Propuesta para la elaboración de un protocolo de triaje en el contexto de la pandemia de COVID-19

Este documento ofrece una propuesta desde la perspectiva de la bioética para la elaboración de un protocolo de triaje en el contexto de la pandemia de COVID-19. Dicha propuesta incluye recomendaciones sobre las normas procedimentales y normas sustantivas que deben regir la asignación y reasignación de recursos terapéuticos en condiciones de escasez extrema

NOC1 is a direct MYC target, and its protein interactome dissects its activity in controlling nucleolar function

The nucleolus is a subnuclear compartment critical in ribosome biogenesis and cellular stress responses. These mechanisms are governed by a complex interplay of proteins, including NOC1, a member of the NOC family of nucleolar proteins responsible for controlling rRNA processing and ribosomal maturation. This study reveals a novel relationship between NOC1 and MYC transcription factor, known for its crucial role in controlling ribosomal biogenesis, cell growth, and proliferation. Here, we demonstrate that NOC1 functions as a direct target of MYC, as it is transcriptionally induced through a functional MYC-binding E-box sequence in the NOC1 promoter region. Furthermore, protein interactome analysis reveals that NOC1-complex includes the nucleolar proteins NOC2 and NOC3 and other nucleolar components such as Nucleostemin1 Ns1 transporters of ribosomal subunits and components involved in rRNA processing and maturation. In response to MYC, NOC1 expression and localization within the nucleolus significantly increase, suggesting a direct functional link between MYC activity and NOC1 function. Notably, NOC1 over-expression leads to the formation of large nuclear granules and enlarged nucleoli, which co-localize with nucleolar fibrillarin and Ns1. Additionally, we demonstrate that NOC1 expression is necessary for Ns1 nucleolar localization, suggesting a role for NOC1 in maintaining nucleolar structure. Finally, the co-expression of NOC1 and MYC enhances nucleolus size and maintains their co-localization, outlining another aspect of the cooperation between NOC1 and MYC in nucleolar dynamics. This study also reveals an enrichment with NOC1 with few proteins involved in RNA processing, modification, and splicing. Moreover, proteins such as Ythdc1, Flacc, and splenito are known to mediate N6-methyladenosine (m6A) methylation of mRNAs in nuclear export, revealing NOC1’s potential involvement in coordinating RNA splicing and nuclear mRNA export. In summary, we uncovered novel roles for NOC1 in nucleolar homeostasis and established its direct connection with MYC in the network governing nucleolar structure and function. These findings also highlight NOC1’s interaction with proteins relevant to specific RNA functions, suggesting a broader role in addition to its control of nucleolar homeostasis and providing new insight that can be further investigated

Proposta per a l'elaboració d'un protocol de prova en el context de la pandèmia de COVID-19

Este documento ofrece una propuesta desde la perspectiva de la bioética para la elaboración de un protocolo de triaje en el contexto de la pandemia de COVID-19. Dicha propuesta incluye recomendaciones sobre las normas procedimentales y normas sustantivas que deben regir la asignación y reasignación de recursos terapéuticos en condiciones de escasez extrema.This document offers a proposal for the elaboration of a triage guideline in the context of the COVID-19 pandemic. This proposal includes recommendations on the procedural norms and substantive norms that should govern the allocation and reallocation of therapeutic resources in conditions of extreme scarcity.Aquest document ofereix una proposta des de la perspectiva de la bioètica per a l'elaboració d'un protocol de triatge en el context de la pandèmia de COVID-19. L'esmentada proposta inclou recomanacions sobre les normes procedimentals i normes substantives que han de regir l'assignació i reassignació de recursos terapèutics en condicions d'escassetat extrema.Fil: Rivera López, Eduardo Enrique. Universidad Torcuato Di Tella; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Investigaciones Filosóficas - Sadaf; ArgentinaFil: Abal, Federico German. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Investigaciones Filosóficas - Sadaf; ArgentinaFil: Frontalini Rekers, Romina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Holzer, Felicitas Sofia. Facultad Latinoamericana de Ciencias Sociales. Sede Académica Argentina Buenos Aires. Programa de Bioética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Melamed, Irene. Facultad Latinoamericana de Ciencias Sociales. Sede Académica Argentina Buenos Aires. Programa de Bioética; ArgentinaFil: Salmún, Diana. No especifíca;Fil: Belli, Laura Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Tres de Febrero; Argentina. Universidad Torcuato Di Tella; Argentina. Universidad de Buenos Aires; ArgentinaFil: Terlizzi, María Sol. Facultad Latinoamericana de Ciencias Sociales. Sede Académica Argentina Buenos Aires. Programa de Bioética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alegre, Marcelo. Universidad de Buenos Aires. Facultad de Derecho. Instituto de Investigaciones Jurídicas y Sociales "Dr. Ambrosio L. Gioja"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bianchini, Alahi Dana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Facultad Latinoamericana de Ciencias Sociales. Sede Académica Argentina Buenos Aires. Programa de Bioética; ArgentinaFil: Mastroleo, Ignacio Damian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto de Investigaciones Sociales de América Latina. - Facultad Latinoamericana de Ciencias Sociales. Instituto de Investigaciones Sociales de América Latina; Argentina. Facultad Latinoamericana de Ciencias Sociales. Sede Académica Argentina Buenos Aires. Programa de Bioética; Argentin

