Biology subjects

Schultz, J.

Publications and source records attributed to Schultz, J..

15 recordsLinked to original sources

bioRxiv2026

Prenatal Dibutyl Phthalate Exposure Dysregulates Fetal-Placental Vascular Function and Placental Vasculature-Specific Lipid Metabolism

IntroductionIn humans, prenatal dibutyl phthalate (DBP) exposure is associated with increased risks of adverse fetal outcomes as well as metabolic and cardiovascular diseases in the offspring in a fetal sex-specific manner. However, mechanisms underlying these prenatal DBP exposure-associated adverse fetal/offspring outcomes are unclear. We hypothesize that environmentally relevant low-dose prenatal DBP exposure dysregulates fetal-placental vascular function and lipid metabolism in a fetal sex-specific manner, thereby impairing placental efficiency and programming adverse offspring metabolic outcomes. MethodsFemale CD-1 adult mice (8-10 weeks) were orally dosed with vehicle or an environmentally relevant low-dose DBP (0.1g/kg/day) daily from 30 days pre-pregnancy through gestational day (GD) 18.5. Fetal-placental vascular hemodynamics of these dams were examined using high-frequency ultrasound at multiple timepoints. The effect of prenatal environmentally relevant low-dose DBP exposure on placental efficiency, spatial transcriptomic profiles, lipid homeostasis, and placental vascular endothelial cells function in male and female fetuses were evaluated at gestational day (GD) 18.5. ResultsThe prenatal low-dose DBP exposure dysregulated the fetal-placental vascular hemodynamic indices from mid-to late gestation. DBP exposure impairs placental efficiency in male, but not female placenta at GD18.5. Further, female placentas exhibited fetal labyrinth vasculature-specific transcriptomic adaptations that preserves placental efficiency and endothelial function. In contrast, male placentas exhibited minimum transcriptomic adaptation, together with compromised placental efficiency and endothelial function associated with lipotoxic lipid profile. ConclusionsIn conclusion, prenatal low-dose DBP exposure dysregulates placental vascular function and lipid homeostasis in a fetal sex-specific manner, with male fetuses being more susceptible to DBP exposure.

physiology↗

bioRxiv2025

Illuminating the Role of Asymmetric Mitochondrial Fission on Beta-Cell Health

Mitochondrial dynamics play a critical role in the development of aging-related diseases such as type 2 diabetes mellitus. To investigate how mitochondrial dynamics influence cellular behavior in pancreatic beta-cells, we developed a rule-based, multi-level simulation model of insulin secretion. The pancreatic beta cell model encompasses metabolic pathways (glycolysis and oxidative phosphorylation), compartmental processes (mitochondrial fusion and fission), and cellular processes (insulin secretion), allowing for the investigation of their interplay. The rule-based simulation model captures the high plasticity of these organelles and integrates and builds upon insights from various experimental studies and previous simulation models. Its rule-based specification facilitates the exploration of new hypotheses, the integration of new knowledge and data, and the successive extension of the model. The results of our simulation experiments underscore the importance of peripheral, sorted mitochondrial fission in maintaining mitochondrial health. Downregulation of the fission-associated anchor proteins Fis1 and MFF impacts mitochondrial structure and function differently, highlighting their distinct roles in maintaining mitochondrial health and cellular biogenesis, respectively. With respect to insulin secretion, Drp1 suppression shows that beta cells become unresponsive to glucose, whereas Fis1 downregulation only attenuates the cellular response. The simulation model and simulation results corroborates experimental findings and contribute to a deeper understanding of the mechanisms involved in mitochondrial dynamics of pancreatic beta cells and their relation to metabolic dysregulation in type 2 diabetes mellitus. Author summaryMitochondria, often described as the powerhouses of the cell, undergo constant changes through fusion and fission processes. These dynamics are essential for maintaining cell health and proper functioning. In type 2 diabetes mellitus, this balance can be disrupted. In this work, we developed a multi-level, rule-based simulation model to analyze processes of mitochondrial dynamics and their impact on insulin secretion within pancreatic beta cells. Our model captures diverse biological processes that operate at different but interconnected organizational levels, including energy metabolism, mitochondrial dynamics, and insulin secretion. We found that peripheral fission plays a crucial role in determining whether cells secrete insulin properly. In addition, downregulation of the fission-associated proteins MFF and Fis1 reveals a distinct impact on the structure and function of the mitochondrial network, as well as on insulin secretion in pancreatic beta cells. The simulation model and results provide insights into how mitochondrial dynamics affect beta cell metabolism and insulin release. It enables the study of dynamics at different organizational levels, and its rule-based approach facilitates the integration of new knowledge (e.g., by updating or adding specific rules) and experimental data.

