Biology subjects

Hess, A.

Publications and source records attributed to Hess, A..

14 recordsLinked to original sources

bioRxiv2026

Tracking Inflammation and Fibroblast Activation in Hypertensive Heart Failure Across the Cardio-Renal Axis

Hypertension and heart failure are associated with increased risk of chronic kidney disease. Cardiorenal syndrome is characterized by excessive systemic inflammation and progressive fibrosis. We hypothesized that transient hypertension in mice due to infusion of angiotensin II and phenylephrine (Ang/Phe) would induce parallel immune cell and fibroblast activation in both the heart and kidney, where the intensity of inflammation and fibroblast activity would predict decline in function of both organs. Adult male C57Bl/6N mice were randomized to receive 7d infusion of either Ang/Phe (n=41) or vehicle (n=27) by subcutaneous osmotic minipump. Despite removal of minipumps at 7d, Ang/Phe mice displayed persistent myocyte hypertrophy, interstitial fibrosis, and modestly reduced systolic function to 6 weeks. Molecular imaging of chemokine receptor CXCR4 using 68Ga-pentixafor at 3d of Ang/Phe infusion revealed transient inflammation in the left ventricle. Imaging of fibroblast activation protein (FAP) revealed diffuse fibroblast activity in the left ventricle. Both imaging signals predicted subsequent functional decline. Magnetic resonance imaging of the kidney revealed transient prolongation of T1 relaxation in at 2 weeks after Ang/Phe infusion that returned to normal by 6wk, despite a progressive reduction in renal perfusion. CXCR4 and FAP PET displayed no change in kidney inflammation or fibroblast activation. Comparison of imaging data described a direct correlation between cardiac and renal CXCR4 PET signal at 3d and FAP PET signal at 7d. The intensity of cardiac inflammation correlated with subchronic fibrosis in the kidney cortex. Total body molecular imaging enables simultaneous evaluation of the immune-fibrosis network in heart-kidney crosstalk after short term hypertension and may provide valuable guidance of novel therapies.

physiology↗

bioRxiv2026

Regulation of protein abundance in neurons by selective translation of 3'UTR isoforms

The precise regulation of protein synthesis is essential for cellular function and survival. In particular, in neurons, dysregulated mRNA translation is linked to impaired memory formation and is a hallmark of neurodegenerative diseases. Neurons are characterized by tissue-specific, long 3' untranslated regions (3'UTRs); in this study, we demonstrate that mRNA isoforms with these neuronal 3'UTRs are less efficiently translated than their short counterparts in Drosophila and mammalian brains. 3'UTR-dependent translation is based on a negative feedback mechanism centered around the two neural-enriched proteins ELAV and Pumilio. The long elav 3'UTR inhibits production of the neuronal ELAV protein, which in turn mediates 3'UTR extension of hundreds of neuronal genes. Those long 3'UTR isoforms are preferentially bound and translationally inhibited by Pumilio. The regulatory loop maintains optimal neuronal 3'UTR and protein levels in conditions of genetic and environmental perturbations; its disruption reduces animal viability and lowers stress resilience, and causes severe developmental phenotypes in flies and in human brain organoids. We propose 3'UTR-mediated translational control as an evolutionarily conserved mechanism for the maintenance of cell-type-specific proteostasis.

molecular biology↗

bioRxiv2025

Gene expression patterns decompose fMRI activation in a sub-region-specific manner in mice after nociceptive stimulation

The results of functional magnetic resonance imaging (fMRI) cannot be interpreted directly at the molecular or genetic level. Our integrative workflow aims to add such a new dimension to the functional interpretation using a publicly available mouse brain gene expression database from the Allen Institute for Brain Science (ABA). From an average of 164 in-house measured mouse thermal pain fMRI datasets, we identified the top and bottom 5% of voxels according to their activation probability (AP) in response to warm and hot hind paw stimulation. Here, we investigated whether high AP voxels differ from low AP voxels in terms of gene expression: Analyzing nine core brain regions of the pain/saliency system, the top (high AP) and bottom (low AP) 5% of voxels showed distinct gene expression profiles. In nearly all regions, only high AP voxels were significantly enriched for gene ontology (GO) terms related to neurotransmitter activity, synaptic structure and neuronal function, while only the dorsal striatum showed GO term enrichment in low AP voxels. Notably, randomly selected voxels showed no significant enrichment, demonstrating the reliability of this approach. These results highlight the potential of gaining knowledge by integrating gene expression and fMRI data. Despite the limitations of using fixed gene expression data from the ABA cohort, this approach may provide new insights into physiological processes and improve the parcellation and interpretation of imaging data.

neuroscience↗

bioRxiv2024

Activation mapping in multi-center rat sensory-evoked functional MRI datasets using a unified pipeline.

