A type I interferon regulatory network for human plasmacytoid dendritic cells based on heparin, membrane-bound and soluble BDCA-2.

Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFNs) after sensing viral/bacterial RNA or DNA by toll-like receptor (TLR) 7 or TLR9, respectively. However, aberrant pDCs activation can cause adverse effects on the host and contributes to the pathogenesis of type I IFN-related autoimmune diseases. Here, we show that heparin interacts with the human pDCs-specific blood dendritic cell antigen 2 (BDCA-2) but not with related lectins such as DCIR or dectin-2. Importantly, BDCA-2-heparin interaction depends on heparin sulfation and receptor glycosylation and results in inhibition of TLR9-driven type I IFN production in primary human pDCs and the pDC-like cell line CAL-1. This inhibition is mediated by unfractionated and low-molecular-weight heparin, as well as endogenous heparin from plasma, suggesting that the local blood environment controls the production of IFN-α in pDCs. Additionally, we identified an activation-dependent soluble form of BDCA-2 (solBDCA-2) in human plasma that functions as heparin antagonist and thereby increases TLR9-driven IFN-α production in pDCs. Of importance, solBDCA-2 levels in the serum were increased in patients with scrub typhus (an acute infectious disease caused by Orientia tsutsugamushi) compared to healthy control subjects and correlated with anti-dsDNA antibodies titers. In contrast, solBDCA-2 levels in plasma from patients with bullous pemphigoid or psoriasis were reduced. In summary, this work identifies a regulatory network consisting of heparin, membrane-bound and solBDCA-2 modulating TLR9-driven IFN-α production in pDCs. This insight into pDCs function and regulation may have implications for the treatment of pDCs-related autoimmune diseases.

Red Vetchling (Lathyrus cicera L.), a Promising Crop for the Sustainable Replacement of Soybean Meal and Reducing the Carbon Footprint of European Aquafeeds.

In fish diets, soybean meal (SBM) is still positioned as the most widely used alternative to replace fishmeal. Red vetchling (Lathyrus cicera), a crop locally produced in Europe, is here evaluated as a substitute for SBM. Rainbow trout (Oncorhynchus mykiss) juveniles (10.34 ± 0.04 g) were fed for 90 days. Six experimental diets replacing the SBM content at 0, 8, 16, 33, 66, and 100% (Named Control, T8, T16, T33, T66, and T100) were tested. Growth performance and fish fillet amino acid composition were only significantly reduced in fish fed the T100 diet. Histopathological analysis showed that no major alterations were observed in the intestine, while T100 fish had a higher density of pyknotic nuclei in the hepatocytes than the Control, but similar hepatocyte surface coverage. Finally, postprandial levels of glucose and triglycerides in blood plasma decreased when red vetchling content was increased, but was only not fully restored after 24 h in the case of glucose in T66 and T100 fish. According to these results, red vetchling meal can replace up to 66% of the SBM without a negative effect on fish growth or physiology, representing a good alternative raw material for reducing European aquaculture's dependency on SBM imports and the carbon footprint of aquafeeds.

Commonalities between the Atacama Desert and Antarctica rhizosphere microbial communities.

Plant-microbiota interactions have significant effects on plant growth, health, and productivity. Rhizosphere microorganisms are involved in processes that promote physiological responses to biotic and abiotic stresses in plants. In recent years, the interest in microorganisms to improve plant productivity has increased, mainly aiming to find promising strains to overcome the impact of climate change on crops. In this work, we hypothesize that given the desertic environment of the Antarctic and the Atacama Desert, different plant species inhabiting these areas might share microbial taxa with functions associated with desiccation and drought stress tolerance. Therefore, in this study, we described and compared the composition of the rhizobacterial community associated with Deschampsia antarctica (Da), Colobanthus quitensis (Cq) from Antarctic territories, and Croton chilensis (Cc), Eulychnia iquiquensis (Ei) and Nicotiana solanifolia (Ns) from coastal Atacama Desert environments by using 16S rRNA amplicon sequencing. In addition, we evaluated the putative functions of that rhizobacterial community that are likely involved in nutrient acquisition and stress tolerance of these plants. Even though each plant microbial rhizosphere presents a unique taxonomic pattern of 3,019 different sequences, the distribution at the genus level showed a core microbiome with a higher abundance of Haliangium, Bryobacter, Bacillus, MND1 from the Nitrosomonadaceae family, and unclassified taxa from Gemmatiamonadaceae and Chitinophagaceae families in the rhizosphere of all samples analyzed (781 unique sequences). In addition, species Gemmatirosa kalamazoonesis and Solibacter usitatus were shared by the core microbiome of both Antarctic and Desert plants. All the taxa mentioned above had been previously associated with beneficial effects in plants. Also, this microbial core composition converged with the functional prediction related to survival under harsh conditions, including chemoheterotrophy, ureolysis, phototrophy, nitrogen fixation, and chitinolysis. Therefore, this study provides relevant information for the exploration of rhizospheric microorganisms from plants in extreme conditions of the Atacama Desert and Antarctic as promising plant growth-promoting rhizobacteria.

