Cell competition is driven by Xrp1-mediated phosphorylation of eukaryotic initiation factor 2α

生体から不良細胞を除去する「細胞競合」の仕組みの一端を解明 --不良細胞は小胞体ストレス応答機構を使ってタンパク質合成量を低下させ除去される--. 京都大学プレスリリース. 2021-12-08.Cell competition is a context-dependent cell elimination via cell-cell interaction whereby unfit cells (‘losers’) are eliminated from the tissue when confronted with fitter cells (‘winners’). Despite extensive studies, the mechanism that drives loser’s death and its physiological triggers remained elusive. Here, through a genetic screen in Drosophila, we find that endoplasmic reticulum (ER) stress causes cell competition. Mechanistically, ER stress upregulates the bZIP transcription factor Xrp1, which promotes phosphorylation of the eukaryotic translation initiation factor eIF2α via the kinase PERK, leading to cell elimination. Surprisingly, our genetic data show that different cell competition triggers such as ribosomal protein mutations or RNA helicase Hel25E mutations converge on upregulation of Xrp1, which leads to phosphorylation of eIF2α and thus causes reduction in global protein synthesis and apoptosis when confronted with wild-type cells. These findings not only uncover a core pathway of cell competition but also open the way to understanding the physiological triggers of cell competition

Physiological and Pathological Mitochondrial Clearance Is Related to Pectoralis Major Muscle Pathogenesis in Broilers With Wooden Breast Syndrome

Wooden breast syndrome (WB) constitutes an emerging myopathy in the pectoralis major muscle (PM) of broiler chickens, characterized by myofiber hypertrophy and degeneration along with severe fibrosis. WB pathogenesis has been considered to involve hypoxia induced by rapid growth of the PM. In this study, we focused on mitochondrial morphology and dynamics in the myofibers, as these organelles are sensitive to damage by hypoxia, and examined the effects on WB pathogenesis. Specifically, the PMs of a flock of 35 broilers at 50 days of age were evaluated. First, the severity of disease in each bird was determined by measuring histopathological indices including the fibrotic area (FA) in the muscle and circularity of myofibers (CM). These values were 29.4 ± 9.6% and 0.70 ± 0.042, respectively, showing variety among the flock. Myofiber vacuolization was observed in all birds including numerous small- or large-rimmed vacuoles, with the former consisting of ultrastructurally autophagosome-like vacuoles engulfing degenerated mitochondria. The large-rimmed vacuoles frequently occurred in the PMs with more severe FA and CM, indicating a relationship between altered autophagy/mitophagy and WB severity. Next, the expression levels of hypoxia-adaptive and mitochondrial dynamics-related genes were analyzed, and their correlations with the histopathological indices were examined. The histopathological indices were negatively correlated with the expression of vascular endothelial growth factor A (VEGFA), indicating that less angiogenesis owing to weakened hypoxia-inducible factor signaling induces more severe WB pathology. In addition, the observed negative correlation with mitochondrial dynamics-related genes implied that WB pathology deteriorates concomitant with reduced mitochondrial dynamics. Furthermore, the expression of mitochondrial dynamics-related genes showed strong positive correlation with that of VEGFA and autophagy-/mitophagy-related genes. These results revealed that the PMs of broilers possess the mechanism of physiological clearance of mitochondria damaged by the hypoxia resulting from the continuous mitochondrial dynamics and autophagy/mitophagy accompanying rapid PM growth. In turn, the altered mitochondrial clearance induced by chronic hypoxia and the accumulation of damaged mitochondria likely underly the severe pathological features of WB.ArticleFrontiers in Pharmacology.11:579(2020)journal articl

Desempeños del alumnado de Educación Secundaria en la evaluación de una investigación científica en el contexto de la industria láctea

En este estudio se analizan los desempeños de estudiantes de 2.º, 3.º y 4.º de ESO (14, 15 y 16 años) que cursan la asignatura de Física y química, cuando evalúan el diseño de una investigación sobre un problema de precipitación identificado en la industria láctea. Los desempeños se examinan por separado para cada dimensión del diseño: identificación de la cuestión objeto de investigación, formulación de hipótesis, planificación de la investigación y selección del criterio de finalización. Para el análisis de resultados, se recogen sus propuestas, en las que han de estar desarrolladas las siguientes tareas: seleccionar la mejor opción, justificar su elección y modificar la opción alternativa para convertirla en correcta. Los resultados menos adecuados corresponden a las dos últimas dimensiones citadas.In this paper we analyse the performance of 8th, 9th and 10th grade students (14, 15 and 16 years old respectively), attending Physics and Chemistry lessons, when assessing the design of scientific research on a precipitation problem identified in the dairy industry. Students' performances are examined separately for each dimension involved in the design: identifying the issue to be studied, posing the hypotheses, planning the research and selecting the ending criterion. For the analysis, we collect participants' individual proposals, which have to include the following tasks: selecting the best option, justifying their choice and modifying the alternative option so that it will be correct. The less adequate results correspond to the last two dimensions

Relatório de estágio em farmácia comunitária

Relatório de estágio realizado no âmbito do Mestrado Integrado em Ciências Farmacêuticas, apresentado à Faculdade de Farmácia da Universidade de Coimbr

CD133 is a useful surrogate marker for predicting chemosensitivity to neoadjuvant chemotherapy in breast cancer.

Neoadjuvant chemotherapy (NAC) is a standard care regimen for patients with breast cancer. However, the pathologic complete response (pCR) rate remains at 30%. We hypothesized that a cancer stem cell marker may identify NAC-resistant patients, and evaluated CD133 and ALDH1 as a potential surrogate marker for breast cancer. The aim of this study was to find a surrogate maker to predict chemosensitivity of NAC for breast cancer.A total of 102 patients with breast cancer were treated with NAC consisting of epirubicin followed by paclitaxel. Core needle biopsy (CNB) specimens and resected tumors were obtained from all patients before and after NAC, respectively. Chemosensitivity and prognostic potential of CD133 or ALDH1 expression was evaluated by immunohistochemistry. Clinical CR (cCR) and pCR rates were 18% (18/102) and 29% (30/102), respectively. Forty-seven (46%) patients had CD133-positive tumors before NAC, and CD133 expression was significantly associated with a low pCR rate (p=0.035) and clinical non-responders. Multivariate analysis revealed that CD133 expression was significantly (p=0.03) related to pCR. Recurrence was more frequent in patients with CD133-positive tumors (21/47, 45%) than that in patients with CD133-negative tumors (7/55, 13%). The number of patients with CD133-positive tumors (62%) after NAC was higher than that (46%) before NAC. Furthermore, most patients with CD133-positive tumors before NAC maintained the same status after NAC.CD133 before NAC might be a useful marker for predicting the effectiveness of NAC and recurrence of breast cancer after NAC