Biology subjects

Peterson, A.

Publications and source records attributed to Peterson, A..

At least 19 recordsLinked to original sources

bioRxiv2026

ADSS1 is a suppressed metabolic control node in dystrophic skeletal muscle

Duchenne muscular dystrophy is initiated by dystrophin loss but is accompanied by profound metabolic remodelling. Here, we identify suppression of the muscle-enriched adenylosuccinate synthase, ADSS1, and the purine nucleotide cycle in mdx muscle. Integrated multi-omic profiling revealed a compensated purine-stress state in which nucleotide salvage and quality control were increased to preserve adenine nucleotide abundance and buffer consequential toxic/disruptive deoxy-/nucleotide production. Purine metabolism was the highest-impact joint pathway with metabolite and transcript hits in mdx muscle, and its maintenance program was directionally conserved in human ADSS1 myopathy. Interventions positioned around ADSS1 separated the outputs of this node. Ribose and dimethyl fumarate remodelled upstream or downstream stress programs, whereas only adenylosuccinic acid bypassed ADSS1 to expand the adenine nucleotide pool and remodel CoA/acetyl-CoA metabolism. All three interventions suppressed pro-adipogenic transcription without broadly correcting the lipidome. These findings identify ADSS1 as a regulated metabolic control node that couples purine retention to inflammatory and adipogenic remodelling in dystrophic muscle.

molecular biology↗

bioRxiv2026

Obligate multicellularity circumvents population genetic barriers to collective-level adaptation

Complex multicellularity has evolved in just five lineages (animals, plants, brown algae, red algae, and fungi) and in each case, these organisms develop clonally and are obligately multicellular. While prior work has shown that clonal development plays a critical role in the evolution of complex multicellularity, none has disentangled this from the impact of obligate vs facultative multicellular life cycles. Here we use experimental evolution with engineered snowflake yeast (Saccharomyces cerevisiae) to directly test how life cycle structure affects multicellular adaptation. We created isogenic strains capable of switching between unicellular and clonal multicellular phases, then evolved populations for 192 days under obligately multicellular, facultatively multicellular, and obligately unicellular regimes. Obligately multicellular populations rapidly evolved larger size, primarily driven by a whole genome duplication, in all five replicates. Facultative populations showed dramatically constrained evolution, with tetraploidy evolving in only 2/10 facultative populations despite experiments demonstrating that it is strongly beneficial across the full life cycle. Mathematical modeling reveals the mechanistic basis for this constraint: facultative life cycles create establishment barriers through two population genetic effects. Group formation dramatically reduces the number of units of selection, making beneficial multicellular mutations vulnerable to drift. This asymmetry in population size between life cycle phases also allows cell-level selection to overpower group-level selection, eliminating mutations that provide group-level benefits but carry cell-level costs. These findings demonstrate that obligate multicellularity circumvents fundamental population genetic barriers to collective-level adaptation, helping explain why complex multicellularity has evolved exclusively in obligately multicellular lineages, and suggesting similar constraints may operate in other evolutionary transitions in individuality.

evolutionary biology↗

bioRxiv2026

Whole-brain cellular-resolution functional network properties of seizure susceptibility

Despite its prevalence and clinical impacts, epilepsy remains incompletely understood in terms of the population dynamics that mediate seizure susceptibility, initiation, and propagation across brain-wide networks. In this study, we have performed calcium imaging in zebrafish, brain-wide and at cellular resolution, at baseline and as seizures are induced using the GABAA receptor antagonist pentylenetetrazol (PTZ). We have then modeled the network architecture in wild-type and scn1lab-/- larvae, which are seizure-prone and serve as a model for Dravet syndrome. scn1lab-/- larvae show increased pair-wise correlations between neurons when exposed to PTZ, and graph analyses of these correlations revealed genotype-specific network alterations during seizures, identifying regions and metrics linked to seizure onset. Using generative network modeling, we then explored the wiring rules that govern activity in these networks, identifying specific network properties linked to seizure susceptibility that were only detectable using large-scale, cellular-resolution data. Even at baseline in the absence of seizures, these rules differed by genotype in a way that enabled the identification of scn1lab-/- larvae and predicted individuals seizure risk independently of their observable phenotype. These findings uncover the cellular-resolution network properties of a zebrafish model of Dravet syndrome and establish a predictive framework for seizure susceptibility grounded in multi-scale functional connectivity.