Integrative species delimitation in the common ophiuroid Ophiothrix angulata (Echinodermata: Ophiuroidea): insights from COI, ITS2, arm coloration, and geometric morphometrics.

Ophiothrix angulata (Say, 1825) is one of the most common and well-known ophiuroids in the Western Atlantic, with a wide geographic and bathymetric range. The taxonomy of this species has been controversial for a century because of its high morphological variability. Here we integrate information from DNA sequence data, color patterns, and geometric morphometrics to assess species delimitation and geographic differentiation in O. angulata. We found three deeply divergent mtDNA-COI clades (K2P 17.0-27.9%). ITS2 nuclear gene and geometric morphometrics of dorsal and ventral arm plates differentiate one of these lineages, as do integrative species delineation analyses, making this a confirmed candidate species.

Unnexin is a protein subunit of a large-pore channel expressed by unicellular organisms.

Cells of vertebrate and invertebrate organisms express proteins specialized in membrane channel-based cell-cell communication that are absent in unicellular organisms. We recently described the prediction of some members of the large-pore channel family in kinetoplastids, consisting of proteins called unnexins, which share several structural features with innexin and pannexin proteins. Here, we demonstrated that the unnexin1 protein (Unx1) is delivered to the cell membrane, displaying a topology consisting of four transmembrane domains with C and N termini on the cytoplasmic side and form large-pore channels that are permeable to small molecules. Low extracellular Ca2+/Mg2+ levels or extracellular alkalinization, but not mechanical stretching, increases channel activity. The Unx1 channel mediates the influx of Ca2+ and does not form intercellular dye coupling between HeLa Unx1 transfected cells. Unx1 channel function was further evidenced by its ability to mediate ionic currents when expressed in Xenopus oocytes. Downregulation of Unx1 mRNA with morpholine contains Trypanosoma cruzi invasion. Phylogenetic analysis revealed the presence of Unx1 homologs in other protozoan parasites, suggesting a conserved function for these channel parasites in other protists. Our data demonstrate that Unx1 forms large-pore membrane channels, which may serve as a diffusional pathway for ions and small molecules that are likely to be metabolic substrates or waste products, and signaling autocrine and paracrine molecules that could be involved in cell invasion. As morpholinos-induced downregulation of Unx1 reduces the infectivity of trypomastigotes, the Unx1 channels might be an attractive target for developing trypanocide drugs.

Specific Blood Plasma Circulating miRs Are Associated with the Physiological Impact of Total Fish Meal Replacement with Soybean Meal in Diets for Rainbow Trout (Oncorhynchus mykiss).

High dietary SBM content is known to induce important physiological alterations, hampering its use as a major FM alternative. Rainbow trout (Oncorhynchus mykiss) juveniles were fed two experimental diets during 9 weeks: (i) a FM diet containing 12% FM; and (ii) a vegetable meal (VM) diet totally devoid of FM and based on SBM (26%). Fish fed the VM diet did not show reduced growth performance when compared with fish fed the FM diet. Nevertheless, fish fed the VM diet had an increased viscerosomatic index, lower apparent fat digestibility, higher aminopeptidase enzyme activity and number of villi fusions, and lower α-amylase enzyme activity and brush border integrity. Small RNA-Seq analysis identified six miRs (omy-miR-730a-5p, omy-miR-135c-5p, omy-miR-93a-3p, omy-miR-152-5p, omy-miR-133a-5p, and omy-miR-196a-3p) with higher expression in blood plasma from fish fed the VM diet. Bioinformatic prediction of target mRNAs identified several overrepresented biological processes known to be associated with high dietary SBM content (e.g., lipid metabolism, epithelial integrity disruption, and bile acid status). The present research work increases our understanding of how SBM dietary content has a physiological impact in farmed fish and suggests circulating miRs might be suitable, integrative, and less invasive biomarkers in fish.

