Marie Sklodowska-Curie Grant Agreement Research Articles

Gut bacteriome and mood disorders in women with PCOS.

How does the gut bacteriome differ based on mood disorders (MDs) in women with polycystic ovary syndrome (PCOS), and how can the gut bacteriome contribute to the associations between these two conditions? Women with PCOS who also have MDs exhibited a distinct gut bacteriome with reduced alpha diversity and a significantly lower abundance of Butyricicoccus compared to women with PCOS but without MDs. Women with PCOS have a 4- to 5-fold higher risk of having MDs compared to women without PCOS. The gut bacteriome has been suggested to influence the pathophysiology of both PCOS and MDs. This population-based cohort study was derived from the Northern Finland Birth Cohort 1966 (NFBC1966), which includes all women born in Northern Finland in 1966. Women with PCOS who donated a stool sample at age 46years (n = 102) and two BMI-matched controls for each case (n = 205), who also responded properly to the MD criteria scales, were included. A total of 102 women with PCOS and 205 age- and BMI-matched women without PCOS were included. Based on the validated MD criteria, the subjects were categorized into MD or no-MD groups, resulting in the following subgroups: PCOS no-MD (n = 84), PCOS MD (n = 18), control no-MD (n = 180), and control MD (n = 25). Clinical characteristics were assessed at age 31years and age 46years, and stool samples were collected from the women at age 46years, followed by the gut bacteriome analysis using 16 s rRNA sequencing. Alpha diversity was assessed using observed features and Shannon's index, with a focus on genera, and beta diversity was characterized using principal components analysis (PCA) with Bray-Curtis Dissimilarity at the genus level. Associations between the gut bacteriome and PCOS-related clinical features were explored by Spearman's correlation coefficient. A P-value for multiple testing was adjusted with the Benjamini-Hochberg false discovery rate (FDR) method. We observed changes in the gut bacteriome associated with MDs, irrespective of whether the women also had PCOS. Similarly, PCOS MD cases showed a lower alpha diversity (Observed feature, PCOS no-MD, median 272; PCOS MD, median 208, FDR = 0.01; Shannon, PCOS no-MD, median 5.95; PCOS MD, median 5.57, FDR = 0.01) but also a lower abundance of Butyricicoccus (log-fold changeAnalysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC)=-0.90, FDRANCOM-BC=0.04) compared to PCOS no-MD cases. In contrast, in the controls, the gut bacteriome did not differ based on MDs. Furthermore, in the PCOS group, Sutterella showed positive correlations with PCOS-related clinical parameters linked to obesity (BMI, r2=0.31, FDR = 0.01; waist circumference, r2=0.29, FDR = 0.02), glucose metabolism (fasting glucose, r2=0.46, FDR < 0.001; fasting insulin, r2=0.24, FDR = 0.05), and gut barrier integrity (zonulin, r2=0.25, FDR = 0.03). Although this was the first study to assess the link between the gut bacteriome and MDs in PCOS and included the largest PCOS dataset for the gut microbiome analysis, the number of subjects stratified by the presence of MDs was limited when contrasted with previous studies that focused on MDs in a non-selected population. The main finding is that gut bacteriome is associated with MDs irrespective of the PCOS status, but PCOS may also modulate further the connection between the gut bacteriome and MDs. This research was funded by the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant Agreement (MATER, No. 813707), the Academy of Finland (project grants 315921, 321763, 336449), the Sigrid Jusélius Foundation, Novo Nordisk Foundation (NNF21OC0070372), grant numbers PID2021-12728OB-100 (Endo-Map) and CNS2022-135999 (ROSY) funded by MCIN/AEI/10.13039/501100011033 and ERFD A Way of Making Europe. The study was also supported by EU QLG1-CT-2000-01643 (EUROBLCS) (E51560), NorFA (731, 20056, 30167), USA/NIH 2000 G DF682 (50945), the Estonian Research Council (PRG1076, PRG1414), EMBO Installation (3573), and Horizon 2020 Innovation Grant (ERIN, No. EU952516). The funders did not participate in any process of the study. We have no conflicts of interest to declare. N/A.

