Biology subjects

Steiner, J.

Publications and source records attributed to Steiner, J..

13 recordsLinked to original sources

bioRxiv2026

Systemic stress states are reversed by NPBWR1 inhibition

Chronic stress is widely studied as a brain-centered driver of depression, yet its effects across the body remain unclear. Here, we define chronic stress as a coordinated molecular state across tissues in mice. Using a whole-body proteomic atlas of 13 tissues, we find that stress effects are strongest in peripheral metabolic and endocrine organs, whereas classical stress-associated brain regions show comparatively modest changes. Cross-organ analyses reveal structured, tissue-specific responses rather than uniform shifts. Inhibition of the stress-regulated receptor NPBWR1 reverses both behavioral deficits and proteomic alterations across organs in both sexes, indicating that this state is dynamically modifiable. Integration with human serum proteomics identifies shared, sex-specific signatures. Across tissues, lipid metabolism emerges as a common stress-responsive pathway, confirmed by hepatic lipid remodeling that is normalized by NPBWR1 inhibition. To facilitate exploration of these data, we provide an interactive cross-organ web-based resource. Together, these findings challenge the brain-centric view of stress pathology and define chronic stress as an organism-wide molecular state.

systems biology↗

bioRxiv2025

Remodeling Activity of ChAHP Restricts Transcription Factor Access to Chromatin

Transcription in eukaryotes is regulated by chromatin-based mechanisms that control nucleosome occupancy, chromatin modifications, and transcription factor binding. We have previously shown that the transcription factor ADNP forms the ChAHP complex with the chromatin remodeler CHD4 and HP1 proteins, acting as a site-specific regulator of transcription and antagonist of CTCF binding. However, the molecular basis of these functions remained unclear. Here, we demonstrate that the CHD4 subunit is essential to antagonize CTCF and silence transcription of transposons, while HP1 proteins are dispensable. Although the remodeling activity of CHD4 is not required for ChAHP chromatin association, it is critical for both transposon repression and CTCF antagonism. Our findings support a model wherein ADNP recruits chromatin remodeling activity in a sequence-specific manner, enabling transcriptional control and local modulation of chromatin architecture.

molecular biology↗

bioRxiv2025

ChAHP Silences SINE Retrotransposons by Inhibiting TFIIIB Recruitment

Short interspersed nuclear elements (SINEs) are abundant non-autonomous transposable elements derived from RNA polymerase III (POL III)-transcribed short non-coding RNAs. SINEs retain sequence features recognized by the POL III machinery and constitute a substantial portion of vertebrate genomes. Despite their impact on genome stability and evolution, the mechanisms governing SINE transcription remain poorly understood. Although DNA methylation and heterochromatin formation have been implicated in their repression, we find these pathways play only a minor role in mouse embryonic stem cells. Instead, we identify the ChAHP complex as a key repressor of SINE B2 elements. ChAHP directly inhibits POL III transcription by blocking TFIIIB recruitment without affecting TFIIIC binding. This selective interference prevents transcription initiation and highlights a distinct regulatory mechanism. Our findings establish ChAHP as a non-canonical repressor of POL III-dependent SINE transcription, offering new insights into the control of this pervasive class of non-coding genomic elements.

molecular biology↗

bioRxiv2025

A novel frameshift mutation in Phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1) causes immunodeficiency and Amyotrophic Lateral Sclerosis (ALS)

Mutations in PIK3R1, a regulatory subunit of Class I PI3K, are implicated in immune disorders and neurological conditions. We identified a novel heterozygous pathogenic frameshift mutation (c.1710dup) in PIK3R1 in a patient with common variable immunodeficiency who developed slowly progressive Amyotrophic Lateral Sclerosis. Induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs) demonstrated that this mutation resulted in PIK3R1 haploinsufficiency, with downstream activation of AKT, disruption of neuronal electrical function and increased apoptosis in iPSC-derived motor neurons. Single-cell RNA sequencing (scRNA-seq) and pathway analysis of differentially expressed genes showed apoptosis pathways were upregulated in neuronal clusters from iMNs harboring the PIK3R1c.1710 dup mutation. Mutated iPSC-derived brain organoids were smaller than matched controls. scRNA-seq of brain organoids showed more active apoptosis in neuronal clusters of patient-derived brain organoids. These findings identify a critical and novel role for PIK3R1 haploinsufficiency in neuronal function and survival.

neuroscience↗

bioRxiv2023

Comprehensive Assessment of Blood-Brain Barrier Opening and Sterile Inflammatory Response: Unraveling the Therapeutic Window

