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Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithiums possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P

Abstract Alzheimer’s disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease’s impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

Weather forecasts at subseasonal-to-seasonal (S2S) timescales have little forecast skill in the troposphere: individual ensemble members are mostly uncorrelated and span a range of atmospheric evolutions that are possible for the given set of external forcings. The uncertainty of such a probabilistic forecast is then determined by this range of possible evolutions – often quantified in terms of ensemble spread. Various dynamical processes can affect the ensemble spread within a given region, including extreme events simulated in individual members. For forecasts of geopotential height at 1000 hPa (Z1000) over Europe, such extremes are mainly comprised of synoptic storms propagating along the North Atlantic storm track. We use ECMWF reforecasts from the S2S database to investigate the connection between different storm characteristics and ensemble spread in more detail. We find that the presence of storms in individual ensemble members at S2S timescales contributes about 20 % to the total Z1000 forecast uncertainty over northern Europe. Furthermore, certain atmospheric conditions associated with substantial anomalies in the North Atlantic storm track show reduced Z1000 ensemble spread over northern Europe. For example, during periods with a weak stratospheric polar vortex, the genesis frequency of Euro-Atlantic storms is reduced and their tracks are shifted equatorwards. As a result, we find weaker storm magnitudes and lower storm counts, and hence anomalously low subseasonal ensemble spread, over northern Europe.

Abstract To evaluate the intra- and interdevice repeatability of microperimetry (MP) assessments in patients with diabetic macular edema (DME) two consecutive MP testings (45 fovea-centered stimuli, 4–2 staircase strategy) were performed using MP3 (NIDEK, Aichi, Japan) and MAIA (CenterVue, Padova, Italy), respectively. Intraretinal fluid (IRF) and ellipsoid zone (EZ) thickness were automatically segmented by published deep learning algorithms. Hard exudates (HEs) were annotated semi-automatically and disorganization of retinal inner layers (DRIL) was segmented manually. Point-to-point registration of MP stimuli to corresponding spectral-domain OCT (Spectralis, Heidelberg Engineering, Germany) locations was performed for both devices. Repeatability was assessed overall and in areas of disease-specific OCT biomarkers using Bland-Altmann coefficients of repeatability (CoR). A total of 3600 microperimetry stimuli were tested in 20 eyes with DME. Global CoR was high using both devices (MP3: ± 6.55 dB, MAIA: ± 7.69 dB). Higher retest variances were observed in stimuli with IRF (MP3: CoR ± 7.4 dB vs. ± 6.0 dB, p = 0.001, MAIA: CoR ± 9.2dB vs. ± 6.8 dB, p = 0.002) and DRIL on MP3 (CoR ± 6.9 dB vs. ± 3.2 dB, p

Purpose: To assess the potential of a paper diary for strengthening accountability in public agricultural extension services. Therefore a paper diary called 'Diary for Agricultural Extension Officers' was developed and tested in Uganda. Design/methodology/approach: A qualitative case study research approach was applied for the development and assessment of the diary. Data were collected using focus group discussions and individual face-to-face interviews. Data analysis was conducted using the content analysis method. Findings: Paper diaries can strengthen accountability in public agricultural extension services by enabling alignment of the extension activities of the field agents to the goals of the extension service and to the needs of the beneficiaries, in addition to mitigating information asymmetry about the extension activities. However, the implementation of paper diaries requires sensitization of the beneficiaries on the need for verification and feedback. Practical Implications: This study is centred around addressing a practical problem of field agents' accountability and results have the potential to improve management of public services such as agricultural extension. Moreover, the findings could also be relevant for all types of organizations and service delivery methods. Theoretical implications: This study expanded the boundaries of the principal-agent theory by applying it to the accountability of agricultural extension services using paper diaries, which have hitherto not been widely applied. Originality/value: This study advances the debates of accountability and coordination of agricultural extension services by assessing the potential of a paper diary as the literature has to date assessed the potential of electronic diaries.