A pipeline to generate large-scale, realistic cardiac ultrasound recordings including clinically relevant artefacts

Simulated ultrasound (US) data are widely used to develop and validate (machine learning-based) US data processing algorithms. In this regard, the quantity and quality of the simulated US data are crucial. Here, we have developed an US simulation pipeline to generate realistic cardiac US recordings on a large scale. In this pipeline, we used clinical cardiac US scans to sample the echogenicity of the US scattering sites. In parallel, a non-linear US simulator, k-wave, was employed to generate clinical artifacts due to the presence of ribs and lungs, including reverberation and shadowing. The position of the ventricle, the probe, and the simulated artifact data were then spatially registered in order to modify the originally sampled echogenicities. Motion of the myocardial scattering sites was kinematically governed by a stable mechanical heart model (CircAdapt). The resulting dynamic echogenicity map was fed into a fast convolution-based ultrasound simulator (COLE) to generate cardiac US recordings with clinical appearance including artefacts. The generated US data follow realistic speckle statistics and is a potential augmentation tool for machine learning based US data processing algorithms. [Work funded by European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 860745.]

InDEStruct: Bridge the gap between academia and industry

What lessons can we take from the InDEStruct project, which aims to bridge the gap between academia and industry to benefit industrial knowledge, innovation and employment opportunities? What significance did the project hold for Vestas aircoil A/S? Claus H. Ibsen, PhD, Group R&amp;D Director, provides the answers. The InDEStruct initiative was an EU-funded project to support projects through financial resources. It envisions bridging the gap between academia and industry to enhance industrial knowledge, drive innovation, and generate employment opportunities. Our project received funding from the EU Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement.

Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes.

The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]).

A telescopic paradox: the artisans of the Accademia del Cimento, their instruments and their (in)visibility

ABSTRACT The brief life of the Accademia del Cimento (1657–1667), the first known society with a purely experimental programme,1 is entangled with the most surprising advancements in the history of scientific instruments of that century, from the telescope to the microscope, the thermometer to the barometer, the hygrometer to the pendulum as a time-regulator, and more. The making of instruments at the Florentine court shows the interaction of princely, scholarly and artisanal actors. This paper explores this collaboration and shows how the supposed “invisibility’ of artisans depended on their proximity to the academicians and princes, who mainly communicated verbally with them, directly or through middlemen. The visibility of artisans increases proportionally to their physical distance from the Court. In this essay I unveil the identity of the artisans of the Cimento and, finally, attempt to attribute five instruments (some lost and others still extant) to specific makers, shedding light also on relations between the artisan and his patron.

Local conduction velocities determined by non-invasive electrocardiographic imaging predict arrhythmia-free survival after pulmonary vein isolation

