14 research outputs found
The Human Melanoma Proteome AtlasâComplementing the melanoma transcriptome
The MM500 metaâstudy aims to establish a knowledge basis of the tumor proteome to serve as a complement to genome and transcriptome studies. Somatic mutations and their effect on the transcriptome have been extensively characterized in melanoma. However, the effects of these genetic changes on the proteomic landscape and the impact on cellular processes in melanoma remain poorly understood. In this study, the quantitative massâspectrometryâbased proteomic analysis is interfaced with pathological tumor characterization, and associated with clinical data. The melanoma proteome landscape, obtained by the analysis of 505 wellâannotated melanoma tumor samples, is defined based on almost 16Â 000 proteins, including mutated proteoforms of driver genes. More than 50 million MS/MS spectra were analyzed, resulting in approximately 13,6 million peptide spectrum matches (PSMs). Altogether 13Â 176 proteinâcoding genes, represented by 366Â 172 peptides, in addition to 52Â 000 phosphorylation sites, and 4 400 acetylation sites were successfully annotated. This data covers 65% and 74% of the predicted and identified human proteome, respectively. A high degree of correlation (Pearson, up to 0.54) with the melanoma transcriptome of the TCGA repository, with an overlap of 12Â 751 gene products, was found. Mapping of the expressed proteins with quantitation, spatiotemporal localization, mutations, splice isoforms, and PTM variants was proven not to be predicted by genome sequencing alone. The melanoma tumor molecular map was complemented by analysis of blood protein expression, including data on proteins regulated after immunotherapy. By adding these key proteomic pillars, the MM500 study expands the knowledge on melanoma disease
New evidence of plant food processing in Italy before 40ka
Evidence of plant food processing is a significant indicator of the human ability to exploit environmental
resources. The recovery of starch grains associated with use-wear on Palaeolithic grinding tools offers
proof of a specific technology for making flour among Pleistocene hunter-gatherers. Here we present the
analysis of five grindstones from two Italian sites, Riparo Bombrini and Grotta di Castelcivita, both
inhabited during a crucial phase spanning the decline of the Neanderthals and the establishment of
Sapiens. The recovery of starch grains on a Mousterian grindstone at Bombrini suggests that the last
Neanderthals not only consumed and processed plants but also made flour 43e41,000 years ago. Starch
grains attributable to Triticeae on Protoaurignacian grindstones at both sites testify that Sapiens were
processing wild cereals at least 41,500e36,500 years ago when they expanded into Eurasia, long before
the dawn of agriculture. These new data suggest a profound knowledge of available plant resources in
both human groups
New evidence of plant food processing in Italy before 40ka
Evidence of plant food processing is a significant indicator of the human ability to exploit environmental
resources. The recovery of starch grains associated with use-wear on Palaeolithic grinding tools offers
proof of a specific technology for making flour among Pleistocene hunter-gatherers. Here we present the
analysis of five grindstones from two Italian sites, Riparo Bombrini and Grotta di Castelcivita, both
inhabited during a crucial phase spanning the decline of the Neanderthals and the establishment of
Sapiens. The recovery of starch grains on a Mousterian grindstone at Bombrini suggests that the last
Neanderthals not only consumed and processed plants but also made flour 43e41,000 years ago. Starch
grains attributable to Triticeae on Protoaurignacian grindstones at both sites testify that Sapiens were
processing wild cereals at least 41,500e36,500 years ago when they expanded into Eurasia, long before
the dawn of agriculture. These new data suggest a profound knowledge of available plant resources in
both human groups
Early consequences of the phospholamban mutation PLN-R14del<sup>+/â</sup> in a transgenic mouse model
Aims: The heterozygous phospholamban (PLN) mutation R14del (PLN R14del+/â) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. âSuperinhibitionâ of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to (1) to evaluate Ca2+ dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; (2) to test whether they are causally connected.Methods: Ca2+ dynamics, energy metabolism parameters, reporters of mitochondrial integrity, energy, and redox homeostasis were measured in ventricular myocytes of 8â12 weeks-old, phenotypically silent, TG mice. Mutation effects were compared to pharmacological PLN antagonism and analyzed during modulation of sarcoplasmic reticulum (SR) and cytosolic Ca2+ compartments. Transcripts and proteins of relevant signaling pathways were evaluated.Results: The mutation was characterized by hyperdynamic Ca2+ handling, compatible with a loss of SERCA2a inhibition by PLN. All components of energy metabolism were depressed; myocyte energy charge was preserved under quiescence but reduced during stimulation. Cytosolic Ca2+ buffering or SERCA2a blockade reduced O2 consumption with larger effect in the mutant. Signaling changes suggest cellular adaptation to perturbed Ca2+ dynamics and response to stress.Conclusions: (1) PLN R14del+/â loses its ability to inhibit SERCA2a, which argues against SERCA2a superinhibition as a pathogenetic mechanism; (2) depressed energy metabolism, its enhanced dependency on Ca2+ and activation of signaling responses point to an early involvement of metabolic stress in the pathogenesis of this ACM model.</p
