Biology subjects

Vogel, C.

Publications and source records attributed to Vogel, C..

At least 19 recordsLinked to original sources

bioRxiv2025

Tight translation regulation of the canonical C9ORF72 through a multi-component system

C9ORF72 is involved in multiple neuronal functions and a major factor in Amyotrophic Lateral Sclerosis, a fatal neurodegenerative disease. Pathogenicity is implemented through an intronic repeat expansion in the genes mRNA leader that produces long, repetitive RNA and dipeptides when translated through a non-canonical mechanism. In contrast, despite the presence of ribosome-occupied, regulatory elements in the mRNA leader, nothing is known about C9ORF72 translation regulation under normal conditions. Surprisingly, when analyzing a series of mutants of the C9ORF72 mRNA leader, we found that translation of C9ORF72 is tightly regulated through a multi-layer system. First, non-canonical, multi-initiation upstream open reading frames (nc-uORFs) in all three frames, a start-stop element in frame 2, and a canonical uORF in frame 1work together to keep baseline C9ORF72 translation very low. Second, a strong secondary structure enhances these repressive elements, mainly the two nc-uORFs in frames 0 and 2. Finally, as initiation at the nc-uORFs reduces initiation at the downstream start-stop, the nc-uORFs effectively dampen the start-stops repressive function, forming a feedforward loop. We hypothesize that this buffered repressor system has likely evolved to ensure reliable, noise-insensitive expression of this critical regulator of neuronal function.

molecular biology↗

bioRxiv2025

Telmisartan and Lisinopril Show Potential Benefits in Rescuing Cognitive-Behavioral Function Despite Limited Improvements in Neuropathological Outcomes in Tg-SwDI Mice

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease that results from beta-amyloid (A{beta}) accumulation in the vessel walls that is associated with cognitive impairment and other neurological pathologies. There are currently no medications approved to treat CAA. This study investigated whether renin-angiotensin system (RAS)-targeting drugs, commonly prescribed to treat hypertension, can be repurposed to treat CAA, and whether their effects differ by sex. Male and female Tg-SwDI mice were treated for 5 months with sub-depressor doses of either telmisartan [angiotensin II receptor blocker (ARB)] or lisinopril [angiotensin-converting enzyme (ACE) inhibitor] starting at 3 months of age. Blood pressure monitoring was performed 2 and 4 months after the start of treatment, followed by behavior testing at 7 months of age. Histochemical analyses were conducted to determine vasculopathy, A{beta} pathology, and neuroinflammation (microgliosis and astrogliosis). Outcomes in drug-treated and untreated Tg-SwDI mice were compared to each other and with wild-type (C57BL/6J) controls. Overall, both drugs were able to rescue some cognitive-behavioral functions; however, no reductions in A{beta} levels were observed, and only limited improvements in vascular density and neuroinflammatory markers were detected. Notably, some treatment effects varied with sex, the specific behavioral task, and the brain region analyzed. These findings support the hypothesis that RAS-targeting drugs exert neuroprotective effects through mechanisms beyond blood pressure control offering a promising therapeutic avenue for CAA.

neuroscience↗

bioRxiv2025

Ketogenic Diet Enhances Cognitive-Behavioral Function and Hippocampal Neurogenesis While Attenuating Amyloid Pathology in Tg-SwDI Mice

The ketogenic diet (KD), characterized by high-fat, low-carbohydrate, and moderate protein intake, has gained attention for its therapeutic potential in patients with neurodegenerative diseases, including Alzheimers disease. Studies in Alzheimers rodent models report that KD and/or ketogenic supplements attenuate cognitive-behavioral impairments, neuroinflammation, amyloid-beta plaques and tau pathology. However, it is unknown whether KD can similarly benefit individuals with cerebral amyloid angiopathy (CAA), a prevalent condition in which amyloid accumulates in cerebral vessels. CAA is highly comorbid in patients with Alzheimers and, on its own, increases the risk of stroke, cognitive impairment, and dementia, yet no effective treatments currently exist. The objective of this study was to determine whether KD can improve cognitive-behavioral and neuropathological outcomes in a mouse model with CAA. Male Tg-SwDI mice were fed either a standard chow or KD from 3.5 to 7.5 months of age. Following [~]3 months of dietary intervention, glucose and ketone-body levels were assessed, then mice underwent a battery of behavioral tests to evaluate locomotor activity, anxiety-related behaviors, and cognition. Immunohistochemistry was performed to assess amyloid pathology, vascular density, neuroinflammation, white matter integrity, and hippocampal neurogenesis. In addition to KD inducing nutritional ketosis and achieving metabolic benefits, mice on KD exhibited increased activity, enhanced spatial learning and memory, and a trend toward improved spatial working memory. These cognitive benefits were accompanied by an attenuation of amyloid pathology and increased hippocampal neurogenesis. These findings suggest that a ketogenic diet may be safe and effective in Alzheimers and dementia patients with CAA.