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This project has received funding from the European Union's Horizon Research and Innovation Programme under the Marie-Sklodowska Curie Grant Agreement No. 860974 Background Recurrence rates after atrial fibrillation (AF) ablation are still unsatisfactory. As catheter ablation is primarily targeting pulmonary vein (PV) ectopic activity, it is not surprising that extra-PV arrythmogenic substrate is a key determinant of arrhythmia recurrence. Against this background, several studies have proposed assessment of extra-PV substrate in terms of atrial fibrosis or locally reduced conduction velocities (CV) to guide treatment. However, to date no non-invasive method directly assessing electrical arrhythmogenic substrate has been established in clinical practice, and treatment decisions are commonly based on crude surrogates like AF type or left atrial size. Here we establish and validate a novel non-invasive method based on electrocardiographic imaging (ECGi) to determine atrial arrhythmogenic substrate in terms of reduced local CVs and its predictive value regarding arrhythmia recurrence after PVI. Methods and results 52 consecutive patients scheduled for AF ablation (PVI-only) and 19 healthy controls were prospectively included and received ECGi to assess left and right atrial arrhythmogenic substrate. This ECGi-based method uses 64 electrodes placed on the torso. Subsequently, a 3D model of the torso is acquired as an anatomical reference using a 3D reconstruction camera. A personalised 3D atrial geometry is then derived from a database of human atria using an artificial intelligence-based algorithm. Finally, unipolar surface electrograms are projected onto the cardiac geometry and local CVs are estimated. Mean ECGi-determined atrial CVs were significantly lower in AF patients than in healthy controls, both in a global analysis (1.45±0.15 m/s vs. 1.64±0.15 m/s; p&amp;lt;0.0001) and a regional analysis of 19 predefined left and right atrial segments (Fig. 1). Considering only the segments with the lowest average CV in each patient, differences in CVs were more pronounced (0.80±0.22 vs. 1.08±0.26 m/s; p&amp;lt;0.0001). Multivariate logistic regression analyses combined with c-statistics including other previously proposed predictors found this mean CV of the "slowest" segment to be the strongest predictor of arrhythmia recurrence. A ROC analysis revealed that a cut-off for this variable of 0.72 m/s best discriminates PVI responders from non-responders: patients with a mean CV &amp;gt;0.72 m/s in all atrial regions showed a 6-months arrhythmia-free survival of 90.9%, whereas patients with one or more atrial regions with a mean CV &amp;lt;0.72 m/s had a poor outcome with an arrhythmia-free survival rate of only 57.9% (Fig. 2). Conclusion This was the first study to investigate local atrial CV non-invasively and to validate their predictive value regarding outcome after PVI. The absence of ECGi-determined areas of slow conduction well discriminated PVI responders from non-responders. Such non-invasive assessment of electrical arrhythmogenic substrate may guide treatment strategies and be an important step towards personalised AF therapy.

Agri-food firms’ attitude toward digital data exploitation in the product development

THE AIMS OF THE PAPER This paper explores digital data exploitation behaviours and shows how these conducts change according to the data sources used by agri-food firms when developing their products. METHODOLOGY We adopt an exploratory multiple-case study to provide a theoretical framework for agri-food firms utilising digital data for product development. MOST IMPORTANT RESULTS The article shows two prominent firms’ behaviours that we labelled data explorers and data receivers and a third behaviour which is a combination of the main ones. RECOMMENDATIONS This article offers guidelines to support agri-food firms to distinguish how such firms may benefit from the digital transformation by gaining competitiveness improving production efficiency and supporting the development of their products. Acknowledgments: This paper has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 101030185. This article is an outcome of the project FooDization.

The Saga of Water and Halide Perovskites: Evidence of Water in Methylammonium Lead Tri‐Iodide

DOI: 10.1002/adfm.202204283 The following funding information is added to the Acknowledgments: This project received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No. 893194. These errors do not affect the conclusions of the report. The authors apologize for any inconvenience caused.

The Microbiome-Gut-Brain axis regulates social cognition &craving in young binge drinkers.

Binge drinking is the consumption of an excessive amount of alcohol in a short period of time. This pattern of consumption is highly prevalent during the crucial developmental period of adolescence. Recently, the severity of alcohol use disorders (AUDs) has been linked with microbiome alterations suggesting a role for the gut microbiome in its development. Furthermore, a strong link has emerged too between microbiome composition and socio-emotional functioning across different disorders including AUD. The aim of this study was to investigate the potential link (and its predictive value) between alcohol-related altered microbial profile, social cognition, impulsivity and craving. Young people (N=71) aged 18-25 reported their alcohol use and underwent a neuropsychological evaluation. Craving was measured at baseline and three months later. Diet was controlled for. Blood, saliva and hair samples were taken for inflammatory, kynurenine and cortisol analysis. Stool samples were provided for shotgun metagenomic sequencing and short-chain fatty acids (SCFAs) were measured. Binge drinking was associated with distinct microbiome alterations and emotional recognition difficulties. Associations were found for several microbiome species with emotional processing and impulsivity. Craving showed a strong link with alterations in microbiome composition and neuroactive potential over time. In conclusion, this research demonstrates alterations in the gut microbiome of young binge drinkers (BDs) and identifies early biomarkers of craving. Associations between emotional processing and microbiome composition further support the growing literature on the gut microbiome as a regulator of social cognition. These findings are of relevance for new gut-derived interventions directed at improving early alcohol-related alterations during the vulnerability period of adolescence. C.C. and R.G-C. received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 754535. APC Microbiome Ireland is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan [grant no. SFI/12/RC/2273_P2]. J.F.C has research support from Cremo, Pharmavite, DuPont and Nutricia. He has spoken at meetings sponsored by food and pharmaceutical companies. G.C. has received honoraria from Janssen, Probi, and Apsen as an invited speaker; is in receipt of research funding from Pharmavite, Fonterra, Nestle and Reckitt; and is a paid consultant for Yakult, Zentiva and Heel pharmaceuticals. All the authors declare no competing interests.

