Heterotypic liquid-liquid phase separation of tau and α-synuclein: Implications for overlapping neuropathologies.

Tauopathies and synucleinopathies are characterized by the aggregation of Tau and α-synuclein (AS) into amyloid structures, respectively. Individuals with these neuropathies have an elevated risk of developing subsequent neurodegenerative or comorbid disorders. Intriguingly, post-mortem brain examinations have revealed co-localization of Tau and AS aggregates, suggesting a synergistic pathological relationship with an adverse prognosis. The role of liquid-liquid phase separation (LLPS) in the development of neurodegenerative diseases is currently receiving significant attention, as it can contribute to the aggregation and co-deposition of amyloidogenic proteins. In this study, we investigated the phase separation behavior of Tau and AS under various insults, some of which are implicated in disease progression. Our findings demonstrate the formation of heterotypic droplets composed of Tau and AS at physiologically relevant mole ratios that mimic neurons' soma and terminal buttons. Importantly, these heterotypic droplets exhibit increased resistance to electrostatic screening compared to homotypic condensates. Moreover, we observed that biologically relevant biomolecules, known to be dysregulated in disease, exert different effects on these droplets. Additionally, we provide evidence that phase separation itself influences the amyloid aggregation of Tau and AS, underscoring the significance of this process in the development of aggregopathies.

Physiologic Voice Rehabilitation Based on Water Resistance Therapy With Connected Speech in Subjects With Vocal Fatigue.

PURPOSE: The present study aimed to assess the effectiveness of a physiologic voice therapy program based on water resistance therapy (WRT) exercises including connected speech in a group of subjects with voice complaints (vocal effort and fatigue). METHODS: Twenty-four participants with behavioral dysphonia were randomly assigned to one of two treatment groups: (1) voice treatment with WRT plus vocal hygiene program (n = 12), and (2) vocal hygiene program only (n = 12). Laryngoscopic assessment was performed in all subjects. Before and after voice therapy, participants underwent aerodynamic and electroglottographic assessment. The Voice Handicap Index (VHI) and self-assessment of resonant voice were also performed. The treatment included six voice therapy sessions. For the experimental group, the exercises consisted of a sequence of seven phonatory tasks performed with two different voice training devices (PocketVox and MaskVox). Comparison for all variables was performed between experimental group and control group. RESULTS: Significant differences were found for experimental group for VHI physical subscale, and self-perceived resonant voice when comparing pre-post conditions. A strong negative correlation between self-perceived resonant voice and VHI physical sub-score was also reported. No significant differences were found for instrumented variables. CONCLUSION: Physiologic voice therapy based on WRT exercises including connected speech seems to be an effective tool to improve self-perceived voice in subjects diagnosed with voice complaints. Apparently, changes are more prone to occur in perceptual variables related with physical discomfort associate with voice production. A reduction in phonatory effort and perceptual aspects of vocal fatigue are the main improvements.

ORBI Score Validation as Predictor of Cardiogenic Shock in Patients With St Elevation Myocardial Infarction in Two Medical Centers in Argentina.

Cardiogenic shock(CS) after ST-segment elevation myocardial infarction(STEMI) has an in-hospital mortality of 50%. The ORBI score identifies patients at risk of CS after primary angioplasty. We aim to validate the score in an Argentinian cohort. A retrospective validation analysis was carried out from a cohort of patients with STEMI in 2 centers in Buenos Aires Metropolitan Area. The predictive value of the score were estimated through its discrimination power by AUC-ROC and calibration with the Hosmer Lemeshow (HL) goodness of fit test. Four hundred and twenty-four patients were analyzed. The incidence of CS was 8.5%. The median ORBI score was 10 (IQR 7-13) vs 5 in those without CS (IQR 3-7) (P < 0.0001). The performance of the test showed an AUC-ROC of 0.80 (95%CI 0.73-0.87; P < 0.0001); and a HL X² of 4.26 (P = 0.74). The ORBI score presented an adequate predictive capacity and calibration, suggesting its possible application in this population.

Modulation of α-synuclein phase separation by biomolecules.

