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The proliferation of debris in Low Earth Orbit (LEO) represents a significant threat to space sustainability and spacecraft safety. Active Debris Removal (ADR) has emerged as a promising approach to address this issue, utilising Orbital Transfer Vehicles (OTVs) to facilitate debris deorbiting, thereby reducing future collision risks. However, ADR missions are substantially complex, necessitating accurate planning to make the missions economically viable and technically effective. Moreover, these servicing missions require a high level of autonomous capability to plan under evolving orbital conditions and changing mission requirements. In this paper, an autonomous decision-planning model based on Deep Reinforcement Learning (DRL) is developed to train an OTV to plan optimal debris removal sequencing. It is shown that using the proposed framework, the agent can find optimal mission plans and learn to update the planning autonomously to include risk handling of debris with high collision risk.

We present GeoSP, a parallel method that creates a parcellation of the cortical mesh based on a geodesic distance, in order to consider gyri and sulci topology. The method represents the mesh with a graph and performs a K-means clustering in parallel. It has two modes of use, by default, it performs the geodesic cortical parcellation based on the boundaries of the anatomical parcels provided by the Desikan-Killiany atlas. The other mode performs the complete parcellation of the cortex. Results for both modes and with different values for the total number of sub-parcels show homogeneous sub-parcels. Furthermore, the execution time is 82 s for the whole cortex mode and 18 s for the Desikan-Killiany atlas subdivision, for a parcellation into 350 sub-parcels. The proposed method will be available to the community to perform the evaluation of data-driven cortical parcellations. As an example, we compared GeoSP parcellation with Desikan-Killiany and Destrieux atlases in 50 subjects, obtaining more homogeneous parcels for GeoSP and minor differences in structural connectivity reproducibility across subjects., Comment: This research has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Actions H2020-MSCA-RISE-2015 BIRDS GA No. 690941, ANID PFCHA/DOCTORADO NACIONAL/2016-21160342, ANID FONDECYT 1190701, ANID PIA/Anillo de Investigaci\'on en Ciencia y Tecnolog\'ia ACT172121, and ANID Basal Project FB0008

We present a hybrid method that performs the complete parcellation of the cerebral cortex of an individual, based on the connectivity information of the white matter fibers from a whole-brain tractography dataset. The method consists of five steps, first intra-subject clustering is performed on the brain tractography. The fibers that make up each cluster are then intersected with the cortical mesh and then filtered to discard outliers. In addition, the method resolves the overlapping between the different intersection regions (sub-parcels) throughout the cortex efficiently. Finally, a post-processing is done to achieve more uniform sub-parcels. The output is the complete labeling of cortical mesh vertices, representing the different cortex sub-parcels, with strong connections to other sub-parcels. We evaluated our method with measures of brain connectivity such as functional segregation (clustering coefficient), functional integration (characteristic path length) and small-world. Results in five subjects from ARCHI database show a good individual cortical parcellation for each one, composed of about 200 subparcels per hemisphere and complying with these connectivity measures., Comment: This research has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Actions H2020-MSCA-RISE-2015 BIRDS GA No. 690941, CONICYT PFCHA/ DOCTORADO NACIONAL/2016-21160342, CONICYT FONDECYT 1190701, CONICYT PIA/Anillo de Investigaci\'on en Ciencia y Tecnolog\'ia ACT172121 and CONICYT Basal Center FB0008

We present an optimized algorithm that performs automatic classification of white matter fibers based on a multi-subject bundle atlas. We implemented a parallel algorithm that improves upon its previous version in both execution time and memory usage. Our new version uses the local memory of each processor, which leads to a reduction in execution time. Hence, it allows the analysis of bigger subject and/or atlas datasets. As a result, the segmentation of a subject of 4,145,000 fibers is reduced from about 14 minutes in the previous version to about 6 minutes, yielding an acceleration of 2.34. In addition, the new algorithm reduces the memory consumption of the previous version by a factor of 0.79., Comment: This research has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie Actions H2020-MSCA-RISE-2015 BIRDS GA No. 690941, CONICYT PFCHA/ DOCTORADO NACIONAL/2016-21160342, CONICYT FONDECYT 1161427, CONICYT PIA/Anillo de Investigaci\'on en Ciencia y Tecnolog\'ia ACT172121, CONICYT BASAL FB0008 and from CONICYT Basal FB0001

