Biology subjects

Winter, C.

Publications and source records attributed to Winter, C..

12 recordsLinked to original sources

bioRxiv2024

Forest dieback in drinking water protection areas - a hidden threat to water quality

For centuries, forests have been considered a natural safeguard for drinking water quality. We challenge this view in light of the rising frequency of climate extremes, such as droughts coinciding with high temperatures, which have caused unprecedented pulses of forest dieback globally. Drought-induced forest diebacks may jeopardize the crucial role of forests in protecting water quality, potentially even turning forests into sources of contamination. To underscore the critical importance of the topic, here we provide the first comprehensive assessment of forest cover, type, and dieback (assessed as canopy cover loss) across drinking Water Protection Areas (WPAs) in Germany, one of the countries hit most severely by the unprecedented Central European drought of 2018-2020. Our findings reveal a high forest cover of 43% in WPAs, from which a substantial amount of 5% canopy cover got lost within only three years as a direct or indirect consequence of the drought. Spruce-dominated forests, constituting 28% of all forests in WPAs, were particularly susceptible, but other dominant tree species also experienced anomalously high mortality rates. Combining this assessment with exemplary records of nitrate concentrations in the groundwater of WPAs revealed that forest dieback can significantly impair drinking quality. On average, nitrate concentrations more than doubled in WPAs with severe forest dieback, whereas nitrate concentrations did not significantly change in undisturbed WPAs. However, we also found pronounced differences between WPAs affected by forest dieback, underlining the need for further data and research to derive a generalizable understanding of the underlying mechanisms and controls. Based on this assessment, we deduce critical data and knowledge gaps essential to developing well-informed prediction, adaptation, and mitigation strategies. We call for interdisciplinary research addressing the hidden threat forest dieback poses for our drinking water resources.

biochemistry↗

bioRxiv2024

Somatic gene delivery for flexible in vivo modeling of high-risk sarcoma

A particular challenge hampering therapeutic advancements for high-risk sarcoma patients is the broad spectrum of molecularly distinct sarcoma entities and the corresponding lack of suitable model systems to recapitulate and study these diseases. To overcome this predicament, we developed a novel genetically-controlled, yet versatile mouse modeling platform allowing delivery of different genetic lesions by electroporation (EPO) of the thigh muscle wildtype mice. This optimized sarcoma EPO-GEMM (EPO-based genetically engineered mouse model) platform allowed the generation of ten biologically distinct sarcoma entities, including Synovial Sarcoma (SS), fusion-positive and fusion-negative Rhabdomyosarcoma (RMS), Alveolar Soft Part Sarcoma (ASPS), Undifferentiated Pleomorphic Sarcoma (UPS) and Infantile Fibrosarcoma (IFS). Comprehensive molecular profiling and cross-species analyses confirmed faithful recapitulation of the human disease, including the expression of relevant immunotherapy targets. Syngeneic allografting enabled reliable preservation and scalability of Sarcoma-EPO-GEMMs for treatment trials, such as B7-H3-directed CAR-T cell therapy in an immunocompetent background.

cancer biology↗

bioRxiv2023

The ER folding sensor UGGT1 acts on TAPBPR-chaperoned peptide-free MHC I

Adaptive immune responses are triggered by antigenic peptides presented on major histocompatibility complex class I (MHC I) at the surface of pathogen-infected or cancerous cells. Formation of stable peptide-MHC I complexes is facilitated by tapasin and TAPBPR, two related MHC I-specific chaperones that catalyze selective loading of suitable peptides onto MHC I in a process called peptide editing or proofreading. On their journey to the cell surface, MHC I complexes must pass a quality control step performed by UGGT1, which senses the folding status of the transiting N-linked glycoproteins in the endoplasmic reticulum (ER). UGGT1 reglucosylates non-native glycoproteins and thereby allows them to revisit the ER folding machinery. Here, we describe a reconstituted in-vitro system of purified human proteins that enabled us to delineate the function of TAPBPR during the UGGT1-catalyzed quality control and reglucosylation of MHC I. By combining glycoengineering with liquid chromatography-mass spectrometry, we show that TAPBPR promotes reglucosylation of peptide-free MHC I by UGGT1. Thus, UGGT1 cooperates with TAPBPR in fulfilling a crucial function in the quality control mechanisms of antigen processing and presentation.

