Caldendrin Is a Repressor of PIEZO2 Channels and Touch Sensation in Mice.

The sense of touch is crucial for cognitive, emotional, and social development and relies on mechanically activated (MA) ion channels that transduce force into an electrical signal. Despite advances in the molecular characterization of these channels, the physiological factors that control their activity are poorly understood. Here, we used behavioral assays, electrophysiological recordings, and various mouse strains (males and females analyzed separately) to investigate the role of the calmodulin-like Ca2+ sensor, caldendrin, as a key regulator of MA channels and their roles in touch sensation. In mice lacking caldendrin (Cabp1 KO), heightened responses to tactile stimuli correlate with enlarged MA currents with lower mechanical thresholds in dorsal root ganglion neurons (DRGNs). The expression pattern of caldendrin in the DRG parallels that of the major MA channel required for touch sensation, PIEZO2. In transfected cells, caldendrin interacts with and inhibits the activity of PIEZO2 in a manner that requires an alternatively spliced sequence in the N-terminal domain of caldendrin. Moreover, targeted genetic deletion of caldendrin in Piezo2-expressing DRGNs phenocopies the tactile hypersensitivity of complete Cabp1 KO mice. We conclude that caldendrin is an endogenous repressor of PIEZO2 channels and their contributions to touch sensation in DRGNs.

Epilepsy in cardiofaciocutaneous syndrome: Clinical burden and response to anti-seizure medication.

Treatment-resistant epilepsy is among the most serious complications of cardiofaciocutaneous syndrome (CFCS), a rare disorder caused by germline variants in the RAS-MAPK signaling pathway. This study analyzed the clinical characteristics of epilepsy and response to anti-seizure medications (ASMs) in a multinational CFCS cohort. A caregiver survey provided data regarding seizure history, use of ASMs and other treatment approaches, adverse effects, caregiver perception of treatment response, and neurological disease burden impact among individuals with CFCS. Results from 138 survey responses were quantitatively analyzed in conjunction with molecular genetic results and neurological records. The disease burden impact of CFCS was higher among individuals with epilepsy (n = 74/138), especially those with more severe seizure presentation. Oxcarbazepine, a sodium-channel blocker, had the best seizure control profile with relatively infrequent adverse effects. The most commonly prescribed ASM, levetiracetam, demonstrated comparatively poor seizure control. ASM efficacy was generally similar for individuals with BRAF and MAP2K1 gene variants. The high proportion of patients with CFCS who experienced poor seizure control despite use of multiple ASMs highlights a substantial unmet treatment need. Prospective study of ASM efficacy and clinical trials of therapies to attenuate RAS-MAPK signaling may improve avenues for clinical management.

Sensitivity of CNN image analysis to multifaceted measurements of neurite growth.

Quantitative analysis of neurite growth and morphology is essential for understanding the determinants of neural development and regeneration, however, it is complicated by the labor-intensive process of measuring diverse parameters of neurite outgrowth. Consequently, automated approaches have been developed to study neurite morphology in a high-throughput and comprehensive manner. These approaches include computer-automated algorithms known as 'convolutional neural networks' (CNNs)-powerful models capable of learning complex tasks without the biases of hand-crafted models. Nevertheless, their complexity often relegates them to functioning as 'black boxes.' Therefore, research in the field of explainable AI is imperative to comprehend the relationship between CNN image analysis output and predefined morphological parameters of neurite growth in order to assess the applicability of these machine learning approaches. In this study, drawing inspiration from the field of automated feature selection, we investigate the correlation between quantified metrics of neurite morphology and the image analysis results from NeuriteNet-a CNN developed to analyze neurite growth. NeuriteNet accurately distinguishes images of neurite growth based on different treatment groups within two separate experimental systems. These systems differentiate between neurons cultured on different substrate conditions and neurons subjected to drug treatment inhibiting neurite outgrowth. By examining the model's function and patterns of activation underlying its classification decisions, we discover that NeuriteNet focuses on aspects of neuron morphology that represent quantifiable metrics distinguishing these groups. Additionally, it incorporates factors that are not encompassed by neuron morphology tracing analyses. NeuriteNet presents a novel tool ideally suited for screening morphological differences in heterogeneous neuron groups while also providing impetus for targeted follow-up studies.

Safety and efficacy of mesenchymal stem cells therapy in the treatment of rheumatoid arthritis disease: A systematic review and meta-analysis of clinical trials.

