Insights into Zika Virus Pathogenesis and Potential Therapeutic Strategies.

Zika virus (ZIKV) has emerged as a significant public health threat, reaching pandemic levels in 2016. Human infection with ZIKV can manifest as either asymptomatic or as an acute illness characterized by symptoms such as fever and headache. Moreover, it has been associated with severe neurological complications in adults, including Guillain-Barre syndrome, and devastating fetal abnormalities, like microcephaly. The primary mode of transmission is through Aedes spp. mosquitoes, and with half of the world's population residing in regions where Aedes aegypti, the principal vector, thrives, the reemergence of ZIKV remains a concern. This comprehensive review provides insights into the pathogenesis of ZIKV and highlights the key cellular pathways activated upon ZIKV infection. Additionally, we explore the potential of utilizing microRNAs (miRNAs) and phytocompounds as promising strategies to combat ZIKV infection.

GPS, LiDAR and VNIR data to monitor the spatial behavior of grazing sheep

Traditional knowledge about the behavior of grazing livestock is about to disappear. Shepherds well know that sheep behavior follows non-random patterns. As a novel alternative to seeking behavioral patterns, this study quantified the grazing activities of two sheep flocks of Churra breed (both in the same area but separated by 10 years) based on Global Position System (GPS) monitoring and remote monitoring sensing techniques. In the first monitoring period (2009-10), geolocations were recorded every 5 min (4,240 records), while in the second one (2018-20), records were taken every 30 min (7,636 records). The data were clustered based on the day/night and the activity (resting, moving, or grazing). An airborne LiDAR dataset was used to study the slope, aspect, and vegetation height. Four visible-infrared orthophotographs were mosaicked and classified to obtain the land use/land cover (LU/LC) map. Then, GPS locations were overlain on the terrain features, and a Chi-square test evaluated the relationships between locations and terrain features. Three spatial statistics (directional distribution, Kernel density, and Hot Spot analysis) were also calculated. Results in both monitoring periods suggested that the spatial distribution of free-grazing ewes was non-random. The flocks showed strong preferences for grazing areas with gentle north-facing slopes, where the herbaceous layer formed by pasture predominates. The geostatistical analyses of the sheep locations corroborated those preferences. Geotechnologies have emerged as a potent tool to demonstrate the influence of environmental and terrain attributes on the non-random spatial behavior of grazing sheep.

Osmolyte Signatures for the Protection of Aspergillus sydowii Cells under Halophilic Conditions and Osmotic Shock.

Aspergillus sydowii is a moderate halophile fungus extensively studied for its biotechnological potential and halophile responses, which has also been reported as a coral reef pathogen. In a recent publication, the transcriptomic analysis of this fungus, when growing on wheat straw, showed that genes related to cell wall modification and cation transporters were upregulated under hypersaline conditions but not under 0.5 M NaCl, the optimal salinity for growth in this strain. This led us to study osmolyte accumulation as a mechanism to withstand moderate salinity. In this work, we show that A. sydowii accumulates trehalose, arabitol, mannitol, and glycerol with different temporal dynamics, which depend on whether the fungus is exposed to hypo- or hyperosmotic stress. The transcripts coding for enzymes responsible for polyalcohol synthesis were regulated in a stress-dependent manner. Interestingly, A. sydowii contains three homologs (Hog1, Hog2 and MpkC) of the Hog1 MAPK, the master regulator of hyperosmotic stress response in S. cerevisiae and other fungi. We show a differential regulation of these MAPKs under different salinity conditions, including sustained basal Hog1/Hog2 phosphorylation levels in the absence of NaCl or in the presence of 2.0 M NaCl, in contrast to what is observed in S. cerevisiae. These findings indicate that halophilic fungi such as A. sydowii utilize different osmoadaptation mechanisms to hypersaline conditions.

Haloadaptative Responses of Aspergillus sydowii to Extreme Water Deprivation: Morphology, Compatible Solutes, and Oxidative Stress at NaCl Saturation.