neuroscience↗

bioRxiv2025

Enhancer Dynamics and Spatial Organization Drive Anatomically Restricted Cellular States in the Human Spinal Cord

Here, we report the spatial organization of RNA transcription and associated enhancer dynamics in the human spinal cord at single-cell and single-molecule resolution. We expand traditional multiomic measurements to reveal epigenetically poised and bivalent active transcriptional enhancer states that define cell type specification. Simultaneous detection of chromatin accessibility and histone modifications in spinal cord nuclei reveals previously unobserved cell-type specific cryptic enhancer activity, in which transcriptional activation is uncoupled from chromatin accessibility. Such cryptic enhancers define both stable cell type identity and transitions between cells undergoing differentiation. We also define glial cell gene regulatory networks that reorganize along the rostrocaudal axis, revealing anatomical differences in gene regulation. Finally, we identify the spatial organization of cells into distinct cellular organizations and address the functional significance of this observation in the context of paracrine signaling. We conclude that cellular diversity is best captured through the lens of enhancer state and intercellular interactions that drive transitions in cellular state. This study provides fundamental insights into the cellular organization of the healthy human spinal cord.

neuroscience↗

bioRxiv2024

Three-dimensional analysis of mitochondria in a patient-derived xenograft model of triple negative breast cancer reveals mitochondrial network remodeling following chemotherapy treatments

Mitochondria are hubs of metabolism and signaling, playing crucial roles in tumorigenesis, therapeutic resistance, and metastasis in many types of cancer. Various laboratory models of cancer demonstrate the extraordinary dynamics of mitochondrial structure, but little is known about the full extent of the complexity of the mitochondrial network, nor its regulation upon exposure to therapeutic stressors. We previously demonstrated the importance of mitochondrial structure and oxidative phosphorylation in the survival of chemotherapy-refractory triple negative breast cancer (TNBC) cells. As TNBC is a highly aggressive breast cancer subtype with few targeted therapy options, conventional chemotherapies remain the backbone of TNBC treatment. Unfortunately, approximately 45% of TNBC patients retain substantial residual tumor burden following chemotherapy, associated with abysmal prognoses. Herein we present the first three-dimensional analysis of mitochondrial networks in human tumor tissues. Use of two experimentally tractable orthotopic patient-derived xenograft (PDX) models TNBC enabled us to conduct longitudinal analyses to construct mitochondrial networks in treatment-naive and residual tumors persisting after exposure to a variety of conventional chemotherapies. Further, we modeled lipid droplet (LD) structures and their physical contacts with mitochondria. In total, we reconstructed 3,750 mitochondria and 800 LDs in three dimensions using serial block-face scanning electron microscopy (SBF-SEM), providing unprecedented insights into the complexity and intra-tumoral heterogeneity of mitochondria in TNBC. Both carboplatin (CRB) and docetaxel (DTX) chemotherapies produced residual tumors that harbored mitochondria with significantly increased areas, volumes, and perimeters in both PDX models. Additionally, treatment with the conventional combinations DTX plus CRB or Adriamycin plus cyclophosphamide (AC), led to reduced mitochondrial branching and elongation. In contrast, DTX or CRB alone elicited model-specific changes in mitochondrial complexity. Further, the extensive intra-tumoral heterogeneity of mitochondrial structure in untreated PDX tumors significantly decreased in residual tumors. Analyses of LDs revealed significant and consistent elevation of the number and physical proximity of MLCs in residual tumors, congruent with our previous studies providing evidence for transcriptomic and proteomic rewiring of lipid metabolism in residual TNBC. These results highlight the potential for structure-based monitoring of chemotherapeutic metabolic reprogramming and suggest unique molecular mechanisms that may underlie chemoresistance in TNBC. Furthermore, our findings provide novel insights into a new type of intratumoral heterogeneity, that of mitochondrial intratumoral heterogeneity, which complements our understanding of the genomic, epigenomic, transcriptomic, and proteomic complexity of TNBC.