BACKGROUND AND OBJECTIVES: Some patients have insufficient treatment response to conventional disease-modifying antirheumatic drugs (cDMARD); although biologics have proven to be an effective treatment for RA, the effects that bDMARDs have on integumentary, cardiac, and immune systems and the high costs associated with these treatments, make that mesenchymal stem cell-based therapies (MSCs) for RA are being considered potential treatment methods. This work analyses the performance in safety and efficacy terms of MSCs techniques. METHODS AND FINDING: A literature search was performed in PubMed, EMBASE, Cochrane Library, Web of Science, and Open Grey databases from inception to October 28, 2022. Three randomized controlled trials (RCTs) and one non-randomized controlled trial (non-RCTs), including 358 patients met our inclusion criteria and were included in qualitative synthesis; only RCTs were eligible for quantitative synthesis (meta-analysis). Meta-analysis of adverse events (AE) in RCTs showed no significant differences in the incidence of AE in the MSCs group compared to the control group (Risk ratio: 2.35; 95% CI, 0.58 to 9.58; I2 = 58.80%). The pooled Risk ratio for non-serious and serious adverse events showed no statistical difference between intervention and control groups concerning the incidence of non-serious and serious adverse events (Risk ratio: 2.35; 95% CI, 0.58 to 9.51; I2 = 58.62%) and (Risk ratio: 1.10; 95% CI, 0.15 to 7.97; I2 = 0.0%) respectively. The Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS28) decreased in agreement with the decreasing values of C-reactive protein (CRP) and Erythrocyte sedimentation rate (ESR). Additionally, a trend toward clinical efficacy was observed; however, this improvement was not shown in the studies after 12 months of follow-up without continuous treatment administration. CONCLUSION: This Systematic review and meta-analysis showed a favorable safety profile, without life-threatening events in subjects with RA, and a trend toward clinical efficacy that must be confirmed through high-quality RCTs, considerable sample size, and extended follow-up in subjects with RA.

Guía de presión encarcelada en el tratamiento percutáneo de las bifurcaciones coronarias: daño estructural y resultados clínicos / Jailed pressure wire technique for coronary bifurcation lesions: structural damage and clinical outcomes

Introducción y objetivos: El uso de una guía de presión encarcelada para evaluar los resultados de la rama lateral durante la técnica del stent provisional parece factible. Sin embargo, existen dudas sobre su seguridad por el daño mecánico de la guía y son escasos los datos referentes al pronóstico de los pacientes. El objetivo de este estudio fue evaluar el daño estructural de la guía de presión en la técnica de la guía encarcelada y examinar los resultados clínicos a medio plazo. Métodos: Se incluyó a 99 pacientes con lesiones bifurcadas tratadas mediante la técnica de guía de presión encarcelada y, como control histórico, a 114 pacientes tratados mediante la técnica de la guía encarcelada con guías no poliméricas. Se evaluó el daño de la guía mediante microscopía estereoscópica. El objetivo primario fue localizar la presencia de daño microscópico significativo. Se examinaron eventos cardiovasculares adversos mayores a los dos años de seguimiento. Resultados: El daño microscópico significativo fue más frecuente en las guías de presión que en las no poliméricas (53,5% vs 22,8%, p <0,001). No hubo fracturas en ningún grupo. Hubo menos intervenciones de la rama lateral en el grupo de la guía de presión (posdilatación 32,3% vs 56,1%, p=0,001; stent, 0,0% vs 2,6%, p=0,104). El riesgo de eventos cardiovasculares a los 2 años fue similar en ambos grupos (HRadj=0,42; IC95%, 0,10-1,73; p=0,229). Conclusiones: La guía de presión fue menos resistente al encarcelamiento que la guía no polimérica. Los pacientes tratados con guía de presión requirieron menos intervenciones de la rama lateral, pero tuvieron similar riesgo de eventos a los 2 años de seguimiento. (AU)

Introduction and objectives: The use of a pressure wire as a jailed wire to evaluate side branch results during provisional stenting seems feasible. However, safety concerns exist due to the mechanical damage of the wire and the lack of prospective data evaluating the prognosis of patients treated using this technique. This study sought to evaluate the structural damage of the pressure wire in patients treated using the jailed pressure wire technique and to assess mid-term clinical outcomes. Methods: We enrolled 99 patients with single bifurcation lesions and provisional stenting as the strategy of choice. A jailed pressure wire was used to guide side branch intervention according to the instantaneous wave-free ratio (iFR). A total of 114 patients and the respective nonpolymer-coated jailed wires were used as historical controls. Guidewire damage was evaluated by stereomicroscopy. The primary endpoint was significant microscopic damage. Major adverse cardiac events were evaluated at 2-year follow-up. Results: Significant microscopic damage was more frequent in pressure wires than in nonpolymer-coated wires (53.5% vs 22.8%, P<.001). There were no fractures in either group. There were fewer side branch interventions in the pressure wire group (postdilation/kissing balloon, 32.3% vs 56.1%, P=.001; stenting, 0.0% vs 2.6%, P=.104). The 2-year rate of major adverse cardiac events was similar between the 2 groups (HRadj, 0.42; 95%CI, 0.10-1.73; P=.229). Conclusions: Pressure wires were less resistant to jailing than conventional nonpolymer-coated wires. Patients treated with iFR-guided provisional stenting required fewer side branch interventions but had similar 2-year clinical outcomes than patients treated with the angiography-guided technique. (AU)

Caldendrin represses neurite regeneration and growth in dorsal root ganglion neurons.

