Abstract The effect of peptide toxins on voltage-gated ion channels can be reliably assessed using electrophysiological assays, such as the patch-clamp technique. However, much of the toxinological research done in Central and South America aims at purifying and characterizing biochemical properties of the toxins of vegetal or animal origin, lacking electrophysiological approaches. This may happen due to technical and infrastructure limitations or because researchers are unfamiliar with the techniques and cellular models that can be used to gain information about the effect of a molecule on ion channels. Given the potential interest of many research groups in the highly biodiverse region of Central and South America, we reviewed the most relevant conceptual and methodological developments required to implement the evaluation of the effect of peptide toxins on mammalian voltage-gated ion channels using patch-clamp. For that, we searched MEDLINE/PubMed and SciELO databases with different combinations of these descriptors: “electrophysiology”, “patch-clamp techniques”, “Ca2+ channels”, “K+ channels”, “cnidarian venoms”, “cone snail venoms”, “scorpion venoms”, “spider venoms”, “snake venoms”, “cardiac myocytes”, “dorsal root ganglia”, and summarized the literature as a scoping review. First, we present the basics and recent advances in mammalian voltage-gated ion channel’s structure and function and update the most important animal sources of channel-modulating toxins (e.g. cnidarian and cone snails, scorpions, spiders, and snakes), highlighting the properties of toxins electrophysiologically characterized in Central and South America. Finally, we describe the local experience in implementing the patch-clamp technique using two models of excitable cells, as well as the participation in characterizing new modulators of ion channels derived from the venom of a local spider, a toxins’ source less studied with electrophysiological techniques. Fostering the implementation of electrophysiological methods in more laboratories in the region will strengthen our capabilities in many fields, such as toxinology, toxicology, pharmacology, natural products, biophysics, biomedicine, and bioengineering. voltagegated voltage gated assays patchclamp patch clamp However origin approaches patchclamp. clamp. MEDLINEPubMed MEDLINE PubMed descriptors electrophysiology, electrophysiology , “electrophysiology” techniques, techniques” Ca2+ Ca2 Ca “Ca2 channels, channels” K+ K “K venoms, venoms venoms” scorpion spider snake cardiac myocytes, myocytes myocytes” dorsal ganglia, ganglia ganglia” review First channel s channelmodulating modulating e.g. eg e g (e.g snails scorpions spiders snakes, snakes snakes) Finally cells fields toxinology toxicology pharmacology products biophysics biomedicine bioengineering “electrophysiology “Ca e.g

Resumen La hipertensión arterial pulmonar (HAP) representa el 2,6% de los trasplantes pulmonares (TP), con una mediana de supervivencia condi cional (desde los 30 días del TP) de 9,8 años. Son frecuentes, el rechazo celular agudo (ACR) y la disfunción crónica del injerto (CLAD), mientras que es infrecuente el rechazo mediado por anticuerpos (AMR). El retrasplante pulmonar (RTP) constituye el 4% del TP mundial, debido a complicaciones en la vía aérea, disfunción primaria del injerto, ACR y CLAD. Mujer de 22 años, portadora de HAP idiopática (HAPI) desde el año 2013, trasplantada bipulmonar (TBP) en enero de 2018. A los 16 meses presentó neumonía adquirida en la comuni dad. En una internación posterior, presentó ACR y a pesar de pulsos de metilprednisolona, progresó a requerimientos de cánula de alto flujo y ventilación mecánica no invasiva hospitalaria, caída del VEF1, y tomografía de tórax con vidrio esmerilado difuso y engrosamiento irregular reticular del intersticio subpleural; interpretándose como CLAD a predominio de síndrome de bronquiolitis obliterante (BOS), con presencia de anticuerpos específicos contra el donante (DSA). En enero de 2020 se realizó nuevo TP y ante cross-match positivo, se realizó plasmaféresis y reposición de IgG. Al mes del egreso, no se observaron signos de rechazo en control de biopsias transbronquiales. Entre 2 y 10% de los pacientes con indicación primaria de TP por HAPI son sometidos a retrasplante pulmonar (RTP). La presencia de DSA y el miss-match de HLA, no son contraindicaciones para el RTP.

Abstract Pulmonary arterial hypertension (PAH) represents 2.6% of lung transplantations (LT), with a conditional median survival (from 30 days after LT) of 9.8 years. Acute cellular rejection (ACR) and chronic lung allograft dysfunction (CLAD) are common; whereas the antibody-mediated rejection (AMR) is not. Lung retransplantation (LR) accounts for 4% of global LTs for complications in the airways, primary allograft dys function, ACR and CLAD. 22-year-old woman with idiopathic PAH (IPAH) since 2013, who underwent a double-lung transplantation (DLT) in January 2018. 16 months after transplantation she presented community-acquired pneumonia. During a subsequent hospitalization, she presented ACR. Despite the fact that she received pulse methylprednisolone, she required high-flow cannula therapy and hospital non-invasive mechanical ventilation; the FEV1 was reduced and she underwent a chest tomography with diffuse ground glass opacities and irregular reticular thickening of the subpleural interstitium; interpreting the predominance of BOS (bronchiolitis obliterans syndrome) as CLAD, with presence of donor-specific antibodies (DSA). In January 2020, she received a new DLT and due to a positive crossmatch, she was treated with plasmapheresis and IgG replacement. One month after hospital discharge, no signs of rejection were observed at the BTB (bone-patellar tendon-bone) control. Between 2 to 10% of patients with primary indication of LT for IPAH are subjected to lung retransplantation (LR). The presence of DSA and HLA (human leucocyte antigen) mismatch aren’t contraindications to LR.