neuroscience↗

bioRxiv2024

Different hydrological conditions after permafrost thaw result in distinct microbial community compositions

Permafrost degradation leads to the formation of contrasting hydrological conditions such as water-saturated anoxic and dry oxic soils, which significantly influence the bacterial community structure and abundance. To investigate the bacterial abundance and diversity under these hydrological conditions, we collected soil samples from different horizons of both dry and wet degraded permafrost soils and non-degraded intact permafrost soil for comparison. The bacterial alpha diversity, measured by the Observed and Chao1 indices, was significantly greater in wet degraded permafrost soil (wet site) and intact permafrost soil (intact site) than in dry degraded permafrost soils (dry site). Notably, the wet and intact sites exhibited similar levels of alpha diversity as well as shared greater number of zOTUs. The relative proportion of most bacterial taxa was significantly differed among the sites. At the class level, dry site was dominated mainly by K-strategic bacteria like aliphatic degraders (Thermoleophilia), acidophilic and cellulolytic (Acidobacteriae), while wet site was dominated by mainly r-strategic bacteria from class Gammaproteobacteria and anoxygenic aerobic phototrophs (Gemmatimonadetes). According to Spearman correlation analysis, the relative proportion of bacterial taxa in dry and wet sites showed significant correlation with soil physicochemical parameters, whereas fewer correlations were found in intact site. The relative proportion of Pseudomonadota classes and Acidobacteriota were positively correlated with SOC, N, and C:N ratio, but were negatively correlated with pH in both dry and wet sites. In contrast, anaerobic methylotrophs (Methylomirabilota), anoxygenic photoheterotrops (Chloroflexota), Gemmatimonadota and filamentous Actinobacteriota were negatively correlated with SOC, N, and C:N. Additionally, strong correlations were observed between bacterial taxa and extracellular enzyme activities, where Alphaproteobacteria, Gammaproteobacteria, and Acidobacteriota showed positive correlations with both hydrolytic and oxidative enzymes in dry and wet sites, except for PerOx in wet site where they showed negative correlation. Conversely, Gemmatimonadota and Actinobacteriota displayed negative correlations with enzymes in dry and wet site, except for the PerOx in wet site, where they showed positive correlation.

ecology↗

bioRxiv2024

Stick together: Isolation and characterization of exopolysaccharide producing bacteria from degraded permafrost soils

Bacterial exopolysaccharides (EPSs) are the high-molecular-weight polymers secreted into their surrounding that play a crucial role in bacterial survival, environmental adaptation, biofilms formation, and interaction with surrounding matrices. EPSs may also contribute to soil structure development by enhancing soil aggregate stability, promoting soil cohesion, and interacting with soil particles through their diverse functional group constituents and conditioning film characteristics. This study aimed to isolate and characterize potential EPSs-producing bacteria from the active layer of two different hydrological landscape of degraded permafrost soils, and from undisturbed intact permafrost soil. A total of 54 bacterial isolates were obtained, representing three phyla: Firmicutes, Actinomycetota, and Pseudomonadota. EPSs production was assessed by determining the polysaccharide content measured as glucose equivalent, and 26 isolates were identified as potential EPSs producers. Among the isolates, Curtobacterium oceanosedimentum, Frigoribacterium faeni, Streptomyces strains, Neobacillus bataviensis and Mesobacillus subterraneus exhibited the highest polysaccharide yield. The carbohydrate content of the extracted EPSs varied in both composition and quantity across the different isolates. Uronic acids such as glucuronic acid was found in the EPSs produced by the isolates closely related to Curtobacterium oceanosedimentum and Neobacillus bataviensis, while the amino hexoses were identified in EPSs extracted from various isolates, including those affiliated with Bacillus, Streptomyces, Luteimonas, and Phyllobacterium. The potential EPSs producing bacteria were also found inhabiting in the different horizons of both degraded permafrost soil and undisturbed intact permafrost soil, by determining their relative proportion within the total bacterial community based on 16S rRNA gene sequences similarities.

