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Herein, we report the synthesis and biological evaluation of a novel series of heparinoid amphiphiles as inhibitors of heparanase and SARS-CoV-2. By employing a tailor-made synthetic strategy, a library of highly sulfated homo-oligosaccharides bearing d-glucose or a C5-epimer (i.e., l-idose or l-iduronic acid) conjugated with various lipophilic groups was synthesized and investigated for antiviral activity. Sulfated higher oligosaccharides of d-glucose or l-idose with lipophilic aglycones displayed potent anti-SARS-CoV-2 and antiheparanse activity, similar to or better than pixatimod (PG545), and were more potent than their isosteric l-iduronic acid congeners. Lipophilic groups such as cholestanol and C18-aliphatic substitution are more advantageous than functional group appended lipophilic moieties. These findings confirm that fine-tuning of higher oligosaccharides, degree of sulfation, and lipophilic groups can yield compounds with potent anti-SARS-CoV-2 activity.

Purpose: To characterize the retinal phenotype in RNU4ATAC-associated Roifman syndrome. Methods: Ten patients (including 8 males) with molecularly confirmed Roifman syndrome underwent detailed ophthalmologic evaluation including fundus imaging, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (SD-OCT), and electroretinography (ERG). Six patients had follow-up eye exams. All patients also underwent comprehensive examination for features of extra-retinal Roifman syndrome. Results: All patients had biallelic RNU4ATACvariants. Nyctalopia was common (7/10). Visual acuity at presentation ranged from 20/20 to 20/200 (Age Range: 5–41 years). Retinal exam revealed features of generalized retinopathy with mid-peripheral pigment epithelial changes. A para or peri-foveal ring of hyper-autofluorescence was the commonest FAF abnormality noted (6/8). The SD-OCT demonstrated relative preservation of the foveal ellipsoid zone in six cases; associated features included cystoid changes (5/10) and posterior staphyloma (3/10). The ERG was abnormal in all patients; nine showed generalized rod-cone dystrophy, whilst one patient with sectoral retinal involvement only had isolated rod dystrophy (20 years old). On follow-up examination (Mean duration: 8.16 years), progressive loss of visual acuity (2/6), mid-peripheral retinal atrophy (3/6) or shortening of ellipsoid zone width (1/6) were observed. Conclusion: This study has characterized the retinal phenotype in RNU4ATAC-associated Roifman syndrome. Retinal involvement is universal, early-onset, and overall, the retinal and FAF features are consistent with rod-cone degeneration that is slowly progressive over time. The sub-foveal retinal ultrastructure is relatively preserved in majority of patients. Phenotypic variability independent of age exists, and more study of allelic- and sex-based determinants of disease severity are necessary.

Coronavirus disease-2019 (COVID-19) is primarily a respiratory disease, however, an increasing number of reports indicate that SARS-CoV-2 infection can also cause severe neurological manifestations, including precipitating cases of probable Parkinson’s disease. As microglial NLRP3 inflammasome activation is a major driver of neurodegeneration, here we interrogated whether SARS-CoV-2 can promote microglial NLRP3 inflammasome activation. Using SARS-CoV-2 infection of transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) as a COVID-19 pre-clinical model, we established the presence of virus in the brain together with microglial activation and NLRP3 inflammasome upregulation in comparison to uninfected mice. Next, utilising a model of human monocyte-derived microglia, we identified that SARS-CoV-2 isolates can bind and enter human microglia in the absence of viral replication. This interaction of virus and microglia directly induced robust inflammasome activation, even in the absence of another priming signal. Mechanistically, we demonstrated that purified SARS-CoV-2 spike glycoprotein activated the NLRP3 inflammasome in LPS-primed microglia, in a ACE2-dependent manner. Spike protein also could prime the inflammasome in microglia through NF-κB signalling, allowing for activation through either ATP, nigericin or α-synuclein. Notably, SARS-CoV-2 and spike protein-mediated microglial inflammasome activation was significantly enhanced in the presence of α-synuclein fibrils and was entirely ablated by NLRP3-inhibition. Finally, we demonstrate SARS-CoV-2 infected hACE2 mice treated orally post-infection with the NLRP3 inhibitory drug MCC950, have significantly reduced microglial inflammasome activation, and increased survival in comparison with untreated SARS-CoV-2 infected mice. These results support a possible mechanism of microglial innate immune activation by SARS-CoV-2, which could explain the increased vulnerability to developing neurological symptoms akin to Parkinson’s disease in COVID-19 infected individuals, and a potential therapeutic avenue for intervention.

