Structural and functional characterization of phosphomimetic mutants of cytochrome c at threonine 28 and serine 47

Protein function is frequently modulated by post-translational modifications of specific residues. Cytochrome c, in particular, is phosphorylated in vivo at threonine 28 and serine 47. However, the effect of such modifications on the physiological functions of cytochrome c – namely, the transfer of electrons in the respiratory electron transport chain and the triggering of programmed cell death – is still unknown. Here we replace each of these two residues by aspartate, in order to mimic phosphorylation, and report the structural and functional changes in the resulting cytochrome c variants. We find that the T28D mutant causes a 30-mV decrease on the midpoint redox potential and lowers the affinity for the distal site of Arabidopsis thaliana cytochrome c1 in complex III. Both the T28D and S47D variants display a higher efficiency as electron donors for the cytochrome c oxidase activity of complex IV. In both protein mutants, the peroxidase activity is significantly higher, which is related to the ability of cytochrome c to leave the mitochondria and reach the cytoplasm. We also find that both mutations at serine 47 (S47D and S47A) impair the ability of cytoplasmic cytochrome c to activate the caspases cascade, which is essential for triggering programmed cell death.Peer reviewe

Ositos de agua (Tardigrada) de México: Los famosos desconocidos

Los tardígrados popularmente llamados ositos de agua forman un phylum de invertebrados microscópicos poco conocidos que se encuentran en hábitats de agua dulce, marinos y terrestres. Desde su descubrimiento han sido objeto de estudio por su capacidad de entrar en criptobiosis, esta adaptación fisiológica les da la capacidad de sobrevivir a condiciones ambientales extremas. Globalmente se han descrito un poco más de 1,300 especies de tardígrados, México cuenta con 56 especies registradas, pero este bajo número es debido al poco conocimiento que se tienen sobre estos espectaculares organismos en el paí

Can harmonisation of outcomes bridge the translation gap for pre-clinical research? A systematic review of outcomes measured in mouse models of type 2 diabetes

Background: In pre-clinical research, systematic reviews have the potential to mitigate translational challenges by facilitating understanding of how pre-clinical studies can inform future clinical research. Yet their conduct is encumbered by heterogeneity in the outcomes measured and reported, and those outcomes may not always relate to the most clinically important outcomes. We aimed to systematically review outcomes measured and reported in pre-clinical in vivo studies of pharmacological interventions to treat high blood glucose in mouse models of type 2 diabetes. Methods: A systematic review of pre-clinical in vivo studies of pharmacological interventions aimed at addressing elevated blood glucose in mouse models of type 2 diabetes was completed. Studies were screened for eligibility and outcomes extracted from the included studies. The outcomes were recorded verbatim and classified into outcome domains using an existing outcome taxonomy. Outcomes were also compared to those identified in a systematic review of registered phase 3/4 clinical trials for glucose lowering interventions in people with type 2 diabetes. Results: Review of 280 included studies identified 532 unique outcomes across 19 domains. No single outcome, or domain, was measured in all studies and only 132 (21%) had also been measured in registered phase 3/4 clinical trials. A core outcome set, representing the minimum that should be measured and reported, developed for type 2 diabetes effectiveness clinical trials includes 18 core outcomes, of these 12 (71%) outcomes were measured and reported in one or more of the included pre-clinical studies. Conclusions: There is heterogeneity of outcomes reported in pre-clinical research. Harmonisation of outcomes across the research pathway using a core outcome set may facilitate interpretation, evidence synthesis and translational success, and may contribute to the refinement of the use of animals in research. Systematic review registration: The study was prospectively registered on the PROSPERO Database, registration number CRD4201810683

