Lymphocytes in Alzheimer’s Disease Pathology: Altered Signaling Pathways

Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive impairment of cognitive ability. Patients with AD display neuropathological lesions including plaques, neurofibrillary tangles, and neuronal loss in brain regions linked to cognitive functions. Despite progress in uncovering many of the factors that contribute to the etiology of this disease, the cause of neuronal death is largely unknown. Neuroinflammation seems to play a critical role in the pathogenesis of AD. Inflammatory processes in the brain are mainly mediated by the intrinsic innate immune system consisting of astrocytes and microglial cells, and cytokine, chemokine, and growth factor signaling molecules. However mounting evidence suggest that the Central Nervous System (CNS) is accessible to lymphocytes and monocytes from the blood stream, indicating that there is an intense crosstalk between the immune and the CN systems. On the other hand, some AD-specific brain-derived proteins or metabolites may enter the plasma through a deficient blood-brain barrier, and exert some measurable signaling properties in peripheral cells. The goals of this review are: 1) to explore the evidences of changes in signaling pathways that could mediate both central and peripheral manifestations of AD, and 2) to explore whether changes in immune cells, particularly lymphocytes, could contribute to AD pathogenesis

Hematuria is associated with more severe acute tubulointerstitial nephritis

Acute tubulointerstitial nephritis (ATIN) is a common cause of acute kidney injury. Although haematuria is a risk factor for the development of renal disease, no previous study has analyzed the significance of haematuria in ATIN. Retrospective, observational analysis of 110 patients with biopsy-proven ATIN was conducted. Results: Haematuria was present in 66 (60%) ATIN patients. A higher percentage of ATIN patients with haematuria had proteinuria than patients without haematuria (89.4% vs. 59.1%, p = 0.001) with significantly higher levels of proteinuria (median (interquartile range) protein:creatinine ratio 902.70 (513–1492) vs. 341.00 (177–734) mg/g, p <0.001). Moreover, those patients with more haematuria intensity had a higher urinary protein:creatinine ratio (1352.65 (665–2292) vs. 849.60 (562–1155) mg/g, p = 0.02). Those patients with higher proteinuria were more likely to need renal replacement therapy (22.7 vs. 0%, p = 0.03) and to su er relapse (4 vs. 0%, p = 0.03). At the end of follow up, haematuric ATIN patients had higher serum creatinine levels (3.19 2.91 vs. 1.91 1.17 mg/dL, p = 0.007), and a trend towards a higher need for acute dialysis (7 vs. 1%, p = 0.09) and renal replacement therapy (12.1 vs. 2.3%, p = 0.12). Haematuria is common in ATIN and it is associated with worse renal function outcomesSupported by FIS/FEDER PI17/00130 and PI19/00815, Spanish Ministry of Science and Innovation (RYC-2017-22369 and DTS18/00032), Sociedad Española de Nefrología, Fundacion Renal Iñigo Álvarez de Toledo (FRIAT), ISCIII-RETIC REDinREN RD016/0009 Fondos FEDER, Comunidad de Madrid B2017/BMD-3686CIFRA2-CM, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071)

Familial Alzheimer's Disease Lymphocytes Respond Differently Than Sporadic Cells to Oxidative Stress: Upregulated p53-p21 Signaling Linked with Presenilin 1 Mutants

Familial (FAD) and sporadic (SAD) Alzheimer's disease do not share all pathomechanisms, but knowledge on their molecular differences is limited. We previously reported that cell cycle control distinguishes lymphocytes from SAD and FAD patients. Significant differences were found in p21 levels of SAD compared to FAD lymphocytes. Since p21 can also regulate apoptosis, the aim of this study was to compare the response of FAD and SAD lymphocytes to oxidative stress like 2-deoxy-D-ribose (2dRib) treatment and to investigate the role of p21 levels in this response. We report that FAD cells bearing seven different PS1 mutations are more resistant to 2dRib-induced cell death than control or SAD cells: FAD cells showed a lower apoptosis rate and a lower depolarization of the mitochondrial membrane. Despite that basal p21 cellular content was lower in FAD than in SAD cells, in response to 2dRib, p21 mRNA and protein levels significantly increased in FAD cells. Moreover, we found a higher cytosolic accumulation of p21 in FAD cells. The transcriptional activation of p21 was shown to be dependent on p53, as it can be blocked by PFT-α, and correlated with the increased phosphorylation of p53 at Serine 15. Our results suggest that in FAD lymphocytes, the p53-mediated increase in p21 transcription, together with a shift in the nucleocytoplasmic localization of p21, confers a survival advantage against 2dRib-induced apoptosis. This compensatory mechanism is absent in SAD cells. Thus, therapeutic and diagnostic designs should take into account possible differential apoptotic responses in SAD versus FAD cells