microbiology↗

bioRxiv2024

Patient Subtyping Analysis of Baseline Multi-omic Data Reveals Distinct Pre-immune States Predictive of Vaccination Responses

Understanding the molecular mechanisms that underpin diverse vaccination responses is a critical step toward developing efficient vaccines. Molecular subtyping approaches can offer valuable insights into the heterogeneous nature of responses and aid in the design of more effective vaccines. In order to explore the molecular signatures associated with the vaccine response, we analyzed baseline transcriptomics data from paired samples of whole blood, proteomics and glycomics data from serum, and metabolomics data from urine, obtained from influenza vaccine recipients (2019-2020 season) prior to vaccination. After integrating the data using a network-based model, we performed a subtyping analysis. The integration of multiple data modalities from 62 samples resulted in five baseline molecular subtypes with distinct molecular signatures. These baseline subtypes differed in the expression of pre-existing adaptive or innate immunity signatures, which were linked to significant variation across subtypes in baseline immunoglobulin A (IgA) and hemagglutination inhibition (HAI) titer levels. It is worth noting that these significant differences persisted through day 28 post-vaccination, indicating the effect of initial immune state on vaccination response. These findings highlight the significance of interpersonal variation in baseline immune status as a crucial factor in determining vaccine response and efficacy. Ultimately, incorporating molecular profiling could enable personalized vaccine optimization.

immunology↗

bioRxiv2023

Stem-loop induced ribosome queuing in the uORF2/ATF4 overlap fine-tunes stress-induced human ATF4 translational control

ATF4 is a master transcriptional regulator of the integrated stress response leading cells towards adaptation or death. ATF4s induction under stress was thought to be mostly due to delayed translation reinitiation, where the reinitiation-permissive uORF1 plays a key role. Accumulating evidence challenging this mechanism as the sole source of ATF4 translation control prompted us to investigate additional regulatory routes. We identified a highly conserved stem-loop in the uORF2/ATF4 overlap, immediately preceded by a near-cognate CUG, which introduces another layer of regulation in the form of ribosome queuing. These elements explain how the inhibitory uORF2 can be translated under stress, confirming prior observations, but contradicting the original regulatory model. We also identified two highly conserved, potentially modified adenines performing antagonistic roles. Finally, we demonstrate that the canonical ATF4 translation start site is substantially leaky-scanned. Thus, ATF4s translational control is more complex than originally described underpinning its key role in diverse biological processes.

molecular biology↗

bioRxiv2023

DEK oncoprotein participates in heterochromatin replication via SUMO-dependent nuclear bodies

The correct inheritance of chromatin structure is key for maintaining genome function and preventing cellular transformation. DEK, a conserved chromatin protein, has recognized tumor-promoting properties, its overexpression being associated with poor prognosis in various cancer types. At the cellular level, DEK displays pleiotropic functions, influencing differentiation, apoptosis, and stemness, but a characteristic oncogenic mechanism remains elusive. Here, we report the identification of DEK bodies, focal assemblies of DEK occurring at specific, yet unidentified sites of heterochromatin replication. In these bodies, DEK localizes in direct proximity to active replisomes suggesting a function in the early maturation of heterochromatin. A high-throughput siRNA screen identifies SUMO as a major regulator of DEK body formation, linking DEK to the SUMO network that controls chromatin states and cell fate. This work combines and refines our previous data on DEK as a factor essential for heterochromatin integrity and facilitating replication under stress and delineates an avenue of further study for unraveling DEKs contribution to cancer development.

