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Delineating human cardiac pathologies and their basic molecular mechanisms relies on research conducted in model organisms. Yet translating findings from preclinical models to humans present a significant challenge, in part due to differences in cardiac protein expression between humans and model organisms. Proteins immediately determine cellular function, yet their large-scale investigation in hearts has lagged behind those of genes and transcripts. Here, we set out to bridge this knowledge gap: By analyzing protein profiles in humans and commonly used model organisms across cardiac chambers, we determine their commonalities and regional differences. We analyzed cardiac tissue from each chamber of human, pig, horse, rat, mouse, and zebrafish in biological replicates. Using mass spectrometry-based proteomics workflows, we measured and evaluated the abundance of approximately 7,000 proteins in each species. The resulting knowledgebase of cardiac protein signatures is accessible through an online database: atlas.cardiacproteomics.com. Our combined analysis allows for quantitative evaluation of protein abundances across cardiac chambers, as well as comparisons of cardiac protein profiles across model organisms. Up to a quarter of proteins with differential abundances between atria and ventricles showed opposite chamber-specific enrichment between species; these included numerous proteins implicated in cardiac disease. The generated proteomics resource facilitates translational prospects of cardiac studies from model organisms to humans by comparisons of disease-linked protein networks across species.

The responses of forest carbon dynamics to fluctuations in environmental conditions at a global scale remain elusive. Despite the understanding that favourable environmental conditions promote forest growth, these responses have been challenging to observe across different ecosystems and climate gradients. Based on a global annual time series of aboveground biomass (AGB) estimated from radar satellites between 1992 and 2018, we present forest carbon changes and provide insights on their sensitivities to environmental conditions across scales. Our findings indicate differences in forest carbon changes across AGB classes, with regions with carbon stocks of 50–125 MgC ha−1 depict the highest forest carbon gains and losses, while regions with 125–150 MgC ha−1 have the lowest forest carbon gains and losses in absolute terms. Net forest carbon change estimates show that the arc-of-deforestation and the Congo Basin were the main hotspots of forest carbon loss, while a substantial part of European forest gained carbon during the last three decades. Furthermore, we observe that changes in forest carbon stocks were systematically positively correlated with changes in forest cover fraction. At the same time, it was not necessarily the case with other environmental variables, such as air temperature and water availability at the bivariate level. We also used a model attribution method to demonstrate that atmospheric conditions were the dominant control of forest carbon changes (56% of the total study area) followed by water-related (29% of the total study area) and vegetation (15% of the total study area) conditions. Regionally, we find evidence that carbon gains from long-term forest growth covary with long-term carbon sinks inferred from atmospheric inversions. Our results describe the contributions from the atmosphere, water-related and vegetation conditions to forest carbon changes and provide new insights into the underlying mechanisms of the coupling between forest growth

Genetic and genomic research has greatly advanced our understanding of heart disease. Yet, comprehensive, in-depth, quantitative maps of protein expression in hearts of living humans are still lacking. Using samples obtained during valve replacement surgery in patients with mitral valve prolapse (MVP), we set out to define inter-chamber differences, the intersect of proteomic data with genetic or genomic datasets, and the impact of left atrial dilation on the proteome of patients with no history of atrial fibrillation (AF). We collected biopsies from right atria (RA), left atria (LA) and left ventricle (LV) of seven male patients with mitral valve regurgitation with dilated LA but no history of AF. Biopsy samples were analyzed by high-resolution mass spectrometry (MS), where peptides were pre-fractionated by reverse phase high-pressure liquid chromatography prior to MS measurement on a Q-Exactive-HF Orbitrap instrument. We identified 7,314 proteins based on 130,728 peptides. Results were confirmed in an independent set of biopsies collected from three additional individuals. Comparative analysis against data from post-mortem samples showed enhanced quantitative power and confidence level in samples collected from living hearts. Our analysis, combined with data from genome wide association studies suggested candidate gene associations to MVP, identified higher abundance in ventricle for proteins associated with cardiomyopathies and revealed the dilated LA proteome, demonstrating differential representation of molecules previously associated with AF, in non-AF hearts. This is the largest dataset of cardiac protein expression from human samples collected in vivo. It provides a comprehensive resource that allows insight into molecular fingerprints of MVP and facilitates novel inferences between genomic data and disease mechanisms. We propose that over-representation of proteins in ventricle is consequent not to redundancy but to functional need, and conclude that cha

