich IM docking sites for 40 translocating proteins via pH-dependent protein-protein interactions. We further determine that 34% of translocating proteins correlate with obesity in human subcutaneous adipose tissue among which the top factor, acyl-CoA thioesterase 9 (ACOT9), enzymatically deactivates and prevents the utilization of acetyl-CoA in thermogenesis and promotes obesity. Overall, this study introduces stress-induced submitochondrial protein translocation as a new mitochondrial mechanism. One-Sentence SummaryMitochondrial stress regulates energy utilization by forcing translocation of IM-bound proteins into the matrix.

molecular biology↗

bioRxiv2023

A neuronal least-action principle for real-time learning in cortical circuits

AO_SCPLOWBSTRACTC_SCPLOWOne of the most fundamental laws of physics is the principle of least action. Motivated by its predictive power, we introduce a neuronal least-action principle for cortical processing of sensory streams to produce appropriate behavioural outputs in real time. The principle postulates that the voltage dynamics of cortical pyramidal neurons prospectively minimizes the local somato-dendritic mismatch error within individual neurons. For output neurons, the principle implies minimizing an instantaneous behavioural error. For deep network neurons, it implies the prospective firing to overcome integration delays and correct for possible output errors right in time. The neuron-specific errors are extracted in the apical dendrites of pyramidal neurons through a cortical microcircuit that tries to explain away the feedback from the periphery, and correct the trajectory on the fly. Any motor output is in a moving equilibrium with the sensory input and the motor feedback during the ongoing sensory-motor transform. Online synaptic plasticity reduces the somato-dendritic mismatch error within each cortical neuron and performs gradient descent on the output cost at any moment in time. The neuronal least-action principle offers an axiomatic framework to derive local neuronal and synaptic laws for global real-time computation and learning in the brain.

neuroscience↗

bioRxiv2022

Dendritic modulation enables multitask representation learning in hierarchical sensory processing pathways

While sensory representations in the brain depend on context, it remains unclear how such modulations are implemented at the biophysical level, and how processing layers further in the hierarchy can extract useful features for each possible contextual state. Here, we first demonstrate that thin dendritic branches are well suited to implementing contextual modulation of feedforward processing. Such neuron-specific modulations exploit prior knowledge, encoded in stable feedforward weights, to achieve transfer learning across contexts. In a network of biophysically realistic neuron models with context-independent feedforward weights, we show that modulatory inputs to thin dendrites can solve linearly non-separable learning problems with a Hebbian, error-modulated learning rule. Finally, we demonstrate that local prediction of whether representations originate either from different inputs, or from different contextual modulations of the same input, results in representation learning of hierarchical feedforward weights across processing layers that accommodate a multitude of contexts.

neuroscience↗

bioRxiv2022

Inability to make facial expressions dampens emotion perception.

Humans rely heavily on facial expressions for social communication to convey their thoughts and emotions and to understand them in others. One prominent but controversial view is that humans learn to recognize the significance of facial expressions by mimicking the expressions of others. This view predicts that an inability to make facial expressions (e.g., facial paralysis) would result in reduced perceptual sensitivity to others facial expressions. To test this hypothesis, we developed a diverse battery of sensitive emotion recognition tasks to characterize emotion perception in individuals with Moebius Syndrome (MBS), a congenital neurological disorder that causes facial palsy. Using computer-based emotion detection tasks we systematically assessed emotion perception thresholds for static and dynamic face and body expressions. We found that while MBS individuals were able to perform challenging perceptual control tasks, they were less efficient at extracting emotion from facial expressions, compared to matched controls. Exploratory analyses of fMRI data from a small group of MBS participants suggested potentially reduced engagement of the amygdala in MBS participants during expression processing relative to matched controls. Collectively, these results support the role of facial mimicry and consequent facial feedback and motor experience in the perception of others expressions.