Gene expression and volatile production during melon ripening

[SPA] Se realizó una secuenciación de transcriptoma para analizar los genes implicados en la formación de aromas expresados durante la maduración y para comprender los mecanismos moleculares que diferencian una línea casi isogénica (NIL) SC10-2 de melón y su parental Piel de Sapo (PS). El gen CmLOX18 (similar a la lipoxigenasa 4) se expresó diferencialmente comparando la NIL SC10-2 y PS y se asoció a la producción de hexanal, un compuesto diana e indicador del proceso de maduración no climatérica. La expresión del gen de la CmACO1 (1-aminocyclopropane-1-carboxylate oxidase 1) implicado en la biosíntesis de etileno no manifestó diferencias durante la maduración. La introgresión en LG X estuvo asociada a la diferente producción de hexanal entre la NIL y PS. Se propone un eQTL en el LG X que controla la producción de aromas del gen CmLOX18 localizado en LG I. [ENG] Transcriptome sequencing was performed in order to analyze the genes associated to volatile synthesis expressed during ripening and to understand the molecular mechanisms that differentiate a melon Near-isogenic Line (NIL) SC10-2 and its parental Piel de Sapo (PS). CmLOX18 gene (Similar to Lipoxygenase 18) was differentially expressed in the NIL SC10-2 compared with PS associated with the aroma volatile compound hexanal as a target compound of the non-climacteric ripening. The expression of CmACO1 (1-aminocyclopropane-1-carboxylate oxidase 1) gene associated with ethylene biosynthesis did not change during ripening. The introgression in LG X was associated with the differential hexanal production of the NIL and PS. An eQTL located in LG X is probably controlling the production of aroma volatiles due to CmLOX18 in LG I.Financial support: Fundación Séneca de la Región de Murcia (11784/PI/09), MINECO & UE-FEDER funds (AGL2010-20858). Thanks for the technical assistance to P. Varó and his team in CIFEA-Torre Pacheco (Consejería de Agricultura, Región de Murcia), N. Dos-Santos, E. Cuadros, M. García-Gutiérrez, A. Hakmaoui (UPCT), M.J. Roca (SAIT-UPCT), and IRTA-CRAG for the seeds of the NIL

High relative expression of two genes of a melon near-isogenic line versus its parental during ripening

[SPA] Con el fin de comparar la expresión génica de una línea casi isogénica (NIL) SC10-2 de melón y su Piel de Sapo (PS) parental durante la maduración y para comprender los mecanismos de diferenciación, se realizó una secuenciación de transcriptoma. Los genes CmTCP15 (Factor de actividad de transcripción) y CmGDSL (actividad de la esterasa y la lipasa) tenían una alta expresión diferencial en el NIL SC10-2 en comparación con el PS debido a la introgresión en LG X. En consecuencia, algunos atributos de calidad de fruto como el aroma, dulzura y, probablemente otros pueden estar afectados por tales genes. [ENG] In order to compare the gene expression of a melon Near-isogenic Line (NIL) SC10-2 and its parental Piel de Sapo (PS) during ripening and to understand the differentiate mechanisms, a transcriptome sequencing was performed. CmTCP15 (Transcription factor activity) and CmGDSL (Esterase and lipase activity) genes were high differentially expressed in the NIL SC10-2 compared with PS due to the introgression in LG X. Consequently, some fruit quality traits such as aroma, sweetness and probably others can be affected by such genes.Financial support: Fundación Séneca de la Región de Murcia (11784/PI/09), MINECO & UE-FEDER funds (AGL2010-20858). Thanks for the technical assistance to P. Varó and his team in CIFEA-Torre Pacheco (Consejería de Agricultura, Región de Murcia), N. Dos-Santos, E. Cuadros, M. García-Gutiérrez, A. Hakmaoui (UPCT), M.J. Roca (SAIT-UPCT), and IRTA-CRAG for the seeds of the NIL

Lower relative differential expression of two genes is associated with delayed ripening in melon