Microbubbles (MBs) combined with focused ultrasound (FUS) have emerged as a promising noninvasive technique to permeabilize the blood-brain barrier (BBB) for drug delivery to the brain. However, the safety and biological consequences of BBB opening remain incompletely understood. This study investigates the effects of varying microbubble volume doses (MVD) and ultrasound mechanical indices (MI) on BBB opening and the sterile inflammatory response (SIR) using high-resolution ultra-high field MRI-guided FUS in mouse brains. The results demonstrate that both MVD and MI significantly influence the extent of BBB opening, with higher doses and mechanical indices leading to increased permeability. Moreover, RNA sequencing reveals upregulated inflammatory pathways and immune cell infiltration after BBB opening, suggesting the presence and extent of SIR. Gene set enrichment analysis identifies 12 gene sets associated with inflammatory responses that are upregulated at higher doses of MVD or MI. A therapeutic window is established between significant BBB opening and the onset of SIR, providing operating regimes for avoiding each three classes of increasing damage from stimulation of the NF{kappa}B pathway via TNFL signaling to apoptosis. This study contributes to the optimization and standardization of BBB opening parameters for safe and effective drug delivery to the brain and sheds light on the underlying molecular mechanisms of the sterile inflammatory response. Significance StatementThe significance of this study lies in its comprehensive investigation of microbubble-facilitated focused ultrasound for blood-brain barrier (BBB) opening. By systematically exploring various combinations of microbubble volume doses and ultrasound mechanical indices, the study reveals their direct impact on the extent of BBB permeability and the induction of sterile inflammatory response (SIR). The establishment of a therapeutic window between significant BBB opening and the onset of SIR provides critical insights for safe and targeted drug delivery to the brain. These findings advance our understanding of the biological consequences of BBB opening and contribute to optimizing parameters for clinical applications, thus minimizing potential health risks, and maximizing the therapeutic potential of this technique.

bioengineering↗

bioRxiv2023

MRI-Guided Focused Ultrasound Blood-Brain Barrier Opening Increases Drug Delivery and Efficacy in a Diffuse Midline Glioma Mouse Model

Diffuse intrinsic pontine glioma (DIPG) is the most common and deadliest pediatric brainstem tumor and is difficult to treat with chemotherapy in part due to the blood-brain barrier (BBB). Focused ultrasound (FUS) and microbubbles (MBs) have been shown to cause BBB disruption (BBBD), allowing larger chemotherapeutics to enter the parenchyma. Panobinostat is an example of a promising in vitro agent in DIPG with poor clinical efficacy due to low BBB penetrance. In this study, we hypothesized that using FUS to disrupt the BBB allows higher concentrations of panobinostat to accumulate in the tumor, providing a therapeutic effect. Mice were orthotopically injected with a patient-derived DMG cell line, BT-245. MRI was used to guide FUS/MB (1.5 MHz, 0.615 MPa PNP, 1 Hz PRF, 10 ms PL, 3 min treatment time) / (25 {micro}L/kg, IV) targeting to the tumor location. In animals receiving panobinostat (10 mg/kg, IP) in combination with FUS/MB, a 3-fold increase in tumor panobinostat concentration was observed, with only insignificant increase of the drug in the forebrain. In mice receiving three weekly treatments, the combination of panobinostat and FUS/MB led to a 71% reduction of tumor volumes by MRI (p = 0.01). Furthermore, FUS/MB improved the mean survival from 21 to 31 days (p < 0.0001). Our study demonstrates that FUS-mediated BBBD can increase the delivery of panobinostat to an orthotopic DMG tumor, providing a strong therapeutic effect and increased survival. One Sentence SummaryFUS and microbubbles can increase the delivery of panobinostat to a patient-derived xenograft (PDX) orthotopic DMG tumor, providing a strong therapeutic effect and increased survival.