Early consequences of the phospholamban mutation PLN-R14del<sup>+/â</sup> in a transgenic mouse model
Aims: The heterozygous phospholamban (PLN) mutation R14del (PLN R14del+/â) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. âSuperinhibitionâ of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to (1) to evaluate Ca2+ dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; (2) to test whether they are causally connected. Methods: Ca2+ dynamics, energy metabolism parameters, reporters of mitochondrial integrity, energy, and redox homeostasis were measured in ventricular myocytes of 8â12 weeks-old, phenotypically silent, TG mice. Mutation effects were compared to pharmacological PLN antagonism and analyzed during modulation of sarcoplasmic reticulum (SR) and cytosolic Ca2+ compartments. Transcripts and proteins of relevant signaling pathways were evaluated. Results: The mutation was characterized by hyperdynamic Ca2+ handling, compatible with a loss of SERCA2a inhibition by PLN. All components of energy metabolism were depressed; myocyte energy charge was preserved under quiescence but reduced during stimulation. Cytosolic Ca2+ buffering or SERCA2a blockade reduced O2 consumption with larger effect in the mutant. Signaling changes suggest cellular adaptation to perturbed Ca2+ dynamics and response to stress. Conclusions: (1) PLN R14del+/â loses its ability to inhibit SERCA2a, which argues against SERCA2a superinhibition as a pathogenetic mechanism; (2) depressed energy metabolism, its enhanced dependency on Ca2+ and activation of signaling responses point to an early involvement of metabolic stress in the pathogenesis of this ACM model.</p
Early consequences of the phospholamban mutation PLN-R14del<sup>+/â</sup> in a transgenic mouse model
Aims: The heterozygous phospholamban (PLN) mutation R14del (PLN R14del+/â) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. âSuperinhibitionâ of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to (1) to evaluate Ca2+ dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; (2) to test whether they are causally connected.Methods: Ca2+ dynamics, energy metabolism parameters, reporters of mitochondrial integrity, energy, and redox homeostasis were measured in ventricular myocytes of 8â12 weeks-old, phenotypically silent, TG mice. Mutation effects were compared to pharmacological PLN antagonism and analyzed during modulation of sarcoplasmic reticulum (SR) and cytosolic Ca2+ compartments. Transcripts and proteins of relevant signaling pathways were evaluated.Results: The mutation was characterized by hyperdynamic Ca2+ handling, compatible with a loss of SERCA2a inhibition by PLN. All components of energy metabolism were depressed; myocyte energy charge was preserved under quiescence but reduced during stimulation. Cytosolic Ca2+ buffering or SERCA2a blockade reduced O2 consumption with larger effect in the mutant. Signaling changes suggest cellular adaptation to perturbed Ca2+ dynamics and response to stress.Conclusions: (1) PLN R14del+/â loses its ability to inhibit SERCA2a, which argues against SERCA2a superinhibition as a pathogenetic mechanism; (2) depressed energy metabolism, its enhanced dependency on Ca2+ and activation of signaling responses point to an early involvement of metabolic stress in the pathogenesis of this ACM model.</p
Early consequences of the phospholamban mutation PLN-R14del<sup>+/â</sup> in a transgenic mouse model
Aims: The heterozygous phospholamban (PLN) mutation R14del (PLN R14del+/â) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. âSuperinhibitionâ of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to (1) to evaluate Ca2+ dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; (2) to test whether they are causally connected. Methods: Ca2+ dynamics, energy metabolism parameters, reporters of mitochondrial integrity, energy, and redox homeostasis were measured in ventricular myocytes of 8â12 weeks-old, phenotypically silent, TG mice. Mutation effects were compared to pharmacological PLN antagonism and analyzed during modulation of sarcoplasmic reticulum (SR) and cytosolic Ca2+ compartments. Transcripts and proteins of relevant signaling pathways were evaluated. Results: The mutation was characterized by hyperdynamic Ca2+ handling, compatible with a loss of SERCA2a inhibition by PLN. All components of energy metabolism were depressed; myocyte energy charge was preserved under quiescence but reduced during stimulation. Cytosolic Ca2+ buffering or SERCA2a blockade reduced O2 consumption with larger effect in the mutant. Signaling changes suggest cellular adaptation to perturbed Ca2+ dynamics and response to stress. Conclusions: (1) PLN R14del+/â loses its ability to inhibit SERCA2a, which argues against SERCA2a superinhibition as a pathogenetic mechanism; (2) depressed energy metabolism, its enhanced dependency on Ca2+ and activation of signaling responses point to an early involvement of metabolic stress in the pathogenesis of this ACM model.</p