Caldendrin is a Ca2+ binding protein that interacts with multiple effectors, such as the Cav1 L-type Ca2+ channel, which play a prominent role in regulating the outgrowth of dendrites and axons (i.e., neurites) during development and in response to injury. Here, we investigated the role of caldendrin in Cav1-dependent pathways that impinge upon neurite growth in dorsal root ganglion neurons (DRGNs). By immunofluorescence, caldendrin was localized in medium- and large- diameter DRGNs. Compared to DRGNs cultured from WT mice, DRGNs of caldendrin knockout (KO) mice exhibited enhanced neurite regeneration and outgrowth. Strong depolarization, which normally represses neurite growth through activation of Cav1 channels, had no effect on neurite growth in DRGN cultures from female caldendrin KO mice. Remarkably, DRGNs from caldendrin KO males were no different from those of WT males in terms of depolarization-dependent neurite growth repression. We conclude that caldendrin opposes neurite regeneration and growth, and this involves coupling of Cav1 channels to growth-inhibitory pathways in DRGNs of females but not males.

Jailed pressure wire technique for coronary bifurcation lesions: structural damage and clinical outcomes.

INTRODUCTION AND OBJECTIVES: The use of a pressure wire as a jailed wire to evaluate side branch results during provisional stenting seems feasible. However, safety concerns exist due to the mechanical damage of the wire and the lack of prospective data evaluating the prognosis of patients treated using this technique. This study sought to evaluate the structural damage of the pressure wire in patients treated using the jailed pressure wire technique and to assess mid-term clinical outcomes. METHODS: We enrolled 99 patients with single bifurcation lesions and provisional stenting as the strategy of choice. A jailed pressure wire was used to guide side branch intervention according to the instantaneous wave-free ratio (iFR). A total of 114 patients and the respective nonpolymer-coated jailed wires were used as historical controls. Guidewire damage was evaluated by stereomicroscopy. The primary endpoint was significant microscopic damage. Major adverse cardiac events were evaluated at 2-year follow-up. RESULTS: Significant microscopic damage was more frequent in pressure wires than in nonpolymer-coated wires (53.5% vs 22.8%, P<.001). There were no fractures in either group. There were fewer side branch interventions in the pressure wire group (postdilation/kissing balloon, 32.3% vs 56.1%, P=.001; stenting, 0.0% vs 2.6%, P=.104). The 2-year rate of major adverse cardiac events was similar between the 2 groups (HRadj, 0.42; 95%CI, 0.10-1.73; P=.229). CONCLUSIONS: Pressure wires were less resistant to jailing than conventional nonpolymer-coated wires. Patients treated with iFR-guided provisional stenting required fewer side branch interventions but had similar 2-year clinical outcomes than patients treated with the angiography-guided technique.

Green Synthesis of Silver Nanoparticles Using Pecan Nut (Carya illinoinensis) Shell Extracts and Evaluation of Their Antimicrobial Activity.

Nowadays, the increase in bacteria resistant to multiple antibiotics has become a real threat to the human health, forcing researchers to develop new strategies. Silver nanoparticles (AgNPs) may be a viable solution to this problem. The green synthesis of AgNPs is considered a green, ecological and low-priced process that provides small and biocompatible nanostructures with antimicrobial activity with a potential application in medicine. In this work, pecan nut shell extracts were analyzed in order to determine their viability for the production of AgNPs. These NPs were synthesized using an extract rich in bioactive molecules, varying the reaction time and silver nitrate (AgNO3) concentration. AgNPs production was confirmed by FT-IR, UV-Vis and EDX spectroscopy, while their morphology and size were determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The antibacterial activity of AgNPs was evaluated by the agar diffusion method against Salmonella typhi, Staphylococcus aureus and Proteus mirabilis. The results showed that it is possible to obtain nanoparticles from an extract rich in antioxidant molecules with a size between 39.9 and 98.3 nm with a semi-spherical morphology. In addition, it was shown that the reaction time and the concentration of the precursor influence the final nanoparticles size. Antimicrobial tests showed that there is greater antimicrobial inhibition against Gram-negative than Gram-positive microorganisms, obtaining inhibition zone from 0.67 to 5.67 mm.

RNA induces unique tau strains and stabilizes Alzheimer's disease seeds.

