Osmotically Sensitive TREK Channels in Rat Articular Chondrocytes: Expression and Functional Role.

Articular chondrocytes are the primary cells responsible for maintaining the integrity and functionality of articular cartilage, which is essential for smooth joint movement. A key aspect of their role involves mechanosensitive ion channels, which allow chondrocytes to detect and respond to mechanical forces encountered during joint activity; nonetheless, the variety of mechanosensitive ion channels involved in this process has not been fully resolved so far. Because some members of the two-pore domain potassium (K2P) channel family have been described as mechanosensors in other cell types, in this study, we investigate whether articular chondrocytes express such channels. RT-PCR analysis reveals the presence of TREK-1 and TREK-2 channels in these cells. Subsequent protein expression assessments, including Western blotting and immunohistochemistry, confirm the presence of TREK-1 in articular cartilage samples. Furthermore, whole-cell patch clamp assays demonstrate that freshly isolated chondrocytes exhibit currents attributable to TREK-1 channels, as evidenced by activation by arachidonic acid (AA) and ml335 and further inhibition by spadin. Additionally, exposure to hypo-osmolar shock activates currents, which can be attributed to the presence of TREK-1 channels, as indicated by their inhibition with spadin. Therefore, these findings highlight the expression of TREK channels in rat articular chondrocytes and suggest their potential involvement in regulating the integrity of cartilage extracellular matrix.

Alternative molecular mechanisms for force transmission at adherens junctions via ß-catenin-vinculin interaction.

Force transmission through adherens junctions (AJs) is crucial for multicellular organization, wound healing and tissue regeneration. Recent studies shed light on the molecular mechanisms of mechanotransduction at the AJs. However, the canonical model fails to explain force transmission when essential proteins of the mechanotransduction module are mutated or missing. Here, we demonstrate that, in absence of α-catenin, ß-catenin can directly and functionally interact with vinculin in its open conformation, bearing physiological forces. Furthermore, we found that ß-catenin can prevent vinculin autoinhibition in the presence of α-catenin by occupying vinculin´s head-tail interaction site, thus preserving force transmission capability. Taken together, our findings suggest a multi-step force transmission process at AJs, where α-catenin and ß-catenin can alternatively and cooperatively interact with vinculin. This can explain the graded responses needed to maintain tissue mechanical homeostasis and, importantly, unveils a force-bearing mechanism involving ß-catenin and extended vinculin that can potentially explain the underlying process enabling collective invasion of metastatic cells lacking α-catenin.

Mechanobiological Modulation of In Vitro Astrocyte Reactivity Using Variable Gel Stiffness.

After traumatic brain injury, the brain extracellular matrix undergoes structural rearrangement due to changes in matrix composition, activation of proteases, and deposition of chondroitin sulfate proteoglycans by reactive astrocytes to produce the glial scar. These changes lead to a softening of the tissue, where the stiffness of the contusion "core" and peripheral "pericontusional" regions becomes softer than that of healthy tissue. Pioneering mechanotransduction studies have shown that soft substrates upregulate intermediate filament proteins in reactive astrocytes; however, many other aspects of astrocyte biology remain unclear. Here, we developed a platform for the culture of cortical astrocytes using polyacrylamide (PA) gels of varying stiffness (measured in Pascal; Pa) to mimic injury-related regions in order to investigate the effects of tissue stiffness on astrocyte reactivity and morphology. Our results show that substrate stiffness influences astrocyte phenotype; soft 300 Pa substrates led to increased GFAP immunoreactivity, proliferation, and complexity of processes. Intermediate 800 Pa substrates increased Aggrecan+, Brevican+, and Neurocan+ astrocytes. The stiffest 1 kPa substrates led to astrocytes with basal morphologies, similar to a physiological state. These results advance our understanding of astrocyte mechanotransduction processes and provide evidence of how substrates with engineered stiffness can mimic the injury microenvironment.

Blood flow-bearing physical forces, endothelial glycocalyx, and liver enzyme mobilization: A hypothesis.