Liquid-liquid phase separation (LLPS) is currently recognized as a common mechanism involved in the regulation of a number of cellular functions. On the other hand, aberrant phase separation has been linked to the biogenesis of several neurodegenerative disorders since many proteins that undergo LLPS are also found in pathological aggregates. The formation of mixed protein coacervates may constitute a risk factor in overlapping neuropathologies, such as Parkinson's (PD) and Alzheimer's (AD) diseases. In this work, we evaluated the homotypic and heterotypic phase behaviour of the PD-related protein α-synuclein (AS) in the presence of the biologically relevant molecules ATP, polyamines, and the AD-related protein Tau. We found that AS exhibits a low propensity to form homotypic liquid droplets, yet phase separates into liquid-like or solid-like phases depending on the interacting biomolecule. We further demonstrated the synergistic droplet formation of AS and Tau providing support for a mechanism in which mixed condensates might contribute to the biogenesis of AS/Tau pathologies.

State estimation and nonlinear tracking control simulation approach. Application to a bioethanol production system.

Tracking control of specific variables is key to achieve a proper fermentation. This paper analyzes a fed-batch bioethanol production process. For this system, a controller design based on linear algebra is proposed. Moreover, to achieve a reliable control, on-line monitoring of certain variables is needed. In this sense, for unmeasurable variables, state estimators based on Gaussian processes are designed. Cell, ethanol and glycerol concentrations are predicted with only substrates measurement. Simulation results when the controller and estimators are coupled, are shown. Furthermore, the algorithms were tested with parametric uncertainties and disturbances in the control action, and are compared, in all cases, with neural networks estimators (previous work). Bayesian estimators show a performance improvement, which is reflected in a decrease of the total error. Proposed techniques give reliable monitoring and control tools, with a low computational and economic cost, and less mathematical complexity than neural network estimators.

Clinical features and possible founder mutation of the 8bp duplication mutation in the SLC4A11 gene causing corneal dystrophy and perceptive deafness in three South American families.

BACKGROUND: Corneal Dystrophy and Perceptive Deafness (CDPD) or Harboyan syndrome is an autosomal recessive rare disorder, characterized by congenital corneal opacities and progressive sensorineural hearing loss, which usually begins after the second decades of life. This study reports the ophthalmic, audiological and genetic features, in five CDPD affected patients from three Chilean families. MATERIALS AND METHODS: Five individuals affected with CDPD from three unrelated Chilean families were clinically and genetically examined. To evaluate a putative founder mutation 7 SNPs were analyzed in the three families, an Argentinian patient (carrier of the same mutation previously reported) and 87 Chilean controls. RESULTS: The ophthalmic symptoms in the five patients were bilateral and symmetric, starting before one year of age, and visual acuity varied from 0.1 to 0.3. In all cases, hearing loss began over 8 years old. The sequence of the 19 exons of SLC4A11 gene of all the affected patients exhibited homozygous eight nucleotide sequence duplication (c.2233_2240dup TATGACAC, p.(Ile748Metfs*5)) at the end of exon 16. All the affected patients of the three families were homozygous for a haplotype composed of five SNPs and covering 4,1 Mb. The same haplotype was present in one allele of the heterozygous Argentinean patient and has a frequency of 2.76% in Chilean population. CONCLUSIONS: The five CDPD patients were homozygous for the same mutation in the SLC4A11 gene. Haplotype analysis of all the affected, including the case reported from Argentina was in accordance with a founder mutation.

[Clopidogrel versus prasugrel in acute coronary syndrome treated with coronary angioplasty]. / Clopidogrel versus prasugrel en síndrome coronario agudo tratado con angioplastia.

Greater antithrombotic potency new antiplatelet agents have been added such as prasugrel (PR) and ticagrelor to the traditional use of clopidogrel (CL) in the treatment of acute coronary syndrome (ACS). This study was aimed at comparing the incidence of long term ischemic and hemorrhagic events in patients treated with CL or PR during hospitalization. Retrospective ACS data base analysis performed by our cardiology service was completed prospectively. There were consecutively included all patients with percutaneous coronary intervention (PCI) during hospitalization due to ACS from December 2011 thru December 2012. A total of 398 ACS patients who underwent PCI with stent implantation were recruited. No differences in cardiovascular related deaths were observed in both groups (PR 2.9% vs. CL 2.5%, p=0.48). PR group showed less re-infraction (1.9% vs. 6.8%, p=0.01) with more total bleedings (18.5% vs. 8.5%, p=0.001) and minor bleedings (12.4% vs. 3.4%, p<0.001) with no differences in major and life threatening bleedings (p=ns). Multivariate analysis showed that independent predictors of cardiovascular mortality were age (OR 1.08, CI 95% 1.02-1.16) and renal failure (OR 6.98, CI 95% 1.23-39.71). Independent predictors for total bleeding were age (OR 1.06, CI 95% 1.02-1.09),ST segment elevation myocardial infarction (OR 1.99, CI 95% 1.05-3.79), renal failure (OR 3.32, CI 95% 1.62-6.78) and prasugrel use (OR 3.97, CI 95% 1.87-8.41). Use of prasugrel, in the ACS that requires PCI with stent, is associated with a lower myocardial infarction a year after follow-up, and it also leads to an increase of milder hemorrhage. No significant differences were observed in the cardiovascular mortality of both groups.