bioengineering↗

bioRxiv2023

A systematic review on leptospirosis in cattle: a European perspective

BackgroundLeptospirosis is a zoonotic disease which is globally distributed. Bovine leptospirosis often results in economic losses through its severe impact on reproduction performance. However, a clear overview of the disease characteristics in European cattle is lacking. The objective of this review was to summarise the current knowledge and state of the research on the epidemiology of bovine leptospirosis in Europe. MethodologyWe conducted a systematic literature review following the PRISMA guidelines. We screened four electronic databases (Pubmed, Web of Science, Scopus, CABI) and included studies published between 2001 and 2021, in English, German, and French. Identified papers were filtered according to predefined inclusion and exclusion criteria. ResultsSixty-two studies were included. Reported seroprevalences were remarkably variable among studies, probably reflecting local variations but also heterogeneity in the study designs, laboratory methods, and sample sizes. The five most reported circulating serogroups in European cattle were Sejroe, Australis, Grippotyphosa, Icterohaemorrhagiae, and Pomona. Abortion and fertility disorders were the most frequently reported signs of leptospirosis in European cattle and were generally associated with chronic infections. The acute form primarily affected juveniles and foetuses. Risk factors positively associated with leptospirosis in cattle were diverse, related to environmental (e.g. geographic location), climatic (e.g. flooding), and medical (e.g. presence of other diseases) parameters, as well as farming practices (e.g. purchase policy, herd size) and individual factors (e.g. animal age and breed). ConclusionsClinical features of bovine leptospirosis in Europe cover a large range of signs and confirmation of infection requires laboratory tests. The epidemiology of the disease is very local, most probably influenced by context-specific factors. This work highlights several research gaps, including a lack of research data from several countries, a lack of methodological harmonisation, a lack of large-scale studies, an underrepresentation of beef herds in the studies, and a lack of molecular investigations. Author SummaryLeptospirosis is a zoonotic disease that has been reported in cattle worldwide. This review systematically evaluated the available literature (2001-2021) on (i) the methods of diagnostics, (ii) (sero)prevalence, (iii) circulating serogroups/serovars, (iv) clinical signs, (v) and risk factors associated with leptospirosis in European cattle. We found that the prevalence of the disease was very variable among studies. Similarly, a wide range of clinical signs were described, but the most frequently reported ones were abortion and fertility disorders. Risk factors of infection in cattle included herd size, purchase of animals, access to pasture and natural water sources, contact with other animal species, presence of other diseases on farm, animal age, and occurrence of extreme weather events. This review highlights that leptospirosis should be considered as a differential diagnosis in case of abortion or reproductive failure in European cattle and emphasises the need for integrated disease prevention and control measures at farm or regional level. We identified several research gaps, particularly a lack of research data from several countries, a lack of large-scale studies, an underrepresentation of beef herds, and a limited use of molecular tools in the studies.

microbiology↗

bioRxiv2022

Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity.

Late-life-initiated dietary interventions negligibly extend longevity or reduce frailty, yet the reason remains unknown. We investigated the age-related changes associated with the fasting response in adipose tissue of the short-lived killifish N. furzeri. Transcriptomic analysis revealed the presence of a fasting-like transcriptional program (FLTP) in old animals that is irrespective of their nutritional status and characterized by widespread suppression of anabolic processes. FLTP is associated with reduced expression of the AMPK {gamma}1 regulatory subunit. Accordingly, refeeding positively regulates {gamma}1 expression in young but not in old animals. Fish having sustained AMPK{gamma}1 activation had no sign of FLTP in old age and exhibited metabolic health and longevity. In humans, we found that {gamma}1 expression declines with age and is associated with multimorbidity and multidimensional frailty risk. Our study highlights the importance of the refeeding arm in promoting health and longevity and identifies the AMPK{gamma}1 complex as a potential target to prevent age-related diseases in humans.

physiology↗

bioRxiv2020

Cell size is a determinant of stem cell potential during aging

Stem cells are remarkably small in size. Whether small size is important for stem cell function is unknown. We find that murine hematopoietic stem cells (HSCs) enlarge under conditions known to decrease stem cell function. This decreased fitness of large HSCs is due to reduced proliferative potential. Preventing HSC enlargement by inhibiting macromolecule biosynthesis or reducing large HSCs size by shortening G1 averts the loss of stem cell potential under conditions causing stem cell exhaustion. Finally, we show that a fraction of murine and human HSCs enlarge during aging. Preventing this age-dependent enlargement improves HSC function. We conclude that small cell size is important for stem cell function in vivo and propose that stem cell enlargement contributes to their functional decline during aging. One Sentence SummarySize increase drives stem cell aging.

cell biology↗

bioRxiv2020

Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits

Epidemiological studies suggest a link between type-2 diabetes and Parkinsons disease (PD) risk. Treatment of type-2 diabetes with insulin sensitizing drugs lowers the risk of PD. We previously showed that the insulin sensitizing drug, MSDC-0160, ameliorates pathogenesis in some animal models of PD. MSDC-0160 reversibly binds the mitochondrial pyruvate carrier (MPC) protein complex, which has an anti-inflammatory effect and restores metabolic deficits. Since PD is characterized by the deposition of -synuclein (Syn), we hypothesized that inhibiting the MPC might directly inhibit Syn aggregation in vivo in mammals. To answer if modulation of MPC can reduce the development of Syn assemblies, and reduce neurodegeneration, we treated two chronic and progressive mouse models; a viral vector-based Syn overexpressing model and a pre-formed fibril (PFF) Syn seeding model with MSDC-0160. These two models present with distinct types of Syn pathology but lack inflammatory or autophagy deficits. Contrary to our hypothesis, we found that a modulation of MPC in these models did not reduce the accumulation Syn aggregates or mitigate neurotoxicity. Instead, MSDC-0160 changed the post-translational modification and aggregation features of the Syn. These results are consistent with the lack of a direct effect on MPC modulation on synuclein clearance in these models.

