Novel applications for hierarchical natural move Monte Carlo simulations: from proteins to nucleic acids

Biological molecules often undergo large structural changes to perform their function. Computational methods can provide a fine-grained description at the atomistic scale. Without sufficient approximations to accelerate the simulations, however, the time-scale on which functional motions often occur is out of reach for many traditional methods. Natural Move Monte Carlo belongs to a class of methods that were introduced to bridge this gap. I present three novel applications for Natural Move Monte Carlo, two on proteins and one on DNA epigenetics. In the second part of this thesis I introduce a new protocol for the testing of hypotheses regarding the functional motions of biological systems, named customised Natural Move Monte Carlo. Two different case studies are presented aimed at demonstrating the feasibility of customised Natural Move Monte Carlo

Analysis Of Rhythm Generation In The Caenorhabditis Elegans Motor Circuit

Understanding the neuronal control of movement has been a central goal of neuroscience for decades. In many organisms, chains of neural oscillators underlie the generation of coordinated rhythmic movements. However, the sheer complexity of spinal locomotor circuits has made understanding the mechanisms underlying rhythmic locomotion in vertebrates challenging. The roundworm C. elegans generates rhythmic undulatory movements that resemble those of swimming vertebrates, but using only a few hundred neurons. The relative simplicity of this organism has allowed a complete synaptic map of the nervous system to be developed. Moreover, C. elegans has a three-day life cycle and is amenable to a powerful battery of genetic techniques that allow the molecular basis of circuit functions to be probed much more rapidly than is possible in more complex organisms. Because of these advantages, C. elegans offers the possibility of understanding the network, cellular, and molecular principles of rhythmic locomotion in deeper detail than has been possible in any other model organism. However, it is currently unclear where in the C. elegans motor circuit rhythms are generated, and whether there exists more than one rhythm generator. I used optogenetic and lesioning experiments to probe the nature of rhythm generation in the locomotor circuit. I found that rhythmic activity in different parts of the body can be decoupled by both methods, implying that multiple sections of forward locomotor circuitry are capable of independently generating rhythms. By perturbing different components of the motor circuit, I localized at least two rhythmic sources to a network of cholinergic motor neurons that are distributed along the body. Moreover, I used rhythmic optogenetic manipulations to show that imposed rhythmic signals in any portion of the motor circuit can entrain oscillatory activity in the rest of the body, suggesting bidirectional coupling within the motor circuit. This organization, in which distributed oscillating circuits exist along the body but are closely linked by bidirectional coupling, is found in wide range of vertebrate and invertebrate animals. My results show that the functional architecture of the C. elegans motor circuit is highly analogous to that of much more complex organisms

pARam: Leveraging Parametric Design in Extended Reality to Support the Personalization of Artifacts for Personal Fabrication

Extended Reality (XR) allows in-situ previewing of designs to be manufactured through Personal Fabrication (PF). These in-situ interactions exhibit advantages for PF, like incorporating the environment into the design process. However, design-for-fabrication in XR often happens through either highly complex 3D-modeling or is reduced to rudimentary adaptations of crowd-sourced models. We present pARam, a tool combining parametric designs (PDs) and XR, enabling in-situ configuration of artifacts for PF. In contrast to modeling- or search-focused approaches, pARam supports customization through embodied and practical inputs (e.g., gestures, recommendations) and evaluation (e.g., lighting estimation) without demanding complex 3D-modeling skills. We implemented pARam for HoloLens 2 and evaluated it (n=20), comparing XR and desktop conditions. Users succeeded in choosing context-related parameters and took their environment into account for their configuration using pARam. We reflect on the prospects and challenges of PDs in XR to streamline complex design methods for PF while retaining suitable expressivity.Comment: 17 pages, 17 figures. Accepted to ACM CHI 2024 (ACM CHI conference on Human Factors in Computing Systems

Explainable machine learning identifies multi-omics signatures of muscle response to spaceflight in mice.

