Biology subjects

Strobel, A.

Publications and source records attributed to Strobel, A..

4 recordsLinked to original sources

bioRxiv2023

A gut meta-interactome map reveals modulation of human immunity by microbiome effectors

The molecular mechanisms by which the gut microbiome influences human health remain largely unknown. Pseudomonadota is the third most abundant phylum in normal gut microbiomes. Several pathogens in this phylum can inject so-called virulence effector proteins into host cells. We report the identification of intact type 3 secretion systems (T3SS) in 5 - 20% of commensal Pseudomonadota in normal human gut microbiomes. To understand their functions, we experimentally generated a high-quality protein-protein meta-interactome map consisting of 1,263 interactions between 289 bacterial effectors and 430 human proteins. Effector targets are enriched for metabolic and immune functions and for genetic variation of microbiome-influenced traits including autoimmune diseases. We demonstrate that effectors modulate NF-{kappa}B signaling, cytokine secretion, and adhesion molecule expression. Finally, effectors are enriched in metagenomes of Crohns disease, but not ulcerative colitis patients pointing toward complex contributions to the etiology of inflammatory bowel diseases. Our results suggest that effector-host protein interactions are an important regulatory layer by which the microbiome impacts human health.

microbiology↗

bioRxiv2021

A map of direct SARS-CoV-2 protein interactions implicates specific human host processes

Key steps in viral propagation, immune suppression, and pathology are mediated by direct, binary, physical interactions between viral and host proteins. To understand the biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we generated an unbiased systematic map of binary interactions between viral and host proteins, complementing previous co-complex association maps by conveying more direct mechanistic understanding and potentially enabling targeted disruption of direct interactions. To this end, we deployed two parallel strategies, identifying 205 virus-host and 27 intraviral binary interactions amongst 171 host and 19 viral proteins, and confirming high quality of these interactions via a calibrated orthogonal assay. Host proteins interacting with SARS-CoV-2 proteins are enriched in various cellular processes, including immune signaling and inflammation, protein ubiquitination, and membrane trafficking. Specific subnetworks provide new hypotheses related to viral modulation of host protein homeostasis and T-cell regulation. The binary virus-host protein interactions we identified can now be prioritized as targets for therapeutic intervention. More generally, we provide a resource of systematic maps describing which SARS-CoV-2 and human proteins interact directly.

systems biology↗

bioRxiv2019

Dynamic integration of forward planning and heuristic preferences during multiple goal pursuit

Selecting goals and successfully pursuing them in an uncertain and dynamic environment is an important aspect of human behaviour. In order to decide which goal to pursue at what point in time, one has to evaluate the consequences of ones actions over future time steps by forward planning. However, when the goal is still temporally distant, detailed forward planning can be prohibitively costly. One way to select actions at minimal computational costs is to use heuristics. It is an open question how humans mix heuristics with forward planning to balance computational costs with goal reaching performance. To test a hypothesis about dynamic mixing of heuristics with forward planning, we used a novel stochastic sequential two-goal task. Comparing participants decisions with an optimal full planning agent, we found that at the early stages of goal-reaching sequences, in which both goals are temporally distant and planning complexity is high, on average 42% (SD = 19%) of participants choices deviated from the agents optimal choices. Only towards the end of the sequence, participants behaviour converged to near optimal performance. Subsequent model-based analyses showed that participants used heuristic preferences when the goal was temporally distant and switched to forward planning when the goal was close. Author summaryWhen we pursue our goals, there is often a moment when we recognize that we did not make the progress that we hoped for. What should we do now? Persevere to achieve the original goal, or switch to another goal? Two features of real-world goal pursuit make these decisions particularly complex. First, goals can lie far into an unpredictable future and second, there are many potential goals to pursue. When potential goals are temporally distant, human decision makers cannot use an exhaustive planning strategy, rendering simpler rules of thumb more appropriate. An important question is how humans adjust the rule of thumb approach once they get closer to the goal. We addressed this question using a novel sequential two-goal task and analysed the choice data using a computational model which arbitrates between a rule of thumb and accurate planning. We found that participants decision making progressively improved as the goal came closer and that this improvement was most likely caused by participants starting to plan ahead.

animal behavior and cognition↗

bioRxiv2019

Modeling dynamic allocation of effort in a sequential task using discounting models

Most rewards in our lives require effort to obtain them. It is known that effort is seen by humans as carrying an intrinsic disutility which devalues the obtainable reward. Established models for effort discounting account for this by using participant-specific discounting parameters inferred from experiments. These parameters offer only a static glance into the bigger picture of effort exertion. The mechanism underlying the dynamic changes in a participants willingness to exert effort is still unclear and an active topic of research. Here, we modeled dynamic effort exertion as a consequence of effort- and probability-discounting mechanisms during goal reaching, sequential behavior. To do this, we developed a novel sequential decision-making task in which participants make binary choices to reach a minimum number of points. Importantly, the time points and circumstances of effort allocation are decided by participants according to their own preferences and not imposed directly by the task. Using the computational model to analyze participants choices, we show that the dynamics of effort exertion arise from a combination of changing task needs and forward planning. In other words, the interplay between a participants inferred discounting parameters is sufficient to explain the dynamic allocation of effort during goal reaching. Using formal model comparison, we also infer the forward-planning strategy used by participants. The model allows us to characterize a participants effort exertion in terms of only a few parameters. Moreover, the model can be adapted to a number of tasks used in establishing the neural underpinnings of forward-planning behavior and meta-control, allowing for the characterization of behavior in terms of model parameters.

neuroscience↗