Proneurogenic actions of follicle-stimulating hormone on neurospheres derived from ovarian cortical cells in vitro.

BACKGROUND: Neural stem and progenitor cells (NSPCs) from extra-neural origin represent a valuable tool for autologous cell therapy and research in neurogenesis. Identification of proneurogenic biomolecules on NSPCs would improve the success of cell therapies for neurodegenerative diseases. Preliminary data suggested that follicle-stimulating hormone (FSH) might act in this fashion. This study was aimed to elucidate whether FSH promotes development, self-renewal, and is proneurogenic on neurospheres (NS) derived from sheep ovarian cortical cells (OCCs). Two culture strategies were carried out: (a) long-term, 21-days NS culture (control vs. FSH group) with NS morphometric evaluation, gene expression analyses of stemness and lineage markers, and immunolocalization of NSPCs antigens; (b) NS assay to demonstrate FSH actions on self-renewal and differentiation capacity of NS cultured with one of three defined media: M1: positive control with EGF/FGF2; M2: control; and M3: M2 supplemented with FSH. RESULTS: In long-term cultures, FSH increased NS diameters with respect to control group (302.90 ± 25.20 µm vs. 183.20 ± 7.63 on day 9, respectively), upregulated nestin (days 15/21), Sox2 (day 21) and Pax6 (days 15/21) and increased the percentages of cells immunolocalizing these proteins. During NS assays, FSH stimulated NSCPs proliferation, and self-renewal, increasing NS diameters during the two expansion periods and the expression of the neuron precursor transcript DCX during the second one. In the FSH-group there were more frequent cell-bridges among neighbouring NS. CONCLUSIONS: FSH is a proneurogenic hormone that promotes OCC-NSPCs self-renewal and NS development. Future studies will be necessary to support the proneurogenic actions of FSH and its potential use in basic and applied research related to cell therapy.

One-year longitudinal changes of peripheral CD4+ T-lymphocyte counts, gut microbiome, and plaque vulnerability after an acute coronary syndrome.

Background: Longitudinal changes in gut microbiome and inflammation may be involved in the evolution of atherosclerosis after an acute coronary syndrome (ACS). We aimed to characterize repeated profiles of gut microbiota and peripheral CD4+ T lymphocytes during the first year after an ACS, and to address their relationship with atherosclerotic plaque changes. Methods: Over one year we measured the microbiome, peripheral counts of CD4+ T populations and cytokines in 67 patients shortly after a first ACS. We compared baseline measurements to those of a matched population of 40 chronic patients. A subgroup of 20 ACS patients underwent repeated assessment of fibrous cap thickness (FCT) of a non-culprit lesion. Results: At admission, ACS patients showed gut dysbiosis compared with the chronic group, which was rapidly reduced and remained low at 1-year. Also, their Th1 and Th2 CD4+ T counts were increased but decreased over time. The CD4+ T counts were related to ongoing changes in gut microbiome. Unsupervised clustering of repeated CD4+ Th0, Th1, Th2, Th17 and Treg counts in ACS patients identified two different cell trajectory patterns, related to cytokines. The group of patients following a high-CD4+ T cell trajectory showed a one-year reduction in their FCT [net effect = -24.2 µm; p = 0.016]. Conclusions: Patients suffering an ACS show altered profiles of microbiome and systemic inflammation that tend to mimic values of chronic patients after 1-year. However, in one-third of patients, this inflammatory state remains particularly dysregulated. This persistent inflammation is likely related to plaque vulnerability as evident by fibrous cap thinning (Clinical Trial NCT03434483).

Evaluation of the Relation between Ictal EEG Features and XAI Explanations.

Epilepsy is a neurological disease with one of the highest rates of incidence worldwide. Although EEG is a crucial tool for its diagnosis, the manual detection of epileptic seizures is time consuming. Automated methods are needed to streamline this process; although there are already several works that have achieved this, the process by which it is executed remains a black box that prevents understanding of the ways in which machine learning algorithms make their decisions. A state-of-the-art deep learning model for seizure detection and three EEG databases were chosen for this study. The developed models were trained and evaluated under different conditions (i.e., three distinct levels of overlap among the chosen EEG data windows). The classifiers with the best performance were selected, then Shapley Additive Explanations (SHAPs) and Local Interpretable Model-Agnostic Explanations (LIMEs) were employed to estimate the importance value of each EEG channel and the Spearman's rank correlation coefficient was computed between the EEG features of epileptic signals and the importance values. The results show that the database and training conditions may affect a classifier's performance. The most significant accuracy rates were 0.84, 0.73, and 0.64 for the CHB-MIT, Siena, and TUSZ EEG datasets, respectively. In addition, most EEG features displayed negligible or low correlation with the importance values. Finally, it was concluded that a correlation between the EEG features and the importance values (generated by SHAP and LIME) may have been absent even for the high-performance models.