Study of the Antibacterial Capacity of a Biomaterial of Zeolites Saturated with Copper Ions (Cu2+) and Supported with Copper Oxide (CuO) Nanoparticles.

In this work, copper (II) ions were saturated and copper oxide nanoparticles (CuO NPs) were supported in natural zeolite from Chile; this was achieved by making the adsorbent material come into contact with a copper ion precursor solution and using mechanical agitation, respectively. The kinetic and physicochemical process of the adsorption of copper ions in the zeolite was studied, as well as the effect of the addition of CuO NPs on the antibacterial properties. The results showed that the saturation of copper (II) ions in the zeolite is an efficient process, obtaining a 27 g L-1 concentration of copper ions in a time of 30 min. The TEM images showed that a good dispersion of the CuO NPs was obtained via mechanical stirring. The material effectively inhibited the growth of Gram-negative and Gram-positive bacteria that have shown resistance to methicillin and carbapenem. Furthermore, the zeolite saturated with copper at the same concentration had a better bactericidal effect than the zeolite supported with CuO NPs. The results suggested that the ease of processing and low cost of copper (II) ion-saturated zeolitic material could potentially be used for dental biomedical applications, either directly or as a bactericidal additive for 3D printing filaments.

Electrical properties of tissues from a microscopic model of confined electrolytes.

Objective. In the presence of oscillatory electric fields, the motion of electrolyte ions in biological tissues is often limited by the confinement created by cell and organelle walls. This confinement induces the organization of the ions into dynamic double layers. This work determines the contribution of these double layers to the bulk conductivity and permittivity of tissues.Approach. Tissues are modeled as repeated units of electrolyte regions separated by dielectric walls. Within the electrolyte regions, a coarse-grained model is used to describe the associated ionic charge distribution. The model emphasizes the role of the displacement current in addition to the ionic current and enables the evaluation of macroscopic conductivities and permittivities.Main results. We obtain analytical expressions for the bulk conductivity and permittivity as a function of the frequency of the oscillatory electric field. These expressions explicitly include the geometric information of the repeated structure and the contribution of the dynamic double layers. The low-frequency limit of the conductivity expression yields a result predicted by the Debye permittivity form. The model also provides a microscopic interpretation of the Maxwell-Wagner effect.Significance. The results obtained contribute to the interpretation of the macroscopic measurements of electrical properties of tissues in terms of their microscopic structure. The model enables a critical assessment of the justification for the use of macroscopic models to analyze the transmission of electrical signals through tissues.

Identification of an Optimal TLR8 Ligand by Alternating the Position of 2'-O-Ribose Methylation.

Recognition of RNA by receptors of the innate immune system is regulated by various posttranslational modifications. Different single 2'-O-ribose (2'-O-) methylations have been shown to convert TLR7/TLR8 ligands into specific TLR8 ligands, so we investigated whether the position of 2'-O-methylation is crucial for its function. To this end, we designed different 2'-O-methylated RNA oligoribonucleotides (ORN), investigating their immune activity in various cell systems and analyzing degradation under RNase T2 treatment. We found that the 18S rRNA-derived TLR7/8 ligand, RNA63, was differentially digested as a result of 2'-O-methylation, leading to variations in TLR8 and TLR7 inhibition. The suitability of certain 2'-O-methylated RNA63 derivatives as TLR8 agonists was further demonstrated by the fact that other RNA sequences were only weak TLR8 agonists. We were thus able to identify specific 2'-O-methylated RNA derivatives as optimal TLR8 ligands.

L-lactate as an indicator for cellular metabolic status: An easy and cost-effective colorimetric L-lactate assay.