Observation of * *Supported in part by National Key R&D Program of China under Contracts Nos. Supported in part by National Key R&D Program of China (2020YFA0406300, 2020YFA0406400); National Natural Science Foundation of China (NSFC) (11975118, 11625523, 11635010, 11735014, 11822506, 11835012, 11935015, 11935016, 11935018, 11961141012, 12022510, 12025502, 12035009, 12035013, 12061131003, 12075252, 12192260, 12192261, 12192262, 12192263, 12192264, 12192265); the Natural Science

Using data taken at 29 center-of-mass energies between 4.16 and 4.70 GeV with the BESIII detector at the Beijing Electron Positron Collider corresponding to a total integrated luminosity of approximately 18.8 , the process is observed for the first time with a statistical significance of . The average Born cross sections in the energy ranges of (4.160, 4.380) GeV, (4.400, 4.600) GeV and (4.610, 4.700) GeV are measured to be fb, fb and fb, respectively, where the first uncertainties are statistical and the second are systematic. The line shapes of the and invariant mass spectra are consistent with phase space distributions, indicating that no hexaquark or di-baryon state is observed.

Mechanisms by which water-mediated hydrogen-bond networks govern pH-dependent reactions at membrane interfaces.

pH-dependent reactions at membrane interfaces are used by cells to maintain pH homeostasis and to ensure normal cell function. Membrane-bound proteins and peptide systems that sense pH typically bind protons using a few titratable sidechains that communicate with the bulk. The identity of these pH-sensing sidechains is central to hypotheses about protein reaction mechanisms and for the rational design of proton detectors. But, as protein groups hypothesized to sense pH in proteins and peptide systems are part of dynamic water-mediated networks, evaluating their pH-sensing functionality may prove difficult. We developed efficient graph-based algorithms and methodologies to evaluate dynamic hydrogen-bond networks of protein and peptide systems known to have a pH-sensing functionality, and to identify sites of hydrogen-bond networks where protons are likely to bind. We find that the assembly of dynamic water-mediated hydrogen-bond networks that include potential proton-sensing groups is a key event along the reaction coordinates of pH-dependent membrane proteins and membrane-bound peptides, and implement graph-based algorithms to characterize the dynamics of these water networks. We further find that polar and basic protein sidechains largely govern the dynamics of the water-mediated hydrogen-bond networks of proton-binding groups, and help maintain acidic sidechains within clusters that collectively can bind and store protons. Taken together, the ensemble of hydrogen-bond network computations we performed for pH-coupled proteins and peptide systems provide a framework to decipher the roles of dynamic water-mediated hydrogen-bond networks in proton binding at membrane interfaces. Research was supported in part by the European Union's Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie grant agreement No 860592, Innovative Training Network ‘Proton and proton-coupled transport’, and by computing time from the Physics Department of the Freie Universität Berlin and from the Forschungszentrum Jülich (JURECA-DC, allocation PHDPORES).