Numerous elements involved in shear stress-induced signaling have been identified, recognizing their functions as mechanotransducing ion channels situated at cellular membranes. This form of mechanical signaling relies on transmembrane proteins and cytoplasmic proteins that restructure the cytoskeleton, contributing to mechanotransduction cascades. Notably, blood flow generates mechanical forces that significantly impact the structure and remodeling of blood vessels. The primary regulation of blood vessel responses occurs through hemodynamic forces acting on the endothelium. These mechanical events intricately govern endothelial biophysical, biochemical, and genetic responses. Endothelial cells, positioned on the intimal surface of blood vessels, have the capability to express components of the glycocalyx. This endothelial structure emerges as a pivotal factor in mechanotransduction and the regulation of vascular tone. The endothelial glycocalyx assumes diverse roles in both health and disease. Our findings propose a connection between the release of specific enzymes from the rat liver and variations in the hepatic blood flow/mass ratio. Importantly, this phenomenon is not correlated with liver necrosis. Consequently, this review serves as an exploration of the potential involvement of membrane proteins in a hypothetical mechanotransducing phenomenon capable of controlling the release of liver enzymes.

Alignment behavior of nerve, vascular, muscle, and intestine cells in two- and three-dimensional strategies.

By harnessing structural hierarchical insights, plausibly simulate better ones imagination to figure out the best choice of methods for reaching out the unprecedented developments of the tissue engineering products as a next level. Constructing a functional tissue that incorporates two-dimensional (2D) or higher dimensions requires overcoming technological or biological limitations in order to orchestrate the structural compilation of one-dimensional and 2D sheets (microstructures) simultaneously (in situ). This approach enables the creation of a layered structure that can be referred to as an ensemble of layers or, after several days of maturation, a direct or indirect joining of layers. Here, we have avoided providing a detailed methodological description of three-dimensional and 2D strategies, except for a few interesting examples that highlight the higher alignment of cells and emphasize rarely remembered facts associated with vascular, peripheral nerve, muscle, and intestine tissues. The effective directionality of cells in conjunction with geometric cues (in the range of micrometers) is well known to affect a variety of cell behaviors. The curvature of a cell's environment is one of the factors that influence the formation of patterns within tissues. The text will cover cell types containing some level of stemness, which will be followed by their consequences for tissue formation. Other important considerations pertain to cytoskeleton traction forces, cell organelle positioning, and cell migration. An overview of cell alignment along with several pivotal molecular and cellular level concepts, such as mechanotransduction, chirality, and curvature of structure effects on cell alignments will be presented. The mechanotransduction term will be used here in the context of the sensing capability that cells show as a result of force-induced changes either at the conformational or the organizational levels, a capability that allows us to modify cell fate by triggering downstream signaling pathways. A discussion of the cells' cytoskeleton and of the stress fibers involvement in altering the cell's circumferential constitution behavior (alignment) based on exposed scaffold radius will be provided. Curvatures with size similarities in the range of cell sizes cause the cell's behavior to act as if it was in an in vivo tissue environment. The revision of the literature, patents, and clinical trials performed for the present study shows that there is a clear need for translational research through the implementation of clinical trial platforms that address the tissue engineering possibilities raised in the current revision. This article is categorized under: Infectious Diseases > Biomedical Engineering Neurological Diseases > Biomedical Engineering Cardiovascular Diseases > Biomedical Engineering.

Absence of HDAC3 by Matrix Stiffness Promotes Chromatin Remodeling and Fibroblast Activation in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease characterized by progressive and irreversible lung scarring associated with persistent activation of fibroblasts. Epigenetics could integrate diverse microenvironmental signals, such as stiffness, to direct persistent fibroblast activation. Histone modifications by deacetylases (HDAC) may play an essential role in the gene expression changes involved in the pathological remodeling of the lung. Particularly, HDAC3 is crucial for maintaining chromatin and regulating gene expression, but little is known about its role in IPF. In the study, control and IPF-derived fibroblasts were used to determine the influence of HDAC3 on chromatin remodeling and gene expression associated with IPF signature. Additionally, the cells were grown on hydrogels to mimic the stiffness of a fibrotic lung. Our results showed a decreased HDAC3 in the nucleus of IPF fibroblasts, which correlates with changes in nucleus size and heterochromatin loss. The inhibition of HDAC3 with a pharmacological inhibitor causes hyperacetylation of H3K9 and provokes an increased expression of Col1A1, ACTA2, and p21. Comparable results were found in hydrogels, where matrix stiffness promotes the loss of nuclear HDAC3 and increases the profibrotic signature. Finally, latrunculin b was used to confirm that changes by stiffness depend on the mechanotransduction signals. Together, these results suggest that HDAC3 could be a link between epigenetic mechanisms and the fibrotic microenvironment.