Effects of Intra-operative Cardiopulmonary Variability On Post-operative Pulmonary Complications in Major Non-cardiac Surgery: A Retrospective Cohort Study.

Intraoperative cardiopulmonary variables are well-known predictors of postoperative pulmonary complications (PPC), traditionally quantified by median values over the duration of surgery. However, it is unknown whether cardiopulmonary instability, or wider intra-operative variability of the same metrics, is distinctly associated with PPC risk and severity. We leveraged a retrospective cohort of adults (n = 1202) undergoing major non-cardiothoracic surgery. We used multivariable logistic regression to evaluate the association of two outcomes (1)moderate-or-severe PPC and (2)any PPC with two sets of exposure variables- (a)variability of cardiopulmonary metrics (inter-quartile range, IQR) and (b)median intraoperative cardiopulmonary metrics. We compared predictive ability (receiver operating curve analysis, ROC) and parsimony (information criteria) of three models evaluating different aspects of the intra-operative cardiopulmonary metrics: Median-based: Median cardiopulmonary metrics alone, Variability-based: IQR of cardiopulmonary metrics alone, and Combined: Medians and IQR. Models controlled for peri-operative/surgical factors, demographics, and comorbidities. PPC occurred in 400(33%) of patients, and 91(8%) experienced moderate-or-severe PPC. Variability in multiple intra-operative cardiopulmonary metrics was independently associated with risk of moderate-or-severe, but not any, PPC. For moderate-or-severe PPC, the best-fit predictive model was the Variability-based model by both information criteria and ROC analysis (area under the curve, AUCVariability-based = 0.74 vs AUCMedian-based = 0.65, p = 0.0015; AUCVariability-based = 0.74 vs AUCCombined = 0.68, p = 0.012). For any PPC, the Median-based model yielded the best fit by information criteria. Predictive accuracy was marginally but not significantly higher for the Combined model (AUCCombined = 0.661) than for the Median-based (AUCMedian-based = 0.657, p = 0.60) or Variability-based (AUCVariability-based = 0.649, p = 0.29) models. Variability of cardiopulmonary metrics, distinct from median intra-operative values, is an important predictor of moderate-or-severe PPC.

Nanopatterned Monolayers of Bioinspired, Sequence-Defined Polypeptoid Brushes for Semiconductor/Bio Interfaces.

The ability to control and manipulate semiconductor/bio interfaces is essential to enable biological nanofabrication pathways and bioelectronic devices. Traditional surface functionalization methods, such as self-assembled monolayers (SAMs), provide limited customization for these interfaces. Polymer brushes offer a wider range of chemistries, but choices that maintain compatibility with both lithographic patterning and biological systems are scarce. Here, we developed a class of bioinspired, sequence-defined polymers, i.e., polypeptoids, as tailored polymer brushes for surface modification of semiconductor substrates. Polypeptoids featuring a terminal hydroxyl (-OH) group are designed and synthesized for efficient melt grafting onto the native oxide layer of Si substrates, forming ultrathin (∼1 nm) monolayers. By programming monomer chemistry, our polypeptoid brush platform offers versatile surface modification, including adjustments to surface energy, passivation, preferential biomolecule attachment, and specific biomolecule binding. Importantly, the polypeptoid brush monolayers remain compatible with electron-beam lithographic patterning and retain their chemical characteristics even under harsh lithographic conditions. Electron-beam lithography is used over polypeptoid brushes to generate highly precise, binary nanoscale patterns with localized functionality for the selective immobilization (or passivation) of biomacromolecules, such as DNA origami or streptavidin, onto addressable arrays. This surface modification strategy with bioinspired, sequence-defined polypeptoid brushes enables monomer-level control over surface properties with a large parameter space of monomer chemistry and sequence and therefore is a highly versatile platform to precisely engineer semiconductor/bio interfaces for bioelectronics applications.

A Late Antiquity case of a chronic osteomyelitis from the population of Cortijo Coracho, Córdoba, Spain (IV-VIII centuries AD).