Replicate palaeoclimate multi-proxy data series from different speleothems from N. Italy: reproducibility of the data and new methodologies

Research Doctorate - Doctor of Philosophy (PhD)Changes in geochemical and physical properties of speleothems are considered to be accurate proxies of climate variability. However, the climate signal is modified by the internal dynamics of the whole karst system. The aim of the research was to obtain reproducible data extracted by established and non-conventional techniques from two coeval speleothems removed at Grotta Savi cave (Italy), to gain information about regional climate responses across the Last Glacial Maximum to Holocene transition. Different past hydrological regimes for the two stalagmites’ drips were reconstructed on the basis of stalagmites’ physical characteristics and this helped to disentangle the global from the local phenomena. This non-conventional approach, was applied here for the first time on fossil sample, resulting in a benchmark for interpreting the chemical proxies, and enabling assessment of calcite formation environment, hitherto not possible. The interpretation of δ¹⁸O values as reflecting past hydrology was then validated by using the Hydrology Index. The Index, developed in this study, considers two independent proxies: the Mg concentrations and the fraction of Sr uptake that is not dictated by growth rates. The method allowed recognition of a non-hydrological component encapsulated in δ¹⁸O values, then interpreted as changes of air mass provenance and rainfall seasonality. The δ¹³C was chiefly driven by temperature-dependent soil respiration rate. However, a hydrological component was also detected in the δ¹³C by using dead carbon proportion (dcp) and ⁸⁷Sr/⁸⁶Sr ratios. Increases of ⁸⁷Sr/⁸⁶Sr ratios suggest increases of aeolian dust deflated from proximal subalpine periglacial regions facilitated by vegetation-cover reduction, soil destabilisation and windier conditions, which in turn enhanced drier conditions. Although, the dcp trend was likely related to a local, faster, soil organic matter turnover, enhanced by warmer conditions, episodes of high dcp values were possibly hydrologically induced, as a result of wetter conditions. Furthermore, the Hydrology Index and δ¹³C signal allowed reconstructing that wet conditions occurred during climate cooling, an improvement relative to the state of the art of δ¹³C interpretation, where more commonly wet conditions occurs during warming. The comparison of δ¹³C trend of Savi with another stalagmite with similar physical characteristics, but from a cave (Sofular) located in Turkey, revealed a common trend despite the impact of the last glaciation having been drastic at Savi (no speleothem growth). Such δ¹³C similarity could be related to global phenomena and point to an intriguing possibility, which needs future testing, that speleothems may encode information of the C cycle, similar to soil carbonates. The palaeoclimate interpretation extracted from the Savi records between 15 to 9 ka indicates that the Younger Dryas (YD) was a dramatic climate reversal. In the northern Adriatic, the YD is characterised by high hydrological variability, strong winds and a cooling, which resulted in a decrease of vegetation cover and increase of soil erosion. The wind regime was possibly orographically induced, with the Alps acting as a barrier, deviating westerly winds and causing increased windiness in the northern Adriatic region. The Savi records reveal a significant Early Holocene anomaly (10.4 ka), whose drier and colder conditions were probably amplified by a local synoptic framework