cell biology↗

bioRxiv2022

Complex changes in serum protein levels upon recovery from SARS-CoV2 infection

The COVID-19 pandemic, triggered by severe acute respiratory syndrome coronavirus 2, has affected millions of people worldwide. Much research has been dedicated to our understanding of COVID-19 disease heterogeneity and severity, but less is known about recovery associated changes. To address this gap in knowledge, we quantified the proteome from serum samples from 29 COVID-19 convalescents and 29 age-, race-, and sex-matched healthy controls. Samples were acquired within the first months of the pandemic. Many proteins from pathways known to change during acute COVID-19 illness, such as from the complement cascade, coagulation system, inflammation and adaptive immune system, had returned to levels seen in healthy controls. In comparison, we identified 22 and 15 proteins with significantly elevated and lowered levels, respectively, amongst COVID-19 convalescents compared to healthy controls. Some of the changes were similar to those observed for the acute phase of the disease, i.e. elevated levels of proteins from hemolysis, the adaptive immune systems, and inflammation. In contrast, some alterations opposed those in the acute phase, e.g. elevated levels of CETP and APOA1 which function in lipid/cholesterol metabolism, and decreased levels of proteins from the complement cascade (e.g. C1R, C1S, and VWF), the coagulation system (e.g. THBS1 and VWF), and the regulation of the actin cytoskeleton (e.g. PFN1 and CFL1) amongst COVID-19 convalescents. We speculate that some of these shifts might originate from a transient decrease in platelet counts upon recovery from the disease. Finally, we observed race-specific changes, e.g. with respect to immunoglobulins and proteins related to cholesterol metabolism.

immunology↗

bioRxiv2022

Proteomic signatures of the serological response to flu vaccination in a large human cohort study

The serological response to the influenza virus vaccine is highly heterogeneous for reasons that are not entirely clear. While the impact of demographic factors such as age, body mass index (BMI), sex, prior vaccination and titer levels are known to impact seroconversion, they only explain a fraction of the response. To identify signatures of the vaccine response, we quantified 273 proteins from serum samples of 160 flu vaccine recipients (2019-2020 season). We found that levels of proteins functioning in cholesterol transport were positively associated with seroconversion, likely linking to the known impact of BMI. When adjusting seroconversion for the demographic factors, we identified additional, unexpected signatures: proteins regulating actin cytoskeleton dynamics were significantly elevated in participants with high adjusted seroconversion. Viral strain specific analysis showed that this trend was largely driven by the H3N2 strain. Further, we identified complex associations between adjusted seroconversion and other factors: levels of proteins of the complement system associated positively with adjusted seroconversion in younger participants, while they were associated negatively in the older population. We observed the opposite trends for proteins of high density lipoprotein remodeling, transcription, and hemostasis. In sum, careful integrative modeling can extract new signatures of seroconversion from highly variable data that suggest links between the humoral response as well as immune cell communication and migration.

immunology↗

bioRxiv2022

Re-mining serum proteomics data reveals extensive post-translational modifications upon Zika and dengue infection

Zika virus (ZIKV) and dengue virus (DENV) are two closely related flaviviruses with similar symptoms; understanding differences in their molecular impact on the host is therefore of high interest. Viruses interact with the hosts post-translational modifications, inducing changes visible in serum. As modifications are diverse and of low abundance, they typically require additional sample processing which is not feasible for large cohort studies. Therefore, we tested the potential of next-generation proteomics data in its ability to prioritize specific modifications for later targeted analysis. We re-mined published mass spectra from 122 unenriched serum samples from ZIKV and DENV patients for the presence of phosphorylated, methylated, oxidized, glycosylated/glycated, sulfated, and carboxylated peptides. We identified 272 modified peptides with significantly differential abundance in ZIKV and DENV patients. Amongst these, methionine-oxidized peptides from apolipoproteins and glycosylated peptides from immunoglobulin proteins were more abundant in ZIKV patient serum and generate hypotheses on the potential roles of the modification in the infection. The results demonstrate how data-independent acquisition techniques can help prioritize future analyses of peptide modifications.