systems biology↗

bioRxiv2025

Truncating RELA variants drive autoinflammation and autoimmunity by impairing the negative feedback control of NF-kB

The NF-{kappa}B signaling pathway coordinates inflammation, cell survival, and proliferation, while restraining excessive cell death to maintain immune homeostasis. Truncating mutations in RELA, encoding the NF-{kappa}B subunit p65, have been linked to autoinflammation and autoimmunity, but the underlying mechanisms remain incompletely defined. We investigated six patients from five unrelated families carrying novel heterozygous truncating RELA variants. Despite reduced p65 expression, patients exhibited a broad spectrum of inflammatory manifestations alongside elevated baseline and stimulus-induced pro-inflammatory cytokines. Functional analyses in patient-derived cells and mutant RELA knock-in models showed that upstream NF-{kappa}B signaling was intact, but induction of inhibitory regulators such as I{kappa}B and A20 was impaired. This defective feedback control shifted immune homeostasis toward amplified inflammatory responses that depended on the residual activity of the remaining functional RELA allele. Single-cell transcriptomics revealed distinct cell type-specific consequences: monocytes displayed constitutive type I interferon and NF-{kappa}B activation, B cells retained partial compensatory signaling, whereas T and NK cells exhibited transcriptional signatures of cell death pathways. Patient fibroblasts and mutant RELA knock-in cells further confirmed enhanced TNF-induced inflammatory gene expression and hypersensitivity to apoptosis and necroptosis. These findings establish RELA haploinsufficiency as a cause of systemic immune dysregulation, and link defective NF-{kappa}B feedback control to unchecked inflammation and inflammatory cell death. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/687461v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1f0bfe6org.highwire.dtl.DTLVardef@c6cb60org.highwire.dtl.DTLVardef@1522accorg.highwire.dtl.DTLVardef@177c724_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Detection dog performance state estimation from pre-stimulus video and physiological signals using deep learning and Bayesian inference

Detection dogs play a critical role in operational settings ranging from explosives detection to medical diagnostics. Their unmatched olfactory capabilities allow them to locate trace-level targets that remain beyond the reach of current technology. However, detection performance can decline without overt behavioral signs, posing a challenge for timely and informed deployment decisions. Identifying subtle precursors to missed alerts remains an open problem with both practical and computational significance. To address this, we recorded detection dogs on a treadmill-based scent delivery system under tightly controlled conditions, enabling precise timing of odor presentation. We focused on the 4.5 seconds preceding each odor pulse to capture anticipatory movement through video and physiological state via sensors. Using markerless pose estimation, we extracted high-resolution joint trajectories, while concurrent recordings provided heart rate, heart rate variability, and core temperature. We trained a spatiotemporal deep learning model that integrates Graph Attention Networks and Temporal Convolutional Networks to predict missed indications from these short, pre-stimulus windows. The model successfully identified 85% of missed alerts with 81% precision. Heart rate variability emerged as the most informative physiological input, suggesting a strong autonomic component to declining readiness. To move from isolated predictions to actionable insights, we implemented a Bayesian aggregation framework that estimates each dogs latent miss rate over time. This probabilistic formulation enables adaptation to individual baselines and operational risk thresholds, supporting context-sensitive deployment decisions. While data were collected in a laboratory setting, our findings highlight behavioral and physiological signatures that precede performance failure. This work lays the foundation for real-time readiness monitoring systems that integrate wearable sensing with interpretable machine learning, supporting timely and welfare-conscious deployment decisions. Author summaryDetection dogs are used in high-stakes situations--from finding explosives to diagnosing diseases. But detection work is physically and mentally demanding, and a dogs performance can quietly decline over time. One challenge is that handlers often cant tell when a dog is starting to lose focus or miss targets until its too late. In our study, we used a treadmill-based setup to record dogs as they performed scent detection tasks. We tracked how they moved, monitored their heart rate and temperature, and trained a computer model to recognize patterns that typically show up just before a missed target. Importantly, we built a second layer that transforms the models output into a running estimate of how likely the dog is to miss a target--based on its recent behavior. This second layer can be tuned to the task and the dog. It can issue earlier warnings during high-risk missions like explosives detection and delay warnings for experienced dogs known to perform reliably even under physical and mental strain. The result is a flexible framework--a first step toward tools that could support better decision-making in real-world deployments.

