Relaxation in non-Markovian models: From static to dynamic heterogeneity

[EN] Glass transition processes have often been explained in terms of wide distributions of relaxation times. By means of a simple stochastic model we here show how dynamic heterogeneity is the key to the emergence of the glass transition. A non-Markovian model representing a small open region of the amorphous material was previously shown to reproduce the time and thermal characteristic behavior of supercooled liquids and glasses. Due to the interaction of the open regions with their environment, the temperature dependence of the equilibrium relaxation times differs from the featureless behavior of the relaxation times of closed regions, whose static disorder does not lead to a glass transition, even with wider distributions of equilibrium relaxation times. The dynamic heterogeneity of the open region produces a glass transition between two different regimes: a faster-thanArrhenius and non-diverging growth of the supercooled liquid relaxation times and an average Arrhenius behavior of the ideal glass. The Kovacs' expansion gap was studied by evaluating the nonequilibrium distribution of relaxation times after the temperature quenches.Funding for open access charge: CRUE-Universitat Polit`ecnica de Val`encia. RSS and JMM acknowledge the Spanish Ministry of Science, Innovations and Universities through the RTI2018-097862-B-C21 Project (including the FEDER financial support). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program. CIBER Actions are financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund.Torregrosa Cabanilles, C.; Molina Mateo, J.; Sabater I Serra, R.; Meseguer Dueñas, JM.; Gómez Ribelles, JL. (2022). Relaxation in non-Markovian models: From static to dynamic heterogeneity. Journal of Non-Crystalline Solids. 576. https://doi.org/10.1016/j.jnoncrysol.2021.12124512124557

In vivo and in vitro biocompatible alginate film crosslinked with Ca2+ and Co2+ manifests antiviral, antibacterial and anticancer activity

Alginate crosslinked with calcium cations is a promising hydrogel for biomedical applications as it is non-toxic, has suitable mechanical properties and is insoluble in water. Cobalt has been shown to possess antibacterial capacity against Gram-positive and Gram-negative bacteria, and has an angiogenesis effect. In this study, alginate films were crosslinked with Ca2+ and Co2+ ions to explore their biological properties in terms of antiviral capacity, antibacterial properties, anticancer activity and their toxicity. The results show that the hydrogel with a very small amount of cobalt was biocompatible in vivo using the Caenorhabditis elegans model and in vitro on human keratinocyte cells and it also exhibited antibacterial activity against the life-threatening methicillinresistant Staphylococcus aureus. Furthermore, this hydrogel showed antiviral activity against a surrogate of SARSCoV-2 and anticancer properties against melanoma and colon cancer cells, which render it a promising material for biomedical applications such as wound healing and tissue engineering. Water sorption experiments, Fourier transform infrared spectroscopy, electron microscopy with Energy Dispersive X-ray Spectrometry and degradation analysis in acid aqueous medium were performed to complete the characterization of these new materials.The authors would like to express their gratitude to the Fundacion ´ Universidad Catolica ´ de Valencia San Vicente Martir ´ and to the Spanish Ministry of Science and Innovation for their financial support through Grant 2020-231-006UCV and PID2020-119333RB-I00 / AEI / 10.13039/501100011033, respectively.TheCIBER-BBNinitiativeis funded by the VI National R&D&I Plan 2008 − 2011, Iniciativa Ingenio 2010, Consolider Program.CIBER actions are financed by the Instituto de Salud CarlosIII with assistance from the European Regional Development.Funding support also from Researchers Supporting Project number (RSP-2023R782), King Saud University, Riyadh, Saudi ArabiaBiotecnologí

Filamin C variants are associated with a distinctive clinical and immunohistochemical arrhythmogenic cardiomyopathy phenotype.