Tau aggregation underlies neurodegenerative tauopathies, and transcellular propagation of tau assemblies of unique structure, i.e., strains, may underlie the diversity of these disorders. Polyanions have been reported to induce tau aggregation in vitro, but the precise trigger to convert tau from an inert to a seed-competent form in disease states is unknown. RNA triggers tau fibril formation in vitro and has been observed to associate with neurofibrillary tangles in human brain. Here, we have tested whether RNA exerts sequence-specific effects on tau assembly and strain formation. We found that three RNA homopolymers, polyA, polyU, and polyC, all bound tau, but only polyA RNA triggered seed and fibril formation. In addition, polyA:tau seeds and fibrils were sensitive to RNase. We also observed that the origin of the RNA influenced the ability of tau to adopt a structure that would form stable strains. Human RNA potently induced tau seed formation and created tau conformations that preferentially formed stable strains in a HEK293T cell model, whereas RNA from other sources, or heparin, produced strains that were not stably maintained in cultured cells. Finally, we found that soluble, but not insoluble seeds from Alzheimer's disease brain were also sensitive to RNase. We conclude that human RNA specifically induces formation of stable tau strains and may trigger the formation of dominant pathological assemblies that propagate in Alzheimer's disease and possibly other tauopathies.

Guía de práctica clínica mexicana para el diagnóstico y tratamiento de las dislipidemias y enfermedad cardiovascular aterosclerótica.

ANTECEDENTES: Las enfermedades cardiovasculares son la principal causa mundial de mortalidad y México no es la excepción. Los datos epidemiológicos obtenidos en 1990 mostraron que los padecimientos cardiovasculares representaron el 19.8% de todas las causas de muerte en nuestro país; esta cifra se incrementó de manera significativa a un 25.5% para 2015. Diversas encuestas nacionales sugieren que más del 60% de la población adulta tiene al menos un factor de riesgo para padecer enfermedades cardiovasculares (obesidad o sobrepeso, hipertensión, tabaquismo, diabetes, dislipidemias). Por otro lado, datos de la Organización Panamericana de la Salud han relacionado el proceso de aterosclerosis como la primer causa de muerte prematura, reduciendo la expectativa de vida de manera sensible, lo que tiene una enorme repercusión social. OBJETIVO: Este documento constituye la guía de práctica clínica (GPC) elaborada por iniciativa de la Sociedad Mexicana de Cardiología en colaboración con la Sociedad Mexicana de Nutrición y Endocrinología, A.C., Asociación Nacional de Cardiólogos de México, A.C., Asociación Mexicana para la Prevención de la Aterosclerosis y sus Complicaciones, A.C., Comité Normativo Nacional de Medicina General, A.C., Colegio Nacional de Medicina Geriátrica, A.C., Colegio de Medicina Interna de México, A.C., Sociedad Mexicana de Angiología y Cirugía Vascular y Endovenosa, A.C., Instituto Mexicano de Investigaciones Nefrológicas, A.C. y la Academia Mexicana de Neurología, A.C.; con el apoyo metodológico de la Agencia Iberoamericana de Desarrollo y Evaluación de Tecnologías en Salud, con la finalidad de establecer recomendaciones basadas en la mejor evidencia disponible y consensuadas por un grupo interdisciplinario de expertos. El objetivo de este documento es el de brindar recomendaciones basadas en evidencia para ayudar a los tomadores de decisión en el diagnóstico y tratamiento de las dislipidemias en nuestro país. MATERIAL Y MÉTODOS: Este documento cumple con estándares internacionales de calidad, como los descritos por el Instituto de Medicina de EE.UU., el Instituto de Excelencia Clínica de Gran Bretaña, la Red Colegiada para el Desarrollo de Guías de Escocia y la Red Internacional de Guías de Práctica Clínica. Se integró un grupo multidisciplinario de expertos clínicos y metodólogos con experiencia en revisiones sistemáticas de la literatura y el desarrollo de guías de práctica clínica. Se consensuó un documento de alcances, se establecieron las preguntas clínicas relevantes, se identificó de manera exhaustiva la mejor evidencia disponible evaluada críticamente en revisiones sistemáticas de la literatura y se desarrollaron las recomendaciones clínicas. Se utilizó la metodología de Panel Delphi modificado para lograr un nivel de consenso adecuado en cada una de las recomendaciones contenidas en esta GPC. RESULTADOS: Se consensuaron 23 preguntas clínicas que dieron origen a sus respectivas recomendaciones clínicas. CONCLUSIONES: Esperamos que este documento contribuya a la mejor toma de decisiones clínicas y se convierta en un punto de referencia para los clínicos y pacientes en el manejo de las dislipidemias y esto contribuya a disminuir la morbilidad y mortalidad derivada de los eventos cardiovasculares ateroscleróticos en nuestro país. BACKGROUND: Cardiovascular diseases are the leading cause of mortality worldwide and Mexico is no exception. The epidemiological data obtained in 1990 showed that cardiovascular diseases represented 19.8% of all causes of death in our country. This figure increased significantly to 25.5% for 2015. Some national surveys suggest that more than 60% of the adult population has at least one risk factor for cardiovascular disease (obesity or overweight, hypertension, smoking, diabetes, dyslipidemias). On the other hand, data from the Pan American Health Organization have linked the process of atherosclerosis as the first cause of premature death, significantly reducing life expectancy, which has enormous social repercussions. OBJECTIVE: This document constitutes the Clinical Practice Guide (CPG) prepared at the initiative of the Mexican Society of Cardiology in collaboration with the Mexican Society of Nutrition and Endocrinology, AC, National Association of Cardiologists of Mexico, AC, Mexican Association for the Prevention of Atherosclerosis and its Complications, AC, National Normative Committee of General Medicine, AC, National College of Geriatric Medicine, AC, College of Internal Medicine of Mexico, AC, Mexican Society of Angiology and Vascular and Endovenous Surgery, AC, Mexican Institute of Research Nephrological, AC and the Mexican Academy of Neurology, A.C.; with the methodological support of the Ibero-American Agency for the Development and Evaluation of Health Technologies, in order to establish recommendations based on the best available evidence and agreed upon by an interdisciplinary group of experts. The objective of this document is to provide evidence-based recommendations to help decision makers in the diagnosis and treatment of dyslipidemias in our country. MATERIAL AND METHODS: This document complies with international quality standards, such as those described by the Institute of Medicine of the USA, the Institute of Clinical Excellence of Great Britain, the Scottish Intercollegiate Guideline Network and the Guidelines International Network. A multidisciplinary group of clinical experts and methodologists with experience in systematic reviews of the literature and the development of clinical practice guidelines was formed. A scope document was agreed upon, relevant clinical questions were established, the best available evidence critically evaluated in systematic literature reviews was exhaustively identified, and clinical recommendations were developed. The modified Delphi Panel methodology was used to achieve an adequate level of consensus in each of the recommendations contained in this CPG. RESULTS: 23 clinical questions were agreed upon which gave rise to their respective clinical recommendations. CONCLUSIONS: We consider that this document contributes to better clinical decision-making and becomes a point of reference for clinicians and patients in the management of dyslipidemias and this contributes to reducing the morbidity and mortality derived from atherosclerotic cardiovascular events in our country.

