Biology subjects

Schmid, R.

Publications and source records attributed to Schmid, R..

At least 19 recordsLinked to original sources

bioRxiv2025

Novel peptide targeting CXCR4 disrupt tumor-stroma crosstalk to eliminate migrating cancer stem cells

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and metastatic malignancies worldwide. Migrating cancer stem cells (miCSCs) marked by CD133+CXCR4+ expression drives metastasis but lacks effective drug targets. Here, we show that activated pancreatic stellate cells secrete the CXCR4 ligand CXCL12 to foster stemness, epithelial-to-mesenchymal transition (EMT), and chemoresistance. Protein interaction network analyses links CXCL12/CXCR4 signaling axis and the downstream transcription factor BMI1. Knockdown experiments confirmed the BMI1s role in (mi)CSCs maintenance and survival. Novel CXCR4 inhibitors, i.e., the endogenous human peptide EPI-X4 and its derivatives (e.g., JM#21) strongly inhibited the in vitro migration of miCSCs. In particular, the most potent EPI-X4 derivate JM#21 sufficiently suppressed EMT, stemness, and self-renewal of human PDAC cell lines. In addition, JM#21 sensitized cell lines towards gemcitabine and paclitaxel. Overall, our study reveals that (mi)CSCs are enhanced and maintained via a tumor-stroma crosstalk through BMI1, ultimately promoting metastases and therapeutic resistance in PDAC. Peptide targeting of the CXCL12/CXCR4/BMI1 signaling axis via JM#21 could enhance PDAC combination therapies, offering a promising strategy against this deadly cancer. SynopsisThe study identifies a tumor-stroma interaction mediated by pancreatic stellate cells (PSCs) secreting CXCL12, which binds to CXCR4 on (mi)CSCs, fostering stemness, epithelial-to-mesenchymal transition (EMT), and chemoresistance. The CXCL12/CXCR4 axis activates the downstream BMI1 transcription factor, crucial for migration and stemness maintenance. O_FIG O_LINKSMALLFIG WIDTH=173 HEIGHT=200 SRC="FIGDIR/small/641126v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@14e117org.highwire.dtl.DTLVardef@c5db35org.highwire.dtl.DTLVardef@1ba7d2dorg.highwire.dtl.DTLVardef@702ccf_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LICXCL12 enhances (mi)CSC populations and metastatic potential through CXCR4 signaling. C_LIO_LIBMI1 is identified as a pivotal downstream effector linking CXCR4 to EMT and stemness. C_LIO_LIJM#21 effectively blocks CXCL12-induced migration, EMT, and stemness in vitro, demonstrating superior efficacy compared to other CXCR4 inhibitors. C_LIO_LIEncapsulation of JM#21 in silica nanoparticles enhances its stability and delivery, reducing chemoresistance and miCSC populations in co-culture systems. C_LIO_LICombining JM#21 with chemotherapy significantly impairs colony formation and CSC-mediated drug resistance. C_LI

cancer biology↗

bioRxiv2024

Empirically establishing drug exposure records directly from untargeted metabolomics data

Despite extensive efforts, extracting information on medication exposure from clinical records remains challenging. To complement this approach, we developed the tandem mass spectrometry (MS/MS) based GNPS Drug Library. This resource integrates MS/MS data for drugs and their metabolites/analogs with controlled vocabularies on exposure sources, pharmacologic classes, therapeutic indications, and mechanisms of action. It enables direct analysis of drug exposure and metabolism from untargeted metabolomics data independent of clinical records. Our library facilitates stratification of individuals in clinical studies based on the empirically detected medications, exemplified by drug-dependent microbiota-derived N-acyl lipid changes in a cohort with human immunodeficiency virus. The GNPS Drug Library holds potential for broader applications in drug discovery and precision medicine.

bioinformatics↗

bioRxiv2024

Microbiota metabolized Bile Acids accelerate Gastroesophageal Adenocarcinoma via FXR inhibition