BACKGROUND: In recent times, the study of metabolic pathways has become inevitable and predominant for a variety of research fields as cancer biology and immunology. L-lactate as a product of anaerobic glycolysis has shown to be an important indicator of the cellular metabolic status and can be associated with diverse cellular effects. For this reason, L-lactate assay kits are of high demand when metabolic effects need to be considered. Nevertheless, commercially available kits are not affordable if multiple samples must be evaluated. PRINCIPAL FINDING: In this work, we develop an easy and cost-effective colorimetric assay for quantification of L-lactate suitable for cells with low or high L-lactate production based on LDH activity and suitable for 96 well-plate format. Using different metabolic regulators, we demonstrate the capacity of the assay to detect and quantify L-lactate from the supernatant of HeLa cancer cell line. Furthermore, we validate the assay against a commercially available kit by demonstrating no significant difference between both assays. Finally, we show that the assay is capable of quantifying L-lactate in primary cells such as hPBMCs that were stimulated with toll-like receptor ligands and treated with different metabolic regulators. CONCLUSION: We herein present an easy custom assay that is suitable for cells with low and high L-lactate production at very low cost compared to commercially available kits. These advantages of the custom assay can simplify the research in the field of metabolism and related fields.

TLR8 is activated by 5'-methylthioinosine, a Plasmodium falciparum-derived intermediate of the purine salvage pathway.

The innate immune recognition of the malaria-causing pathogen Plasmodium falciparum (P. falciparum) is not fully explored. Here, we identify the nucleoside 5'-methylthioinosine (MTI), a Plasmodium-specific intermediate of the purine salvage pathway, as a pathogen-derived Toll-like receptor 8 (TLR8) agonist. Co-incubation of MTI with the TLR8 enhancer poly(dT) as well as synthetic or P. falciparum-derived RNA strongly increase its stimulatory activity. Of note, MTI generated from methylthioadenosine (MTA) by P. falciparum lysates activates TLR8 when MTI metabolism is inhibited by immucillin targeting the purine nucleoside phosphorylase (PfPNP). Importantly, P. falciparum-infected red blood cells incubated with MTI or cultivated with MTA and immucillin lead to TLR8-dependent interleukin-6 (IL-6) production in human monocytes. Our data demonstrate that the nucleoside MTI is a natural human TLR8 ligand with possible in vivo relevance for innate sensing of P. falciparum.

Fibrosis epidural postquirúrgica: presentación de un caso con enfoque médico legal / Postsurgical epidural fibrosis: presentation of a case with a medical-legal approach

Resumen La fibrosis epidural es un hallazgo clínico y radiológico el cual se encuentra relacionado directamente en su génesis con los procedimientos quirúrgicos realizados en la columna vertebral. Esta patología es la causa más frecuente del síndrome de cirugía fallida de columna, manifestada clínicamente como un dolor equiparable en severidad al presentado previo a la intervención quirúrgica realizada. La fibrosis epidural es parte del proceso de cicatrización usual de los tejidos circundantes de la columna vertebral, en otras palabras, es esperable que esta suceda, sin embargo, solo una mínima cantidad de las personas intervenidas desarrollan clínicamente la sintomatología. La importancia del análisis de esta patología radica en que estas valoraciones son ingresadas al Departamento de Medicina Legal por asunto de reagravación de alguna secuela ocasionada por algún evento traumático. Es imprescindible conocer a profundidad los diferentes aspectos etiológicos, fisiopatológicos, clínicos, radiológicos y terapéuticos que involucran esta patología vertebral, así como, el respectivo análisis médico legal en este tipo de casos, tomando en consideración todos los elementos de juicio que permitan relacionar este hallazgo con algún hecho denunciado. En el presente artículo se realizará un análisis médico legal de un caso de reagravación por fibrosis epidural valorado en el Departamento de Medicina Legal de Costa Rica, donde el peritado interpone una denuncia contra el ente asegurador al ser rechazada la posibilidad de reapertura del riesgo laboral presentado.

Abstract The epidural fibrosis is a clinical and radiological finding that is related with the surgical procedures performed on the spine. This pathology is the most frequent cause of failed back syndrome or post laminectomy syndrome, that is clinically manifested by an acute pain comparable in severity with the surgical intervention. Epidural fibrosis is part of the usual healing process of the surrounding tissues of the spine, in other words, it's to be expected as a result of this procedures, nevertheless, only a small number of people who have been intervened, actually develop the symptoms clinically. The importance of this pathology lies in the fact that these assessments are attended in the Legal Medicine Department due to the aggravation issues of any sequel caused by a traumatic event. It is essential to know such things as the etiology, pathophysiology, clinical manifestations, radiological findings, and the therapeutic aspects that involve this vertebral disease, as well as, the respective forensic analysis, in order to use all the elements of judgment that allows to relate what is documented with the denounced findings.