3D-Polarized Light Imaging (3D-PLI) is a neuroimaging technique used to study the structural connectivity of the human brain at the meso- and microscale. In 3D-PLI, the complex nerve fiber architecture of the brain is characterized by 3D orientation vector fields that are derived from birefringence measurements of unstained histological brain sections by means of an effective physical model. To optimize the physical model and to better understand the underlying microstructure, numerical simulations are essential tools to optimize the used physical model and to understand the underlying microstructure in detail. The simulations rely on predefined configurations of nerve fiber models (e.g. crossing, kissing, or complex intermingling), their physical properties, as well as the physical properties of the employed optical system to model the entire 3D-PLI measurement. By comparing the simulation and experimental results, possible misinterpretations in the fiber reconstruction process of 3D-PLI can be identified. Here, we focus on fiber modeling with a specific emphasize on the generation of dense fiber distributions as found in the human brain's white matter. A new algorithm will be introduced that allows to control possible intersections of computationally grown fiber structures.

Biased signaling has recently emerged as an interesting mean to modulate the function of many G protein-coupled receptors (GPCRs). Previous studies reported two negative allosteric modulators (NAMs) of follicle-stimulating hormone receptor (FSHR), ADX68692 and ADX68693, with differential effects on FSHR-mediated steroidogenesis and ovulation. In this study, we attempted to pharmacologically profile these NAMs on the closely related luteinizing/chorionic gonadotropin hormone receptor (LH/CGR) with regards to its canonical Gs/cAMP pathway as well as \beta-arrestin recruitment in HEK293 cells. The NAMs effects on progesterone and testosterone production were also assessed in murine Leydig tumor cell line (mLTC-1). We found that both NAMs strongly antagonized LH/CGR signaling in both HEK293 and mLTC-1 cells. ADX68693 appeared more potent than ADX68692 to inhibit hCG-induced cAMP and \beta-arrestin 2 in HEK293 and mLTC-1 cells whereas no significant difference in their efficacy on hCG-promoted \beta-arrestin 2 recruitment. Interestingly, differential antagonism of the two NAMs on hCG-promoted steroidogenesis in mLTC-1 cells was observed with significant inhibition of testosterone but not progesterone production. These observations suggest biased effects of the two NAMs on LH/CGR-dependent pathways controlling steroidogenesis, which appeared to be different to that previously shown on FSHR. This also illustrates the complexity of signaling pathways controlling FSHR- and LH/CGR-mediated steroidogenesis, suggesting differential implication of cAMP and \beta-arrestins. Together, our data demonstrate that ADX68692 and ADX68693 are NAMs at the LH/CGR in addition to FSHR. These pharmacological characteristics are important to consider for potential contraceptive and therapeutic applications based on such compounds.

Pituitary gonadotropins play an essential and pivotal role in the control of human and animal reproduction within the hypothalamic-pituitary-gonadal (HPG) axis. The computational modeling of pituitary gonadotropin signaling encompasses phenomena of different natures such as the dynamic encoding of gonadotropin secretion, and the intracellular cascades triggered by gonadotropin binding to their cognate receptors, resulting in a variety of biological outcomes. We overview historical and ongoing issues in modeling and data analysis related to gonadotropin secretion in the field of both physiology and neuro-endocrinology. We mention the different mathematical formalisms involved, their interest and limits. We discuss open statistical questions in signal analysis associated with key endocrine issues. We also review recent advances in the modeling of the intracellular pathways activated by gonadotropins, which yields promising development for innovative approaches in drug discovery. The greatest challenge to be tackled in computational modeling of pituitary gonadotropin signaling is the embedding of gonadotropin signaling within its natural multi-scale environment, from the single cell level, to the organic and whole HPG level. The development of modeling approaches of G protein-coupled receptor signaling, together with multicellular systems biology may lead to unexampled mechanistic understanding with critical expected fallouts in the therapeutic management of reproduction., Comment: in press