The adverse effects of microgravity exposure on mammalian physiology during spaceflight necessitate a deep understanding of the underlying mechanisms to develop effective countermeasures. One such concern is muscle atrophy, which is partly attributed to the dysregulation of calcium levels due to abnormalities in SERCA pump functioning. To identify potential biomarkers for this condition, multi-omics data and physiological data available on the NASA Open Science Data Repository (osdr.nasa.gov) were used, and machine learning methods were employed. Specifically, we used multi-omics (transcriptomic, proteomic, and DNA methylation) data and calcium reuptake data collected from C57BL/6 J mouse soleus and tibialis anterior tissues during several 30+ day-long missions on the international space station. The QLattice symbolic regression algorithm was introduced to generate highly explainable models that predict either experimental conditions or calcium reuptake levels based on multi-omics features. The list of candidate models established by QLattice was used to identify key features contributing to the predictive capability of these models, with Acyp1 and Rps7 proteins found to be the most predictive biomarkers related to the resilience of the tibialis anterior muscle in space. These findings could serve as targets for future interventions aiming to reduce the extent of muscle atrophy during space travel

Neuroserpin expression during human brain development and in adult brain revealed by immunohistochemistry and single cell RNA sequencing

Neuroserpin is a serine‐protease inhibitor mainly expressed in the CNS and involved in the inhibition of the proteolytic cascade. Animal models confirmed its neuroprotective role in perinatal hypoxia‐ischaemia and adult stroke. Although neuroserpin may be a potential therapeutic target in the treatment of the aforementioned conditions, there is still no information in the literature on its distribution during human brain development. The present study provides a detailed description of the changing spatiotemporal patterns of neuroserpin focusing on physiological human brain development. Five stages were distinguished within our examined age range which spanned from the 7th gestational week until adulthood. In particular, subplate and deep cortical plate neurons were identified as the main sources of neuroserpin production between the 25th gestational week and the first postnatal month. Our immunohistochemical findings were substantiated by single cell RNA sequencing data showing specific neuronal and glial cell types expressing neuroserpin. The characterization of neuroserpin expression during physiological human brain development is essential for forthcoming studies which will explore its involvement in pathological conditions, such as perinatal hypoxia‐ischaemia and adult stroke in human

Neuroserpin expression during human brain development and in adult brain revealed by immunohistochemistry and single cell RNA sequencing

Neuroserpin is a serine-protease inhibitor mainly expressed in the CNS and involved in the inhibition of the proteolytic cascade. Animal models confirmed its neuroprotective role in perinatal hypoxia-ischaemia and adult stroke. Although neuroserpin may be a potential therapeutic target in the treatment of the aforementioned conditions, there is still no information in the literature on its distribution during human brain development. The present study provides a detailed description of the changing spatiotemporal patterns of neuroserpin focusing on physiological human brain development. Five stages were distinguished within our examined age range which spanned from the 7th gestational week until adulthood. In particular, subplate and deep cortical plate neurons were identified as the main sources of neuroserpin production between the 25th gestational week and the first postnatal month. Our immunohistochemical findings were substantiated by single cell RNA sequencing data showing specific neuronal and glial cell types expressing neuroserpin. The characterization of neuroserpin expression during physiological human brain development is essential for forthcoming studies which will explore its involvement in pathological conditions, such as perinatal hypoxia-ischaemia and adult stroke in human

Diagnostic precision of image-guided multisampling core needle biopsy of suspected lymphomas in a primary care hospital

We evaluated the diagnostic quality of image-guided multisampling core needle biopsy (CNB) in patients investigated for suspected lymphoma in a primary care hospital. A total of 112 patients were consecutively assessed during a 3-year period. There were 80 lymphoid site biopsies and 32 non-lymphoid site biopsies. Eight to nine cores were obtained from different parts of the biopsy site. Two cores were systematically frozen, allowing for further morphological, immunochemistry and molecular studies. The diagnostic yield of CNB for malignancy was 100%. Only 47% (41/87) of patients with initial suspicion of lymphoma were finally diagnosed with Lymphoma. The diagnostic yield of CNB for lymphoma typing was 98% (62/63), according to the WHO classification. The diagnostic yield of CNB for complete lymphoma subtyping/grading was 86% (54/63). The diagnostic yield of CNB for a definite diagnosis of benignity was only 47% (8/17). In a primary care setting, multisampling CNB is a minimally invasive, and very accurate procedure for confirming malignancy in patients with suspected lymphoma, presenting with superficial/deep-seated, lymphoid/non-lymphoid site targets. With a very high diagnostic yield for lymphoma typing and a high diagnostic yield for complete lymphoma subtyping/grading a therapeutic decision can be taken in most patients