BackgroundThe incidence of Barrett esophagus (BE) and Gastroesophageal Adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BA) support fat digestion and undergo microbial metabolization in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. The capacity of inhibiting cancer-related processes when activated, make FXR an appealing therapeutic target. In this work, we assess the role of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression. ResultsHere we show that high fat diet (HFD) accelerated tumorigenesis in L2-IL1B mice (BE- and GEAC- mouse model) while increasing BA levels and enriching gut microbiota that convert primary to secondary BA. While upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine organoids and L2-IL1B mice with the FXR agonist obeticholic acid (OCA) deacelerated GEAC progression. ConclusionWe provide a novel concept of GEAC carcinogenesis being accelerated via the diet-microbiome-metabolome axis and FXR inhibition on progenitor cells. Further, FXR activation protected with OCA ameliorated the phenotype in vitro and in vivo, suggesting that FXR agonists have potential as differentiation therapy in GEAC prevention. Statement of significanceIf its inhibition is linked to disease progression and its activation to cancer prevention, exploring the potential of FXR as a therapeutic target has great clinical relevance in GEAC context.

cancer biology↗

bioRxiv2024

plantMASST - Community-driven chemotaxonomic digitization of plants

Understanding the distribution of hundreds of thousands of plant metabolites across the plant kingdom presents a challenge. To address this, we curated publicly available LC-MS/MS data from 19,075 plant extracts and developed the plantMASST reference database encompassing 246 botanical families, 1,469 genera, and 2,793 species. This taxonomically focused database facilitates the exploration of plant-derived molecules using tandem mass spectrometry (MS/MS) spectra. This tool will aid in drug discovery, biosynthesis, (chemo)taxonomy, and the evolutionary ecology of herbivore interactions.

plant biology↗

bioRxiv2024

KRas, in addition to Tp53 is a driver for early carcinogenesis and a molecular target in a mouse model of invasive gastro-esophageal adenocarcinoma

ObjectiveThe incidence of gastro-esophageal adenocarcinoma (GEAC) has increased dramatically and is associated with Barretts Esophagus (BE). Gastric cardia progenitors are the likely origin for BE and GEAC. Here we analyze p53, Rb1 and Kras alterations in Lgr5 progenitor cells during carcinogenesis. DesignWe introduced single and combined genetic alterations (p53, Rb1 and Kras) in Lgr5-expressing progenitor cells at the inflamed gastroesophageal junction in the L2-IL1b (L2) mouse model crossed to Lgr5-CreERTmice. For in-vitro treatment we utilized mouse and human 3D organoids. ResultsInactivation of Tp53 or Rb1 alone (L2-LP and L2-LR mice) resulted in metaplasia, and mild dysplasia, while expression of KrasG12D (L2-LK) accelerated dysplasia in L2-IL1b mice. Dual induction of genetic alteration in L2-LPR, L2-LKP and L2-LKR mice confirmed the accelerating role of mutant Kras, with the development of invasive cancer in mice with combined Tp53 and Kras alteration. All three genetic events in cardia progenitor cells generated invasive cancer at 6 months of age, with chromosomal instability (CNV). The dominant role of Kras prompted us to treat with a SHP2 inhibitor in combination with an ERK or MEK inhibitor, leading to reduced growth in Kras mutant organoids. SHP2 and MEK inhibition in-vivo reduced Kras dependent tumor formation. ConclusionIn the first invasive GEAC mouse model, Kras mutation in combination with loss of tumor suppressor genes Tp53 or Rb1 emerges as a key player in GEAC and with importance of p53 and Rb1 in promoting metaplasia. Targeting this SHP2/MEK/KRAS pathway represents a promising therapeutic option for Kras altered GEAC. What is already known on this topicThe increased incidence of GEAC is challenging current screening and surveillance strategies. Therapeutic and preventive options are limited due to a lack of knowledge on the role of genetic alterations commonly associated with GEAC and their function during progression to dysplasia. What this study addsWe generate the first invasive GEAC model and show that KRAS at least in combination with a second genetic alterations (Tp53 and/or Rb1) may be a driver of tumorigenesis, and targeting KRAS alterations could be a promising now treatment substitution. How this study might affect research, practice or policyTargeting KRAS alterations will be important for GEAC, especially as specific KRAS inhibitor are on the horizon. In addition, a concept of single genetic alteration inducing metaplasia as an adaptation to chronic inflammation might emerge as an important factor for surveillance.

cancer biology↗

bioRxiv2023

A Taxonomically-informed Mass Spectrometry Search Tool for Microbial Metabolomics Data

MicrobeMASST, a taxonomically-informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbial-derived metabolites and relative producers, without a priori knowledge, will vastly enhance the understanding of microorganisms role in ecology and human health.

microbiology↗

bioRxiv2023

A multi-omics strategy for the study of microbial metabolism: application to the human skin's microbiome