Actin Stress Fibers Response and Adaptation under Stretch.

One of the many effects of soft tissues under mechanical solicitation in the cellular damage produced by highly localized strain. Here, we study the response of peripheral stress fibers (SFs) to external stretch in mammalian cells, plated onto deformable micropatterned substrates. A local fluorescence analysis reveals that an adaptation response is observed at the vicinity of the focal adhesion sites (FAs) due to its mechanosensor function. The response depends on the type of mechanical stress, from a Maxwell-type material in compression to a complex scenario in extension, where a mechanotransduction and a self-healing process takes place in order to prevent the induced severing of the SF. A model is proposed to take into account the effect of the applied stretch on the mechanics of the SF, from which relevant parameters of the healing process are obtained. In contrast, the repair of the actin bundle occurs at the weak point of the SF and depends on the amount of applied strain. As a result, the SFs display strain-softening features due to the incorporation of new actin material into the bundle. In contrast, the response under compression shows a reorganization with a constant actin material suggesting a gliding process of the SFs by the myosin II motors.

Mecanosensores en el cambio de fenotipo de la musculatura lisa vascular / Mechanosensors and phenotype changes in vascular smooth muscle

Resumen: Introducción: Las células de la musculatura lisa vascular (CMLV) se caracterizan por mantener cierto grado de desdiferenciación, variando su fenotipo entre el contráctil y el secretor, de acuerdo con las necesidades del tejido, y el contráctil predominante en condiciones fisiológicas. Cualquier alteración del estímulo mecánico, ya sea en el flujo sanguíneo o la tensión mecánica ejercida sobre las CMLV, conducen a cambios de su fenotipo y remodelamiento de la vasculatura, lo que puede constituir el punto de inflexión de varias patologías relevantes en la salud pública como, por ejemplo, la hipertensión arterial. Objetivo: Realizar una revisión sobre los mecanosensores y las vías transduccionales conocidas e implicadas en el cambio de fenotipo de las CMLV. Metodología: Se realizó una búsqueda sistemática en las bases de datos PubMed, Scopus, Google Académico y Scielo sobre la mantención y cambio de fenotipo de las células de la musculatura lisa vascular asociado principalmente a el estrés mecánico, la participación de los mecanosensores más relevantes y las vías de señalización involucrados en este proceso. Conclusión: Los mecanosensores implicados en el cambio de fenotipo de las CMLV contemplan principalmente receptores acoplados a proteína G, moléculas de adhesión y canales iónicos activados por estiramiento. Los estudios se han concentrado en la activación o inhibición de vías como las proteínas quinasas activadas por mitógenos (MAPK), la vía AKT, mTOR y factores transcripcionales que regulan la expresión de genes de diferenciación y/o desdiferenciación, como las miocardinas. Existen además otros receptores involucrados en la respuesta al estrés mecánico, como los receptores tirosina quinasas. A pesar de la importancia que reviste el conocimiento de los mecanosensores y las vías implicadas en el cambio de fenotipo de las CMLV, así como el papel que cumplen en el establecimiento de patologías vasculares, es aún escaso el conocimiento que se tiene sobre los mismos.