Despite being frequently observed in cancer cells, chromosomal instability (CIN) and its immediate consequence, aneuploidy, trigger adverse effects on cellular homeostasis that need to be overcome by anti-stress mechanisms. As such, these safeguard responses represent a tumor-specific Achilles heel, since CIN and aneuploidy are rarely observed in normal cells. Recent data have revealed that epitranscriptomic marks catalyzed by RNA-modifying enzymes change under various stress insults. However, whether aneuploidy is associated with such RNA modifying pathways remains to be determined. Through an in silico search for aneuploidy biomarkers in cancer cells, we found TRMT61B, a mitochondrial RNA methyltransferase enzyme, to be associated with high levels of aneuploidy. Accordingly, TRMT61B protein levels are increased in tumor cell lines with an imbalanced karyotype as well as in different tumor types when compared to control tissues. Interestingly, while TRMT61B depletion induces senescence in melanoma cell lines with low levels of aneuploidy, it leads to apoptosis in cells with high levels. The therapeutic potential of these results was further validated by targeting TRMT61B in transwell and xenografts assays. We show that TRM61B depletion reduces the expression of several mitochondrial encoded proteins and limits mitochondrial function. Taken together, these results identify a new biomarker of aneuploidy in cancer cells that could potentially be used to selectively target highly aneuploid tumors.

The impact of public transportation on the human emotional well-being is certainly under-studied, especially in the developing countries. This study proposes and validates a questionnaire aimed to assess the emotional well-being in the context of public transportation use in Paraguay (as in any other Spanish country).

The production process of recycled paper generates a significant amount of wastewater. In many cases, the companies do not have a fully adequate effluent treatment system, due to the high cost of conventional physical or chemical treatment systems, which leads to contaminated wastewater. Due to this problem, this research aims to evaluate a bioremediation system based on a flotation system with Typha domingensisplants, for the recovery of wastewater generated in the paper recycling process. The effluent treatment system was installed in the vegetation house of the Multidisciplinary Center for Technological Research (CEMIT), San Lorenzo, Paraguay. It consisted of Typhas plants arranged in plastic containers, which were classified in relation to the effluent concentration (100 %; 50 %; 30 %), in three replicates. For the evaluation of efficiency, physicochemical determinations of pH, temperature, turbidity, conductivity, BOD5, COD, total phosphorus and total nitrogen were carried out at 7-day intervals over a 4-week period. The results obtained indicate significant differences in the percentage of removal of the different pollutant concentrations, where the COD and BOD5 parameters showed removal values of 99 % and 92 %. In the case of Total Nitrogen and Total Phosphorus the values were around 92 % and 75 %, respectively, demonstrating the efficiency of the plant in the treatment of the effluent. This kind of wastewater treatment system has the potential to decrease the load of effluent pollutants produced in paper recycling. Therefore, this study concluded that the system composed of T. domingensisis an option as a potential phytoremediation system for the treatment of wastewater from paper recycling.

We examined patterns of dietary overlap of phyllostomid bats in interior Atlantic Forest of Paraguay. In addition, we examined microgeographic, seasonal, and species-specific, differences in dietary patterns. We obtained 4,519 dietary records for bats from two sites in eastern Paraguay representing 26 different kinds of resources. The three most abundant resources made up 85% of all dietary records. No significant difference in diets of phyllostomid bats existed between sites. Overlap was high and significantly greater than random. Overlap at both sites was higher in winter than in summer. Consumption of dietary items was different between seasons and reflected changes in consumption primarily of the three most consumed items. Resource breadth was narrower in winter than summer. Sites, season, and species together accounted for 71% of the variation in dietary items. Unique effects, after controlling for variation shared with other factors, of species and season were significant, whereas that of site was not. While much dietary variation in interior Atlantic Forest falls along phylogenetic lines, such patterns are weak and resource utilization appears to be substantively influenced by generalist ecology of bats and seasonal nature of the environment in this system.