cancer biology↗

bioRxiv2024

Sex, racial, and APOE-ϵ4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSThe effects of sex, race, and Apolipoprotein E (APOE) - Alzheimers disease (AD) risk factors - on white matter integrity are not well characterized. METHODSDiffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 {+/-} 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-{varepsilon}4 carrier status. RESULTSSex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-{varepsilon}4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSIONThere are prominent differences in white matter microstructure by sex, race, and APOE- {varepsilon}4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted. HighlightsO_LISex, race, and APOE-{varepsilon}4 carrier status relate to white matter microstructural integrity C_LIO_LIFemales generally have lower FAFWcorr compared to males C_LIO_LINon-Hispanic Black adults generally have lower FAFWcorr than non-Hispanic White adults C_LIO_LIAPOE-{varepsilon}4 carriers tended to have higher FW than non-carriers C_LI Research in Context Systematic ReviewThe authors used PubMed and Google Scholar to review literature that used conventional and free-water (FW)-corrected microstructural metrics to evaluate sex, race, and APOE-{varepsilon}4 differences in white matter microstructure. While studies have previously explored differences by sex and APOE-{varepsilon}4 status, less is known about racial differences and no large-scale FW-corrected analysis has been performed. InterpretationSex and race were more associated with FAFWcorr while APOE-{varepsilon}4 status was associated with FW metrics. Association, projection, limbic, and occipital transcallosal tracts showed the greatest differences. Future DirectionFuture studies to determine the biological and social pathways that lead to sex, racial, and APOE-{varepsilon}4 differences are warranted. Consent StatementAll participants provided informed consent in their respective cohort studies.

neuroscience↗

bioRxiv2024

lncRNA ADEPTR loss-of-function elicits sex-specific behavioral and spine deficits

Activity-dependent changes in neuronal connections are fundamental to learning and long-term memory storage. However, the precise contribution of long noncoding RNAs (lncRNAs) to these modifications remains unclear. In this study, we assessed the role of the lncRNA ADEPTR, a cAMP-modulated lncRNA localized in dendrites, which is crucial for synapse morphology. By generating two different mouse models--one with a deletion of ADEPTR (L-ADEPTR) and one with a deletion of its protein interaction region (S-ADEPTR)--we investigated the sex-specific impacts of ADEPTR loss of function on learning, memory, dendritic arborization, and synapse morphology. Our behavioral analyses revealed a reduction in anxiety in adult male mice, while learning and memory remained unaffected in both models. Systematic evaluations of neuronal morphology across various developmental stages ([~]3-day-old postnatal neuronal cultures and postnatal 14- and 42-day-old male and female mice) uncovered substantial deficits in neuronal architecture in both S- and L-ADEPTR male and female neuronal cultures. At postnatal day 42, in contrast to their male counterparts, L-ADEPTR female mice exhibited a significant deficiency in thin spines. Additionally, we found that the expression of plasticity-related gene BDNF, and immediate early gene cFOS were enhanced in both the cortex and hippocampus of adult male and female S- and L-ADEPTR mice, suggesting the activation of a compensatory mechanism protecting against learning and memory deficits. Collectively, these observations underscore the sex-specific role of lncRNA ADEPTR in shaping neuronal morphology and anxiety behavior.