Clopidogrel versus prasugrel en síndrome coronario agudo tratado con angioplastia / Clopidogrel versus prasugrel in acute coronary syndrome treated with coronary angioplasty

Al uso del clopidogrel se han agregado nuevos antiagregantes como prasugrel y ticagrelor. El objetivo de este estudio fue comparar la incidencia de eventos isquémicos y hemorrágicos en pacientes que han recibido clopidogrel o prasugrel.Se incluyeron de manera consecutiva todos los pacientes con angioplastia durante la internación por síndrome coronario agudo entre diciembre 2011 y diciembre 2012.Fueron incluidos 398 pacientes. No se observaron diferencias en la mortalidad de causa cardiovascular (clopidogrel 2.5% vs. prasugrel 2.9%, p = 0.48). El grupo prasugrel presentó una reducción en la tasa de infarto (1.9% vs. 6.8%, p = 0.01) con sangrado totales (18.5% vs. 8.5%, p = 0.001) a expensas de sangrados menores (12.4% vs. 3.4%, p < 0.001), sin diferencia en sangrados mayores (p = 0.27) y sangrados con peligro de vida (p =.0.20). Por análisis multivariado los predictores independientes de mortalidad cardiovascular fueron edad (odds ratio 1.08, intervalo de confianza, IC, 95% 1.02-1.16, p = 0.02) insuficiencia renal (odds ratio 6.98, IC 95% 1.23-39.71, p < 0.0001). En cuanto al sangrado total se identificaron la edad (odds ratio 1.06, IC 95% 1.02-1.09, p = 0.002), elevación del segmento ST (odds ratio 1.99, IC 95% 1.05-3.79, p = 0.02), insuficiencia renal (odds ratio 3.32, IC 95% 1.62-6.78, p = 0.002) y utilización de prasugrel (odds ratio 3.97, IC 95% 1.87-8.41, p < 0.0001). La utilización de prasugrel se asocia a una menor tasa de infarto agudo de miocardio al año de seguimiento, con incremento de hemorragias menores. No se observaron diferencias significativas en la mortalidad cardiovascular entre ambos grupos.

Greater antithrombotic potency new antiplatelet agents have been added such as prasugrel (PR) and ticagrelor to the traditional use of clopidogrel (CL) in the treatment of acute coronary syndrome (ACS). This study was aimed at comparing the incidence of long term ischemic and hemorrhagic events in patients treated with CL or PR during hospitalization. Retrospective ACS data base analysis performed by our cardiology service was completed prospectively. There were consecutively included all patients with percutaneous coronary intervention (PCI) during hospitalization due to ACS from December 2011 thru December 2012. A total of 398 ACS patients who underwent PCI with stent implantation were recruited. No differences in cardiovascular related deaths were observed in both groups (PR 2.9% vs. CL 2.5%, p = 0.48). PR group showed less re-infraction (1.9% vs. 6.8%, p = 0.01) with more total bleedings (18.5% vs. 8.5%, p = 0.001) and minor bleedings (12.4% vs. 3.4%, p < 0.001) with no differences in major and life threatening bleedings (p = ns). Multivariate analysis showed that independent predictors of cardiovascular mortality were age (OR 1.08, CI 95% 1.02-1.16) and renal failure (OR 6.98, CI 95% 1.23-39.71). Independent predictors for total bleeding were age (OR 1.06, CI 95% 1.02-1.09),ST segment elevation myocardial infarction (OR 1.99, CI 95% 1.05-3.79), renal failure (OR 3.32, CI 95% 1.62-6.78) and prasugrel use (OR 3.97, CI 95% 1.87-8.41). Use of prasugrel, in the ACS that requires PCI with stent, is associated with a lower myocardial infarction a year after follow-up, and it also leads to an increase of milder hemorrhage. No significant differences were observed in the cardiovascular mortality of both groups.