The sinus node is a collection of highly specialised cells constituting the heart's pacemaker. The molecular underpinnings of its pacemaking abilities are debated. Using high-resolution mass spectrometry, we here quantify >7,000 proteins from sinus node and neighbouring atrial muscle. Abundances of 575 proteins differ between the two tissues. By performing single-nucleus RNA sequencing of sinus node biopsies, we attribute measured protein abundances to specific cell types. The data reveal significant differences in ion channels responsible for the membrane clock, but not in Ca2+ clock proteins, suggesting that the membrane clock underpins pacemaking. Consistently, incorporation of ion channel expression differences into a biophysically-detailed atrial action potential model result in pacemaking and a sinus node-like action potential. Combining our quantitative proteomics data with computational modeling, we estimate ion channel copy numbers for sinus node myocytes. Our findings provide detailed insights into the unique molecular make-up of the cardiac pacemaker.

Rationale: Downregulation of the pacemaking ion channel, HCN4 (hyperpolarization-activated cyclic nucleotide gated channel 4), and the corresponding ionic current, If, underlies exercise training-induced sinus bradycardia in rodents. If this occurs in humans, it could explain the increased incidence of bradyarrhythmias in veteran athletes, and it will be important to understand the underlying processes. Objective: To test the role of HCN4 in the training-induced bradycardia in human athletes and investigate the role of microRNAs (miRs) in the repression of HCN4. Methods and Results: As in rodents, the intrinsic heart rate was significantly lower in human athletes than in nonathletes, and in all subjects, the rate-lowering effect of the HCN selective blocker, ivabradine, was significantly correlated with the intrinsic heart rate, consistent with HCN repression in athletes. Next-generation sequencing and quantitative real-time reverse transcription polymerase chain reaction showed remodeling of miRs in the sinus node of swim-trained mice. Computational predictions highlighted a prominent role for miR-423-5p. Interaction between miR-423-5p and HCN4 was confirmed by a dose-dependent reduction in HCN4 3′-untranslated region luciferase reporter activity on cotransfection with precursor miR-423-5p (abolished by mutation of predicted recognition elements). Knockdown of miR-423-5p with anti-miR-423-5p reversed training-induced bradycardia via rescue of HCN4 and If. Further experiments showed that in the sinus node of swim-trained mice, upregulation of miR-423-5p (intronic miR) and its host gene, NSRP1, is driven by an upregulation of the transcription factor Nkx2.5. Conclusions: HCN remodeling likely occurs in human athletes, as well as in rodent models. miR-423-5p contributes to training-induced bradycardia by targeting HCN4. This work presents the first evidence of miR control of HCN4 and heart rate. miR-423-5p could be a therapeutic target for pat

Climatic stress such as warming would alter physiological pathways in plants leading to changes in tissue chemistry. Elevated CO2 could partly mitigate warming induced moisture stress, and the degree of this mitigation may vary with plant functional types. We studied the composition of structural and non-structural metabolites in senesced tissues of Bouteloua gracilis (C4) and Pascopyrum smithii (C3) at the Prairie Heating and CO2 Enrichment experiment, Wyoming, USA. We hypothesized that P. smithii and B. gracilis would respond to unfavorable global change factors by producing structural metabolites and osmoregulatory compounds that are necessary to combat stress. However, due to the inherent variation in the tolerance of their photosynthetic pathways to warming and CO2, we hypothesized that these species will exhibit differential response under different combinations of warming and CO2 conditions. Due to a lower thermo-tolerance of the C4 photosynthesis we expected B. gracilis to exhibit a greater metabolic response under warming with ambient CO2 (cT) and P. smithii to exhibit a similar response under warming combined with elevated CO2 (CT). Our hypothesis was supported by the differential response of structural compounds in these two species, where cT increased the content of lignin and cuticular-matrix in B. gracilis. In P. smithii a similar response was observed in plants exposed to CT, possibly due to the partial alleviation of moisture stress.With warming, the total cell-wall bound phenolic acids that cross link polysaccharides to lignins increased in B. gracilis and decreased in P. smithii, indicating a potentially adaptive response of C4 pathway to warming alone. Similarly, in B. gracilis, extractable polar metabolites such as sugars and phenolic acids increased with the main effect of warming. Conversely, in P. smithii, only sugars showed a higher abundance in plants exposed to warming treatments indicating that warming alone might be metabolically too disr