Table2_NOC1 is a direct MYC target, and its protein interactome dissects its activity in controlling nucleolar function.XLSX

The nucleolus is a subnuclear compartment critical in ribosome biogenesis and cellular stress responses. These mechanisms are governed by a complex interplay of proteins, including NOC1, a member of the NOC family of nucleolar proteins responsible for controlling rRNA processing and ribosomal maturation. This study reveals a novel relationship between NOC1 and MYC transcription factor, known for its crucial role in controlling ribosomal biogenesis, cell growth, and proliferation. Here, we demonstrate that NOC1 functions as a direct target of MYC, as it is transcriptionally induced through a functional MYC-binding E-box sequence in the NOC1 promoter region. Furthermore, protein interactome analysis reveals that NOC1-complex includes the nucleolar proteins NOC2 and NOC3 and other nucleolar components such as Nucleostemin1 Ns1 transporters of ribosomal subunits and components involved in rRNA processing and maturation. In response to MYC, NOC1 expression and localization within the nucleolus significantly increase, suggesting a direct functional link between MYC activity and NOC1 function. Notably, NOC1 over-expression leads to the formation of large nuclear granules and enlarged nucleoli, which co-localize with nucleolar fibrillarin and Ns1. Additionally, we demonstrate that NOC1 expression is necessary for Ns1 nucleolar localization, suggesting a role for NOC1 in maintaining nucleolar structure. Finally, the co-expression of NOC1 and MYC enhances nucleolus size and maintains their co-localization, outlining another aspect of the cooperation between NOC1 and MYC in nucleolar dynamics. This study also reveals an enrichment with NOC1 with few proteins involved in RNA processing, modification, and splicing. Moreover, proteins such as Ythdc1, Flacc, and splenito are known to mediate N6-methyladenosine (m6A) methylation of mRNAs in nuclear export, revealing NOC1’s potential involvement in coordinating RNA splicing and nuclear mRNA export. In summary, we uncovered novel roles for NOC1 in nucleolar homeostasis and established its direct connection with MYC in the network governing nucleolar structure and function. These findings also highlight NOC1’s interaction with proteins relevant to specific RNA functions, suggesting a broader role in addition to its control of nucleolar homeostasis and providing new insight that can be further investigated.Peer reviewe

DataSheet1_NOC1 is a direct MYC target, and its protein interactome dissects its activity in controlling nucleolar function.XLSX

The nucleolus is a subnuclear compartment critical in ribosome biogenesis and cellular stress responses. These mechanisms are governed by a complex interplay of proteins, including NOC1, a member of the NOC family of nucleolar proteins responsible for controlling rRNA processing and ribosomal maturation. This study reveals a novel relationship between NOC1 and MYC transcription factor, known for its crucial role in controlling ribosomal biogenesis, cell growth, and proliferation. Here, we demonstrate that NOC1 functions as a direct target of MYC, as it is transcriptionally induced through a functional MYC-binding E-box sequence in the NOC1 promoter region. Furthermore, protein interactome analysis reveals that NOC1-complex includes the nucleolar proteins NOC2 and NOC3 and other nucleolar components such as Nucleostemin1 Ns1 transporters of ribosomal subunits and components involved in rRNA processing and maturation. In response to MYC, NOC1 expression and localization within the nucleolus significantly increase, suggesting a direct functional link between MYC activity and NOC1 function. Notably, NOC1 over-expression leads to the formation of large nuclear granules and enlarged nucleoli, which co-localize with nucleolar fibrillarin and Ns1. Additionally, we demonstrate that NOC1 expression is necessary for Ns1 nucleolar localization, suggesting a role for NOC1 in maintaining nucleolar structure. Finally, the co-expression of NOC1 and MYC enhances nucleolus size and maintains their co-localization, outlining another aspect of the cooperation between NOC1 and MYC in nucleolar dynamics. This study also reveals an enrichment with NOC1 with few proteins involved in RNA processing, modification, and splicing. Moreover, proteins such as Ythdc1, Flacc, and splenito are known to mediate N6-methyladenosine (m6A) methylation of mRNAs in nuclear export, revealing NOC1’s potential involvement in coordinating RNA splicing and nuclear mRNA export. In summary, we uncovered novel roles for NOC1 in nucleolar homeostasis and established its direct connection with MYC in the network governing nucleolar structure and function. These findings also highlight NOC1’s interaction with proteins relevant to specific RNA functions, suggesting a broader role in addition to its control of nucleolar homeostasis and providing new insight that can be further investigated.Peer reviewe