BACKGROUND: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level. METHODS: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry. RESULTS: Novel or rare FLNC variants, four null and five variants of unknown significance, were identified in nine ACM probands (7.5%). In FLNC null variant carriers (including family members, n = 16) Task Force diagnostic electrocardiogram repolarization/depolarization abnormalities were uncommon (19%), echocardiography was normal in 69%, while 56% had >500 ventricular ectopics/24 h or ventricular tachycardia on Holter and 67% had late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Ten gene positive individuals (63%) had abnormalities on ECG or CMRI that are not included in the current diagnostic criteria for ARVC. Immunohistochemistry showed altered key protein distribution, distinctive from that observed in ARVC, predominantly in the left ventricle. CONCLUSIONS: ACM associated with FLNC variants presents with a distinctive phenotype characterized by Holter arrhythmia and LGE on CMRI with unremarkable ECG and echocardiographic findings. Clinical presentation in asymptomatic mutation carriers at risk of sudden death may include abnormalities which are currently non-diagnostic for ARVC. At the molecular level, the pathogenic mechanism related to FLNC appears different to classic forms of ARVC caused by desmosomal mutations

Filamin C variants are associated with a distinctive clinical and immunohistochemical arrhythmogenic cardiomyopathy phenotype

Background: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level. Methods: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry. Results: Novel or rare FLNC variants, four null and five variants of unknown significance, were identified in nine ACM probands (7.5%). In FLNC null variant carriers (including family members, n = 16) Task Force diagnostic electrocardiogram repolarization/depolarization abnormalities were uncommon (19%), echocardiography was normal in 69%, while 56% had >500 ventricular ectopics/24 h or ventricular tachycardia on Holter and 67% had late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Ten gene positive individuals (63%) had abnormalities on ECG or CMRI that are not included in the current diagnostic criteria for ARVC. Immunohistochemistry showed altered key protein distribution, distinctive from that observed in ARVC, predominantly in the left ventricle. Conclusions: ACM associated with FLNC variants presents with a distinctive phenotype characterized by Holter arrhythmia and LGE on CMRI with unremarkable ECG and echocardiographic findings. Clinical presentation in asymptomatic mutation carriers at risk of sudden death may include abnormalities which are currently non-diagnostic for ARVC. At the molecular level, the pathogenic mechanism related to FLNC appears different to classic forms of ARVC caused by desmosomal mutations. Keywords: ARVC; Arrhythmogenic cardiomyopathy; Filamin C variants; Immunohistochemistry; Late gadolinium enhancement

Biocompatible Alginate Film Crosslinked with Ca2+ and Zn2+ Possesses Antibacterial, Antiviral, and Anticancer Activities

Alginate is a highly promising biopolymer due to its non-toxic and biodegradable properties. Alginate hydrogels are often fabricated by cross-linking sodium alginate with calcium cations and can be engineered with highly desirable enhanced physical and biological properties for biomedical applications. This study reports on the anticancer, antiviral, antibacterial, in vitro, and in vivo toxicity, water absorption, and compound release properties of an alginate hydrogel crosslinked with calcium and different amounts of zinc cations. The results showed that the calcium alginate hydrogel film crosslinked with the highest amount of zinc showed similar water sorption properties to those of calcium alginate and released a suitable amount of zinc to provide anticancer activity against melanoma and colon cancer cells and has antibacterial properties against methicillin-resistant and antiviral activity against enveloped and non-enveloped viruses. This film is non-toxic in both in vitro in keratinocyte HaCaT cells and in vivo in the model, which renders it especially promising for biomedical applications

Cardiopulmonary Exercise Test in Patients with Hypertrophic Cardiomyopathy: A Systematic Review and Meta-Analysis.