Although metabolomics data acquisition and analysis technologies have become increasingly sophisticated over the past 5-10 years, deciphering a metabolites function from a description of its structure and its abundance in a given experimental setting is still a major scientific and intellectual challenge. To point out ways to address this data to knowledge challenge, we developed a functional metabolomics strategy that combines state-of-the-art data analysis tools and applied it to a human scalp metabolomics dataset: Skin swabs from healthy volunteers with normal or oily scalp (Sebumeter score 60-120, n = 33; Sebumeter score > 120, n = 41) were analyzed by LC-MS/MS, yielding four metabolomics datasets for RP18 or HILIC separation in ESI+ or ESI- ionization mode. Following our data analysis strategy, we were able to obtain increasingly comprehensive structural and functional annotations, by applying the GNPS (Wang et al., Nat. Biotechnol. 2016), SIRIUS (Duhrkop et al. Nat. Methods 2019), and MicrobeMASST (Zuffa et al., bioRxiv 2023) tools. We finally combined the metabolomics data with a corresponding metagenomic sequencing dataset using MMvec (Morton et al., Nat. Methods 2019), gaining insights into the metabolic niche of one of the most prominent microbes on the human skin, Staphylococcus epidermidis. IMPORTANCESystems biology research on host-associated microbiota focuses on two fundamental questions: Which microbes are present and how do they interact with each other, their host, and the broader host environment? Metagenomics provides us with a direct answer to the first part of the question: it unveils the microbial inhabitants, e.g., on our skin, and can provide insight into their functional potential. Yet, it falls short in revealing their active role. Metabolomics shows us the chemical composition of the environment in which microbes thrive and the transformation products they produce. In particular, untargeted metabolomics has the potential to observe a diverse set of metabolites and is thus an ideal complement to metagenomics. However, this potential often remains underexplored due to the low annotation rates in MS-based metabolomics and the necessity for multiple experimental chromatographic and mass spectrometric conditions. Beyond detection, prospecting metabolites functional role in the host/microbiome metabolome requires identifying the biological processes and entities involved in their production and biotransformations. In the present study of the human scalp, we developed a strategy to achieve comprehensive structural and functional annotation of the metabolites in the human scalp environment, thus diving one step deeper into the interpretation of omics data. Leveraging a collection of openly accessible software tools and integrating microbiome data as a source of functional metabolite annotations, we finally identified the specific metabolic niche of Staphylococcus epidermidis, one of the key players of the human skin microbiome.

systems biology↗

bioRxiv2022

Enhanced surface nano-analytics of transient biomolecular processes

The study of the physical and chemical properties of biomolecules enables the characterisation of fundamental molecular processes and mechanisms in health and disease. Bulk and single-molecule analytical methods provide rich information on biomolecules, but often require high concentrations and sample preparation away from physiologically relevant conditions. Here, we present the development and application of a lab-on-a-chip approach which combines rapid sample preparation, mixing and deposition to integrate with a range of nano-analytical methods in chemistry and biology, providing enhanced sensitivity and single molecule resolution. We demonstrate that this method empowers multidimensional study of heterogenous biomolecular systems in physiological buffers and concentrations over multiple length scales by nanoscopy and vibrational spectroscopy. We illustrate the capabilities of this platform by capturing and analysing the structural conformations of transient oligomeric species formed at the early stages of the self-assembly of -synuclein, which are associated with the onset of Parkinsons disease. TEASERMaintaining the heterogeneity and structural integrity of monomers and oligomers enables their quantitative study.

biophysics↗

bioRxiv2022

Comparison of Cosine, Modified Cosine, and Neutral Loss Based Spectral Alignment For Discovery of Structurally Related Molecules

Spectrum alignment of tandem mass spectrometry (MS/MS) data using the modified cosine similarity and subsequent visualization as molecular networks have been demonstrated to be a useful strategy to discover analogs of molecules from untargeted MS/MS-based metabolomics experiments. Recently, a neutral loss matching approach has been introduced as an alternative to MS/MS-based molecular networking, with an implied performance advantage in finding analogs that cannot be discovered using existing MS/MS spectrum alignment strategies. To comprehensively evaluate the scoring properties of neutral loss matching, the cosine similarity, and the modified cosine similarity, similarity measures of 955,228 peptide MS/MS spectrum pairs and 10 million small molecule MS/MS spectrum pairs were compared. This comparative analysis revealed that the modified cosine similarity outperformed neutral loss matching and the cosine similarity in all cases. The data further indicated that the performance of MS/MS spectrum alignment depends on the location and type of the modification, as well as the chemical compound class of fragmented molecules.