Abstract: Introduction: Vascular smooth muscle cells (VS- MCs) are characterized by maintaining a certain de- gree of dedifferentiation. VSMCs may vary their phenotype between contractile and secretory according to tissue needs. Under physiological conditions, the predominant phenotype is contractile. Any alteration of the mechanical stimulus, either in the blood flow or the mechanical stress exerted on the VSMCs, leads to changes in their phenotype and remodeling of the vasculature. These changes can constitute the turning point in several hypertension and other diseases relevant in public health. Objective: To review the main mechanosensor and transduction pathways involved changes in VSMCs phenotype. Methods: A systematic search of PubMed, Scopus, Google Scholar and Scielo databases was carried out to ascertain the state of the art regarding the maintenance and change of VSMCs phenotype mainly associated with mechanical stress. Additionally, the participation of the most relevant mechanosensors and the signaling pathways involved in this process are discussed. Conclusion: The mechanosensors involved in the change in VSMCs phenotype mainly contempla- te G-protein-coupled receptors, adhesion molecules, and stretch-activated ion channels. Studies have been focused on the activation or inhibition of MAPK, AKT, mTOR, pathways and transcriptional factors that regulate the expression of differentiation and/or des differentiation genes such as Myocardins. There are also other receptors involved in the response to mechanical stress such as the tyrosine kinases receptor. Although the importance of understanding mechanosensors, the signaling pathways involved in VSMC phenotype switching and their role in the establishment of vascular pathologies, knowledge about them is limited.

Social-like responses are inducible in asocial Mexican cavefish despite the exhibition of strong repetitive behavior.

Social behavior is a hallmark of complex animal systems; however, some species appear to have secondarily lost this social ability. In these non-social species, whether social abilities are permanently lost or suppressed is unclear. The blind cavefish Astyanax mexicanus is known to be asocial. Here, we reveal that cavefish exhibited social-like interactions in familiar environments but suppressed these interactions in stress-associated unfamiliar environments. Furthermore, the level of suppression in sociality was positively correlated with that of stereotypic repetitive behavior, as seen in mammals. Treatment with a human antipsychotic drug targeting the dopaminergic system induced social-like interactions in cavefish, even in unfamiliar environments, while reducing repetitive behavior. Overall, these results suggest that the antagonistic association between repetitive and social-like behaviors is deeply shared from teleosts through mammals.

Focal adhesion signaling: vascular smooth muscle cell contractility beyond calcium mechanisms.

Smooth muscle cell (SMC) contractility is essential to vessel tone maintenance and blood pressure regulation. In response to vasoconstrictors, calcium-dependent mechanisms promote the activation of the regulatory myosin light chain, leading to increased cytoskeleton tension that favors cell shortening. In contrast, SMC maintain an intrinsic level of a contractile force independent of vasoconstrictor stimulation and sustained SMC contraction beyond the timescale of calcium-dependent mechanisms suggesting the involvement of additional players in the contractile response. Focal adhesions (FAs) are conceivable candidates that may influence SMC contraction. They are required for actin-based traction employed by cells to sense and respond to environmental cues in a process termed mechanotransduction. Depletion of FA proteins impairs SMC contractility, producing arteries that are prone to dissection because of a lack of mechanical stability. Here, we discuss the role of calcium-independent FA signaling mechanisms in SMC contractility. We speculate that FA signaling contributes to the genesis of a variety of SMC phenotypes and discuss the potential implications for mechanical homeostasis in normal and diseased states.

The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises.

The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways' role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.

Pannexin Channel Regulation of Cell Migration: Focus on Immune Cells.

The role of Pannexin (PANX) channels during collective and single cell migration is increasingly recognized. Amongst many functions that are relevant to cell migration, here we focus on the role of PANX-mediated adenine nucleotide release and associated autocrine and paracrine signaling. We also summarize the contribution of PANXs with the cytoskeleton, which is also key regulator of cell migration. PANXs, as mechanosensitive ATP releasing channels, provide a unique link between cell migration and purinergic communication. The functional association with several purinergic receptors, together with a plethora of signals that modulate their opening, allows PANX channels to integrate physical and chemical cues during inflammation. Ubiquitously expressed in almost all immune cells, PANX1 opening has been reported in different immunological contexts. Immune activation is the epitome coordination between cell communication and migration, as leukocytes (i.e., T cells, dendritic cells) exchange information while migrating towards the injury site. In the current review, we summarized the contribution of PANX channels during immune cell migration and recruitment; although we also compile the available evidence for non-immune cells (including fibroblasts, keratinocytes, astrocytes, and cancer cells). Finally, we discuss the current evidence of PANX1 and PANX3 channels as a both positive and/or negative regulator in different inflammatory conditions, proposing a general mechanism of these channels contribution during cell migration.