animal behavior and cognition↗

bioRxiv2025

Probiotic and postbiotic treatment in situ during a marine heat wave improves coral health and promotes specific metabolic and microbiome changes

Microbial therapies are emerging as promising tools for coral protection against heat stress, yet such application was not tested in situ. We tested two coral-derived probiotic consortia and their heat-killed counterparts (postbiotics) on bleaching Acropora cf. valida in the Red Sea during a marine heatwave. Over 15 days, both live and one of the heat-killed treatments maintained photosynthetic efficiency (Fv/Fm), whereas placebo-treated corals exhibited significant thermal stress-induced decline. 16S rRNA gene sequencing profiling showed enrichment of putatively beneficial genera (e.g., Terasakiispira spp., Pseudoalteromonas spp.), and untargeted metabolomics resolved treatment-specific metabolic signatures that differed among consortia and between live and inactivated formulations. These molecular fingerprints illuminate specific underlying protective mechanisms and host-microbiome interactions under heat stress. Together, our results position microbial therapies (probiotics and specific postbiotics) as field-validated, mechanism-informed interventions capable of minimizing impacts on corals during real-world thermal extremes and provide design cues for scalable deployment.

microbiology↗

bioRxiv2025

Highly efficient anogenital transmission of clade Ia mpox virus associated with increased shedding.

The transmission pattern of mpox has shifted from sporadic zoonotic outbreaks to sustained human-to-human spread. Epidemiological data indicate sexual contact as a crucial driver for efficient transmission and the associated devastating mpox outbreaks in recent years. However, our understanding of exact driving factors and transmission determinants is still limited. Here, we investigated MPXV clade Ia virus pathogenicity, shedding kinetics, and transmission potential in a prairie dog model (Cynomys ludovicianus). All tested mucosal inoculation routes (penile/preputial, vaginal, rectal, intranasal) resulted in a productive, systemic infection. Inoculation via urogenital routes generated the highest virus shedding and most severe clinical disease. A simulated sexual contact transmission resulted in 100% transmission efficiency with high virus shedding in sentinels on day 1, even before the onset of clinical signs. Our findings provide critical insights into mpox transmission, emphasizing the role of anogenital mucosal surfaces in facilitating rapid spread. These results advocate for a stronger focus on mucosal infection when evaluating countermeasures.

microbiology↗

bioRxiv2025

Glycolysis-enhancing alpha 1-adrenergic antagonists are neuroprotective in Alzheimers disease

Terazosin (TZ) is an 1-adrenergic receptor antagonist that enhances glycolysis by activating the enzyme phosphoglycerate kinase 1 (PGK1). Epidemiological data suggest that TZ may be neuroprotective in Parkinsons disease and in dementia with Lewy bodies and that glycolysis-enhancing drugs might be protective in other neurodegenerative diseases involving protein aggregation, such as Alzheimers disease (AD). We investigated TZ in AD and report four main results. First, we found that TZ increased ATP levels in a Saccharomyces cerevisiae mutant with impaired energy homeostasis and reduced the aggregation of the AD-associated protein, amyloid beta (A{beta}) 42. Second, in an AD transgenic mouse model (5xFAD) we found that TZ attenuated amyloid pathology in the hippocampus and rescued cognitive impairments in spatial memory and interval timing behavioral assays. Third, using the Alzheimers Disease Neuroimaging Initiative (ADNI) database, we found that AD patients newly started on TZ or related glycolysis-enhancing drugs had a slower progression of both cognitive dysfunction and neuroimaging biomarkers, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), a measure of brain metabolism. Finally, in a large human administrative dataset, we found that patients taking TZ or related glycolysis-enhancing drugs had a lower hazard of being diagnosed with AD compared to those taking tamsulosin or 5-alpha reductase inhibitors. These data further implicate metabolism in neurodegenerative diseases and suggest that glycolysis-enhancing drugs may be neuroprotective in AD.