neuroscience↗

bioRxiv2024

Efficient Genetic Code Expansion Without Host Genome Modifications

Supplementing translation with non-canonical amino acids (ncAAs) can yield protein sequences with new-to-nature functions, but existing ncAA incorporation strategies suffer from low efficiency and context dependence. We uncover codon usage as a previously unrecognized contributor to efficient genetic code expansion using non-native codons. Relying only on conventional E. coli strains with native ribosomes, we develop a novel plasmid-based codon compression strategy that minimizes context dependence and improves ncAA incorporation at quadruplet codons. We confirm that this strategy is compatible with all known genetic code expansion resources, which allows us to identify 12 mutually orthogonal tRNA-synthetase pairs. Enabled by these findings, we evolve and optimize five tRNA-synthetase pairs to incorporate a broad repertoire of ncAAs at orthogonal quadruplet codons. Finally, we extend these resources to an in vivo biosynthesis platform that can readily create >100 new-to-nature peptide macrocycles bearing up to three unique ncAAs. Given the generality of our approach and streamlined resources, our findings will accelerate innovations in multiplexed genetic code expansion and enable the discovery of chemically diverse biomolecules for researcher-defined applications.

synthetic biology↗

bioRxiv2023

Matrix selection for the visualization of small molecules and lipids in brain tumors using untargeted MALDI-TOF mass spectrometry imaging

Matrix-assisted laser desorption/ionization mass spectrometry imaging allows the study of metabolic activity in the tumor microenvironment of brain cancers. The detectable metabolites within these tumors are contingent upon the choice of matrix, deposition technique, and polarity setting. In this study, we compared the performance of three different matrices, two deposition techniques, and use of positive and negative polarity in two different brain cancer types and across two species. Optimal combinations were confirmed by comparative analysis of lipid and small molecule abundance using liquid chromatography-mass spectrometry and RNA-sequencing assessing differential metabolites between normal and tumor regions. Our findings indicate that the recrystallized cyano-4-hydroxycinnamic acid matrix in positive polarity offered superior performance for both detected metabolites and consistency with other techniques. Beyond these implications for brain cancer, our work establishes a workflow to identify optimal matrices for spatial metabolomics studies.

molecular biology↗

bioRxiv2023

Central and peripheral tau retention modulated by an anti-tau antibody.

Tau protein blood levels dependent on its distribution to peripheral organs and possible elimination from the body. Thus, the peripheral distribution of CSF-derived tau protein was explored, especially since there is a transition to blood-based biomarkers and the emerging idea that tau pathology may spread beyond brain. Near infrared fluorescence (NIRF) was mainly used to analyze tau (tau-NIRF) distribution after its intracisternal or intravenous injection. There was a striking uptake of blood- or CSF-derived tau-NIRF protein by the skeletal structures, liver, small intestine (duodenum), gall bladder, kidneys, urinary bladder, lymph nodes, heart, and spleen. In aging and in older APP/PS1 mice, tau uptake in regions, such as the brain, liver, and skeleton, was increased. In bone (femur) injected tau protein was associated with integrin-binding sialoprotein (IBSP), a major non-collagenous glycoprotein that is associated with mineralization. Tau-NIRF was cleared slowly from CSF via mainly across the cribriform plate, and cervical lymph nodes. In brain, some of the CSF injected tau protein was associated with NeuN-positive and PDGFRy-positive cells, which may explain its retention. The presence of tau in the bladders suggested excretion routes of tau. CSF anti-tau antibody increased CSF tau clearance, while blood anti-tau antibody decreased tau accumulation in the femur but not in liver, kidney, and spleen. Thus, the data show a body-wide distribution and retention of CSF-derived tau protein, which increased with aging and in older APP/PS1 mice. Further work is needed to elucidate the relevance of tau accumulation in each organ to tauopathy.

physiology↗

bioRxiv2023

PTP1B phosphatase puts a brake on iPSC-derived neutrophil motility and antimicrobial function