Guía de práctica clínica mexicana para el diagnóstico y tratamiento de las dislipidemias y enfermedad cardiovascular aterosclerótica / Mexican clinical practice guideline for the diagnosis and treatment of dyslipidemias and atherosclerotic cardiovascular disease

resumen está disponible en el texto completo

Abstract Background: Cardiovascular diseases are the leading cause of mortality worldwide and Mexico is no exception. The epidemiological data obtained in 1990 showed that cardiovascular diseases represented 19.8% of all causes of death in our country. This figure increased significantly to 25.5% for 2015. Some national surveys suggest that more than 60% of the adult population has at least one risk factor for cardiovascular disease (obesity or overweight, hypertension, smoking, diabetes, dyslipidemias). On the other hand, data from the Pan American Health Organization have linked the process of atherosclerosis as the first cause of premature death, significantly reducing life expectancy, which has enormous social repercussions. Objective: This document constitutes the Clinical Practice Guide (CPG) prepared at the initiative of the Mexican Society of Cardiology in collaboration with the Mexican Society of Nutrition and Endocrinology, AC, National Association of Cardiologists of Mexico, AC, Mexican Association for the Prevention of Atherosclerosis and its Complications, AC, National Normative Committee of General Medicine, AC, National College of Geriatric Medicine, AC, College of Internal Medicine of Mexico, AC, Mexican Society of Angiology and Vascular and Endovenous Surgery, AC, Mexican Institute of Research Nephrological, AC and the Mexican Academy of Neurology, A.C.; with the methodological support of the Ibero-American Agency for the Development and Evaluation of Health Technologies, in order to establish recommendations based on the best available evidence and agreed upon by an interdisciplinary group of experts. The objective of this document is to provide evidence-based recommendations to help decision makers in the diagnosis and treatment of dyslipidemias in our country. Material and methods: This document complies with international quality standards, such as those described by the Institute of Medicine of the USA, the Institute of Clinical Excellence of Great Britain, the Scottish Intercollegiate Guideline Network and the Guidelines International Network. A multidisciplinary group of clinical experts and methodologists with experience in systematic reviews of the literature and the development of clinical practice guidelines was formed. A scope document was agreed upon, relevant clinical questions were established, the best available evidence critically evaluated in systematic literature reviews was exhaustively identified, and clinical recommendations were developed. The modified Delphi Panel methodology was used to achieve an adequate level of consensus in each of the recommendations contained in this CPG. Results: 23 clinical questions were agreed upon which gave rise to their respective clinical recommendations. Conclusions: We consider that this document contributes to better clinical decision-making and becomes a point of reference for clinicians and patients in the management of dyslipidemias and this contributes to reducing the morbidity and mortality derived from atherosclerotic cardiovascular events in our country.

NeuriteNet: A convolutional neural network for assessing morphological parameters of neurite growth.