Fabrication of Adhesive Substrate for Incorporating Hydrogels to Investigate the Influence of Stiffness on Cancer Cell Behavior.

Stiffness control of cell culture platforms provides researchers in cell biology with the ability to study different experimental models in conditions of mimicking physiological or pathological microenvironments. Nevertheless, the signal transduction pathways and drug sensibility of cancer cells have been poorly characterized widely using biomimetic platforms because the limited experience of cancer cell biology groups about handling substrates with specific mechanical properties. The protein cross-linking and stiffening control are crucial checkpoints that could strongly affect cell adhesion and spreading, misrepresenting the data acquired, and also generating inaccurate cellular models. Here, we introduce a simple method to adhere to polyacrylamide (PAA) hydrogels on glass coverslips without any special treatment for mechanics studies in cancer cell biology. By using a commercial photosensitive glue, Loctite 3525, it is possible to polymerize PAA hydrogels directly on glass surfaces. Furthermore, we describe a cross-linking reaction method to attach proteins to PAA as an alternative method to Sulfo-SANPAH cross-linking, which is sometimes difficult to implement and reproduce. In this chapter, we describe a reliable procedure to fabricate ECM protein-cross-linked PAA hydrogels for mechanotransduction studies on cancer cells.

Bone fracture healing: perspectives according to molecular basis.

Fractures have a great impact on health all around the world and with fracture healing optimization; this problem could be resolved partially. To make a practical contribution to this issue, the knowledge of bone tissue, cellularity, and metabolism is essential, especially cytoskeletal architecture and its transformations according to external pressures. Special physical and chemical characteristics of the extracellular matrix (ECM) allow the transmission of mechanical stimuli from outside the cell to the plasmatic membrane. The osteocyte cytoskeleton is conformed by a complex network of actin and microtubules combined with crosslinker proteins like vinculin and fimbrin, connecting and transmitting outside stimuli through EMC to cytoplasm. Herein, critical signaling pathways like Cx43-depending ones, MAPK/ERK, Wnt, YAP/TAZ, Rho-ROCK, and others are activated due to mechanical stimuli, resulting in osteocyte cytoskeletal changes and ECM remodeling, altering the tissue and, therefore, the bone. In recent years, the osteocyte has gained more interest and value in relation to bone homeostasis as a great coordinator of other cell populations, thanks to its unique functions. By integrating the latest advances in relation to intracellular signaling pathways, mechanotransmission system of the osteocyte and bone tissue engineering, there are promising experimental strategies, while some are ready for clinical trials. This work aims to show clearly and precisely the integration between cytoskeleton and main molecular pathways in relation to mechanotransmission mechanism in osteocytes, and the use of this theoretical knowledge in therapeutic tools for bone fracture healing.

Stretch-Induced Activation of Pannexin 1 Channels Can Be Prevented by PKA-Dependent Phosphorylation.

Pannexin 1 channels located in the cell membrane are permeable to ions, metabolites, and signaling molecules. While the activity of these channels is known to be modulated by phosphorylation on T198, T308, and S206, the possible involvement of other putative phosphorylation sites remains unknown. Here, we describe that the activity of Panx1 channels induced by mechanical stretch is reduced by adenosine via a PKA-dependent pathway. The mechanical stretch-induced activity-measured by changes in DAPI uptake-of Panx1 channels expressed in HeLa cell transfectants was inhibited by adenosine or cAMP analogs that permeate the cell membrane. Moreover, inhibition of PKA but not PKC, p38 MAPK, Akt, or PKG prevented the effects of cAMP analogs, suggesting the involvement of Panx1 phosphorylation by PKA. Accordingly, alanine substitution of T302 or S328, two putative PKA phosphorylation sites, prevented the inhibitory effect of cAMP analogs. Moreover, phosphomimetic mutation of either T302 or S328 to aspartate prevented the mechanical stretch-induced activation of Panx1 channels. A molecular dynamics simulation revealed that T302 and S328 are located in the water-lipid interphase near the lateral tunnel of the intracellular region, suggesting that their phosphorylation could promote conformational changes in lateral tunnels. Thus, Panx1 phosphorylation via PKA could be modulated by G protein-coupled receptors associated with the Gs subunit.