biochemistry↗

bioRxiv2022

B/T cell crosstalk and aberrant inflammatory IgG exacerbate autoimmune intestinal inflammation

Dysregulated B cell responses have been described in inflammatory-bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here described Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1-/-) mice as novel mouse model of spontaneous, chronic colitis modelling human IBD. Concomitant with aberrant IgG production in colonic tissue of Wipf1-/- mice, we identified systemic, hypo-sialylated IgG as drivers of IL-1{beta} production in monocytes. Pathological antibody production was promoted by the hyper-reactivity of Wipf1-/- B cells in response to LPS stimulation, resulting in efficient activation of the MAPK/Erk and mTOR/Akt/4E-BP1 pathways and heightened metabolic activity. In addition to abundant inflammatory IgG, we found that B cells directly promoted the production of pro-inflammatory cytokines by intestinal CD4+ T cells. B/T co-culture assays defined the co-stimulatory molecule CD86 as driver of IFN-{gamma} and GM-CSF production by CD4+ T cells. CD86 expression was further enhanced by the presence of sCD40L, which was elevated in sera of Wipf1-/- mice. Similarly, colonic B cells of IBD patients expressed increased mRNA levels of CD86 correlating with enhanced levels of systemic sCD40L. Together, B cell-mediated pro-inflammatory cytokine secretion and B cell-derived inflammatory antibody production contributed to exacerbated pathogenesis during intestinal inflammation. O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/507066v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1449ae8org.highwire.dtl.DTLVardef@116045borg.highwire.dtl.DTLVardef@77f3f2org.highwire.dtl.DTLVardef@130a271_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryB cells fuel intestinal inflammation

immunology↗

bioRxiv2022

Design of a systemic small molecule clinical STING agonist using physics-based simulations and artificial intelligence

The protein STING (stimulator of interferon genes) is a central regulator of the innate immune system and plays an important role in antitumor immunity by inducing the production of cytokines such as type I interferon (IFN). Activation of STING stems from the selective recognition of endogenous cyclic dinucleotides (CDNs) by the large, polar, and flexible binding site, thus posing challenges to the design of small molecule agonists with drug-like physicochemical properties. In this work we present the design of SNX281, a small molecule STING agonist that functions through a unique self-dimerizing mechanism in the STING binding site, where the ligand dimer approximates the size and shape of a cyclic dinucleotide while maintaining drug-like small molecule properties. SNX281 exhibits systemic exposure, STING-mediated cytokine release, strong induction of type I IFN, potent in vivo antitumor activity, durable immune memory, and single-dose tumor elimination in mouse models via a Cmax-driven pharmacologic response. Bespoke computational methods - a combination of quantum mechanics, molecular dynamics, binding free energy simulations, and artificial intelligence - were developed during the course of the project to design SNX281 by explicitly accounting for the unique self-dimerization mechanism and the large-scale conformational change of the STING protein upon activation. Over the course of the project, we explored millions of virtual molecules while synthesizing and testing only 208 molecules in the lab. This work highlights the value of a multifaceted computationally-driven approach anchored by methods tailored to address target-specific problems encountered along the project progression from initial hit to the clinic.

cancer biology↗

bioRxiv2021

An insight into new glycotherapeutic in glial inflammation: Understanding the role of glycosylation from acute to chronic phase of inflammation