Functional Magnetic Resonance Imaging (fMRI) in rodents is pivotal for understanding the mechanisms underlying Blood Oxygen Level-Dependent (BOLD) signals and phenotyping animal models of disorders, amongst other applications. Despite its growing use, comparing rodent fMRI results across different research sites remains challenging due to variations in experimental protocols. Here, we aggregated and analyzed 22 sensory-evoked rat fMRI datasets from 12 imaging centers, totaling scans from 220 rats, to assess the consistency of results across diverse protocols. We applied a standardized preprocessing pipeline and evaluated the impact of different hemodynamic response function models on group and individual level activity patterns. Our analysis revealed inter-dataset variability attributed to differences in experimental design, anesthesia protocols, and imaging parameters. We identified robust activation clusters in all (22/22) datasets. The comparison between stock human models implemented in software and rat-specific models showed significant variations in the resulting statistical maps. Our findings emphasize the necessity for standardized protocols and collaborative efforts to improve the reproducibility and reliability of rodent fMRI studies. We provide open access to all datasets and analysis code to foster transparency and further research in the field.

neuroscience↗

bioRxiv2024

Pumilio differentially binds to mRNA 3' UTR isoforms to regulate localization of synaptic proteins

In neuronal cells, the regulation of RNA is crucial for the spatiotemporal control of gene expression, but how the correct localization, levels, and function of synaptic proteins are achieved is not well understood. In this study, we globally investigate the role of alternative 3 UTRs in regulating RNA localization in the synaptic regions of the Drosophila brain. We identify direct mRNA targets of the translational repressor Pumilio, finding that mRNAs bound by Pumilio encode proteins enriched in synaptosomes. Pumilio differentially binds to RNA isoforms of the same gene, favoring long, neuronal 3 UTRs. These longer 3 UTRs tend to remain in the neuronal soma, whereas shorter UTR isoforms localize to the synapse. In cultured pumilio mutant neurons, severe axon outgrowth defects were accompanied by mRNA isoform mislocalization, and proteins encoded by these Pumilio targets displayed excessive abundance at synaptic boutons. Our study identifies an important and widespread mechanism for the spatiotemporal regulation of protein function in neurons.

genomics↗

bioRxiv2023

Conserved long noncoding RNA TILAM promotes liver fibrosis through interaction with PML in hepatic stellate cells

Background & AimsFibrosis is the common endpoint for all forms of chronic liver injury, and progression of fibrosis leads to the development of end-stage liver disease. Activation of hepatic stellate cells (HSCs) and their transdifferentiation to myofibroblasts results in the accumulation of extracellular matrix (ECM) proteins that form the fibrotic scar. Long noncoding (lnc) RNAs regulate the activity of HSCs and may provide targets for fibrotic therapies. MethodsWe identified lncRNA TILAM as expressed near COL1A1 in human HSCs and performed loss-of-function studies in human HSCs and liver organoids. Transcriptomic analyses of HSCs isolated from mice defined the murine ortholog of TILAM. We then generated Tilam-deficient GFP reporter mice and quantified fibrotic responses to carbon tetrachloride (CCl4) and choline-deficient L-amino acid defined high fat diet (CDA-HFD). Co-precipitation studies, mass spectrometry, and gene expression analyses identified protein partners of TILAM. ResultsTILAM is conserved between human and mouse HSCs and regulates expression of ECM proteins, including collagen. Tilam is selectively induced in HSCs during the development of fibrosis in vivo. In both male and female mice, loss of Tilam results in reduced fibrosis in the setting of CCl4 and CDA-HFD injury models. TILAM interacts with promyelocytic leukemia protein (PML) to stabilize PML protein levels and promote the fibrotic activity of HSCs. ConclusionTILAM is activated in HSCs and interacts with PML to drive the development of liver fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end stage liver disease.

cell biology↗

bioRxiv2023

Distinct Functional cerebral Hypersensitivity networks during incisional and inflammatory pain in rats