Antigen receptor therapy in bone metastasis via optimal control for different human life stages.

In this work we propose a bone metastasis model using power law growth functions in order to describe the biochemical interactions between bone cells and cancer cells. Experimental studies indicate that bone remodeling cycles are different for human life stages: childhood, young adulthood, and adulthood. In order to include such differences in our study, we estimate the model parameter values for each human life stage via bifurcation analysis. Results reveal an intrinsic relationship between the active period of remodeling cycles and the proliferation of cancer cells. Subsequently, using optimal control theory we analyze a possible antigen receptor therapy as a new treatment for bone metastasis. Theoretical results such as existence of optimal solutions are proved. Numerical simulations for late stages of bone metastasis are presented and a discussion of our results is carried out.

Pimples reduce and dimples enhance flat dielectric surface image repulsion.

In solid-liquid, or liquid-liquid, interfaces with dielectric contrast, charged particles interact with the induced polarization charge of the interface. These interactions contribute to an effective self-energy of the bulk ions and mediate ion-ion interactions. For flat interfaces, the self-energy and the mediated interactions are neatly constructed by the image charge method. For other geometries, explicit results are scarce and the problem must be treated via approximations or direct computation. The case of interfaces with roughness is of great practical importance. This article provides analytical results, valid to first-order in perturbation theory, for the self-energy of particles near rough substrates. Explicit formulas are provided for the case of a sinusoidal deformation of a flat surface. Generic deformations can be treated by superposition. In addition to results for the self-energy, the surface polarization charge is presented as a quadrature. The interaction between an ion and the deformed surface is modified by the change in relative distance as well as by the local curvature of the surface. Solid walls, with a lower dielectric constant than the liquid, repel all ions. We show that the repulsion is reduced by local convexity and enhanced by concavity; dimples are more repulsive than pimples.

Changes in digestive enzyme activities during the early ontogeny of the South American cichlid (Cichlasoma dimerus).

Cichlasoma dimerus is a neotropical cichlid that has been used as a biological model for neuroendocrinology studies. However, its culture is problematic in terms of larval feeding to allow having enough fry quantity and quality. Larviculture requires full knowledge about the digestive system and nutrition; therefore, this study was intended to assess the digestive enzymes' changes at different ages during the early ontogeny. Acid protease activity was detectable from the first day after hatching (dah), increasing to its maximum peaks on 9 dah. In contrast, alkaline proteases had low activity in the first days of life but reached their maximum activity on 17 dah. Chymotrypsin, L-aminopeptidase, and carboxypeptidase A activities increased at 6 dah, while trypsin activity was first detected on 13 dah and reached its maximum activity on 17 dah. Lipase and α-amylase activity were detectable at low levels in the first days of life, but the activity fluctuated and reaching its maximum activity at 21 dah. Alkaline phosphatase continued to oscillate and had two maximum activity peaks, the first at 6 dah and the second at 19 dah. Zymograms of alkaline proteases on day 6 dah six revealed four activity bands with molecular weights from 16.1 to 77.7 kDa. On 13 dah, two more activity bands of 24.4 and 121.9 kDa were detected, having a total of six proteases. The enzymatic activity analyzes indicate the digestive system shows the low activity of some enzymes in the first days after hatching, registering significant increases on 6 dah and the maximum peaks of activities around at 17 dah. Therefore, we recommend replacing live food with dry feed and only providing dry feed after day 17 dah.

Two Archaeal Metagenome-Assembled Genomes from El Tatio Provide New Insights into the Crenarchaeota Phylum.

A phylogenomic and functional analysis of the first two Crenarchaeota MAGs belonging to El Tatio geysers fields in Chile is reported. A soil sample contiguous to a geothermal activity exposed lagoon of El Tatio was used for shotgun sequencing. Afterwards, contigs were binned into individual population-specific genomes data. A phylogenetic placement was carried out for both MAG 9-5TAT and MAG 47-5TAT. Then functional comparisons and metabolic reconstruction were carried out. Results showed that both MAG 9-5TAT and MAG 47-5TAT likely represent new species in the genus Thermoproteus and the genus Sulfolobus, respectively. These findings provide new insights into the phylogenetic and genomic diversity for archaea species that inhabit the El Tatio geysers field and expand the understanding of the Crenarchaeota phylum diversity.

Strange attractors in discrete slow power-law models of bone remodeling.