Relationship between the polymorphism in the interleukin 1-ß and the treatment time of patients subjected to a modified piezocision technique.

AIM: We aimed to evaluate the correlation between the polymorphism of the interleukin 1-Beta (IL1-ß, +3954 C>T) and tooth movement, in a group of Colombian patients undergoing surgically accelerated orthodontic tooth movement. METHODS: The study was nested to a controlled clinical trial. Blood samples were taken from 11 women and 29 healthy Colombian male volunteers between 18 and 40 years old, after 1 year of starting orthodontic treatment. The patients presented malocclusion class I, with grade II or III. To detect the genetic polymorphism of the nucleotide +3954 C to T in the IL-1ß gene, we used a real-time PCR assay. RESULTS: Eleven individuals presented the allele 2 (T) heterozygous with the allele 1 (T/C) and 19 individuals were homozygous for the allele 1 (C/C). When analyzing the presence of the SNP, no significant differences were found in any of the variables. The best treatment was reflected in Group 3 (selective upper and lower alveolar decortication and 3D collagen matrix) and Group 4 (only selective alveolar decortication in the upper arch, with 3D collagen matrix), with 27% and 35% more speed respectively than in the control group. CONCLUSIONS: Our analyses indicated that a reduction in the total treatment time can be mostly potentiated by using decortication and collagen matrices and not for the presence of the allele 2 in the IL-1ß. Nevertheless, it is important that further studies investigate if the polymorphism could be associated with the speed of tooth movement and analyze the baseline protein levels.

OBJETIVO: Evaluar la correlación entre el polimorfismo de la interleucina 1-Beta (IL1-ß, +3954 C> T) y el movimiento de los dientes, en un grupo de pacientes colombianos sometidos a un movimiento dental ortodóncico acelerado quirúrgicamente. MÉTODOS: Este fue un estudio secundario derivado de un ensayo clínico aleatorio controlado. Se tomaron muestras de sangre de 11 mujeres y 29 voluntarios varones colombianos sanos entre 18 y 40 años, después de 1 año de comenzar el tratamiento de ortodoncia. Los pacientes presentaron maloclusión clase I, con grado II o III. Para detectar el polimorfismo genético del nucleótido +3954 C a T en el gen IL-1ß, se usó un ensayo de PCR en tiempo real. RESULTADOS: 11 individuos presentaron el alelo 2 (T) heterocigoto con el alelo 1 (T / C) y 19 individuos fueron homocigotos para el alelo 1 (C / C). Al analizar la presencia del SNP, no se encontraron diferencias significativas en ninguna de las variables. El mejor tratamiento se reflejó en el Grupo 3 (decorticación alveolar superior e inferior selectiva y matriz de colágeno 3D) y el Grupo 4 (solo decorticación alveolar selectiva en el arco superior, con matriz de colágeno 3D), con un 27% y un 35% más de velocidad, respectivamente, que en el grupo de control. CONCLUSIONES: Los análisis indicaron que una reducción en el tiempo total de tratamiento puede potenciarse principalmente mediante el uso de decorticación y matrices de colágeno y no por la presencia del alelo 2 en la IL-1ß. Sin embargo, es importante que otros estudios investiguen si el polimorfismo podría estar asociado con la velocidad del movimiento de los dientes y analizar los niveles de proteína de referencia.

Extracellular matrix stiffness and Wnt/ß-catenin signaling in physiology and disease.