bioinformatics↗

bioRxiv2022

Open Access Repository-Scale Propagated Nearest Neighbor Suspect Spectral Library for Untargeted Metabolomics

Despite the increasing availability of tandem mass spectrometry (MS/MS) community spectral libraries for untargeted metabolomics over the past decade, the majority of acquired MS/MS spectra remain uninterpreted. To further aid in interpreting unannotated spectra, we created a nearest neighbor suspect spectral library, consisting of 87,916 annotated MS/MS spectra derived from hundreds of millions of public MS/MS spectra. Annotations were propagated based on structural relationships to reference molecules using MS/MS-based spectrum alignment. We demonstrate the broad relevance of the nearest neighbor suspect spectral library through representative examples of propagation-based annotation of acylcarnitines, bacterial and plant natural products, and drug metabolism. Our results also highlight how the library can help to better understand an Alzheimers brain phenotype. The nearest neighbor suspect spectral library is openly available through the GNPS platform to help investigators hypothesize candidate structures for unknown MS/MS spectra in untargeted metabolomics data.

bioinformatics↗

bioRxiv2021

Geometrical frustration of phase-separated domains in Coscinodiscus diatom frustules

Diatoms are single-celled organisms with a cell wall made of silica, called the frustule. Even though their elaborate patterns have fascinated scientists for years, little is known about the biological and physical mechanisms underlying their organization. In this work, we take a top-down approach and examine the micron-scale organization of diatoms from the Coscinodiscus family. We find two competing tendencies of organization, which appear to be controlled by distinct biological pathways. On one hand, micron-scale pores organize locally on a triangular lattice. On the other, lattice vectors tend to point globally toward a center of symmetry. This competition results in a frustrated triangular lattice, populated with geometrically necessary defects whose density increases near the center.

biophysics↗

bioRxiv2021

Pulmonary mesenchymal stem cells are engaged in distinct steps of host response to respiratory syncytial virus infection

Lung-resident (LR) mesenchymal stem and stromal cells (MSCs) are key elements of the alveolar niche and fundamental regulators of homeostasis and regeneration. We interrogated their function during virus-induced lung injury using the highly prevalent respiratory syncytial virus (RSV) which causes severe outcomes in infants. We applied complementary approaches with primary pediatric LR-MSCs and a state-of-the-art model of human RSV infection in lamb. Remarkably, RSV-infection of pediatric LR-MSCs led to a robust activation, characterized by a strong antiviral and pro-inflammatory phenotype combined with mediators related to T cell function. In line with this, following in vivo infection, RSV invades and activates LR-MSCs, resulting in the expansion of the pulmonary MSC pool. Moreover, the global transcriptional response of LR-MSCs appears to follow RSV disease, switching from an early antiviral signature to repair mechanisms including differentiation, tissue remodeling, and angiogenesis. These findings demonstrate the involvement of LR-MSCs during virus-mediated acute lung injury and may have therapeutic implications. AUTHOR SUMMARYThis work identifies a novel function of lung-resident MSCs during virus-induced acute lung injury. These findings contribute to the understanding of host response and lung repair mechanisms during a highly prevalent clinical situation and may have therapeutic implications.

microbiology↗

bioRxiv2021

GNPS Dashboard: Collaborative Analysis of Mass Spectrometry Data in the Web Browser

Access to web-based platforms has enabled scientists to perform research remotely. A critical aspect of mass spectrometry data analysis is the inspection, analysis, and visualization of the raw data to validate data quality and confirm statistical observations. We developed the GNPS Dashboard, a web-based data visualization tool, to facilitate synchronous collaborative inspection, visualization, and analysis of private and public mass spectrometry data remotely.

bioinformatics↗

bioRxiv2020

The effect of pasture management on fire ant, Solenopsis invicta (Hymenoptera: Formicidae), abundance and the relationship to arthropod community diversity