Dynamic models of signaling networks allow the formulation of hypotheses on the topology and kinetic rate laws characterizing a given molecular network, in-depth exploration and confrontation with kinetic biological data. Despite its standardization, dynamic modeling of signaling networks still requires successive technical steps that need to be carefully performed. Here, we detail these steps by going through the mathematical and statistical framework. We explain how it can be applied to the understanding of \beta-arrestin-dependent signaling networks. We illustrate our methodology through the modeling of \beta-arrestin recruitment kinetics at the Follicle Stimulating Hormone (FSH) receptor supported by in-house Bioluminescence Resonance Energy Transfer (BRET) data., Comment: in press

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) play essential roles in animal reproduction. They exert their function through binding to their cognate receptors, which belong to the large family of G protein-coupled receptors (GPCRs). This recognition at the plasma membrane triggers a plethora of cellular events, whose processing and integration ultimately lead to an adapted biological response. Understanding the nature and the kinetics of these events is essential for innovative approaches in drug discovery. The study and manipulation of such complex systems requires the use of computational modeling approaches combined with robust in vitro functional assays for calibration and validation. Modeling brings a detailed understanding of the system and can also be used to understand why existing drugs do not work as well as expected, and how to design more efficient ones.

Follicle-stimulating hormone (FSH) is produced in the pituitary and is essential for reproduction. It specifically binds to a membrane receptor (FSHR) expressed in somatic cells of the gonads. The FSH/FSHR system presents many peculiarities compared to classical G protein-coupled receptors (GPCRs). FSH is a large naturally heterogeneous heterodimeric glycoprotein. The FSHR is characterized by a very large NH2-terminal extracellular domain, which binds the FSH and participates to the activation/inactivation switch of the receptor. Once activated, the FSHR couples to G{\alpha}s and, in some instances, to other G{\alpha} subunits. G protein-coupled receptor kinases and \beta-arrestins are also recruited to the FSHR and account for its desensitization, the control of its trafficking and its intracellular signalling. Of note, the FSHR internalization and recycling are very fast and involve very early endosomes instead of early endosomes. All the transduction mechanisms triggered upon FSH stimulation lead to the activation of a complex signalling network that controls gene expression by acting at multiple levels. The integration of these mechanisms leads to context-adapted responses from the target gonadal cells, but also indirectly affects the fate of germ cells. Depending of the physiological/developmental stage, FSH elicits proliferation, differentiation or apoptosis in order to maintain the homeostasis of the reproductive system. Pharmacological tools targeting FSHR recently came to the fore and open promising prospects both for basic research and therapeutic applications. This paper provides an updated review of the most salient aspects and peculiarities of FSHR biology and pharmacology.

OBJECTIVE:Motion-robust multi-slab imaging of hippocampal inner structure in vivo at 7T.MATERIALS AND METHODS:Motion is a crucial issue for ultra-high resolution imaging, such as can be achieved with 7T MRI. An acquisition protocol was designed for imaging hippocampal inner structure at 7T. It relies on a compromise between anatomical details visibility and robustness to motion. In order to reduce acquisition time and motion artifacts, the full slab covering the hippocampus was split into separate slabs with lower acquisition time. A robust registration approach was implemented to combine the acquired slabs within a final 3D-consistent high-resolution slab covering the whole hippocampus. Evaluation was performed on 50 subjects overall, made of three groups of subjects acquired using three acquisition settings; it focused on three issues: visibility of hippocampal inner structure, robustness to motion artifacts and registration procedure performance.RESULTS:Overall, T2-weighted acquisitions with interleaved slabs proved robust. Multi-slab registration yielded high quality datasets in 96 % of the subjects, thus compatible with further analyses of hippocampal inner structure.CONCLUSION:Multi-slab acquisition and registration setting is efficient for reducing acquisition time and consequently motion artifacts for ultra-high resolution imaging of the inner structure of the hippocampus.