[SPA] Con el fin de comparar la expresión génica de un melón cerca de la línea isogénica (NIL) SC10-2 y su parental Piel de Sapo (PS) durante la maduración y para comprender los mecanismos de diferenciación, se realizó una secuenciación transcriptoma. Dos genes de CmGGP (GDP-L-galactosa fosforilasa 1) y CmRAP2-11 (factor de transcripción sensible al etileno RAP2-11) mostraron menor expresión relativa en la NIL SC10 -2 versus PS debido a la introgresión en LG X. Sin embargo, no existieron diferencias en expresión de CmAP2-like X1 (factor de transcripción sensible al etileno, similar a AP2 TOE3 isoforma X1). En consecuencia, la expresión de genes que mapearon en el grupo de ligamiento X como un factor de transcripción de respuesta a etileno o del metabolismo del ácido ascórbico estuvieron probablemente asociados con el retraso de maduración. [ENG] The expression of selected genes during ripening was studied considering a melon Near-isogenic Line (NIL) SC10-2 and its parental “Piel de Sapo” (PS). The expression of CmGGP (GDP-L-galactose phosphorylase 1), CmAP2-like X1 (AP2-like ethylene-responsive transcription factor TOE3 isoform X1) and CmRAP2-11 (ethylene-responsive transcription factor RAP2-11) were differentially expressed in the NIL SC10-2 compared with PS. Consequently, expression of genes that mapped in LG X such as one ethylene response transcription factors or ascorbic acid metabolism gene were probably associated with delayed ripening.Financial support: Fundación Séneca de la Región de Murcia (11784/PI/09), MINECO & UE-FEDER funds (AGL2010-20858). Thanks for the technical assistance to P. Varó and his team in CIFEA-Torre Pacheco (Consejería de Agricultura, Región de Murcia) for crop management and IRTA-CRAG for the seeds of the NIL

Transcriptomic analysis of a near-isogenic line of melon with high fruit flesh firmness during ripening

This is the peer reviewed version of the following article: Zarid, M., García-Carpintero, V., Esteras, C., Esteva, J., Bueso, M.C., Cañizares, J., Picó, M.B., Monforte, A.J. and Fernández-Trujillo, J.P. (2021), Transcriptomic analysis of a near-isogenic line of melon with high fruit flesh firmness during ripening. J Sci Food Agric, 101: 754-777, which has been published in final form at https://doi.org/10.1002/jsfa.10688. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.[EN] BACKGROUND A near-isogenic line (NIL) of melon (SC10-2) with introgression in linkage group X was studied from harvest (at firm-ripe stage of maturity) until day 18 of postharvest storage at 20.5 degrees C together with its parental control ('Piel de Sapo', PS). RESULTS SC10-2 showed higher flesh firmness and whole fruit hardness but lower juiciness than its parental. SC10-2 showed a decrease in respiration rate accompanied by a decrease in ethylene production during ripening, both of which fell to a greater extent than in PS. The introgression affected 11 volatile organic compounds (VOCs), the levels of which during ripening were generally higher in SC10-2 than in PS. Transcriptomic analysis from RNA-Seq revealed differentially expressed genes (DEGs) associated with the effects studied. For example, 909 DEGs were exclusive to the introgression, and only 23 DEGs were exclusive to postharvest ripening time. Major functions of the DEGs associated with introgression or ripening time were identified by cluster analysis. About 37 genes directly and/or indirectly affected the delay in ripening of SC10-2 compared with PS in general and, more particularly, the physiological and quality traits measured and, probably, the differential non-climacteric response. Of the former genes, we studied in more detail at least five that mapped in the introgression in linkage group (LG) X, and 32 outside it. CONCLUSION There is an apparent control of textural changes, VOCs and fruit ripening by an expression quantitative trait locus located in LG X together with a direct control on them due to genes presented in the introgression (CmTrpD,CmNADH1,CmTCP15,CmGDSL esterase/lipase, andCmHK4-like) and CmNAC18.This work was funded by grants 11784/PI/09 (Seneca Foundation, Region of Murcia) and Ministry of Economy and Innovation (AGL2010-20858). M Zarid acknowledges an UE-Erasmus predoctoral fellowship, a program coordinated by the University of Murcia in the framework of CMN. Thanks are due to Semillas Fitó SA (Barcelona, Spain), for providing seeds of PS melons and IRTACRAG for the seeds of SC10-2. We acknowledge the assistance of P Varó and his team in CIFEA-Torre Pacheco for crop management, to N Dos-Santos, M Medina, M García-Gutiérrez, A Hakmaoui, E Cuadros, I Canales and AA Escudero (UPCT) for sampling and technical assistance, to SAIT-UPCT for GC-MS analysis, to AG Sifres (COMAV) for RNA extraction, and to CNAG (Barcelona) for professional assistance in RNA-Seq. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Zarid, M.; García-Carpintero, V.; Esteras Gómez, C.; Esteva, J.; Bueso, MC.; Cañizares Sales, J.; Picó Sirvent, MB.... (2021). Transcriptomic analysis of a near-isogenic line of melon with high fruit flesh firmness during ripening. Journal of the Science of Food and Agriculture. 101(2):754-777. https://doi.org/10.1002/jsfa.10688S7547771012Ríos, P., Argyris, J., Vegas, J., Leida, C., Kenigswald, M., Tzuri, G., … Garcia-Mas, J. (2017). 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Elevated 4R-tau in astrocytes from asymptomatic carriers of the MAPT 10+16 intronic mutation