Agricultural studies mainly rely on quantitative research approaches. Despite growing interest in and uptake of qualitative, participatory, and visual methods due to their perceived advantages in gathering in-depth information and empowering participants, visual-digital research methods have yet to be largely applied. In our study on adaptation strategies to climate change among smallholder farmers in Uganda we compared different data collection methods, including: semi-structured interviews with manual note-taking, participatory impact diagrams, and adapted photovoice and cellphilm methodologies.

Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1-/-) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3-6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.

Critical illness causes disturbances in lipid metabolism. Here, we investigated the levels of apolipoprotein A-IV (apoA-IV), a regulator of triglyceride and cholesterol metabolism, in human sepsis. ApoA-IV (analyzed in 156 patients with systemic inflammatory response syndrome (SIRS)/sepsis) and cholesteryl ester (CE) (analyzed in 121 of these patients) were lower in patients compared to 43 healthy controls. In contrast, triglyceride (TG) levels were elevated in patients. ApoA-IV levels in plasma of the patients did not correlate with these lipids. Patients with SIRS, sepsis or septic shock had comparable apoA-IV, TG, CE and free cholesterol (FC) levels. Patients on dialysis had significantly lower CE levels, whereas apoA-IV levels did not change much. CE levels were elevated in patients with viral sepsis due to SARS-CoV-2 infection in comparison to SIRS/sepsis patients not infected by this virus. CE levels correlated negatively with procalcitonin, interleukin-6 and bilirubin, while TGs were positively associated with bilirubin and C-reactive protein. ApoA-IV, TG, CE and FC levels were not associated with bacterial infection or survival. In conclusion, this analysis suggests that CE levels decline in sepsis-related renal failure and also shows that plasma apoA-IV and CE levels are early biomarkers of sepsis.

Abstract Background Alongside affective episodes, cognitive dysfunction is a core symptom of bipolar disorder. The intracellular parasite T. gondii has been positively associated with both, the diagnosis of bipolar disorder and poorer cognitive performance, across diagnostic boundaries. This study aims to investigate the association between T. gondii seropositivity, serointensity, and cognitive function in an euthymic sample of bipolar disorder. Methods A total of 76 participants with bipolar disorder in remission were tested for T. gondii-specific IgG and IgM antibodies and for cognitive performance using neuropsychological test battery. Cognitive parameters were categorized into three cognitive domains (attention and processing speed, verbal memory, and executive function). Statistical analysis of associations between continuous indicators of cognitive function as dependent variables in relationship to T. gondii, included multivariate analyses of co-variance for seropositivity, and partial correlations with IgG serointensity in IgG seropositives. All analyses were controlled for age and premorbid IQ. Results In seropositives (n = 27), verbal memory showed significant inverse partial correlations with IgG antibody levels (short delay free recall (r=–0.539, p = 0.005), long delay free recall (r=–0.423, p = 0.035), and immediate recall sum trial 1–5 (r=–0.399, p = 0.048)). Cognitive function did not differ between IgG seropositive and seronegative individuals in any of the cognitive domains (F (3,70) = 0.327, p = 0.806, n = 76). IgM positives (n = 7) were too few to be analyzed. Conclusions This investigation is the first to show an association between T. gondii IgG serointensity and memory function in a well-diagnosed bipolar disorder sample. It adds to the existing literature on associations between latent T. gondii infection and cognition in bipolar disorder, while further research is needed to confirm and expand our findings, eliminate potential sources of bias, and establish cause-effect relationships.