In this paper a numerical index for quantifying state controllability for continuous and smooth nonlinear systems is proposed. With information obtained from the reachable and controllable sets, a reversible set at time t for a given system is defined. Size and shape measurements of a reversible set in an n-dimensional space are proposed allowing state controllability on a scale from zero to one. Procedures to compute such indexes are detailed. State controllability index is computed for three study cases verifying its correspondence with real controllability. The inclusion of time and admissible input constraints for state controllability analysis of nonlinear systems showed to be a useful tool for real control system implementation.

En este artículo se propone un índice numérico para cuantificar la controlabilidad de estado para sistemas no lineales suaves y continuos en el tiempo. Con base en la información contenida en los conjuntos alcanzable y controlable, se define el conjunto reversible en un tiempo t para un sistema dado. Se propone una medida del tamaño y de la forma del conjunto reversible en un espacio n-dimensional, las cuales permiten cuantificar la controlabilidad de estado en una escala de cero a uno, y se definen procedimientos de cálculo adecuados. Se calcula el índice de controlabilidad para tres casos de estudio verificando así su correspondencia con la controlabilidad real. La inclusión del factor tiempo y las restricciones en las acciones de control para el análisis de controlabilidad de sistemas no lineales resulta ser una herramienta útil para la implementación de sistemas de control.

A finales del siglo pasado se desarrolló un modelo para explicar observaciones clínicas relacionadas con el crecimiento mandibular, según el cual el músculo pterigoideo lateral (LPM) era uno de los principales moduladores de la diferenciación de las células mesenquimales del cóndilo mandibular a condroblastos u osteoblastos y por lo tanto del crecimiento del cartílago condilar mandibular (CCM). Dos grandes componentes eran los pilares fundamentales del modelo: el humoral y el mecánico. En la actualidad, el componente humoral estaría dado por factores de crecimiento como el IGF-I, el FGF-2 y el VEGF, los cuales parecen estar involucrados en el crecimiento mandibular. Debido a que el músculo esquelético tiene un papel como órgano secretor de ellos, se abre la posibilidad de que el LPM regule el crecimiento del CCM por un mecanismo paracrino o endocrino mediado por estos factores. El componente mecánico nació de las observaciones de que tanto el flujo sanguíneo dentro de la articulación temporomandibular como la acción de la almohadilla retrodiscal en el crecimiento del CCM depende, en parte, de la actividad contráctil del LPM. A pesar de que hay evidencia de que el LPM se activa en situaciones de adelantamiento mandibular, no hay consenso sobre si esto estimula el crecimiento del CCM. En esta revisión se discuten los aportes y limitaciones de los trabajos relacionados con el crecimiento mandibular y se propone un modelo que integra la información disponible para explicar el papel del LPM en el crecimiento del CCM.

At the end of the last century, a model to explain clinical observations related to the mandibular growth was developed. According to it, the lateral pterigoid muscle (LPM) was one of the main modulators of the differentiation of mesenquimal cells inside the condyle to condroblasts or osteoblasts, and therefore of the growth of the mandibular condilar cartilage (CCM). The main components of the model were the humoral and the mechanical. Nowadays, the humoral would include growth factors such as IGF-I, FGF-2 and VEGF, which seem to be involved in mandibular growth. Since skeletal muscle can secrete these growth factors, there is a possibility that LPM modulates the growth of CCM by a paracrine or endocrine mechanism. The mechanical component derived from the observations that both the blood flow inside the temporomandibular joint and the action of the retrodiscal pad on the growth of the CCM, depend, in part, on the contractile activity of the LPM. Despite the fact that there are some results suggesting that LPM is activated under conditions of mandibular protrusion, there is no full agreement on whether this can stimulate the growth of CCM. In this review, the contributions and limitations of the works related to mandibular growth are discussed and a model which integrates the available information to explain the role of the LPM in the growth of the CCM is proposed.

No fim do século passado desenhou-se um modelo para esclarecer as observações clínicas envolvidas no crescimento da mandíbula, no qual o músculo pterigoideo lateral (LPM) foi um dois moduladores principais da diferenciação das células messenquimais do côndilo mandibular em condroblastos ou osteoblastos e porém do crescimento da cartilagem condilar mandibular (CCM). Dois componentes principais possui o modelo: o humoral e o mecânico. Na atualidade, há evidência que o componente humoral é dado pelos fatores de crescimento IGF-1, IGF2 e VEGF que estimulam diretamente o crescimento mandibular. Devido a que o músculo esquelético pode desempenhar uma função endócrina fica aberta a possibilidade que o LPM regule o crescimento do CCM por mecanismos paracrinos ou autocrinos, mediante a secreção desses fatores de crescimento que estimulam diretamente o crescimiento mandibular. O componente mecânico é derivado das observações do que tanto o fluxo sanguíneo na articulação tempo-mandibular quanto a ação da almofadinha retro-discal no crescimento do CCM, dependem parcialmente da atividade contrátil do LPM. Embora, há evidências que o LPM é ativado pelo adiantamento mandibular, ainda não há consenso sob seu possível papel na estimulação do crescimento do CCM. Esta revisão tem o objetivo de discutir as evidencias e limitações de trabalhos relativos ao crescimento mandibular e propõe-se um modelo que integra a informação disponível para explicar a função do IPM no crescimento do CCM.