Glycosylation plays a critical role during inflammation and glial scar formation upon spinal cord injury (SCI) disease progression. Astrocytes and microglia are involved in this cascade to modulate the inflammation and tissue remodelling from acute to chronic phases. Therefore, understating the glycan changes in these glial cells is paramount. Herein a lectin microarray was undertaken using a cytokine-driven inflammatory MGC model, revealing considerable differential glycosylation from the acute to the chronic phase in a cytokine-combination generated inflamed MGC model. It was found that several N- and O-linked glycans associated with glia during SCI were differentially regulated. Pearsons correlation hierarchical clustering showed that groups were separated into several clusters, illustrating the heterogenicity among the control, cytokine combination, and LPS treated groups and the day on which treatment was given. Control and LPS treatments were observed to be in dense clusters. This was further confirmed with lectin immunostaining in which GalNAc, GlcNAc, mannose, fucose and sialic acid-binding residues were detected in astrocytes and microglia. However, this modification (upregulation of sialic acid expression) was inhibited by the sialyltransferase inhibitor which indeed modulates the mitochondrial functions. The present study is the first functional investigation of glycosylation modulation in a MGC (MGC) model which elucidates the role of the glycome in neuroinflammation and identified potential therapeutic targets for future glycol-therapeutics in neuroinflammation

neuroscience↗

bioRxiv2021

A multimodal neuroprosthetic interface to record, modulate and classify electrophysiological correlates of cognitive function

Most mental disorders are characterised by impaired cognitive function and behaviour control. Their often chronic reoccurring nature and the lack of efficient therapies necessitate the development of new treatment strategies. Brain-computer interfaces, equipped with multiple sensing and stimulation abilities, offer a new toolbox, whose suitability for diagnosis and therapy of mental disorders has not yet been explored. Here, we developed a soft and multimodal neuroprosthesis to measure and modulate prefrontal neurophysiological features of neuropsychiatric symptoms. We implanted the device epidurally above the medial prefrontal cortex of rats and obtained auditory event-related brain potentials reflecting intact neural stimulus processing and alcohol-induced neural impairments. Moreover, implant-driven electrical and pharmacological stimulation enabled successful modulation of neural activity. Finally, we developed machine learning algorithms which can deal with sparsity in the data and distinguish effects with high accuracy. Our work underlines the potential of multimodal bioelectronic systems to enable a personalised and optimised therapy.

neuroscience↗

bioRxiv2020

Comparison of manual and automated ventricle segmentation in the maternal immune stimulation rat model of schizophrenia

Maternal immune stimulation (MIS) is strongly implicated in the etiology of neuropsychiatric disorders. Magnetic resonance imaging (MRI) studies provide evidence for brain structural abnormalities in rodents following prenatal exposure to MIS. Reported volumetric changes in adult MIS offspring comprise among others larger ventricular volumes, consistent with alterations found in patients with schizophrenia. Linking rodent models of MIS with non-invasive small animal neuroimaging modalities thus represents a powerful tool for the investigation of structural endophenotypes. Traditionally manual segmentation of regions-of-interest, which is laborious and prone to low intra- and inter-rater reliability, was employed for data analysis. Recently automated analysis platforms in rodent disease models are emerging. However, none of these has been found to reliably detect ventricular volume changes in MIS nor directly compared manual and automated data analysis strategies. The present study was thus conducted to establish an automated, structural analysis method focused on lateral ventricle segmentation. It was applied to ex-vivo rat brain MRI scans. Performance was validated for phenotype induction following MIS and preventive treatment data and compared to manual segmentation. In conclusion, we present an automated analysis platform to investigate ventricular volume alterations in rodent models thereby encouraging their preclinical use in the search for new urgently needed treatments.

neuroscience↗

bioRxiv2020

The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome

Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. Within the Sweden Cancerome Analysis Network-Breast project (SCAN-B; ClinicalTrials.gov NCT02306096), an ongoing study elucidating the tumor transcriptomic profiles for thousands of breast cancers prospectively, we developed an optimized pipeline for detection of single nucleotide variants and small insertions and deletions from RNA sequencing (RNA-seq) data, and profiled a large real-world population-based cohort of 3,217 breast tumors. We use it to describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population-based cohort of patients, and relate it to patient overall survival. We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such as PIK3CA, TP53, and ERBB2, as well as the status of key molecular pathways and tumor mutational burden, and identify potentially druggable genes in 86.8% percent of tumors. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source web-based application, the SCAN-B MutationExplorer, accessible at http://oncogenomics.bmc.lu.se/MutationExplorer. These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling.

cancer biology↗

bioRxiv2019

Social hierarchy regulates ocular dominance plasticity in adult male mice.