Hypoxia supports differentiation of terminally exhausted CD8 T cells

Hypoxia, angiogenesis, and immunosuppression have been proposed to be interrelated events that fuel tumor progression and impair the clinical effectiveness of anti-tumor therapies. Here we present new mechanistic data highlighting the role of hypoxia in fine tuningCD8 T cell exhaustion in vitro, in an attempt to reconcile seemingly opposite evidence regarding the impact of hypoxia on functional features of exhausted CD8 T cells.Focusing on the recently characterized terminally-differentiated and progenitor exhausted CD8 T cells, we found that both hypoxia and its regulated mediator, vascular endothelial growth factor (VEGF)-A, promote the differentiation of PD-1+ TIM-3+ CXCR5+ terminally exhausted-like CD8 T cells at the expense of PD-1+ TIM-3- progenitor-like subsets without affecting tumor necrosis factor (TNF)-a and interferon (IFN)-g production or granzyme B(GZMB) expression by these subpopulations. Interestingly, hypoxia accentuated the proangiogenic secretory profile in exhausted CD8 T cells. VEGF-A was the main factor differentially secreted by exhausted CD8 T cells under hypoxic conditions. In this sense,we found that VEGF-A contributes to generation of terminally exhausted CD8 T cellsduring in vitro differentiation. Altogether, our findings highlight the reciprocal regulation between hypoxia, angiogenesis, and immunosuppression, providing a rational basis to optimize synergistic combinations of antiangiogenic and immunotherapeutic strategies,with the overarching goal of improving the efficacy of these treatments.Fil: Bannoud, Nadia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: D'alotto Moreno, Tomas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Kindgard, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: García, Pablo A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Blidner, Ada Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Mariño, Karina Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Croci Russo, Diego Omar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

Structural basis of mitochondrial dysfunction in response to cytochrome c phosphorylation at tyrosine 48

Regulation of mitochondrial activity allows cells to adapt to changing conditions and to control oxidative stress, and its dysfunction can lead to hypoxia-dependent pathologies such as ischemia and cancer. Although cytochrome c phosphorylation—in particular, at tyrosine 48—is a key modulator of mitochondrial signaling, its action and molecular basis remain unknown. Here we mimic phosphorylation of cytochrome c by replacing tyrosine 48 with p-carboxy-methyl-L-phenylalanine (pCMF). The NMR structure of the resulting mutant reveals significant conformational shifts and enhanced dynamics around pCMF that could explain changes observed in its functionality: The phosphomimetic mutation impairs cytochrome c diffusion between respiratory complexes, enhances hemeprotein peroxidase and reactive oxygen species scavenging activities, and hinders caspase-dependent apoptosis. Our findings provide a framework to further investigate the modulation of mitochondrial activity by phosphorylated cytochrome c and to develop novel therapeutic approaches based on its prosurvival effects.Financial support was provided by the Spanish Ministry of Economy and Competitiveness (Grants BFU2015-71017-P/BMC and BFU2015-19451/BMC, cofounded by FEDER EU), European Union (Bio-MR-00130 and CALIPSO-312284), Ramon Areces Foundation, and Andalusian Government (BIO198). B.M.-B. was awarded a PhD fellowship from the Spanish Ministry of Education (AP2009-4092) and a short-term traveling fellowship from the European Bio-NMR Project. A.G.-C. was awarded a PhD fellowship from the CSIC (JaePre-2011-01248).Peer reviewe

A Bioinformatics-Assisted Review on Iron Metabolism and Immune System to Identify Potential Biomarkers of Exercise Stress-Induced Immunosuppression

The immune function is closely related to iron (Fe) homeostasis and allostasis. The aim of this bioinformatics-assisted review was twofold; (i) to update the current knowledge of Fe metabolism and its relationship to the immune system, and (ii) to perform a prediction analysis of regulatory network hubs that might serve as potential biomarkers during stress-induced immunosuppression. Several literature and bioinformatics databases/repositories were utilized to review Fe metabolism and complement the molecular description of prioritized proteins. The Search Tool for the Retrieval of Interacting Genes (STRING) was used to build a protein-protein interactions network for subsequent network topology analysis. Importantly, Fe is a sensitive double-edged sword where two extremes of its nutritional status may have harmful effects on innate and adaptive immunity. We identified clearly connected important hubs that belong to two clusters: (i) presentation of peptide antigens to the immune system with the involvement of redox reactions of Fe, heme, and Fe trafficking/transport; and (ii) ubiquitination, endocytosis, and degradation processes of proteins related to Fe metabolism in immune cells (e.g., macrophages). The identified potential biomarkers were in agreement with the current experimental evidence, are included in several immunological/biomarkers databases, and/or are emerging genetic markers for different stressful conditions. Although further validation is warranted, this hybrid method (human-machine collaboration) to extract meaningful biological applications using available data in literature and bioinformatics tools should be highlighted.The ‘Bioinformatics-assisted Review’ is a project developed and supported by the Research Division at the Dynamical Business and Science Society—DBSS International SAS. The APC was funded by the Exercise & Sport Nutrition Laboratory (ESNL) at Texas A&M University, the POWER LAB at University of Central Florida and the Sport Genomics Research Group at University of the Basque Country UPV/EHU