The microtubule-associated protein tau gene (MAPT) 10+16 intronic mutation causes frontotemporal lobar degeneration (FTLD) by increasing expression of four-repeat (4R)-tau isoforms. We investigated the potential role for astrocytes in the pathogenesis of FTLD by studying the expression of 4R-tau. We derived astrocytes and neurons from induced pluripotent stem cells from two asymptomatic 10+16 carriers which, compared to controls, showed persistently increased 4R:3R-tau transcript and protein ratios in both cell types. However, beyond 300 days culture, 10+16 neurons showed less marked increase of this 4R:3R-tau transcript ratio compared to astrocytes. Interestingly, throughout maturation, both 10+16 carriers consistently displayed different 4R:3R-tau transcript and protein ratios. These elevated levels of 4R-tau in astrocytes implicate glial cells in the pathogenic process and also suggests a cell-type-specific regulation and may inform and help on treatment of pre-clinical tauopathies

Assessment of ROS Production in the Mitochondria of Live Cells

Production of reactive oxygen species (ROS) in the mitochondria plays multiple roles in physiology, and excessive production of ROS leads to the development of various pathologies. ROS in the mitochondria are generated by various enzymes, mainly in the electron transporvt chain, and it is important to identify not only the trigger but also the source of free radical production. It is important to measure mitochondrial ROS in live, intact cells, because activation of ROS production could be initiated by changes in extramitochondrial processes which could be overseen when using isolated mitochondria. Here we describe the approaches, which allow to measure production of ROS in the matrix of mitochondria in live cells. We also demonstrate how to measure kinetic changes in lipid peroxidation in mitochondria of live cells. These methods could be used for understanding the mechanisms of pathology in a variety of disease models and also for testing neuro- or cardioprotective chemicals

Whole-genome resequencing of Cucurbita pepo morphotypes to discover genomic variants associated with morphology and horticulturally valuable traits

[EN] Cucurbita pepo contains two cultivated subspecies, each of which encompasses four fruit-shape morphotypes (cultivar groups). The Pumpkin, Vegetable Marrow, Cocozelle, and Zucchini Groups are of subsp. pepo and the Acorn, Crookneck, Scallop, and Straightneck Groups are of subsp. ovifera. Recently, a de novo assembly of the C. pepo subsp. pepo Zucchini genome was published, providing insights into its evolution. To expand our knowledge of evolutionary processes within C. pepo and to identify variants associated with particular morphotypes, we performed whole-genome resequencing of seven of these eight C. pepo morphotypes. We report for the first time whole-genome resequencing of the four subsp. pepo (Pumpkin, Vegetable Marrow, Cocozelle, green Zucchini, and yellow Zucchini) morphotypes and three of the subsp. ovifera (Acorn, Crookneck, and Scallop) morphotypes. A high-depth resequencing approach was followed, using the BGISEQ-500 platform that enables the identification of rare variants, with an average of 33.5X. Approximately 94.5% of the clean reads were mapped against the reference Zucchini genome. In total, 3,823,977 high confidence single-nucleotide polymorphisms (SNPs) were identified. Within each accession, SNPs varied from 636,918 in green Zucchini to 2,656,513 in Crookneck, and were distributed homogeneously along the chromosomes. Clear differences between subspecies pepo and ovifera in genetic variation and linkage disequilibrium are highlighted. In fact, comparison between subspecies pepo and ovifera indicated 5710 genes (22.5%) with Fst > 0.80 and 1059 genes (4.1%) with Fst = 1.00 as potential candidate genes that were fixed during the independent evolution and domestication of the two subspecies. Linkage disequilibrium was greater in subsp. ovifera than in subsp. pepo, perhaps reflective of the earlier differentiation of morphotypes within subsp. ovifera. Some morphotype-specific genes have been localized. Our results offer new clues that may provide an improved understanding of the underlying genomic regions involved in the independent evolution and domestication of the two subspecies. Comparisons among SNPs unique to particular subspecies or morphotypes may provide candidate genes responsible for traits of high economic importance.This work has been supported by Hellenic Agricultural Organization (ELGO) Demeter. Furthermore, we thank the Conselleria de Educacio, Investigacio, Cultura i Esport (Generalitat Valenciana) for funding Project Prometeo 2017/078 "Seleccion de Variedades Tradicionales y Desarrollo de Nuevas Variedades de Cucurbitaceas Adaptadas a la Produccion Ecologica". 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