molecular biology↗

bioRxiv2022

Molecular signatures of proteostasis control in motor neurons with different sensitivity to Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a fatal adult neurodegenerative disease characterized by proteostasis dysregulation, resulting in progressive loss of spinal and upper motor neurons. A subset of cranial motor neurons resistant to ALS-stress survive until late stages of the disease. To investigate these differences, we exploited a unique platform of induced cranial and spinal motor neurons (iCrMNs and iSpMNs, respectively). Exposing both cell types to proteotoxic stress, we quantified transcriptome and proteome changes over 36 hours for a core set of >8,200 genes. While mRNA and protein changes under stress were congruent for many genes, cell-type specific differences manifested at either the RNA or protein level, but less at both. At the protein level, iCrMNs and iSpMNs differed significantly with respect to abundance of many membrane proteins, including synaptic proteins, solute carriers, adhesion molecules, and signaling molecules suggesting that the superior stress survival of iCrMNs involve diverse pathways supporting neuronal function. Other differences included genes involved in ribosome biogenesis and subunits of the core proteasome. We investigated the role of proteasomal degradation in more detail. Our data showed that although stress reduces proteasome activity in both neuronal types, iCrMNs had significantly more abundant and active 26S proteasome than iSpMNs, which indicate a higher capacity for the degradation of ubiquitinated proteins. We identified a new regulator of this better performance, i.e. the nuclear proteasome activator Ublcp1, whose inhibition sensitized iCrMNs, but not iSpMNs, to stress and abolished their higher survival rates. The results suggest that the two neuronal cell types regulate and use the degradation machinery differently under normal and stress conditions. Overall, this work demonstrates the value of unbiased system-wide analyses in generating hypotheses on differential proteostasis regulation in cranial and spinal motor neurons.

systems biology↗

bioRxiv2022

Meiotic DNA breaks activate a streamlined phospho-signaling response that largely avoids protein level changes

Meiotic cells introduce a large number of programmed DNA breaks into their genome to stimulate meiotic recombination and ensure controlled chromosome inheritance and fertility. An intricate checkpoint network involving key kinases and phosphatases coordinates the repair of these DNA breaks during meiosis, but the precise DNA break-dependent phosphorylation targets remain poorly understood. It is also unknown whether meiotic DNA breaks change gene expression akin to the canonical DNA-damage response. To address these questions, we analyzed the meiotic DNA break response in Saccharomyces cerevisiae using multiple systems-level approaches. We identified 332 DNA break-dependent phosphorylation sites, vastly expanding the number of known DNA break-dependent phosphorylation events during meiotic prophase. Only about half of these events occurred in recognition motifs for the known meiotic checkpoint kinases Mec1 (ATR), Tel1 (ATM) and Mek1 (CHK2), suggesting that additional kinases contribute to the meiotic DNA break response. Surprisingly, the numerous changes in phosphorylation were accompanied by very few changes in protein levels despite a clearly detectable transcriptional response. To explain this dichotomy, we show that meiotic entry lowers the expression baseline of many mRNAs enough so that subsequent break-dependent mRNA production has no measurable effects on the largely stable proteome.

cell biology↗

bioRxiv2022

Rnf149-related is an FGF/MAPK-independent regulator of pharyngeal muscle fate specification

During embryonic development, cell fate specification gives rise to dedicated lineages that underlie tissue formation. In olfactores, which comprise tunicates and vertebrates, the cardiopharyngeal field is formed by multipotent progenitors to both cardiac and branchiomeric muscles. The ascidian Ciona is a powerful model to study the cardiopharyngeal fate specification with cellular resolution, as only 2 pairs of cardiopharyngeal multipotent progenitors give rise to the heart and to pharyngeal muscles (aka atrial siphon muscles, ASM). These progenitors are multilineage primed, in as much as they express a combination of early ASM- and heart-specific transcripts that become restricted to their corresponding precursors, following oriented asymmetric divisions. Here, we identify the primed gene Rnf149-related (Rnf149-r), which becomes restricted to the heart progenitors, but appears to regulate pharyngeal muscle fate specification in the cardiopharyngeal lineage. CRISPR/Cas9-mediated loss knock-out of Rnf149-r function impairs atrial siphon muscle morphogenesis, and down-regulates Tbx1/10 and Ebf, two key determinants of the pharyngeal muscle fate, while upregulating heart-specific gene expression. These phenotypes are reminiscent of loss of FGF-MAPK signaling in the cardiopharyngeal lineage, and integrated analysis of lineage-specific bulk RNA-seq profiling of loss-of-function perturbations identified a significant overlap between FGF-MAPK and Rnf149-r targets. However, functional interaction assays suggested the Rnf149-r does not directly modulate the activity of the FGF-MAPK-Ets1/2 pathway. Instead, we propose that Rnf149-r acts both in parallel to the FGF-MAPK signaling on shared targets, as well as on FGF-MAPK-independent targets through (a) separate pathway(s).