Crowd-Computer Interaction, a Topic in Need of a Model

Abstract. Crowd-Computer Interaction -CCI -is a form of human-computer interaction -HCI -in which single actions from many individuals are aggregated to produce a different result that would not be achievable otherwise for one individual alone. As a research topic several questions remain open regarding CCI, for example, to what extent the principles and heuristics of interactions design under the paradigm of one-user-one-interface are applicable to crowds interacting with a network of interfaces? If a system is usable for individuals, will it be usable for crowds? Should designs be centered on the individual or on the crowd? A model of how crowds interact with computers is needed to start finding answers, that need is discussed in this paper along with some research proposals to develop that model

Antimalarial activity of cupredoxins: the interaction of Plasmodium Merozoite Surface Protein 119 (MSP119) and Rusticyanin

Background: The interaction of MSP119 with the cupredoxin azurin inhibits the growth of Plasmodium falciparum in red blood cells. Results: Rusticyanin forms a well-defined complex with MSP119 upon binding at the same surface area than inhibitory antibodies. Conclusion: Rusticyanin becomes an excellent therapeutic agent for malaria. Significance: Knowing the rusticyanin- MSP119 interface will allow the design of novel anti-malarial drugsJunta de Andalucía P08-CVI-3876, BIO198Ministerio de Economía y Competitividad SAF2011- 26611Fundación Séneca de la Región de Murcia 15354/PI/10Ministerio de Ciencia e Innovación BFU2010-19451Medical Research Council U117574558, U11753206

Efeito da terapia não cirúrgica sobre parâmetros clínicos periodontais em pacientes consumidores de cannabis

El objetivo fue analizar los efectos de la terapia periodontal no quirúrgica sobre parámetros clínicos periodontales en pacientes consumidores de cannabis. Se realizó un estudio clínico no aleatorizado con voluntarios pertenecientes a la Universidad de Antioquia. Se revisaron 40 sujetos divididos en dos grupos: consumidores de cannabis (fumadores) y no consumidores de cannabis (control). Se registraron medidas de profundidad al sondaje (PD), nivel de inserción (CAL) y sangrado al sondaje (BOP) en el periodontograma al inicio y 3 meses después de la terapia periodontal no quirúrgica. Las diferencias entre grupos fueron analizadas con la prueba Mann Whitney. Todos los datos se analizaron en SPSS y se consideraron diferencias estadísticamente significativas cuando p≤0.05. La frecuencia del consumo de cannabis diario en pacientes fumadores evidencia que el 60 % consumen 3 veces/día, el 10 % 2 veces/día y el 30 % 1 vez/día. En general, los fumadores presentaron mayor porcentaje de BOP en las dos revisiones, en comparación con el grupo de no-fumadores y esta diferencia fue estadísticamente significativa (p<0.05). En profundidad al sondaje, no se observan diferencias entre los dos grupos. Los fumadores muestran un promedio de PD al inicio de 2.09 ± 0.73 mm y 2.15 ± 0.65 mm a los 3 meses; el aumento fue leve entre estas. También, se observa que el nivel de inserción fue ligeramente mayor en pacientes fumadores que en no fumadores. En la población estudiada no se evidencian datos significativos asociados con enfermedad periodontal y el consumo del cannabis. La respuesta de los tejidos periodontales a la terapia no quirúrgica fue similar entre pacientes consumidores y no consumidores de cannabis.The objective was to analyze the effects of non-surgical periodontal therapy on clinical parameters in patients using cannabis. A non-randomized clinical study was conducted with 40 volunteers from Universidad de Antioquia divided into 2 groups: 20 participants using cannabis (smokers) and 20 non-users (control). All clinical parameters regarding probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP) were recorded at baseline and 3 months after non-surgical periodontal therapy. Differences between groups were assessed with the Mann Whitney test and were considered significant when p≤0.05. Data was analyzed using the SPSS statistical software. Participants using cannabis had a frequency of use of 3 times/day (60%), 2 times/day (10%) and 1 time/day (30%). In general, smokers had higher BOP at both examinations as opposed to non-smokers, this difference being statistically significant (p<0.05). No differences were observed for PD with a mean of 2.09 ± 0.73 mm at baseline and 2.15 ± 0.65 mm at 3 months, showing a small increase between the two. CAL was also slightly higher in smokers than in non-users. There was no significant evidence in the studied population relating periodontal disease with cannabis consumption. The response of periodontal tissues to non-surgical therapy was similar between cannabis users and non-users.O objetivo foi analisar os efeitos da terapia periodontal não cirúrgica sobre parâmetros clínicos periodontais em pacientes consumidores de cannabis. Foi realizado um estudo clínico não randomizado com voluntários pertencentes à Universidade da Antioquia. Foram revisados 40 indivíduos divididos em dois grupos: consumidores de cannabis (fumantes) e não consumidores de cannabis (controle). Foram registradas medidas de profundidade à sondagem (PS), nível de inserção (NCI) e sangramento à sondagem (ISS) no periodontograma no início e 3 meses após a terapia periodontal não cirúrgica. As diferenças entre grupos foram analisadas com o teste Mann Whitney. Todos os dados foram analisados no SPSS e consideradas diferenças estatisticamente significativas quando p≤0,05. A frequência do consumo diário de cannabis em pacientes fumantes evidência que 60 % consumem 3 vezes/dia, 10 % 2 vezes/dia e 30 % 1 vez/dia. Em geral, os fumantes apresentaram maior porcentagem de ISS nas duas revisões, em comparação com o grupo de não fumantes e esta diferença foi estatisticamente significativa (p<0,05). Na profundidade à sondagem, não se observam diferenças entre os dois grupos. Os fumantes mostram uma média de PS no início de 2,09 ± 0,73 mm e 2,15 ± 0,65 mm aos 3 meses; o aumento foi leve entre estas. Observa-se, também que o nível de inserção foi ligeiramente maior em pacientes fumantes que em não fumantes. Na população estudada não se evidenciam dados significativos associados à doença periodontal e ao consumo do cannabis. A resposta dos tecidos periodontais à terapia não cirúrgica foi semelhante entre pacientes consumidores e não consumidores de cannabis