BACKGROUND: During development or regeneration, neurons extend processes (i.e., neurites) via mechanisms that can be readily analyzed in culture. However, defining the impact of a drug or genetic manipulation on such mechanisms can be challenging due to the complex arborization and heterogeneous patterns of neurite growth in vitro. New Method: NeuriteNet is a Convolutional Neural Network (CNN) sorting model that uses a novel adaptation of the XRAI saliency map overlay, which is a region-based attribution method. NeuriteNet compares neuronal populations based on differences in neurite growth patterns, sorts them into respective groups, and overlays a saliency map indicating which areas differentiated the image for the sorting procedure. RESULTS: In this study, we demonstrate that NeuriteNet effectively sorts images corresponding to dissociated neurons into control and treatment groups according to known morphological differences. Furthermore, the saliency map overlay highlights the distinguishing features of the neuron when sorting the images into treatment groups. NeuriteNet also identifies novel morphological differences in neurons cultured from control and genetically modified mouse strains. Comparison with Existing Methods: Unlike other neurite analysis platforms, NeuriteNet does not require manual manipulations, such as segmentation of neurites prior to analysis, and is more accurate than experienced researchers for categorizing neurons according to their pattern of neurite growth. CONCLUSIONS: NeuriteNet can be used to effectively screen for morphological differences in a heterogeneous group of neurons and to provide feedback on the key features distinguishing those groups via the saliency map overlay.

Descripción de un servicio de telerreumatología en una institución colombiana / Description of a tele-rheumatology service in a Colombian institution

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ABSTRACT Introduction: Models in health care have been static for a long time, but recently there has been a change in recognising that technology in the area of information and communication could lead to a change in improving health services. Telemedicine has been increasing and its use now extends to the entire process of health care. It is beginning to be implemented in the rheumatology area, in Colombia. The characteristics of a tele-rheumatology service are described, as well as a more detailed observation of a cohort of patients with rheumatoid arthritis (RA), in order to identify strengths and improvements. Methods: A descriptive observational cross-sectional study was conducted on the total population of patients who were treated by the tele-rheumatology service in the synchronous modality for a period of 30 months. As regards the follow-up of patients with RA, all patients were included who were treated exclusively by means of synchronous telemedicine for a minimum period of 6 months with at least three follow-ups, in which it was possible to calculate the clinimetry by Das28 with the use of C reactive protein (CRP). Measures of frequency, central tendency and dispersion according to type of variable will be used for the descriptive analysis. Results: Data was collected from 1905 patients during the period between August 2017 and March 2020. A total of 4864 consultations were made. Non-attendance of 368 (7.85%) consultations was registered. There were 1784 (83%) patients with a definitive diagnosis by the rheumatologist. A total of 284 patients (14.9%) were discharged by the rheumatology service, and 85 (4.46%) were referred for an exclusively face-to-face evaluation. Auxiliary medical care at the place of origin was provided by a general practitioner in 1,749 (91%) cases. There was no security during the care process as regards the physical examination in 46 (2.4%) cases. Of the total number of patients, 184 (9.6%) cases came from rural areas or municipalities far from the place of care. Biological therapies were prescribed in 139 patients, 56 new prescription during the 30 months. Of 479 RA patients, 200 met the criteria for follow-up. Of these, according to the activity measured by DAS28 with the use of ultrasensitive CRP, 54 patients (27%) were found on admission to the program in remission, 23 (11.5%) patients had low activity, 81 (40.5%) patients had moderate activity, and high activity was found in 42 (21%) patients. Regarding the start of follow-up, there was a 47% increase in the number of patients in remission, and low activity to 19.5%, in contrast to a reduction of 25% in patients with moderate activity and in 9% increase high activity in their last measurement, possible during monitoring. In the group of 200 patients from long-term follow-up, biological therapies were used 61 times. Of the 166 patients during follow-up without biological therapies on admission, these were required in 16%. Discussion: A detailed follow-up of the patients was carried out in the telemedicine service in a synchronous way for a period of two and a half years. The low percentage of absences shows a good adherence to the program. Physical examination, the main reason for medical care at the remission site, was not without difficulties, in this minority it was necessary to carry out diagnostic images. It would be important to assess this group of patients where there are doubts regarding the physical examination, those who have a certain number of appointments without a definitive diagnosis, or in whom biological or high-cost therapies would be used should necessarily be referred to face-to-face consultation. In the group of patients with RA, the percentage of biological use is considered high in relation to the expected standards. This may be for several reasons, such as the high number of patients with prior use of biological agents, the majority of patients with long-term disease, and difficulties in accessing follow-up due to rheumatology, as well as the small number of sero-negative patients in the study population, and practices related to non-presential medical practice may overestimate the activity of the disease. In conclusion, telemedicine has great advantages in the care of rheumatology patients, although it requires modifications to improve these services in favour of patients.