neuroscience↗

bioRxiv2021

Complex feline disease mapping using a dense genotyping array

The current feline genotyping array of 63k single nucleotide polymorphisms has proven its utility within breeds, and its use has led to the identification of variants associated with Mendelian traits in purebred cats. However, compared to single gene disorders, association studies of complex diseases, especially with the inclusion of random bred cats with relatively low linkage disequilibrium, require a denser genotyping array and an increased sample size to provide statistically significant associations. Here, we undertook a multi-breed study of 1,122 cats, most of which were admitted and phenotyped for nine common complex feline diseases at the Cornell University Hospital for Animals. Using a proprietary 340k single nucleotide polymorphism mapping array, we identified significant genome-wide associations with hyperthyroidism, diabetes mellitus, and eosinophilic keratoconjunctivitis. These results provide genomic locations for variant discovery and candidate gene screening for these important complex feline diseases, which are relevant not only to feline health, but also to the development of disease models for comparative studies.

genetics↗

bioRxiv2020

Dense encoding of developmental regulatory information may constrain evolvability

Gene regulatory changes underlie much of phenotypic evolution. However, the evolutionary potential of regulatory evolution is unknown, because most evidence comes from either natural variation or limited experimental perturbations. Surveying an unbiased mutation library for a developmental enhancer in Drosophila melanogaster using an automated robotics pipeline, we found that most mutations alter gene expression. Our results suggest that regulatory information is distributed throughout most of a developmental enhancer and that parameters of gene expression--levels, location, and state--are convolved. The widespread pleiotropic effects of most mutations and the codependency of outputs may constrain the evolvability of developmental enhancers. Consistent with these observations, comparisons of diverse drosophilids reveal mainly stasis and apparent biases in the phenotypes influenced by this enhancer. Developmental enhancers may encode a much higher density of regulatory information than has been appreciated previously, which may impose constraints on regulatory evolution. Quote"Rock, robot rock Rock, robot rock Rock, robot rock" Daft Punk (2005)

evolutionary biology↗

bioRxiv2020

Data-driven reduction of dendritic morphologies with preserved dendro-somatic responses

Dendrites shape information flow in neurons. Yet, there is little consensus on the level of spatial complexity at which they operate. We present a flexible and fast method to obtain simplified neuron models at any level of complexity. Through carefully chosen parameter fits, solvable in the least squares sense, we obtain optimal reduced compartmental models. We show that (back-propagating) action potentials, calcium-spikes and NMDA-spikes can all be reproduced with few compartments. We also investigate whether afferent spatial connectivity motifs admit simplification by ablating targeted branches and grouping the affected synapses onto the next proximal dendrite. We find that voltage in the remaining branches is reproduced if temporal conductance fluctuations stay below a limit that depends on the average difference in input impedance between the ablated branches and the next proximal dendrite. Further, our methodology fits reduced models directly from experimental data, without requiring morphological reconstructions. We provide a software toolbox that automatizes the simplification, eliminating a common hurdle towards including dendritic computations in network models.

neuroscience↗

bioRxiv2019

Root morphology and exudate availability is shaped by particle size and chemistry in Brachypodium distachyon

Root morphology and exudation define a plants sphere of influence in soils, and are in turn shaped by the physiochemical characteristics of soil. We explored how particle size and chemistry of growth substrates affect root morphology and exudation of the model grass Brachypodium distachyon. Root fresh weight and root lengths were correlated with particle size, whereas root number and shoot weight remained constant. Mass spectrometry imaging suggested that both, root length and number shape root exudation. Exudate metabolite profiles detected with liquid chromatography / mass spectrometry were comparable for plants growing in glass beads or sand with various particles sizes, but distinct for plants growing in clay. However, when exudates of clay-grown plants were collected by removing the plants from the substrate, their exudate profile was similar to sand- or glass beads-grown plants. Clay particles sorbed 20% of compounds exuded by clay-grown plants, and 70% of compounds of a defined exudate medium. The sorbed compounds belonged to a range of chemical classes, among them nucleosides/nucleotides, organic acids, sugars, and amino acids. Some of the sorbed compounds could be de-sorbed by a rhizobacterium (Pseudomonas fluorescens WCS415), supporting its growth. We show that root morphology is affected by substrate size, and that root exudation in contrast is not affected by substrate size or chemistry. The availability of exuded compounds, however, depends on the substrate present. These findings further support the critical importance of the physiochemical properties of soils are crucial to consider when investigating plant morphology, exudation, and plant-microbe interactions.