The Wnt/ß-catenin signaling pathway plays fundamental roles during development, stem cell differentiation, and homeostasis, and its abnormal activation can lead to diseases. In recent years, it has become clear that this pathway integrates signals not only from Wnt ligands but also from other proteins and signaling routes. For instance, Wnt/ß-catenin signaling involves YAP and TAZ, which are transcription factors with crucial roles in mechanotransduction. On the other hand, Wnt/ß-catenin signaling is also modulated by integrins. Therefore, mechanical signals might similarly modulate the Wnt/ß-catenin pathway. However, and despite the relevance that mechanosensitive Wnt/ß-catenin signaling might have during physiology and diseases such as cancer, the role of mechanical cues on Wnt/ß-catenin signaling has received less attention. This review aims to summarize recent evidence regarding the modulation of the Wnt/ß-catenin signaling by a specific type of mechanical signal, the stiffness of the extracellular matrix. The review shows that mechanical stiffness can indeed modulate this pathway in several cell types, through differential expression of Wnt ligands, receptors and inhibitors, as well as by modulating ß-catenin levels. However, the specific mechanisms are yet to be fully elucidated.

The Endothelial Glycocalyx: A Fundamental Determinant of Vascular Permeability in Sepsis.

OBJECTIVES: Sepsis is a significant cause of morbidity and mortality. Children with sepsis often have alterations in microcirculation and vascular permeability. Our objective is current evidence regarding the role of the endothelial glycocalyx as a determinant of capillary leakage in these patients. DATA SOURCES: We reviewed PubMed, EMBASE, and Google scholar using MeSH terms "glycocalyx", "fluids", "syndecan", "endothelium", "vascular permeability", "edema", "sepsis", "septic shock", "children". STUDY SELECTION: Articles in all languages were included. We include all studies in animals and humans related to glycocalyx and vascular permeability. DATA EXTRACTION: Studies in children and adults, as well as animal studies, were included. DATA SYNTHESIS: One of the fundamental components of the endothelial barrier structure is the glycocalyx. It is a variable thickness layer distributed throughout the whole body, which fulfills a very important function for life: the regulation of blood vessel permeability to water and solutes, favoring vascular protection, modulation, and hemostasis. In the last few years, there has been a special interest in glycocalyx disorders and their relationship to increased vascular permeability, especially in patients with sepsis in whom the alterations that occur in the glycocalyx are unknown when they are subjected to different water resuscitation strategies, vasopressors, etc. This review describes the structural and functional characteristics of the glycocalyx, alterations in patients with sepsis, with regard to its importance in vascular permeability conservation and the possible impact of strategies to prevent and/or treat the injury of this fundamental structure. CONCLUSIONS: The endothelial glycocalyx is a fundamental component of the endothelium and an important determinant of the mechanotransduction and vascular permeability in patients with sepsis. Studies are needed to evaluate the role of the different types of solutions used in fluid bolus, vasoactive support, and other interventions described in pediatric sepsis on microcirculation, particularly on endothelial integrity and the glycocalyx.

Relationship between the polymorphism in the interleukin 1-β and the treatment time of patients subjected to a modified piezocision technique / Relación entre el polimorfismo en la interleucina 1-β y el tiempo de tratamiento de pacientes sometidos a una técnica de piezocisión modificada

Abstract Aim: We aimed to evaluate the correlation between the polymorphism of the interleukin 1-Beta (IL1-β, +3954 C>T) and tooth movement, in a group of Colombian patients undergoing surgically accelerated orthodontic tooth movement. Methods: The study was nested to a controlled clinical trial. Blood samples were taken from 11 women and 29 healthy Colombian male volunteers between 18 and 40 years old, after 1 year of starting orthodontic treatment. The patients presented malocclusion class I, with grade II or III. To detect the genetic polymorphism of the nucleotide +3954 C to T in the IL-1β gene, we used a real-time PCR assay. Results: Eleven individuals presented the allele 2 (T) heterozygous with the allele 1 (T/C) and 19 individuals were homozygous for the allele 1 (C/C). When analyzing the presence of the SNP, no significant differences were found in any of the variables. The best treatment was reflected in Group 3 (selective upper and lower alveolar decortication and 3D collagen matrix) and Group 4 (only selective alveolar decortication in the upper arch, with 3D collagen matrix), with 27% and 35% more speed respectively than in the control group. Conclusions: Our analyses indicated that a reduction in the total treatment time can be mostly potentiated by using decortication and collagen matrices and not for the presence of the allele 2 in the IL-1β. Nevertheless, it is important that further studies investigate if the polymorphism could be associated with the speed of tooth movement and analyze the baseline protein levels.