neuroscience↗

bioRxiv2025

Structural Characterization of Native RNA Polymerase II Transcription Complexes and Nucleosomes in Drosophila melanogaster

Structural studies of eukaryotic RNA polymerase II (Pol II) transcription complexes often depend on in vitro assembly by mixing purified Pol II with synthetic DNA/RNA scaffolds, recombinant transcription factors, and/or histones, followed by stalling transcription at defined positions by adding selected nucleotide triphosphate substrates. These studies have yielded remarkable results for understanding nucleosome transcription by Pol II with elongation factors but may fail to represent transcription in native conditions. To investigate Pol II transcription within metazoan cells, we developed an approach to isolate the native transcription complexes from Drosophila melanogaster embryos. Utilizing one-step FLAG-tag affinity purification and mild chromatin treatment with Micrococcal Nuclease (MNase), we preserved the native transcription complex for cryo-EM and proteomics studies. In silico purification through the cryo-EM classifications determined structures of multiple forms of native transcription complex, nucleosome and other macromolecules. Remarkably, we determined the structures of metazoan Rpb4/Rpb7 stalk-less elongation complex as well as hexameric nucleosome lacking an H2A/H2B dimer, revealing that diverse elongation complexes and nucleosomes are involved in active transcription in vivo. Nucleosome is positioned only downstream of Pol II in the nucleosome elongation complex, underscoring it as a major energy barrier and a time-consuming step during Pol II progression through nucleosomal DNA. Proteomics identified co-purified factors responsible for initiation and elongation stages of transcription, as well as RNA modification factors. This study lays the groundwork for structural study of native transcription in eukaryotes, with future work focused on studies of transient and minor populations of transcription complexes.

molecular biology↗

bioRxiv2023

Hippocampal-occipital connectivity reflects autobiographical memory deficits in aphantasia

Aphantasia refers to reduced or absent visual imagery. While most of us can readily recall decade-old personal experiences (autobiographical memories, AM) with vivid mental images, there is a dearth of information about whether the loss of visual imagery in aphantasics affects their AM retrieval. The hippocampus is thought to be a crucial hub in a brain-wide network underlying AM. One important question is whether this network, especially the connectivity of the hippocampus, is altered in aphantasia. In the current study, we tested 14 congenital aphantasics and 16 demographically matched controls in an AM fMRI task to investigate how key brain regions (i.e., hippocampus and visual-perceptual cortices) interact with each other during AM re-experiencing. All participants were interviewed regarding their autobiographical memory to examine their episodic and semantic recall of specific events. Aphantasics reported more difficulties in recalling AM, were less confident about their memories, and described less internal and emotional details than controls. Neurally, aphantasics displayed decreased hippocampal and increased visual-perceptual cortex activation during AM retrieval compared to controls. In addition, controls showed strong negative functional connectivity between the hippocampus and the visual cortex during AM and resting-state functional connectivity between these two brain structures predicted better visualization skills. Our results indicate that visual mental imagery plays an important role in detail-rich vivid AM, and that this type of cognitive function is supported by the functional connection between the hippocampus and the visual-perceptual cortex.