Neutrophils are rapidly recruited to sites of infection and are critical for pathogen clearance. Neutropenic patients are at high risk for fungal and bacterial infections and can benefit from granulocyte transfusion therapy. Human induced pluripotent stem cells (iPSCs) could provide a robust source of neutrophil-like cells for infusion as they can be generated in large quantities and do not require a donor. However, dampened intracellular signaling limits their cellular activation and response. Here, we show that we can engineer iPSC-derived neutrophils (iNeutrophils) for enhanced motility and anti-microbial functions. Deletion of the PTP1B phosphatase increased iNeutrophil PI3K and ERK signaling and was associated with increased F-actin polymerization, cell migration and phagocytosis. PTP1B deletion also increased production of inflammatory cytokines, including the neutrophil chemoattractant IL-8. Furthermore, PTP1B-KO iNeutrophils displayed a highly activated morphology and were more responsive to the fungal pathogen Aspergillus fumigatus. KO iNeutrophils efficiently migrated to and swarmed hyphae resulting in inhibition of fungal growth. Taken together, deletion of the PTP1B phosphatase removes the "brakes" on iPSC-derived intracellular signaling and neutrophil function. Key pointsDeletion of PTP1B increases iPSC-derived neutrophil intracellular signaling to improve motility and phagocytosis. Deletion of PTP1B enhances iPSC-derived neutrophil swarming response and ability to inhibit fungal growth.

immunology↗

bioRxiv2023

Parallelized Acquisition of Orbitrap and Astral Analyzers Enables High-Throughput Quantitative Analysis.

The growing trend towards high-throughput proteomics demands rapid liquid chromatography-mass spectrometry (LC-MS) cycles that limit the available time to gather the large numbers of MS/MS fragmentation spectra required for identification. Orbitrap analyzers scale performance with acquisition time, and necessarily sacrifice sensitivity and resolving power to deliver higher acquisition rates. We developed a new mass spectrometer that combines a mass resolving quadrupole, the Orbitrap and the novel Asymmetric Track Lossless (Astral) analyzer. The new hybrid instrument enables faster acquisition of high-resolution accurate mass (HRAM) MS/MS spectra compared to state-of-the-art mass spectrometers. Accordingly, new proteomics methods were developed that leverage the strengths of each HRAM analyzer, whereby the Orbitrap analyzer performs full scans with high dynamic range and resolution, synchronized with Astral analyzers acquisition of fast and sensitive HRAM MS/MS scans. Substantial improvements are demonstrated over previous methods using current state-of-the-art mass spectrometers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/543408v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1eedfdeorg.highwire.dtl.DTLVardef@1ab7939org.highwire.dtl.DTLVardef@a3b2f8org.highwire.dtl.DTLVardef@13ac46b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Evaluating the performance of the Astral mass analyzer for quantitative proteomics using data independent acquisition

We evaluate the quantitative performance of the newly released Asymmetric Track Lossless (Astral) analyzer. Using data independent acquisition, the Thermo Scientific Orbitrap Astral mass spectrometer quantifies 5 times more peptides per unit time than state-of-the-art Thermo Scientific Orbitrap mass spectrometers, which have long been the gold standard for high resolution quantitative proteomics. Our results demonstrate that the Orbitrap Astral mass spectrometer can produce high quality quantitative measurements across a wide dynamic range. We also use a newly developed extra-cellular vesicle enrichment protocol to reach new depths of coverage in the plasma proteome, quantifying over 5,000 plasma proteins in a 60-minute gradient with the Orbitrap Astral mass spectrometer.

biochemistry↗

bioRxiv2023

Response to photic stimulation as a measure of cortical excitability in epilepsy patients