Search for hidden-charm tetraquark with strangeness in * *Supported in part by National Key R&D Program of China (Grant Nos. 2020YFA0406400, 2020YFA0406300); National Natural Science Foundation of China (NSFC) (Grant Nos. 11635010, 11735014, 11805086, 11835012, 11935015, 11935016, 11935018, 11961141012, 12022510, 12025502, 12035009, 12035013, 12192260, 12192261, 12192262, 12192263, 12192264, 12192265); the Chinese Academy of Sciences (CAS) Large-Scale Scientific Facility Program; Joint

We report a search for a heavier partner of the recently observed state, denoted as , in the process , based on collision data collected at the center-of-mass energies of , 4.682 and 4.699 GeV with the BESIII detector. The is of interest as it is expected to be a candidate for a hidden-charm and open-strange tetraquark. A partial-reconstruction technique is used to isolate recoil-mass spectra, which are probed for a potential contribution from (). We find an excess of () candidates with a significance of , after considering systematic uncertainties, at a mass of . As the data set is limited in size, the upper limits are evaluated at the 90% confidence level on the product of the Born cross sections () and the branching fraction () of , under different assumptions of the mass from 4.120 to 4.140 MeV and of the width from 10 to 50 MeV at the three center-of-mass energies. The upper limits of are found to be at the level of pb at each energy. Larger data samples are needed to confirm the state and clarify its nature in the coming years.

Observation of the Y(4230) and a new structure in * *Supported in part by National Key R&D Program of China (2020YFA0406300, 2020YFA0406400); National Natural Science Foundation of China (NSFC) under Contracts Nos. (11625523, 11635010, 11735014, 11822506, 11835012, 11935015, 11935016, 11935018, 11961141012, 12022510, 12025502, 12035009, 12035013, 12061131003); the Chinese Academy of Sciences (CAS) Large-Scale Scientific Facility Program; Joint Large-Scale Scientific Facility

The cross sections of at center-of-mass energies from 4.127 to 4.600 GeV are measured based on 15.6 fb data collected with the BESIII detector operating at the BEPCII storage ring. Two resonant structures are observed in the line shape of the cross sections. The mass and width of the first structure are measured to be () MeV and () MeV, respectively. They are consistent with those of the established . The second structure is observed for the first time with a statistical significance greater than 8σ, denoted as . Its mass and width are determined to be () MeV and () MeV, respectively. The first presented uncertainties are statistical and the second ones are systematic. The product of the electronic partial width with the decay branching fraction is reported.

A pipeline to enable large-scale generation of diverse 2D cardiac synthetic ultrasound recordings corresponding to healthy and heart failure virtual patients

Simulated ultrasound (US) data are widely used in echocardiography to develop and validate rapidly growing convolutional neural networks (CNNs) based learning algorithms for image processing and analysis. In this context, a large and diverse database of synthetic US scans is considered vital for CNN training purposes, as clinical US data are scarce and difficult to access. Major hurdles in creating an extensive database are the long US simulation time and unstable heart models for extreme parameter settings. Here, we developed and implemented a cardiac US simulation pipeline that kinematically connects two state-of-the-art solutions in the field of US simulation (COLE) and cardiac modelling (CircAdapt), benefiting from the fast simulation time of the convolution-based ultrasound simulator and stability of the mechanical heart model to produce 2D synthetic cardiac US recordings. Furthermore, using our pipeline, we generated diverse set of 600 2D synthetic cardiac US recordings of healthy and heart failure virtual patients with variations in the shapes, motion patterns, and functions of the heart, along with their ground truth 2D myocardial velocity profiles and deformation curves. The resulting database is a potential tool for augmenting training databases of machine learning based US image processing algorithms. [Work funded by European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 860745.]

Zircon geochronological and geochemical insights into pluton building and volcanic-hypabyssal-plutonic connections: Oki-Dōzen, Sea of Japan - a complex intraplate alkaline volcano

Data collection for this project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 749611 (JHS) and Japan Society for the Promotion of Science postdoctoral fellowship #PE16724 (KJC). We also acknowledge funding from the Spanish grant CGL2017-84469-P.

