Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Proteomic and metagenomic insights into prehistoric Spanish Levantine Rock Art

International audienceThe Iberian Mediterranean Basin is home to one of the largest groups of prehistoric rock art sites in Europe. Despite the cultural relevance of prehistoric Spanish Levantine rock art, pigment composition remains partially unknown, and the nature of the binders used for painting has yet to be disclosed. In this work, we present the first omic analysis applied to one of the flagship Levantine rock art sites: the Valltorta ravine (Castellón, Spain). We used high-throughput sequencing to provide the first description of the bacterial communities colonizing the rock art patina, which proved to be dominated by Firmicutes species and might have a protective effect on the paintings. Proteomic analysis was also performed on rock art microsamples in order to determine the organic binders present in Levantine prehistoric rock art pigments. This information could shed light on the controversial dating of this UNESCO Cultural Heritage, and contribute to defining the chrono-cultural framework of the societies responsible for these paintings. Spanish Levantine rock art is a unique pictorial expression in Prehistoric Europe due to the naturalism of depictions, the narrative component of scenes, and the vast distribution of rock-art shelters in the Iberian Mediterranean basin (Fig. 1a,b). Despite the historical and aesthetic value of Levantine rock art and its unprecedented distribution, its chrono-cultural framework is still unclear, due to the difficulties in radiocarbon dating of pigments 1. Consequently, disparate chronological hypotheses have been proposed and, recently, new arguments have fuelled the debate, resulting in two alternative hypotheses on the chrono-cultural framework for Levantine rock art: one hypothesis proposes a Neolithic origin linked to the Neolithisation process and the spread of the "Neolithic package" in the Iberian Peninsula (from the 6 th to the 3 rd millennium cal. BC) 2,3 while the other argues a Mesolithic affiliation, based mainly on the thematic content of scenes 4,5 , since big game hunting is one of the most frequent activities portrayed in the Levantine graphic tradition. Besides dating, we also lack information on the sequence of technical gestures (chaîne opératoire) of Levantine pigments. Most archaeological research has focused on the characterization of raw materials, rather than the technical processes involved in executing the paintings. This approach is justified by the assumption that Levantine pigments were simple solutions/suspensions rather than complex mixtures, since components such as proteins or lipids, which could act as binders in mixtures, had not been detected at that point. Recently, we developed a new protocol including archaeobotanical microanalysis and experimental archaeology that enabled us to detect binders used to prepare Levantine charcoal pigments; however, we were unsuccessful in identifying them physico-chemically by in situ energy dispersive X-ray spectrometry (EDXRF) and Raman spectroscopy 6. In order to improve the characterization of Levantine pigment composition we also need a better understanding of the microbial communities associated to the rock art patina to assess their putative role in the preservation of the raw materials and binders used. Microbial activity is central to rock-art preservation and degradation 7-9. In particular, microorganisms are known to alter the composition of the mineral patina covering rock art paintings. For instance, the production of oxalic acid and other organic acids as a consequence of microbial metabolism is linked with the reinforcement of the patina, whereas microbial solubilisation of carbonates results in th

Endothelin-1 gene polymorphisms and diabetic kidney disease in patients with type 2 diabetes mellitus

Background and aims: Diabetic kidney disease (DKD) is the leading cause of end stage renal disease worldwide and is associated with increased cardiovascular mortality. The endothelin system has been implicated in the pathogenesis of arterial hypertension and renal dysfunction. In the present study, the association of DKD with polymorphisms in ET-1 (EDN1) and ETRA (EDNRA) genes was analyzed in patients with type 2 diabetes mellitus (T2DM). Methods: A case–control study was conducted in 548 white T2DM patients. Patients with proteinuria or on dialysis were considered cases and patients with normoalbuminuria were considered controls. Two polymorphisms in the EDN1 gene (rs1800541 and rs57072783) and five in EDNRA gene (rs6842241; rs4835083; rs4639051; rs5333 and rs5343) were genotyped and haplotype analyses were performed. Results: The presence of rs57072783 T allele (TT/TG vs. GG) or rs1800541 G allele (GG/GT vs. TT) protected against DKD (OR = 0.69, 95 % CI 0.48–0.99, P = 0.049; and OR = 0.60, 95 % CI 0.41–0.88, P = 0.009, respectively). However in multivariate analyses, only the rs1800541 G allele remained independently associated with DKD (P = 0.046). Conclusions: The present study shows that ET-1 could be involved in the pathogenesis of DKD in patients with T2DM

Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil

Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1, acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7-2.4-fold more transmissible, and that previous (non-P.1) infection provides 54-79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness

Neutralisation of SARS-CoV-2 lineage P.1 by antibodies elicited through natural SARS-CoV-2 infection or vaccination with an inactivated SARS-CoV-2 vaccine: an immunological study

Background Mutations accrued by SARS-CoV-2 lineage P.1—first detected in Brazil in early January, 2021—include amino acid changes in the receptor-binding domain of the viral spike protein that also are reported in other variants of concern, including B.1.1.7 and B.1.351. We aimed to investigate whether isolates of wild-type P.1 lineage SARS-CoV-2 can escape from neutralising antibodies generated by a polyclonal immune response. Methods We did an immunological study to assess the neutralising effects of antibodies on lineage P.1 and lineage B isolates of SARS-CoV-2, using plasma samples from patients previously infected with or vaccinated against SARS-CoV-2. Two specimens (P.1/28 and P.1/30) containing SARS-CoV-2 lineage P.1 (as confirmed by viral genome sequencing) were obtained from nasopharyngeal and bronchoalveolar lavage samples collected from patients in Manaus, Brazil, and compared against an isolate of SARS-CoV-2 lineage B (SARS.CoV2/SP02.2020) recovered from a patient in Brazil in February, 2020. Isolates were incubated with plasma samples from 21 blood donors who had previously had COVID-19 and from a total of 53 recipients of the chemically inactivated SARS-CoV-2 vaccine CoronaVac: 18 individuals after receipt of a single dose and an additional 20 individuals (38 in total) after receipt of two doses (collected 17–38 days after the most recent dose); and 15 individuals who received two doses during the phase 3 trial of the vaccine (collected 134–230 days after the second dose). Antibody neutralisation of P.1/28, P.1/30, and B isolates by plasma samples were compared in terms of median virus neutralisation titre (VNT50, defined as the reciprocal value of the sample dilution that showed 50% protection against cytopathic effects). Findings In terms of VNT50, plasma from individuals previously infected with SARS-CoV-2 had an 8·6 times lower neutralising capacity against the P.1 isolates (median VNT50 30 [IQR <20–45] for P.1/28 and 30 [<20–40] for P.1/30) than against the lineage B isolate (260 [160–400]), with a binominal model showing significant reductions in lineage P.1 isolates compared with the lineage B isolate (p≤0·0001). Efficient neutralisation of P.1 isolates was not seen with plasma samples collected from individuals vaccinated with a first dose of CoronaVac 20–23 days earlier (VNT50s below the limit of detection [<20] for most plasma samples), a second dose 17–38 days earlier (median VNT50 24 [IQR <20–25] for P.1/28 and 28 [<20–25] for P.1/30), or a second dose 134–260 days earlier (all VNT50s below limit of detection). Median VNT50s against the lineage B isolate were 20 (IQR 20–30) after a first dose of CoronaVac 20–23 days earlier, 75 (<20–263) after a second dose 17–38 days earlier, and 20 (<20–30) after a second dose 134–260 days earlier. In plasma collected 17–38 days after a second dose of CoronaVac, neutralising capacity against both P.1 isolates was significantly decreased (p=0·0051 for P.1/28 and p=0·0336 for P.1/30) compared with that against the lineage B isolate. All data were corroborated by results obtained through plaque reduction neutralisation tests. Interpretation SARS-CoV-2 lineage P.1 might escape neutralisation by antibodies generated in response to polyclonal stimulation against previously circulating variants of SARS-CoV-2. Continuous genomic surveillance of SARS-CoV-2 combined with antibody neutralisation assays could help to guide national immunisation programmes. Funding São Paulo Research Foundation, Brazilian Ministry of Science, Technology and Innovation and Funding Authority for Studies, Medical Research Council, National Council for Scientific and Technological Development, National Institutes of Health. Translation For the Portuguese translation of the abstract see Supplementary Materials section