The Cortijo Coracho archaeological site dates from the Late Antiquity period, from the 5th to the 8th century AD. During this period, a number of populations settled in the area (Germanic peoples until Visigothic rule, Byzantine until the arrival of the Arabs, etc.), each of them concentrating the historical characteristics in the Sub-Baetic that are currently known. The Cortijo Coracho archaeological site is currently located in the city of Lucena (Cordoba, Spain), found after the works on the A-45 motorway. The necropolis consists of 294 inhumations and the remains of a basilica, although after a series of surveys it is estimated that there are around 700 additional burials, which would make it the largest necropolis with ad sancti burials surrounding a martyrial basilica dating back to the 4th century AD. Among the burials, 397 subjects were recovered, which implies a large presence of shared and/or reused burials. These subjects were transferred to the city's museum, where they were examined, reorganised and classified. At this point, subjects of scientific interest were found, as is the case of subject 204, the topic of this article. This individual, described as an adult male, is an example of the living conditions of this period, since despite his injury on the left lower extremity, a double fracture aggravated by a chronic osteomyelitis infection, he continued to use that limb. This paper will give the details of that distinctive lesion and the possible hypotheses underlying it.

MicroRNAs modulate immunological and inflammatory responses in Holstein cattle naturally infected with Mycobacterium avium subsp. paratuberculosis.

MicroRNAs (miRNAs) regulate the post-transcriptional expression of genes by binding to their target mRNAs. In this study, whole miRNA sequencing was used to compare the expression of miRNAs in ileocecal valve (ICV) and peripheral blood (PB) samples of cows with focal or diffuse paratuberculosis (PTB)-associated lesions in gut tissues versus (vs) control cows without lesions. Among the eight miRNAs differentially expressed in the PB samples from cows with diffuse lesions vs controls, three (miR-19a, miR-144, miR32) were also down-regulated in cows with diffuse vs focal lesions. In the ICV samples, we identified a total of 4, 5, and 18 miRNAs differentially expressed in cows with focal lesions vs controls, diffuse lesions vs controls, and diffuse vs focal lesions, respectively. The differential expression of five microRNAs (miR-19a, miR-144, miR-2425-3p, miR-139, miR-101) was confirmed by RT-qPCR. Next, mRNA target prediction was performed for each differentially expressed miRNA. A functional analysis using the predicted gene targets revealed a significant enrichment of the RNA polymerase and MAPK signaling pathways in the comparison of cows with focal vs no lesions and with diffuse vs focal lesions, respectively. The identified miRNAs could be used for the development of novel diagnostic and therapeutical tools for PTB control.

Non-atherosclerotic acute cardiac syndromes: spontaneous coronary artery dissection and Takotsubo syndrome. Comparison of long-term clinical outcomes.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) and Takotsubo syndrome (TTS) constitute two common causes of nonatherosclerotic acute cardiac syndrome particularly frequent in women. Currently, there is no information comparing long-term clinical outcomes in unselected patients with these conditions. METHODS: We compared the baseline characteristics, in-hospital outcomes, and the 12-month and long-term clinical outcomes of two large prospective registries on SCAD and TTS. RESULTS: A total of 289 SCAD and 150 TTS patients were included; 89% were women. TTS patients were older with a higher prevalence of cardiovascular risk factors. Precipitating triggers were more frequent in TTS patients, while emotional triggers and depressive disorders were more common in the SCAD group. Left ventricular ejection fraction was lower in TTS patients, but SCAD patients showed higher cardiac biomarkers. In-hospital events (43.3% vs. 5.2%, P <0.01) occurred more frequently in TTS patients. TTS patients also presented more frequent major adverse events at 12-month (14.7% vs. 7.1%, HR 5.3, 95% CI: 2.4-11.7, P <0.01) and long-term (median 36 vs. 31 months, P =0.41) follow-up (25.8% vs. 9.6%, HR 4.5, 95% CI: 2.5-8.2, P <0.01). Atrial fibrillation was also more frequent in TTS patients. Moreover, TTS patients presented a higher 12-month and long-term mortality (5.6% vs. 0.7%, P =0.01; and 12.6% vs. 0.7%, P <0.01) mainly driven by noncardiovascular deaths. CONCLUSION: Compared to SCAD, TTS patients are older and present more cardiovascular risk factors but less frequent depressive disorder or emotional triggers. TTS patients have a worse in-hospital, mid-term, and long-term prognosis with higher noncardiac mortality than SCAD patients.