Table1_NOC1 is a direct MYC target, and its protein interactome dissects its activity in controlling nucleolar function.DOCX

The nucleolus is a subnuclear compartment critical in ribosome biogenesis and cellular stress responses. These mechanisms are governed by a complex interplay of proteins, including NOC1, a member of the NOC family of nucleolar proteins responsible for controlling rRNA processing and ribosomal maturation. This study reveals a novel relationship between NOC1 and MYC transcription factor, known for its crucial role in controlling ribosomal biogenesis, cell growth, and proliferation. Here, we demonstrate that NOC1 functions as a direct target of MYC, as it is transcriptionally induced through a functional MYC-binding E-box sequence in the NOC1 promoter region. Furthermore, protein interactome analysis reveals that NOC1-complex includes the nucleolar proteins NOC2 and NOC3 and other nucleolar components such as Nucleostemin1 Ns1 transporters of ribosomal subunits and components involved in rRNA processing and maturation. In response to MYC, NOC1 expression and localization within the nucleolus significantly increase, suggesting a direct functional link between MYC activity and NOC1 function. Notably, NOC1 over-expression leads to the formation of large nuclear granules and enlarged nucleoli, which co-localize with nucleolar fibrillarin and Ns1. Additionally, we demonstrate that NOC1 expression is necessary for Ns1 nucleolar localization, suggesting a role for NOC1 in maintaining nucleolar structure. Finally, the co-expression of NOC1 and MYC enhances nucleolus size and maintains their co-localization, outlining another aspect of the cooperation between NOC1 and MYC in nucleolar dynamics. This study also reveals an enrichment with NOC1 with few proteins involved in RNA processing, modification, and splicing. Moreover, proteins such as Ythdc1, Flacc, and splenito are known to mediate N6-methyladenosine (m6A) methylation of mRNAs in nuclear export, revealing NOC1’s potential involvement in coordinating RNA splicing and nuclear mRNA export. In summary, we uncovered novel roles for NOC1 in nucleolar homeostasis and established its direct connection with MYC in the network governing nucleolar structure and function. These findings also highlight NOC1’s interaction with proteins relevant to specific RNA functions, suggesting a broader role in addition to its control of nucleolar homeostasis and providing new insight that can be further investigated.Peer reviewe

NOC1 is a direct MYC target, and its protein interactome dissects its activity in controlling nucleolar function

The nucleolus is a subnuclear compartment critical in ribosome biogenesis and cellular stress responses. These mechanisms are governed by a complex interplay of proteins, including NOC1, a member of the NOC family of nucleolar proteins responsible for controlling rRNA processing and ribosomal maturation. This study reveals a novel relationship between NOC1 and MYC transcription factor, known for its crucial role in controlling ribosomal biogenesis, cell growth, and proliferation. Here, we demonstrate that NOC1 functions as a direct target of MYC, as it is transcriptionally induced through a functional MYC-binding E-box sequence in the NOC1 promoter region. Furthermore, protein interactome analysis reveals that NOC1-complex includes the nucleolar proteins NOC2 and NOC3 and other nucleolar components such as Nucleostemin1 Ns1 transporters of ribosomal subunits and components involved in rRNA processing and maturation. In response to MYC, NOC1 expression and localization within the nucleolus significantly increase, suggesting a direct functional link between MYC activity and NOC1 function. Notably, NOC1 over-expression leads to the formation of large nuclear granules and enlarged nucleoli, which co-localize with nucleolar fibrillarin and Ns1. Additionally, we demonstrate that NOC1 expression is necessary for Ns1 nucleolar localization, suggesting a role for NOC1 in maintaining nucleolar structure. Finally, the co-expression of NOC1 and MYC enhances nucleolus size and maintains their co-localization, outlining another aspect of the cooperation between NOC1 and MYC in nucleolar dynamics. This study also reveals an enrichment with NOC1 with few proteins involved in RNA processing, modification, and splicing. Moreover, proteins such as Ythdc1, Flacc, and splenito are known to mediate N6-methyladenosine (m6A) methylation of mRNAs in nuclear export, revealing NOC1's potential involvement in coordinating RNA splicing and nuclear mRNA export. In summary, we uncovered novel roles for NOC1 in nucleolar homeostasis and established its direct connection with MYC in the network governing nucleolar structure and function. These findings also highlight NOC1's interaction with proteins relevant to specific RNA functions, suggesting a broader role in addition to its control of nucleolar homeostasis and providing new insight that can be further investigated.Peer reviewe