AO_SCPLOWBSTRACTC_SCPLOWStudying states and state transitions in the brain is challenging due to nonlinear, complex dynamics. In this research, we analyse the brains response to non-invasive perturbations. Perturbation techniques offer a powerful method for studying complex dynamics, though their translation to human brain data is under-explored. This method involves applying small inputs, in this case via photic stimulation, to a system and measuring its response. Sensitivity to perturbations can forewarn a state transition. Therefore, biomarkers of the brains perturbation response or cortical excitability could be used to indicate seizure transitions. However, perturbing the brain often involves invasive intracranial surgeries or expensive equipment such as transcranial magnetic stimulation (TMS) which is only accessible to a minority of patient groups, or animal model studies. Photic stimulation is a widely used diagnostic technique in epilepsy that can be used as a non-invasive perturbation paradigm to probe brain dynamics during routine electroencephalography (EEG) studies in humans. This involves changing the frequency of strobing light, sometimes triggering a photo-paroxysmal response (PPR), which is an electrographic event that can be studied as a state transition to a seizure state. We investigate alterations in the response to these perturbations in patients with genetic generalised epilepsy (GGE), with (n = 10) and without (n = 10) PPR, and patients with psychogenic non-epileptic seizures (PNES; n = 10), compared to resting controls (n = 10). Metrics of EEG time-series data were evaluated as biomarkers of the perturbation response including variance, autocorrelation, and phase-based synchrony measures. We observed considerable differences in all group biomarker distributions during stimulation compared to controls. In particular, variance and autocorrelation demonstrated greater changes in epochs close to PPR transitions compared to earlier stimulation epochs. Comparison of PPR and spontaneous seizure morphology found them indistinguishable, suggesting PPR is a valid proxy for seizure dynamics. Also, as expected, posterior channels demonstrated the greatest change in synchrony measures, possibly reflecting underlying PPR pathophysiologic mechanisms. We clearly demonstrate observable changes at a group level in cortical excitability in epilepsy patients as a response to perturbation in EEG data. Our work re-frames photic stimulation as a non-invasive perturbation paradigm capable of inducing measurable changes to brain dynamics.

neuroscience↗

bioRxiv2022

Wnt-associated adult stem cell marker Lgr6 is required for osteogenesis and fracture healing

Despite the remarkable regenerative capacity of skeletal tissues, nonunion of bone and failure of fractures to heal properly presents a significant clinical concern. Stem and progenitor cells are present in bone and become activated following injury; thus, elucidating mechanisms that promote adult stem cell-mediated healing is important. Wnt-associated adult stem marker Lgr6 is implicated in the regeneration of tissues with well-defined stem cell niches in stem cell-reliant organs. Here, we demonstrate that Lgr6 is dynamically expressed in osteoprogenitors in response to fracture injury. Using an Lgr6-null mouse model, we find that Lgr6 expression is necessary for maintaining bone volume and efficient postnatal bone regeneration in adult mice. Skeletal progenitors isolated from Lgr6-null mice have reduced colony-forming potential and reduced osteogenic differentiation capacity due to attenuated cWnt signaling. Lgr6-null mice consist of a lower proportion of self-renewing stem cells. In response to fracture injury, Lgr6-null mice have deficient proliferation of periosteal progenitors and reduced ALP activity. Further, analysis of bone regeneration phase and remodeling phase of fracture healing in Lgr6-null mice showed impaired endochondral ossification and reduced mineralization. We propose that in contrast to not being required for successful skeletal development Lgr6-positive cells have a direct role in endochondral bone repair.

cell biology↗

bioRxiv2022

Using light for energy: examining the evolution of phototrophic metabolism via synthetic construction

The origin of phototrophy was pivotal in increasing the size and scale of the biosphere, as it allowed organisms to utilize light-driven energy transport to drive biological processes. Retinalophototrophy, one of two independently evolved phototrophic pathways, consists of a simple system of microbial rhodopsins which have spread broadly through the tree of life via horizontal gene transfer. Here, we sought to determine whether Saccharomyces cerevisiae, a heterotrophic fungus with no known evolutionary history of phototrophy, can function as a facultative artificial phototroph after acquiring a single rhodopsin gene. We transformed S. cerevisiae into a facultative phototroph by inserting a rhodopsin protein from Ustilago maydis into the yeast vacuole, allowing light to pump protons into the vacuolar compartment, a function typically driven by consuming ATP. We show that yeast with rhodopsins gain a selective advantage when grown under green light, growing more rapidly than their non-phototrophic ancestor or rhodopsin-bearing yeast cultured in the dark. These results underscore the remarkable ease with which rhodopsins may be horizontally transferred even in eukaryotes, providing novel biological function without first requiring evolutionary optimization.

cell biology↗

bioRxiv2022

Auditory Brainstem Mechanisms Likely Compensate for Self-imposed Peripheral Inhibition

