85 research outputs found
Ecophysiological studies in microalgae isolated from the acidic system Rio Agrio-Lago Caviahue (Neuquén Province, Argentina)
Se realizaron aislamientos de 11 especies algales cocoides y filamentosas del Río Agrio-Lago Caviahue y del complejo termal Copahue (considerados ambientesextremos por su bajo pH y alta temperatura, respectivamente). Las especies sedeterminaron taxonómicamente al microscopio óptico y mediante microscopíaelectrónica de barrido y transmisión. Las especies seleccionadas para los bioensayos (Keratococcus rhaphidioides, Pseudococcomyxa simplex y Watanabea caviahuensis) sellevaron a axenicidad. A cada una de ellas se les midió la tasa de fotosíntesis y se lesdeterminó el óptimo de crecimiento en bioensayos con pH entre 2 y 7. El efecto de losnutrientes sobre el crecimiento algal se evaluó con dos fuentes de fósforo (fosfato yglicerofosfato), con distintas fuentes de nitrógeno (nitrato, nitrito, amonio, urea, leucinay ácido aspártico) y con distintas fuentes de carbono en luz y oscuridad (CO2, glucosa,acetato de etilo y urea). Las curvas de fotosíntesis revelaron que la irradiancia desaturación fue relativamente baja (100-200 μmol fotón m^-2 s^-1) así como el punto decompensación lumínica, mientras que el pH de crecimiento óptimo estuvo alrededor de 4. Con respecto a los nutrientes, el P no mostró mayores diferencias de crecimientoentre la fuente inorgánica y la orgánica, sin embargo con N las mayores densidades seobtuvieron con nitrato, urea y leucina. En cuanto al carbono, K. rhaphidioides loincorporó principalmente de manera inorgánica (CO2) aunque fue capaz de crecer confuentes orgánicas en presencia de luz. Fue notable que en oscuridad las célulaspermanecieran en estado estacionario manteniendo constante la densidad a lo largo delexperimento. K. rhaphidioides, la especie mayoritaria en biomasa y densidad delfitoplancton del lago Caviahue, mostró que no posee mecanismos de concentración decarbono, con lo que su tasa de fotosíntesis depende principalmente de la disponibilidadde CO2 externo. Los hallazgos de laboratorio permitieron relacionar la distribuciónespacial y temporal de las especies estudiadas con las características ambientalesobservadas en el sistema ácido natural Río Agrio-Lago Caviahue.Eleven algal strains of cocoidal and filamentous habits, were isolated from the Rio Agrio-Lago Caviahue system. These environments are considered extreme due to itslow pH and high temperature, respectively. The species were determined andcharacterized under light and electronic microscopy (SEM and TEM). Three strainswere selected for the bioassays (Keratococcus rhaphidioides, Pseudococcomyxasimplex and Watanabea caviahuensis) and axenic cultures of these were obtained. Thephotosynthesis rate and optimal growth conditions were determined in bioassays withpH between 2 and 7. The effect of different nutrients was also addressed. Among them,two phosphorus sources (phosphate and glicerophosphate), six sources of nitrogen (nitrate, nitrite, ammonium, urea, leucine and aspartic acid) and four sources of carbon (CO2, glucose, etil-acetate and urea) were studied. The photosynthesis studies reveledthat the light compensation point and irradiance saturation were low (100-200 μmolphoton m^-2 s^-1) while optimum pH was 4. Moreover, no significant differences werefound for the growth with the different P sources, but for N, nitrate, urea and leucineyielded higher growth rates and cell densities. With regard to the carbon sources, K.rhaphidioides incorporated all the carbon sources under constant illumination, althoughthe better growth parameters were obtained with CO2. Regardless of the source, nogrowth was registered in darkness, the algae were arrested for the whole experiment. K.rhaphidioides is the most abundant algal species of Lake Caviahue phytoplankton, inbiomass and cell number. It was shown that this algae has no carbon concentratingmechanisms (CCM), reason why the photosynthesis rate depends only on the external CO2 concentration. The laboratory findings of this thesys allowed to connect theseasonal and spatial distribution of the studied species with the environmental featuresof the Rio Agrio-Lake Caviahue system.Fil: Schultz, Sabina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina
Protean proteases: At the cutting edge of lung diseases