Divergent Impact of Enzyme Replacement Therapy on Human Cardiomyocytes and Enterocytes Affected by Fabry Disease: Correlation with Mannose-6-phosphate Receptor Expression

Background: The impact of enzyme replacement therapy (ERT) on cardiomyocytes and intestinal cells, affected by Fabry disease (FD), is still unclear. Methods: Six patients with FD, including five family members with GLA mutation c.666delC and one with GLA mutation c.658C > T, manifesting cardiomyopathy and intestinal symptoms (abdominal pain, diarrhea and malabsorption) were included in the study. Clinical outcome, cardiac magnetic resonance (CMR), endomyocardial and gastro-intestinal biopsies were evaluated before and after 2 years of treatment with agalsidase-α (0.2 mg/kg every other week). Immunohistochemistry and Western blot assessments of mannose-6-phosphate receptors (IGF-II-R) on intestinal and myocardial frozen tissue were obtained at diagnosis and after 2 years of ERT. Results: After ERT left ventricular maximal wall thickness, ranging from pre (<10.5 mm) to mild (<15 mm) and moderate hypertrophy (16 mm), was not associated with significant changes at CMR. Degree of dyspnea, mean cardiomyocyte diameter and % vacuolated areas of cardiomyocytes, representing intracellular GL3, remained unmodified. In contrast, intestinal symptoms improved with disappearance of diarrhea, recovery of anemia and weight gain, correlating with near complete clearance of the enterocytes from GL3 inclusions. IGF-II-R expression was remarkably higher even at histochemistry in intestinal tissue compared with myocardium (p < 0.001) either at baseline and after ERT, thus justifying intestinal recovery. Conclusions: Human cells affected by FD may respond differently to ERT: while cardiomyocytes retain their GL3 content after 2 years of treatment, gastro-intestinal cells show GL3 removal with recovery of function. This divergent response may be related to differences in cellular turnover, as well as tissue IGF-II-R expression

SETD5 Regulates Chromatin Methylation State and Preserves Global Transcriptional Fidelity during Brain Development and Neuronal Wiring

Mutations in one SETD5 allele are genetic causes of intellectual disability and autistic spectrum disorders. However, the mechanisms by which SETD5 regulates brain development and function remain largely elusive. Herein, we found that Setd5 haploinsufficiency impairs the proliferative dynamics of neural progenitors and synaptic wiring of neurons, ultimately resulting in behavioral deficits in mice. Mechanistically, Setd5 inactivation in neural stem cells, zebrafish, and mice equally affects genome-wide levels of H3K36me3 on active gene bodies. Notably, we demonstrated that SETD5 directly deposits H3K36me3, which is essential to allow on-time RNA elongation dynamics. Hence, Setd5 gene loss leads to abnormal transcription, with impaired RNA maturation causing detrimental effects on gene integrity and splicing. These findings identify SETD5 as a fundamental epigenetic enzyme controlling the transcriptional landscape in neural progenitors and their derivatives and illuminate the molecular events that connect epigenetic defects with neuronal dysfunctions at the basis of related human diseases