Resumen Objetivo: Evaluar la correlación entre el polimorfismo de la interleucina 1-Beta (IL1-β, +3954 C> T) y el movimiento de los dientes, en un grupo de pacientes colombianos sometidos a un movimiento dental ortodóncico acelerado quirúrgicamente. Métodos: Este fue un estudio secundario derivado de un ensayo clínico aleatorio controlado. Se tomaron muestras de sangre de 11 mujeres y 29 voluntarios varones colombianos sanos entre 18 y 40 años, después de 1 año de comenzar el tratamiento de ortodoncia. Los pacientes presentaron maloclusión clase I, con grado II o III. Para detectar el polimorfismo genético del nucleótido +3954 C a T en el gen IL-1β, se usó un ensayo de PCR en tiempo real. Resultados: 11 individuos presentaron el alelo 2 (T) heterocigoto con el alelo 1 (T / C) y 19 individuos fueron homocigotos para el alelo 1 (C / C). Al analizar la presencia del SNP, no se encontraron diferencias significativas en ninguna de las variables. El mejor tratamiento se reflejó en el Grupo 3 (decorticación alveolar superior e inferior selectiva y matriz de colágeno 3D) y el Grupo 4 (solo decorticación alveolar selectiva en el arco superior, con matriz de colágeno 3D), con un 27% y un 35% más de velocidad, respectivamente, que en el grupo de control. Conclusiones: Los análisis indicaron que una reducción en el tiempo total de tratamiento puede potenciarse principalmente mediante el uso de decorticación y matrices de colágeno y no por la presencia del alelo 2 en la IL-1β. Sin embargo, es importante que otros estudios investiguen si el polimorfismo podría estar asociado con la velocidad del movimiento de los dientes y analizar los niveles de proteína de referencia.

Phase-Specific Motor Efference during a Rhythmic Motor Pattern.

Neuronal circuits that control motor behaviors orchestrate multiple tasks, including the inhibition of self-generated sensory signals. In the hermaphroditic leech, T and P mechanosensory neurons respond to light touch and pressure on the skin, respectively. We show that the low threshold T cells were also sensitive to topological changes of the animal surface, caused by contraction of the muscles that erect the skin annuli. P cells were unresponsive to this movement. Annuli erection is part of the contraction phase of crawling, a leech locomotive behavior. In isolated ganglia, T cells showed phase-dependent IPSPs during dopamine-induced fictive crawling, whereas P cells were unaffected. The timing and magnitude of the T-IPSPs were highly correlated with the activity of the motoneurons excited during the contraction phase. Together, the results suggest that the central network responsible for crawling sends a reafferent signal onto the T cells, concomitant with the signal to the motoneurons. This reafference is specifically targeted at the sensory neurons that are affected by the movements; and it is behaviorally relevant as excitation of T cells affected the rhythmic motor pattern, probably acting upon the rhythmogenic circuit. Corollary discharge is a highly conserved function of motor systems throughout evolution, and we provide clear evidence of the specificity of its targets and timing and of the benefit of counteracting self-generated sensory input.SIGNIFICANCE STATEMENT Neuronal circuits that control motor behaviors orchestrate multiple tasks, including inhibition of sensory signals originated by the animal movement, a phenomenon known as corollary discharge. Leeches crawl on solid surfaces through a sequence of elongation and contraction movements. During the contraction, the skin topology changes, affecting a subpopulation of mechanosensory receptors, T (touch) neurons, but not P (pressure) sensory neurons. In the isolated nervous system, T neurons were inhibited during the contraction but not during the elongation phase, whereas P cells were unaffected throughout crawling. Excitation of T cells during the contraction phase temporarily disrupted the rhythmic pattern. Thus, corollary discharge was target (T vs P) and phase (contraction vs elongation) specific, and prevented self-generated signals to perturb motor behaviors.