developmental biology↗

bioRxiv2021

Regulatory start-stop elements in 5' untranslated regions pervasively modulate translation

Sequence elements within the 5 untranslated region (UTR) of eukaryotic genes, e.g. upstream open reading frames (uORFs), control translation of eukaryotic genes. We describe an element consisting of a start codon immediately followed by a stop codon which is distinct from uORFs in the lack of an elongation step. Start-stops have been described for specific cases, but their widespread impact has been overlooked. Start-stop elements occur in the 5UTR of 1, 417 human genes and are more often occupied with a ribosome than canonical uORFs or control sequences. Start-stops efficiently halt ribosomes without evidence for accelerated RNA turnover, therefore acting as a barrier for the scanning of the small ribosomal subunit and repressing downstream translation. Our results suggest a model by which the ribosome undergoes repeated cycles of termination and partial ribosomal recycling, during which the large subunit detaches, but the 40S subunit with the Met-tRNAiMet remains associated with the mRNA to be rejoined by the 60S subunit. Start-stop elements occur in many transcription factors and signaling genes, and affect cellular fate via different routes. We investigate the start-stop element in several genes, i.e. MORF4L1, SLC39A1, and PSPC1, and in more detail in ATF4.

systems biology↗

bioRxiv2021

Sex-specific glycosylation of secreted immunomodulatory proteins in the filarial nematode Brugia malayi

The extended persistence of filarial nematodes within a host suggests immunomodulatory mechanisms that allow the parasites to resist or evade the host immune response. There is increasing evidence for immunomodulatory glycans expressed by a diversity of parasitic worms. In this study, we integrate multiple layers of the host-parasite interface to investigate the glycome of a model filarial parasite, Brugia malayi. We report a significant overrepresentation of terminal GalNAc moieties in adult female worms coupled with an overall upregulation in O-glycosylation, T-antigen expression, and a bias for galactose containing glycans. Adult males preferentially displayed a bias for terminal GlcNAc containing glycans, and fucosylated epitopes. Subsequent proteomic analysis confirmed sex-biases in protein glycosylation and highlighted the sex-specific glycosylation of well characterized immunomodulators expressed and secreted by B. malayi. We identify sex-specific effectors at that interface and suggest approaches to selectively interfere with the parasitic life cycle and potentially control transmission.

microbiology↗

bioRxiv2019

High-resolution proteomics identifies potential new markers of Zika and dengue infections

Distinguishing between Zika and dengue virus infections is critical for treatment and anticipation of complications. However, existing biomarkers have high error rates. To identify new potential diagnostic signatures, we used next-generation proteomics to profile 122 serum samples from 62 Zika or dengue patients. We quantified >500 proteins and identified 26 proteins that were significantly differentially expressed. These proteins typically function in infection and wound healing, with several also linked to pregnancy and brain. Integrating machine learning approaches, we used 7 proteins to predict ZIKV infection correctly in 72% of the cases, outperforming other tools. The three most predictive proteins were Platelet Factor 4 Variant 1, Fibrinogen Alpha, and Gelsolin. Finally, we showed that temporal changes in protein signatures from the same patient can disambiguate some diagnoses and serve as indicators for past infections. Taken together, we demonstrate that serum proteomics can be highly valuable to diagnose even challenging samples.

systems biology↗

bioRxiv2019

A simple method to quantify proteins from one thousand cells

The rise of single-cell transcriptomics has created an urgent need for similar approaches that use a minimal number of cells to quantify expression levels of proteins. We integrated and optimized multiple recent developments to establish a proteomics workflow to quantify proteins from as few as 1,000 mammalian stem cells. The method uses chemical peptide labeling, does not require specific equipment other than cell lysis tools, and quantifies >2,500 proteins with high reproducibility. We validated the method by comparing mouse embryonic stem cells and in vitro differentiated motor neurons. We identify differentially expressed proteins with small fold-changes, and a dynamic range in abundance similar to that of standard methods. Protein abundance measurements obtained with our protocol compare well to corresponding transcript abundance and to measurements using standard inputs. The protocol is also applicable to other systems, such as FACS-purified cells from the tunicate Ciona. Therefore, we offer a straightforward and accurate method to acquire proteomics data from minimal input samples.

systems biology↗