Recomendaciones para reumatólogos sobre el manejo farmacológico durante la emergencia sanitaria por COVID-19: opinión de un grupo de expertos / Recommendations for rheumatologists on pharmacological management during the COVID-19 health emergency: Expert group opinion

RESUMEN La enfermedad por Coronavirus 2019 (COVID-19) es una pandemia inesperada que ha pro vocado un estado de emergencia y que ha generado cambios drásticos en los protocolos de atención clínica. Para su tratamiento se ha descrito el papel de algunos medicamen tos usados habitualmente en artritis reumatoide, lupus eritematoso sistémico y otras enfermedades autoinmunitarias sistémicas. Debido a ello, existe un inminente riesgo de desabastecimiento, por lo cual el objetivo de esta revisión narrativa y opinión de expertos es formular recomendaciones generales clínicas y administrativas sobre el manejo de pacien tes ambulatorios con enfermedad autoinmunitaria o inflamatoria sistémica en el contexto de la pandemia por COVID-19.

ABSTRACT Coronavirus 2019 (COVID-19) is an unexpected pandemic that has caused a state of emergency, as well as generating drastic changes in clinical care protocols. Some drugs commonly used in rheumatoid arthritis, systemic lupus erythematosus, and other systemic autoimmune diseases have been described for its treatment. Therefore, there is an imminent risk of shortages. The aim of this narrative review and expert opinion is to present general recommendations on the clinical and administrative management of outpatients with autoimmune or systemic inflammatory disease, in the context of the COVID-19 pandemic.

Zinc Oxide Nanoparticles and Zinc Sulfate Impact Physiological Parameters and Boosts Lipid Peroxidation in Soil Grown Coriander Plants (Coriandrum sativum).

The objective of this study was to determine the oxidative stress and the physiological and antioxidant responses of coriander plants (Coriandrum sativum) grown for 58 days in soil with zinc oxide nanoparticles (ZnO NPs) and zinc sulfate (ZnSO4) at concentrations of 0, 100, 200, 300, and 400 mg of Zn/kg of soil. The results revealed that all Zn compounds increased the total chlorophyll content (CHLt) by at least 45%, compared to the control group; however, with 400 mg/kg of ZnSO4, chlorophyll accumulation decreased by 34.6%. Zn determination by induction-plasma-coupled atomic emission spectrometry (ICP-AES) showed that Zn absorption in roots and shoots occurred in plants exposed to ZnSO4 at all concentrations, which resulted in high levels of hydrogen peroxide (H2O2) and malondialdehyde (MDA). Only at 400 mg/kg of ZnSO4, a 78.6% decrease in the MDA levels was observed. According to the results, the ZnSO4 treatments were more effective than the ZnO NPs to increase the antioxidant activity of catalase (CAT), ascorbate peroxidase (APX), and peroxidases (POD). The results corroborate that phytotoxicity was higher in plants subjected to ZnSO4 compared to treatments with ZnO NPs, which suggests that the toxicity was due to Zn accumulation in the tissues by absorbing dissolved Zn++ ions.

Functional impact of a congenital stationary night blindness type 2 mutation depends on subunit composition of Cav1.4 Ca2+ channels.

Voltage-gated Cav1 and Cav2 Ca2+ channels are comprised of a pore-forming α1 subunit (Cav1.1-1.4, Cav2.1-2.3) and auxiliary ß (ß1-4) and α2δ (α2δ-1-4) subunits. The properties of these channels vary with distinct combinations of Cav subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Cav subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Cav1.4 channels typical of those in human retina: Cav1.4 splice variants with or without exon 47 (Cav1.4+ex47 and Cav1.4Δex47, respectively), and the auxiliary subunits, ß2X13 and α2δ-4. We find that IT caused both Cav1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits ß2X13 and α2δ-4 but not in those with ß2A and α2δ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Cav1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of ß2X13 and α2δ-4. Our results reveal complex actions of IT in modifying the properties of Cav1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors.

Foliar Application of Zinc Oxide Nanoparticles and Zinc Sulfate Boosts the Content of Bioactive Compounds in Habanero Peppers.

The physiological responses of habanero pepper plants (Capsicum chinense Jacq.) to foliar applications of zinc sulphate and zinc nano-fertilizer were evaluated in greenhouse trials. The effect of the supplement on fruit quality of habanero pepper was particularly observed. Habanero pepper plants were grown to maturity, and during the main stages of phenological development, they were treated with foliar applications of Zn at concentrations of 1000 and 2000 mg L-1 in the form of zinc sulfate (ZnSO4) and zinc oxide nanoparticles (ZnO NPs). Additional Zn was not supplied to the control treatment plants. ZnO NPs at a concentration of 1000 mg L-1 positively affected plant height, stem diameter, and chlorophyll content, and increased fruit yield and biomass accumulation compared to control and ZnSO4 treatments. ZnO NPs at 2000 mg L-1 negatively affected plant growth but significantly increased fruit quality, capsaicin content by 19.3%, dihydrocapsaicin by 10.9%, and Scoville Heat Units by 16.4%. In addition, at 2000 ZnO NPs mg L-1 also increased content of total phenols and total flavonoids (soluble + bound) in fruits (14.50% and 26.9%, respectively), which resulted in higher antioxidant capacity in ABTS (2,2'azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)), DPPH (2,2-diphenyl-1-picrylhydrazyl), and FRAP (ferric reducing antioxidant power) (15.4%, 31.8%, and 20.5%, respectively). These results indicate that application of ZnO NPs could be employed in habanero pepper production to improve yield, quality, and nutraceutical properties of fruits.