neuroscience↗

bioRxiv2020

Alpha-synuclein expression supports interferon stimulated gene expression in neurons

The protein alpha-synuclein (asyn) is predominantly expressed in neurons and is associated with neurodegenerative diseases like Parkinsons disease (PD); yet, a functional role for asyn in neurons is not clearly established. We have previously shown that asyn expression is up-regulated following viral infection in neurons and is critical for host immune responses to RNA virus infections. Here, we investigate the mechanisms underlying asyn-dependent immune responses to RNA virus infection in the brain. Using asyn knock-out (KO) mice and human neuronal models, we show that asyn is required for expression of the full repertoire of interferon-stimulated genes (ISGs) in neurons following acute RNA virus infection. Furthermore, treatment of asyn KO human neurons with poly I:C or type I interferon also fail to induce expression of the full complement of ISGs suggesting that asyn plays an important role in modulating neuronal innate immune responses. In brain tissue, asyn-dependent ISG expression is independent of microglia activation and supports activation of infiltrating lymphocytes following viral challenge. We also show that virus infections lead to accumulation of phosphorylated S129 asyn in human and non-human primate neuronal tissues. In a model of pS129 asyn pathology, we found that infection with West Nile virus increases microglia activation but does not significantly alter pS129 asyn pathology in the mouse model. Taken together, our results establish asyn as a novel, neuron-specific modulator of innate immunity by a mechanism that promotes interferon-stimulated gene expression and links responses to virus infection with formation of phosphorylated S129-asyn in neuronal tissue.

neuroscience↗

bioRxiv2020

Changes in the blood plasma lipidome associated with response to atypical antipsychotic treatments in schizophrenia

Atypical antipsychotics are widely used to manage schizophrenia symptoms. However, these drugs can induce deleterious side effects, such as MetS, which are associated with an increased cardiovascular risk to patients. Lipids play a central role in this context, and changes in lipid metabolism have been implicated in schizophrenias pathobiology. Furthermore, recent evidence suggests that lipidome changes may be related to antipsychotic treatment response. The aim of this study was to evaluate the lipidome changes in blood plasma samples of schizophrenia patients before and after 6 weeks of treatment with either risperidone, olanzapine, or quetiapine. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis showed changes in the levels of ceramides (Cer), glycerophosphatidic acids (PA), glycerophosphocholines (PC), phosphatidylethanolamines (PE), phosphatidylinositols (PI), glycerophosphoglycerols (PG), and phosphatidylserines (PS) for all treatments. However, the treatment with risperidone also affected diacylglycerides (DG), ceramide 1-phosphates (CerP), triglycerides (TG), sphingomyelins (SM), and ceramide phosphoinositols (PI-Cer). Moreover, specific lipid profiles were observed that could be used to distinguish poor and good responders to the different antipsychotics. As such, further work in this area may lead to lipid-based biomarkers that could be used to improve the clinical management of schizophrenia patients.

biochemistry↗

bioRxiv2020

T cells limit accumulation of aggregate pathology following intrastriatal injection of α-synuclein fibrils

Background: -Synuclein (-syn) is the predominant protein in Lewy-body inclusions, which are pathological hallmarks of -synucleinopathies, such as Parkinsons disease (PD) and multiple system atrophy (MSA). Other hallmarks include activation of microglia, elevation of pro-inflammatory cytokines, as well as the activation of T and B cells. These immune changes point towards a dysregulation of both the innate and the adaptive immune system. T cells have been shown to recognize epitopes derived from -syn and altered populations of T cells have been found in PD and MSA patients, providing evidence that these cells can be key to the pathogenesis of the disease. Objective: To study the role of the adaptive immune system with respect to -syn pathology. Methods: We injected human -syn preformed fibrils (PFFs) into the striatum of immunocompromised mice (NSG) and assessed accumulation of phosphorylated -syn pathology, proteinase K-resistant -syn pathology and microgliosis in the striatum, substantia nigra and frontal cortex. We also assessed the impact of adoptive transfer of naive T and B cells into PFF-injected immunocompromised mice. Results: Compared to wildtype mice, NSG mice had an 8-fold increase in phosphorylated -syn pathology in the substantia nigra. Reconstituting the T cell population decreased the accumulation of phosphorylated -syn pathology and resulted in persistent microgliosis in the striatum when compared to non-transplanted mice. Conclusion: Our work provides evidence that T cells play a role in the pathogenesis of experimental -synucleinopathy.

neuroscience↗