Although the pathophysiology of pain has been investigated tremendously, there are still many open questions, especially with regard to specific pain entities and their pain-related symptoms. To increase the translational impact of (preclinical) animal pain neuroimaging studies, the use of disease-specific pain models, as well as relevant stimulus modalities, are critical. Yet, the challenges of identifying neuroimaging signatures at a pain entity- and modality-specific level are manifold. Therefore, we developed a comprehensive framework for brain network analysis in disease-specific pain models combining functional MRI with graph-theory and data classification by linear discriminant analysis. This enabled us to expand our knowledge of stimulus (mechanical vs. electrical) modality processing under incisional (INC) and pathogen-induced inflammatory (CFA) pain entities compared to acute pain conditions. In short, graph-theoretical analyses revealed distinct Network Signatures of Pain Hypersensitivity (NSPH) for INC and CFA, resulting in impaired discrimination of stimulus modalities in both pain models compared to control conditions (CTR). Such specific neuroimaging signatures are an important step toward identifying novel pain biomarkers for certain diseases and relevant outcomes to evaluate target engagement of novel therapeutic options, which ultimately can be translated to the clinic.

neuroscience↗

bioRxiv2022

Human liver organoids model progressive inflammatory and fibrotic injury in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing cause of morbidity with few treatment options available. Thus, accurate in vitro systems to test new therapies are indispensable. Recently, human liver organoid (HLO) NAFLD models have emerged. However, a systematic evaluation of their translational potential is currently missing. Here, we develop a structured approach to evaluate NAFLD-HLO models, testing oleic acid (OA) and palmitic acid (PA) in comparison to TGF-{beta}1 for disease induction. Through analysis of [~]100K single-cell transcriptomes of the HLO injury landscape, we find all three models induce inflammatory signatures. However, only TGF-{beta}1 promotes collagen production, fibrosis, and hepatic stellate cell (HSC) expansion. In striking contrast, OA ameliorates fibrotic signatures and reduces the HSC population. Integrating data from each model with that of NAFLD patients across disease progression further demonstrates PA and TGF-{beta}1 more robustly model inflammation and fibrosis. Our findings highlight the importance to stratify NAFLD-HLO models by clinical disease progression, provide a single-cell reference to benchmark future organoid injury models, and allow us to study evolving steatohepatitis, fibrosis, and HSC susceptibility to injury in a dynamic, multi-lineage human in vitro system.

molecular biology↗

bioRxiv2022

Capturing early human memory consolidation utilizing the higher functional specificity of 7T compared to 3T-fMRI

Functional magnetic resonance imaging (fMRI) visualizes brain structures at increasingly higher resolution and better signal-to-noise ratio (SNR) as field strength increases. Yet, mapping the BOLD response to distinct neuronal processes continues to be challenging. Here, we performed 3T and 7T-fMRI analysis of motor-task activation and resting-state connectivity with adjusted SNR. We then applied graph theory to analyze resting-state neuronal networks detected by fMRI after a simple motor task. Despite adjusted SNR, 7T achieved a higher functional specificity of the BOLD response than 3T-fMRI. Following the motor task, 7T-fMRI therefore enabled the detection of an offline replay that was directly linked to brain regions associated with memory consolidation. These findings reveal how memory processing is initiated even after simple motor tasks and begins earlier than previously shown. Thus, the superior capability of 7T-fMRI to detect subtle functional dynamics promises to improve diagnostics and therapeutic assessment of neurological diseases.

neuroscience↗

bioRxiv2019

A large-scale resource for tissue-specific CRISPR mutagenesis in Drosophila

Genetic screens are powerful tools for the functional annotation of genomes. In the context of multicellular organisms, interrogation of gene function is greatly facilitated by methods that allow spatial and temporal control of gene abrogation. Here, we describe a large-scale transgenic short guide (sg) RNA library for efficient CRISPR-based disruption of specific target genes in a constitutive or conditional manner. The library consists currently of more than 2600 plasmids and 1600 fly lines with a focus on targeting kinases, phosphatases and transcription factors, each expressing two sgRNAs under control of the Gal4/UAS system. We show that conditional CRISPR mutagenesis is robust across many target genes and can be efficiently employed in various somatic tissues, as well as the germline. In order to prevent artefacts commonly associated with excessive amounts of Cas9 protein, we have developed a series of novel UAS-Cas9 transgenes, which allow fine tuning of Cas9 expression to achieve high gene editing activity without detectable toxicity. Functional assays, as well as direct sequencing of genomic sgRNA target sites, indicates that the vast majority of transgenic sgRNA lines mediate efficient gene disruption. Furthermore, we conducted the so far largest fully transgenic CRISPR screen in any metazoan organism, which further supported the high efficiency and accuracy of our library and revealed many so far uncharacterized genes essential for development.