Abstract Background Due to increasing ecological concerns, microbial production of biochemicals from sustainable carbon sources like acetate is rapidly gaining importance. However, to successfully establish large-scale production scenarios, a solid understanding of metabolic driving forces is required to inform bioprocess design. To generate such knowledge, we constructed isopropanol-producing Escherichia coli W strains. Results Based on strain screening and metabolic considerations, a 2-stage process was designed, incorporating a growth phase followed by a nitrogen-starvation phase. This process design yielded the highest isopropanol titers on acetate to date (13.3 g L−1). Additionally, we performed shotgun and acetylated proteomics, and identified several stress conditions in the bioreactor scenarios, such as acid stress and impaired sulfur uptake. Metabolic modeling allowed for an in-depth characterization of intracellular flux distributions, uncovering cellular demand for ATP and acetyl-CoA as limiting factors for routing carbon toward the isopropanol pathway. Moreover, we asserted the importance of a balance between fluxes of the NADPH-providing isocitrate dehydrogenase (ICDH) and the product pathway. Conclusions Using the newly gained system-level understanding for isopropanol production from acetate, we assessed possible engineering approaches and propose process designs to maximize production. Collectively, our work contributes to the establishment and optimization of acetate-based bioproduction systems. Graphical Abstract

Abstract AF1q associates with tumor progression and metastases upon WNT signaling. The downstream WNT target CD44 has demonstrated prognostic significance in gastric cancer (GC). This study evaluates the impact of AF1q on tumor stage and survival in GC patients. Immunohistochemical marker expression was analyzed and data were processed to correlation and survival analysis. Out of 182 GC samples, 178 (97.8%) showed moderate to high AF1q expression (p

A 30-year (1980–2010) climatology of the major variables and terms of the transformed Eulerian-mean (TEM) momentum and thermodynamic equations is constructed by using four global atmospheric reanalyses: the Modern-Era Retrospective analysis for Research and Applications, Version 2 (MERRA-2); the Japanese 55-year Reanalysis (JRA-55); the European Centre for Medium-Range Weather Forecasts (ECMWF) interim reanalysis (ERA-Interim); and the Climate Forecast System Reanalysis (CFSR). Both the reanalysis ensemble mean (REM) and the differences in each reanalysis from the REM are investigated in the latitude–pressure domain for December–January–February and for June–July–August. For the REM investigation, two residual vertical velocities (the original one and one evaluated from residual meridional velocity) and two mass streamfunctions (from meridional and vertical velocities) are compared. Longwave (LW) radiative heating and shortwave (SW) radiative heating are also shown and discussed. For the TEM equations, the residual terms are also calculated and investigated for their potential usefulness, as the residual term for the momentum equation should include the effects of parameterized processes such as gravity waves, while that for the thermodynamic equation should indicate the analysis increment. Inter-reanalysis differences are investigated for the mass streamfunction, LW and SW heating, the two major terms of the TEM momentum equation (the Coriolis term and the Eliassen–Palm flux divergence term), and the two major terms of the TEM thermodynamic equation (the vertical temperature advection term and the total diabatic heating term). The spread among reanalysis TEM momentum balance terms is around 10 % in Northern Hemisphere winter and up to 50 % in Southern Hemisphere winter. The largest uncertainties in the thermodynamic equation (about 50 %) are found in the vertical advection, for which the structure is inconsistent with the differences in heating. The results shown in this paper provide basic information on the degree of agreement among recent reanalyses in the stratosphere and upper troposphere in the TEM framework.

Abstract Background Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Abstract Extreme states of the polar stratospheric circulation during winter tend to be followed by anomalies in the near-surface circulation for several weeks, especially over the North Atlantic/Eurasia (NAE) sector. Previous research has highlighted an associated robust increase in subseasonal to seasonal (S2S) forecast skill related to forecast ensemble mean anomalies. Here we explore the additional impact of polar stratospheric circulation extremes on ensemble spread, a key measure of forecast uncertainty and the associated predictability. We find that over the Norwegian Sea and around Scandinavia S2S ensemble spread in near-surface geopotential height is significantly reduced following weak polar vortex states (enhanced predictability), whereas it is increased following strong polar vortex states (reduced predictability), with anomaly magnitudes reaching as high as 20%. Notably, modulations of forecast uncertainty are found even over regions of near-zero ensemble mean anomaly. We find decreased forecast uncertainty to be linked to decreased synoptic-scale storm activity and vice versa for increased forecast uncertainty. Our results furthermore suggest that modulation of S2S forecast uncertainty by the stratosphere dominates over NAE, whereas over the North Pacific modulations due to El Niño/ La Niña are more important.