Mortality due to non-AIDS-defining cancers among people living with HIV in Spain over 18 years of follow-up

Purpose: Our aim was to describe non-AIDS-defining cancer (NADC) mortality among people living with HIV (PLWH), to compare it with that of the general population, and to assess potential risk factors. Methods: We included antiretroviral-naive PLWH from the multicentre CoRIS cohort (2004-2021). We estimated mortality rates and standardised mortality ratios (SMRs). We used cause-specific Cox models to identify risk factors. Results: Among 17,978 PLWH, NADC caused 21% of all deaths observed during the follow-up. Mortality rate due to NADC was 1.58 (95%CI 1.36, 1.83) × 1000 person-years and lung and liver were the most frequent cancer-related causes of death. PLWH had 79% excess NADC mortality risk compared to the general population with the highest SMR found for Hodgkin lymphoma, anal and liver cancers. The SMRs decreased with age and were the highest in age groups under 50 years. The most important prognostic factor was low CD4 count, followed by smoking, viral hepatitis and HIV transmission through heterosexual contact or injection drug use. Conclusion: Non-AIDS cancers are an important cause of death among PLWH. The excess mortality related to certain malignancies and the association with immunodeficiency, smoking, and coinfections highlights the need for early detection and treatment of cancer in this population.Purpose: Our aim was to describe non-AIDS-defining cancer (NADC) mortality among people living with HIV (PLWH), to compare it with that of the general population, and to assess potential risk factors. Methods: We included antiretroviral-naive PLWH from the multicentre CoRIS cohort (2004-2021). We estimated mortality rates and standardised mortality ratios (SMRs). We used cause-specific Cox models to identify risk factors. Results: Among 17,978 PLWH, NADC caused 21% of all deaths observed during the follow-up. Mortality rate due to NADC was 1.58 (95%CI 1.36, 1.83) × 1000 person-years and lung and liver were the most frequent cancer-related causes of death. PLWH had 79% excess NADC mortality risk compared to the general population with the highest SMR found for Hodgkin lymphoma, anal and liver cancers. The SMRs decreased with age and were the highest in age groups under 50 years. The most important prognostic factor was low CD4 count, followed by smoking, viral hepatitis and HIV transmission through heterosexual contact or injection drug use. Conclusion: Non-AIDS cancers are an important cause of death among PLWH. The excess mortality related to certain malignancies and the association with immunodeficiency, smoking, and coinfections highlights the need for early detection and treatment of cancer in this population.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This research was supported by CIBER -Consorcio Centro de Investigación Biomédica en Red- (CB21/13/00091), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea – NextGenerationEU, the Gilead Scholarship Program for Biomedical Research (GLD19_00106) and the ISCIII- Miguel Servet CP19CIII—00002 contract.S