The red imported fire ant, Solenopsis invicta, is one of the most prolific invasive species to the Southeastern U.S. These invaders preferentially colonize highly disturbed land and grassland habitat. Management of livestock in pasture systems can have a profound impact on the level of disturbance in grassland habitats, and we hypothesized that pasture management would have a significant effect on S. invicta abundance in the Southeastern U.S., and arthropod diversity would negatively correlate with this invasive species. We studied the effects that pasture management systems (based on stocking density, rotation frequency, and insecticide application rates) have on fire ant mound abundance and arthropod diversity for the soil, foliar, and dung communities. S. invicta mounds were quantified and mound areas were documented along transect lines in six pastures. Soil and foliar arthropod communities were collected along the same transect lines, and dung communities sampled from pats within the pasture system. Pastures managed under adaptive multi-paddock (AMP) practices had 3.35x more S. invicta mounds and 4.64x more mound area than their conventionally managed counterparts. However, arthropod diversity did not correlate with S. invicta abundance for any of the three arthropod communities sampled. This study shows pasture management can have a significant impact on S. invicta mound abundance, but arthropod communities in AMP managed pastures did not suffer decreased diversity from increased abundance of S. invicta. Additionally, this study demonstrates that this invasive species does not necessarily contribute to diversity decline, at least under AMP pasture systems.

ecology↗

bioRxiv2020

Ion Identity Molecular Networking in the GNPS Environment

Molecular networking connects tandem mass spectra of molecules based on the similarity of their fragmentation patterns. However, during ionization, molecules commonly form multiple ion species with different fragmentation behavior. To connect ion species of the same molecule, we developed Ion Identity Molecular Networking. These new relationships improve network connectivity, are shown to reveal novel ion-ligand complexes, enhance annotation within molecular networks, and facilitate the expansion of spectral libraries.

bioinformatics↗

bioRxiv2019

Native Electrospray-based Metabolomics Enables the Detection of Metal-binding Compounds

Metals are essential for the molecular machineries of life, and microbes have evolved a variety of small molecules to acquire, compete for, and utilize metals. Systematic methods for the discovery of metal-small molecule complexes from biological samples are limited. Here we describe a two-step native electrospray ionization mass spectrometry method, in which double-barrel post-column metal-infusion and pH adjustment is combined with ion identity molecular networking, a rule-based informatics workflow. This method can be used to identify metal-binding compounds in complex samples based on defined mass (m/z) offsets of ion features with the same chromatographic profiles. As this native metal metabolomics approach can be easily implemented on any liquid chromatography-based mass spectrometry system, this method has the potential to become a key strategy for elucidating and understanding the role of metal-binding molecules in biology.

biochemistry↗

bioRxiv2019

Feature-based Molecular Networking in the GNPS Analysis Environment

Molecular networking has become a key method used to visualize and annotate the chemical space in non-targeted mass spectrometry-based experiments. However, distinguishing isomeric compounds and quantitative interpretation are currently limited. Therefore, we created Feature-based Molecular Networking (FBMN) as a new analysis method in the Global Natural Products Social Molecular Networking (GNPS) infrastructure. FBMN leverages feature detection and alignment tools to enhance quantitative analyses and isomer distinction, including from ion-mobility spectrometry experiments, in molecular networks.

bioinformatics↗

bioRxiv2019

Volume and intramuscular fat content of upper extremity muscles in individuals with chronic hemiparetic stroke

Stroke survivors often experience upper extremity deficits that make activities of daily living (ADLs) like dressing, cooking and bathing difficult or impossible. Survivors experience paresis, the inability to efficiently and fully activate muscles, which combined with decreased use of the upper extremity, will lead to muscle atrophy and potentially an increase in intramuscular fat. Muscle atrophy has been linked to weakness post stroke and is an important contributor to upper extremity deficits. However, the extent of upper extremity atrophy post hemiparetic stroke is unknown and a better understanding of these changes is needed to inform the direction of intervention-based research. In this study, the volume of contractile tissue and intramuscular fat in the elbow and wrist flexors and extensors were quantified in the paretic and non-paretic upper limb using MRI and the Dixon technique for the first time. Total muscle volume (p[≤]0.0005) and contractile element volume (p[≤]0.0005) were significantly smaller in the paretic upper extremity, for all muscle groups studied. The average percent difference between limbs and across participants was 21.3% for muscle volume and 22.9% for contractile element volume. We also found that while the percent intramuscular fat was greater in the paretic limb compared to the non-paretic (p[≤]0.0005), however, the volume of intramuscular fat was not significantly different between upper limbs (p=0.231). The average volumes of intramuscular fat for the elbow flexors/extensors and wrist flexors/extensors were 28.1, 28.8 and 19.9, 8.8 cm3 in the paretic limb and 29.6, 27.7 and 19.7, 8.8 cm3 in the non-paretic limb. In short, these findings indicate a decrease in muscle volume and not an increase in intramuscular fat, which will contribute to the reduction in strength in the paretic upper limb.

bioengineering↗