We here show that social rank, as assessed by competition for a running wheel, influences ocular dominance plasticity in adult male mice. Dominant animals showed a clear ocular dominance shift after four days of MD, whereas their submissive cage mates did not. NMDA receptor activation, reduced GABA inhibition, and serotonin transmission were necessary for this plasticity, but not sufficient to explain the difference between dominant and submissive animals. In contrast, prefrontal dopamine concentration was higher in dominant than submissive mice, and systemic manipulation of dopamine transmission bidirectionally changed ocular dominance plasticity. Thus, we could show that a social hierarchical relationship influences ocular dominance plasticity in the visual cortex via higher-order cortices, most likely the medial prefrontal cortex. Further studies will be needed to elucidate the precise mechanisms by which this regulation takes place.

neuroscience↗

bioRxiv2018

Cross-modal restoration of juvenile-like ocular dominance plasticity after increasing GABAergic inhibition

In juvenile and \"young adult\" mice monocular deprivation (MD) shifts the ocular dominance (OD) of binocular neurons in the primary visual cortex (V1) away from the deprived eye. However, OD plasticity is completely absent in mice older than 110 days, but can be reactivated by treatments which decrease GABA levels in V1. Typically, these OD shifts can be prevented by increasing GABAergic transmission with diazepam. We could recently demonstrate that both bilateral whisker and auditory deprivation (WD, AD), can also restore OD plasticity in mice older than 110 days, since MD for 7 days in WD mice caused a potentiation of V1 input through the ipsilateral (open) eye, the characteristic feature of OD plasticity of \"young adult\" mice. Here we examined whether WD for 7 days also decreases GABA levels. For this, we performed post mortem HPLC analysis of V1 tissue. Indeed, we found that WD significantly decreased GABA levels in V1. Surprisingly, enhancing GABAergic inhibition by diazepam did not abolish OD shifts in WD mice, as revealed by repeated intrinsic signal imaging. On the contrary, this treatment led to a depression of V1 input through the previously closed contralateral eye, the characteristic signature of OD plasticity in juvenile mice during the critical period. Interestingly, the same result was obtained after AD. Taken together, these results suggest that cross-modally restored OD plasticity does not only depend on reduction of GABA levels in V1, but also requires other, so far unknown mechanisms.

neuroscience↗

bioRxiv2018

Visual deprivation independent shift of ocular dominance induced by cross-modal plasticity

There is convincing evidence that the deprivation of one sense can lead to adaptive neuronal changes in the spared primary sensory cortices. However, the repercussions of late-onset sensory deprivations on functionality of the remaining sensory cortices are poorly understood. Using repeated intrinsic signal imaging we investigated the effects of whisker or auditory deprivation (WD or AD, respectively) on responsiveness of the binocular primary visual cortex (V1) in fully adult mice. The binocular zone of mice is innervated by both eyes, with the contralateral eye always dominating V1 input over ipsilateral eye input, the normal ocular dominance (OD) ratio. Strikingly, we found that 3 days after WD or AD there was a transient shift of OD, which was mediated by a potentiation of V1 input through the ipsilateral eye. This cross-modal effect was accompanied by strengthening of V1 layer 4 synapses, required visual experience through the ipsilateral eye and was mediated by an increase of the excitation/inhibition ratio in V1. Finally, we demonstrate that both WD and AD induced a long-lasting improvement of visual performance. Our data provide evidence that the deprivation of a non-visual sensory modality cross-modally induces experience dependent V1 plasticity and improves visual behavior, even in adult mice.

neuroscience↗