BACKGROUND: Patients with chronic diseases frequently adapt their lifestyles to their functional limitations. Functional capacity in Hypertrophic Cardiomyopathy (HCM) can be assessed by stress testing. We aim to review and analyze the available data from the literature on the value of Cardiopulmonary Exercise Test (CPET) in HCM. Objective measurements from CPET are used for evaluation of patient response to traditional and new developing therapeutic measurements. METHODS: A systematic review of the literature was conducted in PubMed, Web of Science and Cochrane in Mar-20. The original search yielded 2628 results. One hundred and two full texts were read after the first screening, of which, 69 were included for qualitative synthesis. Relevant variables to be included in the review were set and 17 were selected, including comorbidities, body mass index (BMI), cardiac-related symptoms, echocardiographic variables, medications and outcomes. RESULTS: Study sample consisted of 69 research articles, including 11,672 patients (48 ± 14 years old, 65.9%/34.1% men/women). Treadmill was the most common instrument employed (n = 37 studies), followed by upright cycle-ergometer (n = 16 studies). Mean maximal oxygen consumption (VO2max) was 22.3 ± 3.8 mL·kg-1·min-1. The highest average values were observed in supine and upright cycle-ergometer (25.3 ± 6.5 and 24.8 ± 9.1 mL·kg-1·min-1; respectively). Oxygen consumption in the anaerobic threshold (ATVO2) was reported in 18 publications. Left ventricular outflow tract gradient (LVOT) > 30 mmHg was present at baseline in 31.4% of cases. It increased to 49% during exercise. Proportion of abnormal blood pressure response (ABPRE) was higher in severe (>20 mm) vs. mild hypertrophy groups (17.9% vs. 13.6%, p < 0.001). Mean VO2max was not significantly different between severe vs. milder hypertrophy, or for obstructive vs. non-obstructive groups. Occurrence of arrhythmias during functional assessment was higher among younger adults (5.42% vs. 1.69% in older adults, p < 0.001). Twenty-three publications (9145 patients) evaluated the prognostic value of exercise capacity. There were 8.5% total deaths, 6.7% cardiovascular deaths, 3.0% sudden cardiac deaths (SCD), 1.2% heart failure death, 0.6% resuscitated cardiac arrests, 1.1% transplants, 2.6% implantable cardioverter defibrillator (ICD) therapies and 1.2 strokes (mean follow-up: 3.81 ± 2.77 years). VO2max, ATVO2, METs, % of age-gender predicted VO2max, % of age-gender predicted METs, ABPRE and ventricular arrhythmias were significantly associated with major outcomes individually. Mean VO2max was reduced in patients who reached the combined cardiovascular death outcome compared to those who survived (-6.20 mL·kg-1·min-1; CI 95%: -7.95, -4.46; p < 0.01). CONCLUSIONS: CPET is a valuable tool and can safely perform for assessment of physical functional capacity in patients with HCM. VO2max is the most common performance measurement evaluated in functional studies, showing higher values in those based on cycle-ergometer compared to treadmill. Subgroup analysis shows that exercise intolerance seems to be more related to age, medication and comorbidities than HCM phenotype itself. Lower VO2max is consistently seen in HCM patients at major cardiovascular risk

Evolutionary dynamics at the tumor edge reveal metabolic imaging biomarkers

Human cancers are biologically and morphologically heterogeneous. A variety of clonal populations emerge within these neoplasms and their interaction leads to complex spatiotemporal dynamics during tumor growth. We studied the reshaping of metabolic activity in human cancers by means of continuous and discrete mathematical models and matched the results to positron emission tomography (PET) imaging data. Our models revealed that the location of increasingly active proliferative cellular spots progressively drifted from the center of the tumor to the periphery, as a result of the competition between gradually more aggressive phenotypes. This computational finding led to the development of a metric, normalized distance from F-18-fluorodeoxyglucose (F-18-FDG) hotspot to centroid (NHOC), based on the separation from the location of the activity (proliferation) hotspot to the tumor centroid. The NHOC metric can be computed for patients using F-18-FDG PET-computed tomography (PET/CT) images where the voxel of maximum uptake (standardized uptake value [SUV]max) is taken as the activity hotspot. Two datasets of F-18-FDG PET/CT images were collected, one from 61 breast cancer patients and another from 161 non-small-cell lung cancer patients. In both cohorts, survival analyses were carried out for the NHOC and for other classical PET/CT-based biomarkers, finding that the former had a high prognostic value, outperforming the latter. In summary, our work offers additional insights into the evolutionary mechanisms behind tumor progression, provides a different PET/CT-based biomarker, and reveals that an activity hotspot closer to the tumor periphery is associated to a worst patient outcome