To determine the quality of life related to health, functional capacity and mood to hip fracture and one month after surgery.

Determinar la calidad de vida relacionada con la salud, la capacidad funcional y el estado de ánimo previo a la fractura de cadera y al mes de la intervención quirúrgica.

Analizar el nivel de conocimiento y uso, y las características del uso, de los mecanismos de coordinación clínica entre niveles de atención en redes de servicios de salud de seis países de Latinoamérica.

During an inflammatory process of the testis, the network of somatic, immune, and germ cell interactions is altered leading to organ dysfunction. In testicular biopsies of infertile men, spermatogenesis impairment is associated with reduced spermatogonia proliferation, increased number of immune cells, and content of pro-inflammatory cytokines. TNFα-TNFR and nitric oxide (NO)-NO synthase systems are up-regulated in models of testicular damage and in human testis with maturation arrest. The purpose of this study was to test the hypothesis that TNFα-TNFR system and NO alter the function of spermatogonia in the inflamed testis. We studied the effect of TNFα and NO on GC-1 spermatogonia cell cycle progression and death by flow cytometry. GC-1 cells expressed TNFR1 and TNFR2 (immunofluorescence). TNFα (10 and 50 ng/ml) and DETA-Nonoate (0.5 and 2 mM), a NO releaser, increased the percentage of cells in S-phase of the cell cycle and reduced the percentage in G1, inducing also cell apoptosis. TNFα effect was not mediated by oxidative stress unlike NO, since the presence of N-acetyl-l-cysteine (2.5 and 5.0 mM) prevented NO induced cell cycle arrest and death. GC-1 spermatogonia overpass NO induced cell cycle arrest but no TNFα, since after removal of NO, spermatogonia progressed through the cell cycle. We propose TNFα and NO might contribute to impairment of spermatogenesis by preventing adequate functioning of the spermatogonia population. Our results showed that TNFα and NO impaired spermatogonia cell cycle, inducing GC-1 arrest in the S phase.

Determinar si el estado cognitivo basal influye en la recuperación funcional a los 6 meses de la fractura de cadera.

Scheme of the asymmetric supercapacitor cell and variation of the power density vs. the energy density for two aqueous electrolytes, 1 M Na2SO4and 1 M KOH.

Na-ion batteries are nowadays receiving renewed attention because of its propitiousness for large-scale stationary applications. Although the Na storage mechanism is still not completely understood, TiO2nanoparticles are very promising active anode materials in Na-ion batteries provided that a correct dispersion is achieved within the battery electrode. Whilst the structural changes, either in crystallinity or crystalline phase, that occur during operation are receiving much recent attention, the nanometric morphological evolution of the TiO2nanoparticles within the electrode is yet to be thoroughly addressed, despite its implication in battery efficiency. In the present work, operandosmall-angle x-ray scattering studies on TiO2/Na-ion batteries show that whereas the nanoparticle size is preserved during the discharge-charge cycles, the mean distance between nanoparticles increases. The observed morphological changes are consistent with electrode swelling and nanoparticle aggregation during operation, being one phenomenon dominant over the other depending on the applied density current; thus, depending on the differences in ion diffusion within the electrode.

Este trabajo cuantifica el crecimiento del producto agrario y del producto agrario per cápita en cuatro provincias castellanas entre las últimas décadas del siglo XVIy el tercer cuarto del XVIII. Para ello utiliza la vía del producto y se basa en la documentación decimal generada por las diócesis de Ávila, Burgos, Salamanca y Segovia para el reparto del subsidio y del excusado. Su principal conclusión no corrobora la imagen negativa que ofrece parte de la historiografía reciente sobre la evolución del sector primario castellano en los siglos XVIy XVIII: entre 1588-1592 y 1771-1775, tanto el producto agrario como el producto agrario por habitante, lejos de reducirse, crecieron en la región estudiada.