neuroscience↗

bioRxiv2022

The influence of familiarity on the neural coding of face sex

In behaviour, humans have been shown to represent the sex of faces categorically when the faces are familiar to them. This leads to them judging faces crossing the category boundary (i.e. from male to female) as more different than faces that are within the same category. In this study, we investigated how faces of different sexes are encoded in the brain, and how familiarity changes the neural coding of sex. We recorded participants brain activity using fMRI while they viewed both familiar and unfamiliar faces that were morphed in their sex characteristics (i.e. between male and female). Participants viewed pairs of faces that were either identical, or differed in their sex morph level, with or without a categorical change in perceived sex (i.e. crossing the perceived male/female category boundary). This allowed us to disentangle physical and categorical neural coding of face sex, and to investigate if neural coding of face categories was enhanced by face familiarity. Our results show that the sex of familiar, but not unfamiliar, faces was encoded categorically in the medial prefrontal and orbitofrontal cortex as well as in the right intraparietal sulcus. In contrast, the fusiform face area showed a sensitivity to the physical changes in the sex of faces that was unaffected by face familiarity. The occipital face area showed its highest responses to faces towards the ends of the sex morph continuum (i.e. the most male or most female faces), and these responses were also unaffected by face familiarity. These results suggest that there is a dissociation between the brain regions encoding physical and categorical representations of face sex, with occipital and fusiform face regions encoding physical face sex properties and frontal and parietal regions encoding high-level categorical face sex representations that are linked to face identity.

neuroscience↗

bioRxiv2022

Directed Functional Connectivity by Variational Cross-mapping of Psychophysiological Variables

Understanding the functional connectivity between different brain regions is vital for improving our comprehension of neural processing and cognition. While directed functional connectivity methods can provide us with statistical estimates of information exchange between regions, classic exploratory methods may not capture the nonlinear temporal effects that are observed in fMRI-BOLD data during task-evoked neural activity. To address this limitation, we propose a novel methodology that leverages variational cross-mapping analysis, inspired by psychophysiological interactions, to identify directional influence between connected regions of interest. Our approach can help uncover previously unknown patterns of information exchange and account for nonlinear effects, making it a valuable addition to the toolkit of researchers studying brain function. We demonstrate the effectiveness of our method using simulated neurovascular signals and publicly available fMRI data from 680 human participants performing an emotional face processing task. Our results suggest information flows from the occipital face area to the superior temporal sulcus and the fusiform face area, and additionally from the superior temporal sulcus to the fusiform gyrus. These findings are consistent with previously documented effective connectivity findings in face processing and provide new insights into the exploratory analyses of non-linear directed connectivity for task-evoked data. Overall, our findings contribute to advancing our understanding of directed functional connectivity in the brain and demonstrate the potential of our method to uncover previously unknown patterns of information exchange. Author summaryThe advent of large datasets has made it possible for many research groups to explore functional connectivity between different brain regions. The ability to assess directed connectivity between multiple regions from task-evoked neural responses could potentially uncover connections that were not previously hypothesized based on available data. However, classic methods for exploring task-evoked effects often rely on specific assumptions that are frequently violated by the data, such as nonlinearity, stationarity, and separability of cause from effect. Recent studies have attempted to address these issues using sliding window approaches or parameterized forward causal models, but these methods have limitations such as fixed contextual effect windows or restricted search space for forward models. To overcome these challenges, we propose a Bayesian non-parametric cross-mapping method that can address non-linearity and separability while using specially designed covariance functions to address non-stationarity. We demonstrate through simulations that our proposed method can detect pair-wise interacting neural populations with high sensitivity and specificity, and accurately infer changes in connections between tasks in both acyclical and cyclical neural networks. We also show that our method can replicate known connectivity findings about emotional face processing in a publicly available dataset. Thus, our method represents a promising exploratory connectivity tool for cognitive and behavioral neurosciences.

neuroscience↗

bioRxiv2021

Gaining or cutting SLAC: the evolution of plant guard cell signalling pathways

The evolution of adjustable plant pores (stomata), enabling CO2 acquisition in cuticle wax-sealed tissues was one of the most significant events in the development of life on land. But how did the guard cell signalling pathways that regulate stomatal movements evolve? We investigate this through comparison of fern and angiosperm guard cell transcriptomes. We find that these divergent plant groups share expression of similar genes in guard cells including biosynthesis and signalling genes for the drought stress hormone abscisic acid (ABA). However, despite conserved expression in guard cells, S-type anion channels from the SLAC/SLAH family - known for ABA-mediated stomatal closure in angiosperms - are not activated by the same pathways in ferns, highlighting likely differences in functionality. Examination of other land plant channels revealed a complex evolutionary history, featuring multiple gains or losses of SLAC activation mechanisms, as these channels were recruited to a role in stomatal closure. Taken together, the guard cells of flowering and non-flowering plants share similar core features, but also show lineage-specific and ecological niche-related adaptations, likely underlying differences in behaviour.