Water activity (aw) is critical for microbial growth, as it is severely restricted at aw < 0.90. Saturating NaCl concentrations (~5.0 M) induce extreme water deprivation (aw ≅ 0.75) and cellular stress responses. Halophilic fungi have cellular adaptations that enable osmotic balance and ionic/oxidative stress prevention to grow at high salinity. Here we studied the morphology, osmolyte synthesis, and oxidative stress defenses of the halophile Aspergillus sydowii EXF-12860 at 1.0 M and 5.13 M NaCl. Colony growth, pigmentation, exudate, and spore production were inhibited at NaCl-saturated media. Additionally, hyphae showed unpolarized growth, lower diameter, and increased septation, multicellularity and branching compared to optimal NaCl concentration. Trehalose, mannitol, arabitol, erythritol, and glycerol were produced in the presence of both 1.0 M and 5.13 M NaCl. Exposing A. sydowii cells to 5.13 M NaCl resulted in oxidative stress evidenced by an increase in antioxidant enzymes and lipid peroxidation biomarkers. Also, genes involved in cellular antioxidant defense systems were upregulated. This is the most comprehensive study that investigates the micromorphology and the adaptative cellular response of different non-enzymatic and enzymatic oxidative stress biomarkers in halophilic filamentous fungi.

[Extrapyramidal adverse reactions to metoclopramide. A pharmacovigilance survey]. / Farmacovigilancia activa de metoclopramida 10 mg oral en pacientes del Programa de Alivio del Dolor y Cuidados Paliativos o diabetes mellitus tipo 2 en cinco hospitales del Servicio de Salud Viña del Mar-Quillota.

BACKGROUND: In 2013 the Chilean regulatory sanitary agency issued a warning concerning dose adjustment and use restriction to avoid severe adverse effects of metoclopramide such tardive dyskinesia. AIM: To study dyskinesia type adverse effects in a population using metoclopramide. MATERIAL AND METHODS: A cross sectional observational study was conducted among patients pertaining to palliative care and diabetes mellitus programs and consuming 10 mg/day or more of metoclopramide. Patients were interrogated looking for extrapiramidal signs and symptoms using a questionnaire validated by two neurologists. RESULTS: In 40% of diabetic patients with gastroparesia and 35% of palliative care patients, extrapyramidal adverse reactions to metoclopramide were suspected. Palliative Care patients suffered the largest number of adverse events. The period of use and individual doses of the drug were largely above Chilean regulatory agency recommendations in all cases. CONCLUSIONS: A significant number of patients using metoclopramide could experience extrapyramidal adverse reactions.

Farmacovigilancia activa de metoclopramida 10 mg oral en pacientes del Programa de Alivio del Dolor y Cuidados Paliativos o diabetes mellitus tipo 2 en cinco hospitales del Servicio de Salud Viña del Mar-Quillota / Extrapyramidal adverse reactions to metoclopramide: a pharmacovigilance survey

Background: In 2013 the Chilean regulatory sanitary agency issued a warning concerning dose adjustment and use restriction to avoid severe adverse effects of metoclopramide such tardive dyskinesia. Aim: To study dyskinesia type adverse effects in a population using metoclopramide. Material and Methods: A cross sectional observational study was conducted among patients pertaining to palliative care and diabetes mellitus programs and consuming 10 mg/day or more of metoclopramide. Patients were interrogated looking for extrapiramidal signs and symptoms using a questionnaire validated by two neurologists. Results: In 40% of diabetic patients with gastroparesia and 35% of palliative care patients, extrapyramidal adverse reactions to metoclopramide were suspected. Palliative Care patients suffered the largest number of adverse events. The period of use and individual doses of the drug were largely above Chilean regulatory agency recommendations in all cases. Conclusions: A significant number of patients using metoclopramide could experience extrapyramidal adverse reactions.

Merlin negative regulation by miR-146a promotes cell transformation.

Inactivation of the tumor suppressor Merlin, by deleterious mutations or by protein degradation via sustained growth factor receptor signaling-mediated mechanisms, results in cell transformation and tumor development. In addition to these mechanisms, here we show that, miRNA-dependent negative regulation of Merlin protein levels also promotes cell transformation. We provide experimental evidences showing that miR-146a negatively regulates Merlin protein levels through its interaction with an evolutionary conserved sequence in the 3´ untranslated region of the NF2 mRNA. Merlin downregulation by miR-146a in A549 lung epithelial cells resulted in enhanced cell proliferation, migration and tissue invasion. Accordingly, stable miR-146a-transfectant cells formed tumors with metastatic capacity in vivo. Together our results uncover miRNAs as yet another negative mechanism controlling Merlin tumor suppressor functions.

Oncogenic Transformation Can Orchestrate Immune Evasion and Inflammation in Human Mesenchymal Stem Cells Independently of Extrinsic Immune-Selective Pressure.