This paper provides a procedure for evaluating the capacity or charge of composites consisting of battery-type electrode and supercapacitor-type one. The composites, which are binder-free flexible materials, consist of cobalt oxide (CoOx) electrodeposited on the fibers of a carbon cloth (CC). The deposited CoOx shows battery-type response. The CC substrate shows supercapacitor-type one. The procedure here reported is based on galvanostatic charge/discharge measurements. It is easier, less laborious and faster than the procedure based on the kinetic study by cyclic voltammetry. The two procedures are compared. The dependences of the specific capacities as functions of the current density and voltage scan rate show similar patterns. The contribution of the two types of materials to the specific capacity of the complete electrode is discussed. The electrodedeposited CoOx contributes increasing the specific capacity of the composites at low current densities. The CC substrate dominates the specific capacity of the composites at high current densities.

Introduction: Mucoepidermoid carcinoma represents one of the most frequent malignant neoplasms in the salivary glands. It occurs in major salivary glands such as the parotid gland, and in the case of minor salivary glands, the most commonly affected site is the palate. It is found between the fourth and sixth decade of life, with a predominance in women. Case Report: A 22-year-old male patient with unremarkable medical history attended the School of Dentistry of the National University of Asunción referred by his dentist after noticing a slight discoloration different from the adjacent mucosa. During the anamnesis, the patient related occasional discomfort in the hard palate area for one year. In the intraoral examination, an ovoid lesion was observed on the left side of the hard palate, presenting purplish color, measuring 1 cm in diameter and depressible to palpation. A panoramic x-ray and a computerized axial tomography showed no bone alterations. An incisional biopsy was performed, and the histopathological study resulted in a low-grade mucoepidermoid carcinoma. Conclusions: This specific carcinoma is atypical to be found in young patients, compared to the age range in which it usually appears. In any case, it should be considered in the differential diagnosis due to its clinical characteristics. [ABSTRACT FROM AUTHOR]

Advances in Li metal anode stabilization, solid-state electrolytes, and capabilities to insert a variety of active ions (Li+, Na+, Mg2+, and Al3+) have renewed the interest in layered vanadium oxides. Here we show that crystal characteristics such as size and crystallinity are fundamental variables that control the dissimilar electrochemical capabilities of 1D vanadium oxides immersed in different electrolytes (organic carbonates and safe electrolytes containing 80% of ionic liquid). We show that this opposite behavior can be understood in terms of a subtle interplay between crystal characteristics (size and crystallinity), electrolyte degradability, and the ionic conductivity of the electrolyte. Thus, through this control we are able to obtain pure 1D vanadium oxides that show reversibility in carbonate electrolytes at a cutoff voltage of 1.5 V (voltage region where insertion of more than two lithium ions is possible). Furthermore, these materials are able to uptake ca. 1.0 mol of Li at a rate of 20C (1C = 295 mAh/g) and retain excellent capabilities (Coulombic efficiency of 98% after 200 cycles at a rate of 5C). Finally, what, to our knowledge, is really remarkable is that this optimization allows building vanadium oxide electrodes with an excellent electrochemical response in a safe electrolyte composition (80% of ionic liquid). Specifically, we reach uptakes also at a cutoff voltage of 1.5 V of ca. 1.0 mol of Li after 200 cycles at 5C (charge/discharge) with Coulombic efficiencies higher than 99.5%.

El ictus es la primera causa de discapacidad en adultos. Con frecuencia, el cuidado recae sobre la familia pudiendo afectar a su calidad de vida.

El ictus es un problema de salud de primer orden. La falta de conocimientos con frecuencia está detrás de la demora o retraso en acudir a un centro hospitalario.