Percepción de los alumnos de enfermería de las unidades especiales a través de sus diarios

Conocer la experiencia clínica vivida por los alumnos de 4º curso de enfermería en las unidades de cuidados intensivos y reanimación. Potenciar el diario de prácticas clínicas como herramienta de reflexión durante los procesos de enseñanza aprendizaje clínico en las unidades de cuidados especiales. Introducir al alumno de prácticas clínicas en la rehumanización de los cuidados en unidades especiales (contextos clínicos cerrados y de alta incidencia tecnológica). Metodológicamente se emplearán, por una parte, los diarios de prácticas clínicas enfocados al problema planteado en esta investigación; por otra, se realizarán sesiones con grupos focales para debatir procesualmente, el problema de investigación a la luz de las narrativas vertidas en los diarios. Los principales resultados obtenidos ponen de manifiesto las siguientes categorías:-el miedo y la angustia vivido por los alumnos al comienzo en este tipo de unidades. La relevancia del tutor en este entorno. La importante labor desarrollada por un equipo multidisciplinar. La influencia de la tecnificación sin desatender los cuidados básicos. Ganan seguridad y confianza con el paso de los días siendo conscientes de sus limitaciones

El diario de prácticas clínicas en la unidad de cuidados intensivos

El objetivo de este trabajo se centra en conocer la experiencia clínica vivida por los alumnos de 4º curso de enfermería en las unidades de cuidados especiales. Para la obtención de los datos se empleará la utilización de una herramienta específica como es el diario de prácticas clínicas elaborado por los porpios alumnos donde se recojan las vivencias en las unidades especiales. Por otro lado se realizarán sesiones con grupos focales para debatir procesualmente, el problema de investigación a la luz de las narrativas vertidas en los diarios. Los resultados obtenidos ponen de manifiesto las siguientes categorías:-el miedo y la angustia vivido por los alumnos al comienzo en este tipo de unidades. La relevancia de la figura del tutor en este entorno. La labor desarrollada por un el equipo de soporte de la enseñanza clínica. La influencia de la tecnificación sin desatender los cuidados básicos y por último el aumento de la seguridad y confianza con el entorno con el paso de los día

RNA sequencing-based transcriptome profiling of cardiac tissue Implicados novela putative disease mechanisms in FLNC-associated arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) encompasses a group of inherited cardiomyopathies including arrhythmogenic right ventricular cardiomyopathy (ARVC) whose molecular disease mechanism is associated with dysregulation of the canonical WNT signalling pathway. Recent evidence indicates that ARVC and ACM caused by pathogenic variants in the FLNC gene encoding filamin C, a major cardiac structural protein, may have different molecular mechanisms of pathogenesis. We sought to identify dysregulated biological pathways in FLNC-associated ACM. RNA was extracted from seven paraffin-embedded left ventricular tissue samples from deceased ACM patients carrying FLNC variants and sequenced. Transcript levels of 623 genes were upregulated and 486 genes were reduced in ACM in comparison to control samples. The cell adhesion pathway and ILK signalling were among the prominent dysregulated pathways in ACM. Consistent with these findings, transcript levels of cell adhesion genes JAM2, NEO1, VCAM1 and PTPRC were upregulated in ACM samples. Moreover, several actin-associated genes, including FLNC, VCL, PARVB and MYL7, were suppressed, suggesting dysregulation of the actin cytoskeleton. Analysis of the transcriptome for biological pathways predicted activation of inflammation and apoptosis and suppression of oxidative phosphorylation and MTORC1 signalling in ACM. Our data suggests dysregulated cell adhesion and ILK signalling as novel putative pathogenic mechanisms of ACM caused by FLNC variants which are distinct from the postulated disease mechanism of classic ARVC caused by desmosomal gene mutations. This knowledge could help in the design of future gene therapy strategies which would target specific components of these pathways and potentially lead to novel treatments for ACM