plant biology↗

bioRxiv2019

A genome-wide association study identifies that the GDF5 and COL27A1 genes are associated with knee pain in UK Biobank (N = 171, 516)

ObjectiveKnee pain is one of the most common musculoskeletal complaints that brings people to medical attention. We sought to identify the genetic variants associated with knee pain in 171,516 subjects from the UK Biobank cohort and replicate them using cohorts from 23andMe, the Osteoarthritis Initiative (OAI), and the Johnston County Osteoarthritis Study (JoCo).\n\nMethodsWe performed a genome-wide association study of knee pain in the UK Biobank, where knee pain was ascertained through self-report and defined as \"knee pain in the last month interfering with usual activities\". A total of 22,204 cases and 149,312 controls were included in the discovery analysis. We tested our top and independent SNPs (P < 5 x 10-8) for replication in 23andMe, OAI, and JoCo, then performed a joint meta-analysis between discovery and replication cohorts using GWAMA. We calculated the narrow-sense heritability of knee pain using Genome-wide Complex Trait Analysis (GCTA).\n\nResultsWe identified 2 loci that reached genome-wide significance, rs143384 located in the GDF5 (P = 1.32 x 10-12), a gene previously implicated in osteoarthritis, and rs2808772, located near COL27A1 (P = 1.49 x 10-8). These findings were subsequently replicated in independent cohorts and increased in significance in the joint meta-analysis (rs143384: P = 4.64 x 10-18; rs2808772: P -11 = 2.56 x 10-1). The narrow sense heritability of knee pain was 0.08.\n\nConclusionIn this first reported genome-wide association meta-analysis of knee pain, we identified and replicated two loci in or near GDF5 and COL27A1 that are associated with knee pain.

genetics↗

bioRxiv2018

Transection of the ventral hippocampal commissure impairs spatial but not contextual memory in split-brain mice

Plasticity is a neural phenomenon in which experience induces long-lasting changes to neuronal circuits and is at the center of most neurobiological theories of learning and memory. However, too much plasticity is maladaptive and must be balanced with substrate stability. Area CA3 of the hippocampus is lateralized with the left hemisphere dominant in plasticity and the right specialized for stability. Left and right CA3 project bilaterally to CA1; however, it is not known whether this downstream merging of lateralized plasticity and stability is functional. We hypothesized that interhemispheric integration of input from these pathways is essential for integrating spatial memory stored in the left CA3 with spatial working memory facilitated by the right CA3. To test this, we severed interhemispheric connections between the left and right hippocampi in mice and assessed learning and memory. Despite damage to this major hippocampal fiber tract, hippocampus-dependent spatial working memory and short- and long-term memory were both spared. However, tasks that required the integration of information retrieved from memory with ongoing spatial working memory and navigation were impaired. We propose that one function of interhemispheric communication in the mouse hippocampus is to integrate lateralized processing of plastic and stable circuits to facilitate memory-guided spatial navigation.

neuroscience↗

bioRxiv2017

The Anorexia Nervosa Genetics Initiative: Overview and Methods

BackgroundGenetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13000 individuals with AN as well as ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research.\n\nMethodsANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H.\n\nResultsBlood samples and clinical information were collected from 13,364 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable.\n\nConclusionsOur multipronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection. ANGI is a registered clinical trial: clinicaltrials.gov NCT01916538; https://clinicaltrials.gov/ct2/show/NCT01916538?cond=Anorexia+Nervosa&draw=1&rank=3.

genetics↗