Lateral Interactions and Order–Disorder Phase Transitions of Metal Phthalocyanines on Ag(111)

We gratefully acknowledge support from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Project ID 223848855-SFB 1083 “Structure and Dynamics of Internal Interfaces”. L.F. acknowledges financial support from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement MagicFACE no. 797109. D.S.-P. and A.X.B.-R. acknowledge the Spanish Agencia Estatal de Investigacion (grant nos. MAT2016-78293-C6-4-R and PID2019-107338RB-C66) and Dep. Educacion of the Basque Government and UPV/EHU (grant no. IT1246-19) for support.

RNA-seq profiling of the atrial transcriptome reveals gender-specific patterns and interactions with atrial fibrillation and heart failure

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): TRAIN-HEART Innovative Training Network, funded by the European Union’s Horizon 2020 research and innovation program (under the Marie Sklodowska-Curie grant agreement no. 813716) Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly (CATCH ME), funded by the European Union’s Horizon 2020 research and innovation program (under the grant agreement no. 633196) Background Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with heart failure (HF) and stroke. Clinical and experimental data from previous studies suggest gender differences in mechanisms and phenotypes of AF: women may have more atrial fibrosis, worse outcomes after catheter ablation, and some women carry a higher risk for thromboembolic complications than men. The molecular mechanisms underlying these differences are still poorly understood. Methods Gender-based transcriptional patterns were assessed using paired-end, directional RNA sequencing data generated from atrial tissue biopsies in 199 patients either in sinus rhythm or with paroxysmal or persistent AF as part of the CATCH-ME project. Transcript counts were compared between genders separately in the left and right atria using the DESeq2 package in R. The models were adjusted for potential sources of confounding (age, atrial fibrillation status, heart failure status and sequencing batch). Interaction models were implemented using DESeq2 to compare gender*morbidity interactions for persistent AF and HF. Significance was assessed using likelihood ratio tests comparing models with and without the interaction terms. Results with an adjusted P-value 0.05 were considered significant and utilized for subsequent downstream assessments. Differentially expressed (DE) genes were tested for enrichment of gene ontology (GO) terms and KEGG pathways using the WebGestalt toolkit. Results Transcriptome-wide profiling across the cohort identified 33 sex-differentiated genes in the left atria and 51 in the right atrial samples, with 21 of these showing bilateral differences. Interestingly, 36 (44%) of the results from these analyses were comprised of non-coding transcripts, including long non-coding RNAs (lncRNAs), antisense RNAs and pseudogenes. GO and pathway enrichment analyses for these genes revealed their involvement in critical pathways such as the complement and coagulation cascades and RNA transport. Interaction analyses between gender and AF identified two genes (MPP2 &amp; GNAS-AS1) that were differentially transcribed in the right atria and one gene (MYL2) that was DE in the left atria by gender in persistent AF samples. A similar analysis comparing gender*HF morbidity also revealed evidence of DE. Four transcripts (HLA-DQB1-AS1, EIF1AY, UTY and ZFY-AS1) showed gender-specific differences in expression by HF status in left atria, while HLA-DQB1-AS1 was differentially regulated by gender and HF status in right atrial samples. Conclusions These RNA-seq analyses provide novel insights into gender-related differences in the transcriptional landscape of right and left adult human atrial appendages. Moreover, interaction analyses identified three genes DE in female atria in persistent AF and four DE genes in female atria in heart failure, providing a molecular anchor for the observed differences in atrial diseases phenotypes between men and women.