Proteases were traditionally viewed as mere protein-degrading enzymes with a very restricted spectrum of substrates. A major expansion in protease research has uncovered a variety of novel substrates, and it is now evident that proteases are critical pleiotropic actors orchestrating pathophysiological processes. Recent findings evidenced that the net proteolytic activity also relies upon interconnections between different protease and protease inhibitor families in the protease web.In this review, we provide an overview of these novel concepts with a particular focus on pulmonary pathophysiology. We describe the emerging roles of several protease families including cysteine and serine proteases.The complexity of the protease web is exemplified in the light of multidimensional regulation of serine protease activity by matrix metalloproteases through cognate serine protease inhibitor processing. Finally, we will highlight how deregulated protease activity during pulmonary pathogenesis may be exploited for diagnosis/prognosis purposes, and utilised as a therapeutic tool using nanotechnologies.Considering proteases as part of an integrative biology perspective may pave the way for the development of new therapeutic targets to treat pulmonary diseases related to intrinsic protease deregulation
Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing
molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin
Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context
Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts
Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas
Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN
Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images
Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images
of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL
maps are derived through computational staining using a convolutional neural network trained to
classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and
correlation with overall survival. TIL map structural patterns were grouped using standard
histopathological parameters. These patterns are enriched in particular T cell subpopulations
derived from molecular measures. TIL densities and spatial structure were differentially enriched
among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial
infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic
patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for
the TCGA image archives with insights into the tumor-immune microenvironment
Personalized mechanical ventilation guided by ultrasound in patients with acute respiratory distress syndrome (PEGASUS): study protocol for an international randomized clinical trial
background acute respiratory distress syndrome (ARDS) is a frequent cause of hypoxemic respiratory failure with a mortality rate of approximately 30%. Identifying ARDS subphenotypes based on "focal" or "non-focal" lung morphology has the potential to better target mechanical ventilation strategies of individual patients. however, classifying morphology through chest radiography or computed tomography is either inaccurate or impractical. Lung ultrasound (LUS) is a non-invasive bedside tool that can accurately distinguish "focal" from "non-focal" lung morphology. We hypothesize that LUS-guided personalized mechanical ventilation in ARDS patients leads to a reduction in 90-day mortality compared to conventional mechanical ventilation. methods the personalized mechanical ventilation guided by ultrasound in patients with acute respiratory distress syndrome (PEGASUS) study is an investigator-initiated, international, randomized clinical trial (RCT) that plans to enroll 538 invasively ventilated adult intensive care unit (ICU) patients with moderate to severe ARDS. eligible patients will receive a LUS exam to classify lung morphology as "focal" or "non-focal". thereafter, patients will be randomized within 12 h after ARDS diagnosis to receive standard care or personalized ventilation where the ventilation strategy is adjusted to the morphology subphenotype, i.e., higher positive end-expiratory pressure (PEEP) and recruitment maneuvers for "non-focal" ARDS and lower PEEP and prone positioning for "focal" ARDS. the primary endpoint is all-cause mortality at day 90. secondary outcomes are mortality at day 28, ventilator-free days at day 28, ICU length of stay, ICU mortality, hospital length of stay, hospital mortality, and number of complications (ventilator-associated pneumonia, pneumothorax, and need for rescue therapy). after a pilot phase of 80 patients, the correct interpretation of LUS images and correct application of the intervention within the safe limits of mechanical ventilation will be evaluated. discussion PEGASUS is the first RCT that compares LUS-guided personalized mechanical ventilation with conventional ventilation in invasively ventilated patients with moderate and severe ARDS. If this study demonstrates that personalized ventilation guided by LUS can improve the outcomes of ARDS patients, it has the potential to shift the existing one-size-fits-all ventilation strategy towards a more individualized approach. trial registration the PEGASUS trial was registered before the inclusion of the first patient, https://clinicaltrials.gov/ (ID: NCT05492344)
Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy
AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p
Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy
Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy
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