Immune escape is a hallmark of cancer, but whether it relies upon extrinsic immune-selective pressure or is inherently orchestrated by oncogenic pathways is unresolved. To address this question, we took advantage of an in vitro model of sequentially transformed human mesenchymal stem cells (hMSC). Neoplastic transformation in this model increased the natural immune-evasive properties of hMSC, both by reducing their immunogenicity and by increasing their capacity to inhibit mitogen-driven T-cell proliferation. We also found that IFNγ signaling was globally affected in transformed hMSC. As a consequence, the natural inhibitory effect of hMSC on T-cell proliferation switched from an inducible mechanism depending on IFNγ signaling and mediated by indoleamine 2,3-dioxygenase to a constitutive mechanism that relied upon IL1ß involving both secreted and membrane-expressed molecules. After transformation, increased IL1ß expression both sustained the immunosuppressive properties of hMSC and increased their tumorigenicity. Thus, in this model system, IL1ß acted as intrinsic inflammatory mediator that exerted an autocrine influence on tumor growth by coordinately linking immune escape and tumorigenicity. Collectively, our findings show how oncogenes directly orchestrate inflammation and immune escape to drive the multistep process of cancer progression, independently of any need for immunoediting in the tumor microenvironment.

Oncogenic transformation tunes the cross-talk between mesenchymal stem cells and T lymphocytes.

Stem cells from mesenchymal origin (MSC) exert a plethora of immunomodulatory effects. We created a neoplastic model based on in vitro step-wise transformation to assess whether oncogenic pathways have the capacity to mould the cross-talk of MSC and lymphocytes. Neoplastic MSC exhibit an increased inhibitory effect on T cell proliferation, either directly or mediated by myeloid derived suppressor cells. Additionally, transformation of MSC enhances T cell apoptosis without reducing either the percentage of CD25 expressing cells or the level of this protein expression. Malignant transformation drives MSC to lose dependency on nitric oxide for immunosuppression whilst increasing the constitutive production of PGE2. Our results indicate that oncogenesis tunes the interplay between MSC and immune cells, favoring cancer immune evasion.

Transformation of a dental school's clinical assessment system through Kotter's eight-step change process.

A revision of the clinical assessment system of the University of Puerto Rico School of Dental Medicine was initiated in 2007, with the goal of achieving a system that would be fully understood and used by both faculty and students to improve student performance throughout the curriculum. The transformation process was organized according to Kotter's Eight-Step Change Model. Some of the initial findings in 2007 were as follows: 87 percent of current daily clinical evaluations were scored at the scale's highest level, 33 percent of faculty members lacked knowledge of the evaluation system, and 60 percent of students reported that faculty members were not well calibrated. As a result of the transformation process, a pilot project has been implemented in the comprehensive clinical course for senior students. The revised assessment methods utilized are verbal daily feedback, clinical evaluations once every three months, a digital portfolio, and competency exams. There is also a productivity component included in the course grade. We conclude that adapting Kotter's model for use in the transformation process has been very useful; gaining support from both the administration and faculty has been essential; and the provision of continuous faculty development activities has been empowering. The American Dental Education Association Commission on Change and Innovation in Dental Education (ADEA CCI) Liaisons at the University of Puerto Rico School of Dental Medicine have been effective in producing a greater awareness among the faculty about the value of the competency-based curriculum and the need for change.

Aminoácidos plasmáticos en pacientes con neuropatía epidémica diagnósticados en Cuba / Plams amino acids in patients to whom epidemic neuropathy was diagnosed in Cuba

En los últimos años los estudios en pacientes con neuropatías han reveladocambios bioquímicos importantes que han explicado la pérdida de la visión por lesiones del nervio óptico con desmielización al nivel de la zona axial del nervio y en la cual los aminoácidos azufrados desempeñan un importante papel metabólico. Este estudio se encaminó a determinar la concentración plasmática de aminoácidos en pacientes con neuropatía epidémica diagnósticados en Cuba. Se encontró que la concentración plasmática de aminoácidos azufrados no cambió respecto al grupo control, por lo que creemos que el factor tóxico tenga un papel primordial. Sin embargo, se encontraron variaciones importantes en un grupo de aminoácidos que pensamos pueda deberse a cambios metabólicos de carácter nutricional que generalmente acpmpañan a esta enfermedad