We explore the ability of the atmospheric CO2 record since 1900 to constrain the source of CO2 from land use and land cover change (hereafter "land use"), taking account of uncertainties in other terms in the global carbon budget. We find that the atmospheric constraint favors land use CO2 flux estimates with lower decadal variability and can identify potentially erroneous features, such as emission peaks around 1960 and after 2000, in some published estimates. Furthermore, we resolve an offset in the global carbon budget that is most plausibly attributed to the land use flux. This correction shifts the mean land use flux since 1900 across 20 published estimates down by 0.35 PgC year-1 to 1.04 ± 0.57 PgC year-1 , which is within the range but at the low end of these estimates. We show that the atmospheric CO2 record can provide insights into the time history of the land use flux that may reduce uncertainty in this term and improve current understanding and projections of the global carbon cycle.

Abstract The study presents (a) a 44‐year wintertime climatology of resolved gravity wave (GW) fluxes and forcing in the extratropical stratosphere using ERA5, and (b) their composite evolution around gradual (final warming) and abrupt (sudden warming) transitions in the wintertime circulation, focusing on lateral fluxes. The transformed Eulerian mean equations are leveraged to provide a glimpse of the importance of GW lateral propagation (i.e., horizontal propagation) toward driving the wintertime stratospheric circulation by analyzing the relative contribution of the vertical versus meridional flux dissipation. The relative contribution from lateral propagation is found to be notable, especially in the Austral winter stratosphere where lateral (vertical) momentum flux convergence provides a peak climatological forcing of up to −0.5 (−3.5) m/s/day around 60°S at 40–45 km altitude. Prominent lateral propagation in the wintertime midlatitudes also contributes to the formation of belts of GW activity in both hemispheres.

Abstract Atmospheric prediction at 2–6 weeks lead time (so‐called subseasonal‐to‐seasonal timescales) entails large forecast uncertainty. Here we investigate the flow‐dependence of this uncertainty during Boreal winter. We categorize the large‐scale flow using North Atlantic‐European weather regimes. First, we show that forecast uncertainty of near‐surface geopotential height (Z1000) and temperature (T2m) are strongly sensitive to the prevailing regime. Specifically, forecast uncertainty of Z1000 reduces over northern Europe following Greenland Blocking (enhanced predictability) due to a southward shifting eddy‐driven jet. However, due to strong temperature gradients and variable flow patterns, Greenland blocking is linked to increased forecast uncertainty of T2m over Europe (reduced predictability). Second, we show that forecast uncertainty of weather regimes is modulated via the stratospheric polar vortex. Weak polar vortex states tend to reduce regime‐uncertainty, for example, due to more frequent predicted occurrence of Greenland blocking. These regime changes are associated with increased T2m uncertainty over Europe.

Water vapour in the upper troposphere and lower stratosphere (UTLS) is a key radiative agent and a crucial factor in the Earth's climate system. Here, we investigate a common regional moist bias in the Pacific UTLS during Northern Hemisphere summer in state-of-the-art climate models. We demonstrate, through a combination of climate model experiments and satellite observations, that the Pacific moist bias amplifies local long-wave cooling, which ultimately impacts regional circulation systems in the UTLS. Related impacts involve a strengthening of isentropic potential vorticity gradients, strengthened westerlies in the Pacific westerly duct region, and a zonally displaced anticyclonic monsoon circulation. Furthermore, we show that the regional Pacific moist bias can be significantly reduced by applying a Lagrangian, less-diffusive transport scheme and that such a model improvement could be important for improving the simulation of regional circulation systems, in particular in the Asian monsoon and Pacific region.