Neuromarkers based on EEG Statistics in Time and Frequency Domains to Detect Tinnitus / Neuromarcadores basados en Estadística de EEG en el Dominio Temporal y Frecuencial para Detectar Acufeno

Abstract: Tinnitus detection and characterization requires a carefully elaborated diagnosis mainly owing to its heterogeneity nature. The present investigation aims to find features in Electroencephalographic (EEG) signals from time and frequency domain analysis that could distinguish between healthy and tinnitus sufferers with different levels of hearing loss. For this purpose, 24 volunteers were recruited and equally divided into four groups: 1) controls, 2) slow tinnitus, 3) middle tinnitus and 4) high tinnitus. EEG signals were registered in two states, with eyes closed and opened for 60 seconds. EEG analysis was focused on two bandwidths: delta and alpha band. For time domain, the EEG features estimated were mean, standard deviation, kurtosis, maximum peak, skewness and shape. For frequency domain, the EEG features obtained were mean, skewness, power spectral density. Normality of EEG data was evaluated by the Lilliefors test, and as a result, the nonparametric technique Kruskal-Wallis H statistic to test significance was applied. Results show that EEG features are more differentiable between tinnitus sufferers and controls in frequency domain than in time domain. EEG features from tinnitus patients with high HL are significantly different from the rest of the groups in alpha frequency band activity when shape and skewness are computed.

Resumen: La detección y caracterización del acúfeno requiere un diagnóstico cuidadosamente elaborado debido principalmente a su naturaleza heterogénea. La presente investigación tiene como objetivo encontrar características en las señales electroencefalográficas (EEG) a partir del análisis del dominio del tiempo y frecuencia que podrían distinguir entre pacientes sanos y con acúfeno con diferentes niveles de pérdida auditiva. Para ello, se reclutaron 24 voluntarios y se dividieron por igual en cuatro grupos: 1) controles, 2) acúfeno bajo, 3) acúfeno medio y 4) acufeno alto. La actividad EEG se registró en reposo en dos condiciones: ojos cerrados y abiertos durante un minuto. El análisis de EEG se centró en anchos de banda delta y alfa. Para el dominio del tiempo, las características del EEG estimadas fueron la media, la desviación estándar, la curtosis, el pico máximo, la asimetría y la forma. Para el dominio de la frecuencia, las características de EEG obtenidas fueron media, asimetría, densidad espectral de potencia. La normalidad de los datos del EEG se evaluó mediante la prueba de Lilliefors y, como resultado, se aplicó la técnica no paramétrica del estadístico H de Kruskal-Wallis para probar la significación. Los resultados muestran que las características del EEG son más diferenciables entre los pacientes con acúfeno y los controles en el dominio de la frecuencia que en el dominio del tiempo. Las características del EEG de los pacientes con acúfeno con alta pérdida de audición son significativamente diferentes del resto de los grupos en la actividad de la banda de alfa cuando se calculan la forma y la asimetría.

Increased Chamber Resting Tone Is a Key Determinant of Left Ventricular Diastolic Dysfunction.

BACKGROUND: Twitch-independent tension has been demonstrated in cardiomyocytes, but its role in heart failure (HF) is unclear. We aimed to address twitch-independent tension as a source of diastolic dysfunction by isolating the effects of chamber resting tone (RT) from impaired relaxation and stiffness. METHODS: We invasively monitored pressure-volume data during cardiopulmonary exercise in 20 patients with hypertrophic cardiomyopathy, 17 control subjects, and 35 patients with HF with preserved ejection fraction. To measure RT, we developed a new method to fit continuous pressure-volume measurements, and first validated it in a computational model of loss of cMyBP-C (myosin binding protein-C). RESULTS: In hypertrophic cardiomyopathy, RT (estimated marginal mean [95% CI]) was 3.4 (0.4-6.4) mm Hg, increasing to 18.5 (15.5-21.5) mm Hg with exercise (P<0.001). At peak exercise, RT was responsible for 64% (53%-76%) of end-diastolic pressure, whereas incomplete relaxation and stiffness accounted for the rest. RT correlated with the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide; R=0.57; P=0.02) and with pulmonary wedge pressure but following different slopes at rest and during exercise (R2=0.49; P<0.001). In controls, RT was 0.0 mm Hg and 1.2 (0.3-2.8) mm Hg in HF with preserved ejection fraction patients and was also exacerbated by exercise. In silico, RT increased in parallel to the loss of cMyBP-C function and correlated with twitch-independent myofilament tension (R=0.997). CONCLUSIONS: Augmented RT is the major cause of LV diastolic chamber dysfunction in hypertrophic cardiomyopathy and HF with preserved ejection fraction. RT transients determine diastolic pressures, pulmonary pressures, and functional capacity to a greater extent than relaxation and stiffness abnormalities. These findings support antimyosin agents for treating HF.