Conformational Dynamics and Cooperativity Drive the Specificity of a Protein-Ligand Interaction.

Molecular recognition is critical for the fidelity of signal transduction in biology. Conversely, the disruption of protein-protein interactions can lead to disease. Thus, comprehension of the molecular determinants of specificity is essential for understanding normal biological signaling processes and for the development of precise therapeutics. Although high-resolution structures have provided atomic details of molecular interactions, much less is known about the influence of cooperativity and conformational dynamics. Here, we used the Tiam2 PSD-95/Dlg/ZO-1 (PDZ) domain and a quadruple mutant (QM), engineered by swapping the identity of four residues important for specificity in the Tiam1 PDZ into the Tiam2 PDZ domain, as a model system to investigate the role of cooperativity and dynamics in PDZ ligand specificity. Surprisingly, equilibrium binding experiments found that the ligand specificity of the Tiam2 QM was switched to that of the Tiam1 PDZ. NMR-based studies indicated that Tiam2 QM PDZ, but not other mutants, had extensive microsecond to millisecond motions distributed throughout the entire domain suggesting structural cooperativity between the mutated residues. Thermodynamic analyses revealed energetic cooperativity between residues in distinct specificity subpockets that was dependent upon the identity of the ligand, indicating a context-dependent binding mechanism. Finally, isothermal titration calorimetry experiments showed distinct entropic signatures along the mutational trajectory from the Tiam2 wild-type to the QM PDZ domain. Collectively, our studies provide unique insights into how structure, conformational dynamics, and thermodynamics combine to modulate ligand-binding specificity and have implications for the evolution, regulation, and design of protein-ligand interactions.

Role of a conserved glutamine in the function of voltage-gated Ca2+ channels revealed by a mutation in human CACNA1D.

Voltage-gated Cav Ca2+ channels play crucial roles in regulating gene transcription, neuronal excitability, and synaptic transmission. Natural or pathological variations in Cav channels have yielded rich insights into the molecular determinants controlling channel function. Here, we report the consequences of a natural, putatively disease-associated mutation in the CACNA1D gene encoding the pore-forming Cav1.3 α1 subunit. The mutation causes a substitution of a glutamine residue that is highly conserved in the extracellular S1-S2 loop of domain II in all Cav channels with a histidine and was identified by whole-exome sequencing of an individual with moderate hearing impairment, developmental delay, and epilepsy. When introduced into the rat Cav1.3 cDNA, Q558H significantly decreased the density of Ca2+ currents in transfected HEK293T cells. Gating current analyses and cell-surface biotinylation experiments suggested that the smaller current amplitudes caused by Q558H were because of decreased numbers of functional Cav1.3 channels at the cell surface. The substitution also produced more sustained Ca2+ currents by weakening voltage-dependent inactivation. When inserted into the corresponding locus of Cav2.1, the substitution had similar effects as in Cav1.3. However, the substitution introduced in Cav3.1 reduced current density, but had no effects on voltage-dependent inactivation. Our results reveal a critical extracellular determinant of current density for all Cav family members and of voltage-dependent inactivation of Cav1.3 and Cav2.1 channels.

Large Photothermal Effect in Sub-40 nm h-BN Nanostructures Patterned Via High-Resolution Ion Beam.

The controlled nanoscale patterning of 2D materials is a promising approach for engineering the optoelectronic, thermal, and mechanical properties of these materials to achieve novel functionalities and devices. Herein, high-resolution patterning of hexagonal boron nitride (h-BN) is demonstrated via both helium and neon ion beams and an optimal dosage range for both ions that serve as a baseline for insulating 2D materials is identified. Through this nanofabrication approach, a grating with a 35 nm pitch, individual structure sizes down to 20 nm, and additional nanostructures created by patterning crystal step edges are demonstrated. Raman spectroscopy is used to study the defects induced by the ion beam patterning and is correlated to scanning probe microscopy. Photothermal and scanning near-field optical microscopy measure the resulting near-field absorption and scattering of the nanostructures. These measurements reveal a large photothermal expansion of nanostructured h-BN that is dependent on the height to width aspect ratio of the nanostructures. This effect is attributed to the large anisotropy of the thermal expansion coefficients of h-BN and the nanostructuring implemented. The photothermal expansion should be present in other van der Waals materials with large anisotropy and can lead to applications such as nanomechanical switches driven by light.