genetics↗

bioRxiv2019

Molecular archaeology of the human brain

Mapping the origin of human cognitive traits typically relies on comparing behavioral or neuroanatomical features in human phylogeny. However, such studies rely on inferences from comparative relationships and do not incorporate neurogenetic information, as these approaches are restricted to experimentally accessible species. Here, we fused evolutionary genomics with human functional neuroanatomy to reconstruct the neurogenetic evolution of human brain functions more directly and comprehensively. Projecting genome-wide selection pressure (dN/dS ratios) in sets of chronologically ordered mammalian species onto the human brain reference space unmasked spatial patterns of cumulative neurogenetic selection and co-evolving brain networks from task-evoked functional MRI and functional neuroanatomy. Importantly, this evolutionary atlas allowed imputing functional features to archaic brains from extinct hominin genomes. These data suggest accelerated neurogenetic selection for language and verbal communication across all hominin lineages. In addition, the predictions identified strategic thought and decision making as the dominant traits that may have separated anatomically modern humans (AMH) from archaic hominins.

bioinformatics↗

bioRxiv2019

Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories world-wide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a murine default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

neuroscience↗

bioRxiv2019

Rice bran supplementation modulates growth, microbiome and metabolome in weaning infants: a clinical trial in Nicaragua and Mali

Rice bran supplementation provides nutrients, prebiotics and phytochemicals that enhance gut immunity, reduce enteric pathogens in mice and diarrhea in neonatal pigs, and warranted attention for improvement of environmental enteric dysfunction (EED) in children at risk. EED is a condition that drives childhood stunting via intestinal dysbiosis and impaired nutrient metabolism. This study investigated effects of rice bran supplementation on growth, EED biomarkers, gut microbiome and metabolome in weaning infants from 6 to 12 months old in Nicaragua and Mali. Healthy infants were randomized to a control group or rice bran group that received daily supplementation at increasing doses each month. Stool microbiomes were characterized using 16S rDNA amplicon sequencing. Stool metabolomes were analyzed using ultra-high-performance liquid-chromatography tandem mass-spectrometry. Statistical comparisons were completed at 6, 8, and 12 months of age. Daily consumption of rice bran was safe and feasible for infant growth, decreasing alpha-1 antitrypsin levels, and modulating gut microbiome and metabolome when compared to control. Rice bran merits investigation as a practical intervention strategy that could decrease EED prevalence and risk for children from low- and middle-income countries where rice is grown as a staple food, and bran is used as animal feed or wasted. One Sentence SummaryDietary rice bran supplementation during infant weaning from 6-12 months of age improved growth outcomes, modulated environmental enteric dysfunction biomarkers, and supported metabolism by the gut microbiome. The authors declare no competing financial or non financial interests to disclose as defined by Nature Research. There are also no other interests that might be perceived to influence the results and/or discussion reported in this paper. Correspondence and requests for materials should be addressed to Dr. Elizabeth Ryan (e.p.ryan@colostate.edu).

clinical trials↗

bioRxiv2017

A new analysis of resting state connectivity and graph theory reveals distinctive short-term modulations due to whisker stimulation in rats.

Resting state (RS) connectivity has been increasingly studied in healthy and diseased brains in humans and animals. This paper presents a new method to analyze RS data from fMRI that combines multiple seed correlation analysis with graph-theory (MSRA). We characterize and evaluate this new method in relation to two other graph-theoretical methods and ICA. The graph-theoretical methods calculate cross-correlations of regional average time-courses, one using seed regions of the same size (SRCC) and the other using whole brain structure regions (RCCA). We evaluated the reproducibility, power, and capacity of these methods to characterize short term RS modulation to unilateral physiological whisker stimulation in rats. Graph-theoretical networks found with the MSRA approach were highly reproducible, and their communities showed large overlaps with ICA components. Additionally, MSRA was the only one of all tested methods that had the power to detect significant RS modulations induced by whisker stimulation that are controlled by family-wise error rate (FWE). Compared to the reduced resting state network connectivity during task performance, these modulations implied decreased connectivity strength in the bilateral sensorimotor and entorhinal cortex. Additionally, the contralateral ventromedial thalamus (part of the barrel field related lemniscal pathway) and the hypothalamus showed reduced connectivity. Enhanced connectivity was observed in the amygdala, especially the contralateral basolateral amygdala (involved in emotional learning processes). In conclusion, MSRA is a powerful analytical approach that can reliably detect tiny modulations of RS connectivity. It shows a great promise as a method for studying RS dynamics in healthy and pathological conditions.

neuroscience↗