Human-based computational and experimental investigation of disease mechanisms in mutation-specific hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement 764738. British Heart Foundation Intermediate Basic Science Fellowship (FS/17/22/32644). Background The pathogenic TNNI3R21C/+ variant causes malignant hypertrophic cardiomyopathy (HCM) with high incidence of sudden cardiac death, even in individuals absent of hypertrophy. There is evidence to support a known biophysical defect in the protein, yet the cellular mechanisms that precipitate adverse clinical outcomes remain unclear. Purpose We aim to computationally model and map the TNNI3R21C/+ cellular phenotype observed in induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) to human disease, thereby explaining the key mechanisms driving HCM in TNNI3R21C/+ variant carriers. Methods Wild-type (WT) and TNNI3R21C/+ iPSC-CMs were characterised by calcium transient analysis and direct sarcomere tracking to assess cellular contraction and relaxation. In-vitro data was used to inform the in-silico modelling of human cardiomyocytes. We constructed an in-silico population of WT adult cardiomyocytes and used it to transform the in-vitro data into corresponding adult phenotypes by means of a novel iPSC-to-adult data mapping. We tested the hypothesis that the abnormal TNNI3R21C/+ phenotype observed in iPSC-CMs would be explained by alterations in calcium affinity of troponin and increased myofilament calcium sensitivity. Results Analysis of in-vitro iPSC-CM data showed that TNNI3R21C/+ cells exhibit increased contractility with slowed relaxation when compared to WT. They also exhibited a faster rise in the calcium transient with a slowed calcium decay in comparison to WT. The in-silico adult TNNI3R21C/+ phenotype from the iPSC-to-adult mapping replicated the abnormalities observed in iPSC-CMs. The WT in-silico population accurately covered the ranges of electromechanical biomarkers providing a representative cohort of physiological variability. The TNNI3R21C/+ calcium phenotype could be recovered by our in-silico mutant models. Simulation results suggest that calcium abnormalities in TNNI3R21C/+ are a direct consequence of abnormal calcium buffering by thin filaments, mediated by increases in calcium affinity of troponin and myofilament calcium sensitivity. The TNNI3R21C/+ phenotype could not be recovered if these two factors were considered in isolation. Corresponding contractility analyses of in-silico models showed that the calcium level changes caused by the TNNI3R21C/+ phenotype are associated with hypercontractility and diastolic dysfunction, well-known hallmarks of HCM, which were also observed in the iPSC-CM model of disease. Conclusions This study showcases human-based computational and experimental methodologies that unearth direct mechanistic explanations of phenotypes driven by the TNNI3R21C/+ HCM variant. We show that the TNNI3R21C/+ HCM-causing mutation exhibits multifactorial remodelling of troponin calcium affinity and myofilament calcium sensitivity. Unearthing mechanistic pathways in mutation-specific HCM will be key to develop effective pharmacological interventions for a wide variety of understudied variants.

Dubiofossils from a Mars-analogue subsurface palaeoenvironment: The limits of biogenicity criteria.

The search for a fossil record of Earth's deep biosphere, partly motivated by potential analogies with subsurface habitats on Mars, has uncovered numerous assemblages of inorganic microfilaments and tubules inside ancient pores and fractures. Although these enigmatic objects are morphologically similar to mineralized microorganisms (and some contain organic carbon), they also resemble some abiotic structures. Palaeobiologists have responded to this ambiguity by evaluating problematic filaments against checklists of "biogenicity criteria". Here, we describe material that tests the limits of this approach. We sampled Jurassic calcite veins formed through subseafloor serpentinization, a water-rock reaction that can fuel the deep biosphere and is known to have occurred widely on Mars. At two localities ~4km apart, veins contained curving, branched microfilaments composed of Mg-silicate and Fe-oxide minerals. Using a wide range of analytical techniques including synchrotron X-ray microtomography and scanning transmission electron microscopy, we show that these features meet many published criteria for biogenicity and are comparable to fossilized cryptoendolithic fungi or bacteria. However, we argue that abiotic processes driven by serpentinization could account for the same set of lifelike features, and report a chemical garden experiment that supports this view. These filaments are, therefore, most objectively described as dubiofossils, a designation we here defend from criticism and recommend over alternative approaches, but which nevertheless signifies an impasse. Similar impasses can be anticipated in the future exploration of subsurface palaeo-habitats on Earth and Mars. To avoid them, further studies are required in biomimetic geochemical self-organization, microbial taphonomy and micro-analytical techniques, with a focus on subsurface habitats.

Of mice and men: opposing effects of nicotinamide riboside on skeletal muscle physiology at rest and during exercise.

Of mice and men: opposing effects of nicotinamide riboside on skeletal muscle physiology at rest and during exercise.