It is well known that the medial olivocochlear reflex (MOCR) in the brainstem, part of the efferent network, inhibits the cochlear active gain mechanism. The upstream neural influence of this peripheral inhibition is less understood. When the MOCR is activated, responses generated in the cochlea and cortex undergo putative attenuation, yet the amplitude of responses generated in the brainstem are perplexingly unaffected despite decreased input from the periphery. Based on known neural circuitry, we hypothesized that the inhibition of peripheral input is compensated for by equivalent positive feedback in the brainstem over time. We predicted that the inhibition can be captured at the brainstem with stimuli shorter (1.5 s) than previously employed long durations (4 min) where this inhibition is diminished due to compensation. Results from 18 normal hearing human listeners support our hypothesis in that when the MOCR is activated, there is a robust reduction of responses generated at the periphery, brainstem, and cortex for short stimuli and that brainstem inhibition diminishes for longer stimuli. Our methodology and findings have implications for auditory disorders such as tinnitus, evaluation of efferent function, and provides a novel non-invasive window into potential gain compensation mechanisms in the brainstem.

neuroscience↗

bioRxiv2022

Elucidating Mechanisms of Tolerance to Salmonella Typhimurium Across Long-Term Infections Using the Collaborative Cross

Understanding the molecular mechanisms underlying resistance and tolerance to pathogen infection may present the opportunity to develop novel interventions. Resistance is the absence of clinical disease with low pathogen burden, while tolerance is minimal clinical disease in the face of high pathogen burden. Salmonella is a worldwide health concern. We studied 18 strains of Collaborative Cross mice that survive acute Salmonella Typhimurium (STm) infections. We infected these strains orally and monitored them for three weeks post-infection. Five strains cleared STm by the end of the experiment (resistant), while 6 strains maintained a bacterial load and survived to the end of the experiment (tolerant). The remaining 7 strains survived longer than 7 days but succumbed to infection before the end of the study period and were called "delayed susceptible" to differentiate them from strains that do not survive to day 7 (susceptible). Tolerant strains were colonized in Peyers patches, mesenteric lymph node, spleen and liver, while resistant strains had significantly reduced bacterial colonization. Tolerant strains had lower pre-infection core body temperatures than both delayed susceptible and resistant strains and had disrupted circadian patterns of body temperature post-infection sooner than resistant strains. Tolerant strains had higher circulating total white blood cells than resistant strains, driven by increased numbers of neutrophils. Tolerant strains had more severe tissue damage and higher circulating levels of MCP-1 and IFN-{gamma}, but lower levels of ENA-78 than resistant strains. QTL analysis revealed 1 significant association and 6 suggestive associations. RNA-seq analysis identified 22 genes that are differentially regulated in tolerant versus resistant animals that overlapped with the QTLs we identified and allowed us to identify the top 5 canonical pathways. Fibrinogen genes (Fga, Fgb, and Fgg) were found across the QTL, RNA, and top canonical pathways making them the best candidate genes for differentiating tolerance and resistance. Author SummaryAn infected host can respond in multiple ways to bacterial infection including resistance and tolerance. Resistance is a decrease in pathogen load, while in tolerance mild clinical signs are present despite high pathogen load. We infected a collection of 18 strains of genetically diverse mice with Salmonella Typhimurium for up to three weeks. Five strains were resistant, 6 strains were tolerant, and the remaining 7 strains survived an intermediate amount of time ("delayed susceptible"). Tolerant strains maintained bacterial load across several organs, while resistant strains reduced bacterial load. Tolerant strains had the lowest pre-infection core body temperatures and the most rapid disruption in circadian patterns of body temperature post-infection. Tolerant strains had higher circulating neutrophils, higher circulating levels of MCP-1 and IFN-{gamma}, but lower levels of ENA-78 than resistant strains, in addition to more severe tissue damage than resistant strains. QTL analysis revealed multiple associated regions, and gene expression analysis identified 22 genes that are differentially regulated in tolerant versus resistant animals in these regions. Fibrinogen genes (Fga, Fgb, and Fgg) were found across the QTL, RNA, and top canonical pathways making them the best candidate genes for differentiating tolerance and resistance.

genetics↗