Recently, a family of nonlinear mathematical discrete systems to describe biological interactions was considered. Such interactions are modeled by power-law functions where the exponents involve regulation processes. Considering exponent values giving rise to hyperbolic equilibria, we show that the systems exhibit irregular behavior characterized by strange attractors. The systems are numerically analyzed for different parameter values. Depending on the initial conditions, the orbits of each system either diverge to infinity or approach a periodic orbit or a strange attractor. Such dynamical behavior is identified by their Lyapunov exponents and local dimension. Finally, an application to the biochemical process of bone remodeling is presented. The existence of deterministic chaos in this process reveals a possible explanation of reproducibility failure and variation of effects in clinical experiments.

Skeletal Development and Deformities in Tench (Tinca tinca): From Basic knowledge to Regular Monitoring Procedure.

Skeletal deformities reduce fish viability, growth, wellbeing, and feed efficiency but also degrade the consumer's perception of aquaculture products. Herein, the skeletal development and the incidence of skeletal deformities in tench (Tinca tinca) reared in semi-extensive conditions has been described in detail for the first time. Larval skeletons were assessed through an acid-free double-staining procedure in 157 individuals, while 274 specimens at the juvenile stage were evaluated through X-ray analysis. The first skeletal structures to be formed were those related with breathing and feeding activities (e.g., Meckel's cartilage and opercula) and were visible in larvae of 4 mm of standard length (SL). The axial skeleton was fully ossified in larvae of 12-17 mm of SL, and the caudal fin complex in larvae with 17-26 mm of SL. At the larval stage, no upper-jaw or opercula deformities were observed, while a low incidence (1-9%) of other severe deformities in the heads of the fish (e.g., lower-jaw deformities) were reported. The incidence of vertebral deformities in tench reared in natural ponds was considerable in larvae (54%) and juveniles (52%). Vertebral deformities (fusion and compression) were the most common deformities found in tench larvae (approximately 30%) and vertebral shape deformity in juveniles (around 10%), being mainly located in the caudal region. Thus, a regular monitoring of the skeletal deformities in tench might help to identify better rearing protocols and improve product quality sold at markets. Characterizing the skeletal development not only in semi-extensive systems such as artificial and natural ponds but also under intensive rearing conditions, seems vital for a sustainable and profitable European tench aquaculture.

Epicondilitis: Revisión bibliográfica desde una perspectiva médico legal / Epicondylitis: Literature review from a legal medical perspective

Resumen La valoración médico legal implica establecer un nexo de causalidad entre lo denunciado por los usuarios y los hallazgos encontrados clínica y radiológicamente, esto implica tener un conocimiento amplio de la biomecánica que permita interrelacionar de manera objetiva un mecanismo de trauma que se relacione en su génesis con el movimiento denunciado. En este artículo se realizará una revisión bibliográfica de la epicondilitis, tomando en consideración todos los aspectos de importancia médico legal.

Abstract The forensic evaluation implies establishing the causality between the story and the clinical and radiologic findings, this implies having a broad knowledge of biomechanics that allows an objective interrelation of a trauma mechanism. This article consists in a bibliographical revision about the etiopathogenesis of the epicondylitis and the interpretation of this patology in relation to medico legal analysis.

A simple model of immune and muscle cell crosstalk during muscle regeneration.

Muscle injury during aging predisposes skeletal muscles to increased damage due to reduced regenerative capacity. Some of the common causes of muscle injury are strains, while other causes are more complex muscle myopathies and other illnesses, and even excessive exercise can lead to muscle damage. We develop a new mathematical model based on ordinary differential equations of muscle regeneration. It includes the interactions between the immune system, healthy and damaged myonuclei as well as satellite cells. Our new mathematical model expands beyond previous ones by accounting for 21 specific parameters, including those parameters that deal with the interactions between the damaged and dead myonuclei, the immune system, and the satellite cells. An important assumption of our model is the replacement of only damaged parts of the muscle fibers and the dead myonuclei. We conduce systematic sensitivity analysis to determine which parameters have larger effects on the model and therefore are more influential for the muscle regeneration process. We propose additional validation for these parameters. We further demonstrate that these simulations are species-, muscle-, and age-dependent. In addition, the knowledge of these parameters and their interactions, may suggest targeting or selecting these interactions for treatments that accelerate the muscle regeneration process.