plant biology↗

bioRxiv2020

Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2

An outbreak of a novel coronavirus, now named SARS-CoV-2, causing respiratory disease and a [~]2% case fatality rate started in Wuhan, China in December 2019. Following unprecedented rapid global spread, the World Health Organization declared COVID-19 a pandemic on March 11, 2020. Although data on disease in humans are emerging at a steady pace, certain aspects of the pathogenesis of SARS-CoV-2 can only be studied in detail in animal models, where repeated sampling and tissue collection is possible. Here, we show that SARS-CoV-2 causes respiratory disease in infected rhesus macaques, with disease lasting 8-16 days. Pulmonary infiltrates, a hallmark of human disease, were visible in lung radiographs of all animals. High viral loads were detected in swabs from the nose and throat of all animals as well as in bronchoalveolar lavages; in one animal we observed prolonged rectal shedding. Taken together, the rhesus macaque recapitulates moderate disease observed in the majority of human cases. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease and will aid development and testing of medical countermeasures.

microbiology↗

bioRxiv2018

Recent demographic histories and genetic diversity across pinnipeds are shaped by anthropogenic interactions and mediated by ecology and life-history

A central paradigm in conservation biology is that population bottlenecks reduce genetic diversity and negatively impact population viability and adaptive potential. In an era of unprecedented biodiversity loss and climate change, understanding both the determinants and consequences of bottlenecks in wild populations is therefore an increasingly important challenge. However, as most studies have focused on single species, the multitude of potential drivers and the consequences of bottlenecks remain elusive. Here, we used a comparative approach by integrating genetic data from over 11,000 individuals of 30 pinniped species with demographic, ecological and life history data to elucidate the consequences of large-scale commercial exploitation by 18th and 19th century sealers. We show that around one third of these species exhibit strong genetic signatures of recent population declines, with estimated bottleneck effective population sizes reflecting just a few tens of surviving individuals in the most extreme cases. Bottleneck strength was strongly associated with both breeding habitat and mating system variation, and together with global abundance explained a large proportion of the variation in genetic diversity across species. Overall, there was no relationship between bottleneck intensity and IUCN status, although three of the four most heavily bottlenecked species are currently endangered. Our study reveals an unforeseen interplay between anthropogenic exploitation, ecology, life history and demographic declines, sheds new light on the determinants of genetic diversity, and is consistent with the notion that both genetic and demographic factors influence population viability.

evolutionary biology↗

bioRxiv2017

Draft genome of the Heterotardigrade Milnesium tardigradum sheds light on ecdysozoan evolution

Tardigrades are among the most stress tolerant animals and survived even unassisted exposure to space in low earth orbit. Still, the adaptations leading to these unusual physiological features remain unclear. Even the phylogenetic position of this phylum within the Ecdysozoa is unclear. Complete genome sequences might help to address these questions as genomic adaptations can be revealed and phylogenetic reconstructions can be based on new markers. Here, we present a first draft genome of a species from the family Milnesiidae, namely Milnesium tardigradum. We consistently place M. tardigradum and the two previously sequenced Hypsibiidae species, Hypsibius dujardini and Ramazzottius varieornatus, as sister group of the nematodes with the arthropods as outgroup. Based on this placement, we identify a massive gene loss thus far attributed to the nematodes which predates their split from the tardigrades. We provide a comprehensive catalog of protein domain expansions linked to stress response and show that previously identified tardigrade-unique proteins are erratically distributed across the genome of M. tardigradum. We further suggest alternative pathways to cope with high stress levels that are yet unexplored in tardigrades and further promote the phylum Tardigrada as a rich source of stress protection genes and mechanisms.

evolutionary biology↗