Background/Objectives: Chemerin is an adipokine involved in inflammatory and metabolic diseases, and its circulating levels have been associated with inflammatory parameters in various patient cohorts. Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, which causes COVID-19, triggers inflammatory pathways. However, the association between serum chemerin levels and COVID-19 disease severity and outcomes has not been definitively established. Methods: In this study, serum chemerin levels were analyzed in 64 patients with moderate COVID-19 and 60 patients with severe disease. Results: The results showed that serum chemerin levels were comparable between these two groups and slightly higher than in healthy controls. Notably, COVID-19 patients with hypertension exhibited elevated serum chemerin levels, while those with liver cirrhosis had lower levels. When patients with these comorbidities were excluded from the analyses, serum chemerin levels in COVID-19 patients were similar to those in healthy controls. Positive correlations were observed between serum chemerin levels and markers such as alkaline phosphatase, C-reactive protein, eosinophils, and lymphocytes in the entire cohort, as well as in the subgroup excluding patients with hypertension and cirrhosis. Additionally, urinary chemerin levels were comparable between COVID-19 patients and controls, and neither hypertension nor dialysis significantly affected urinary chemerin levels. Both survivors and non-survivors had similar serum and urinary chemerin levels. Conclusions: In conclusion, this study suggests that comorbidities such as arterial hypertension and liver cirrhosis do have a more significant impact on serum chemerin levels than SARS-CoV-2 infection itself.

Stratospheric ozone is important for both stratospheric and surface climate. In the lower stratosphere during winter, its variability is governed primarily by transport dynamics induced by wave–mean flow interactions. In this work, we analyze interannual co-variations between the distribution of zonal-mean ozone and the strength of the polar vortex as a measure of dynamical activity during northern hemispheric winter. Specifically, we study co-variability between the seasonal means of the ozone field from modern reanalyses and polar-cap-averaged temperature at 100 hPa, which represents a robust and well-defined index for polar vortex strength. We focus on the vertically resolved structure of the associated extratropical ozone anomalies relative to the winter climatology and shed light on the transport mechanisms that are responsible for this response pattern. In particular, regression analysis in pressure coordinates shows that anomalously weak polar vortex years are associated with three pronounced local ozone maxima just above the polar tropopause, in the lower to mid-stratosphere and near the stratopause. In contrast, in isentropic coordinates, using ERA-Interim reanalysis data, only the mid- to lower stratosphere shows increased ozone, while a small negative ozone anomaly appears in the lowermost stratosphere. These differences are related to contributions due to anomalous adiabatic vertical motion, which are implicit in potential temperature coordinates. Our analyses of the ozone budget in the extratropical middle stratosphere show that the polar ozone response maximum around 600 K and the negative anomalies around 450 K beneath both reflect the combined effects of anomalous diabatic downwelling and quasi-isentropic eddy mixing, which are associated with consecutive counteracting anomalous ozone tendencies on daily timescales. We find that approx. 71 % of the total variability in polar column ozone in the stratosphere is associated with year-by-year variations in polar vortex strength based on ERA5 reanalyses for the winter seasons 1980–2022. MLS observations for 2005–2020 show that around 86 % can be explained by these co-variations with the polar vortex.

Abstract Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibroblasts, with expression highest prior to injury and late post-infarct (from ~ day-28 to week-8). In humans, fibulin-3 was upregulated in left ventricular tissue and plasma of heart failure patients. Fibulin-3 knockout (Efemp1 −/−) and wildtype mice were subjected to experimental myocardial infarction. Fibulin-3 deletion resulted in significantly higher rate of cardiac rupture days 3–6 post-infarct, indicating a weak and poorly formed scar, with severe ventricular remodelling in surviving mice at day-28 post-infarct. Fibulin-3 knockout mice demonstrated less collagen deposition at day-3 post-infarct, with abnormal collagen fibre-alignment. RNA-seq on day-3 infarct tissue revealed upregulation of ECM degradation and inflammatory genes, but downregulation of ECM assembly/structure/organisation genes in fibulin-3 knockout mice. GSEA pathway analysis showed enrichment of inflammatory pathways and a depletion of ECM organisation pathways. Fibulin-3 originates from cardiac fibroblasts, is upregulated in human heart failure, and is necessary for correct ECM organisation/structural integrity of fibrotic tissue to prevent cardiac rupture post-infarct.