From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LALD). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal-/- mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal-/- mice exhibited CE accumulation and an increased number of macrophages in the liver and significant hepatic inflammation. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. Along with proteomic analysis of liver tissue, these findings indicate that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver and that KC depletion further exacerbates hepatic CE concentrations and dyslipidemia.

Lung Structure and Longitudinal Change in Cardiac Structure and Function: The MESA COPD Study.

BACKGROUND: Lung structure and cardiac structure and function are associated cross-sectionally. The classic literature suggests relationships of airways disease to cor pulmonale and emphysema to reduced cardiac output (CO) but longitudinal data are lacking. METHODS: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease (COPD) Study was a multi-center longitudinal COPD case-control study of participants 50-79 years with ≥10 pack-years smoking without clinical cardiovascular disease. Segmental airway wall area (WA) and percent emphysema were measured on computed tomography. Right and left ventricle (RV, LV) parameters were assessed on magnetic resonance imaging (MRI) in exams six years apart. Longitudinal and period cross-sectional associations were evaluated with mixed models adjusted for demographics, body size, and smoking. RESULTS: The 187 participants with repeated MRI were 67±7 years old; 42% had COPD; 22% currently smoked; and the race/ethnicity distribution was 54% white, 30% Black, 14% Hispanic, and 3% Asian. Greater WA at enrollment was associated with longitudinal increase in RV mass (3.5 g per 10mm2 WA, 95% CI: 1.1, 5.9). Greater percent emphysema was associated with stably lower LV end diastolic volume (-7.8 mL per 5% emphysema, 95% CI: -10.3, -3.0) and CO (-0.2 L·min-1 per 5% emphysema, 95% CI: -0.4, -0.1). CONCLUSION: Cardiac associations varied by lung structure over six years in this multi-ethnic study. Greater WA at enrollment was associated with longitudinal increases in RV mass; whereas greater percent emphysema was associated with stable decrements in LV filling and CO.

2D Titanium Carbide MXene and Single-Molecule Fluorescence: Distance-Dependent Nonradiative Energy Transfer and Leaflet-Resolved Dye Sensing in Lipid Bilayers.

Despite their growing popularity, many fundamental properties and applications of MXene materials remain underexplored. Here, the nonradiative energy transfer properties of 2D titanium carbide MXene are investigated and their application in single-molecule biosensing is explored for the first time. DNA origami positioners are used for single dye placement immobilized by a specific chemistry based on glycine-MXene interactions, allowing precise control of their orientation on the surface. Each DNA origami structure carries a single dye molecule at predetermined heights. Single-molecule fluorescence confocal microscopy reveals that energy transfer of an organic emitter (ATTO 542) on transparent thin films made of spincast Ti3C2Tx flakes follows a cubic distance dependence, where 50% of energy transfer efficiency is reached at 2.7 nm (d0). MXenes are applied as short-distance spectroscopic nanorulers, determining z distances of dye-labeled supported lipid bilayers fused on MXene's hydrophilic surface. Hydration layer (2.1 nm) and lipid bilayer thickness (4.5 nm) values that agree with the literature are obtained. These results highlight titanium carbide MXenes as promising substrates for single-molecule biosensing of ultrathin assemblies, owing to their sensitivity near the interface, a distance regime that is typically inaccessible to other energy transfer tools.

A New Species of Heligmonellidae (Nematoda) in Euryoryzomys russatus (Rodentia: Sigmodontinae) in the Atlantic Forest of Northeast Brazil.

BACKGROUND: The genus Stilestrongylus (Freitas, Lent, and Almeida, 1937) is defined by having 24 or more subequal cuticular ridges, an asymmetrical caudal bursa, and a hypertrophied genital cone. It comprises 25 recognized species, mainly parasitizing cricetids, and shows significant diversification linked to the evolution of its hosts. Stilestrongylus magnumspiculum n. sp. is a newly described nematode species identified in the small intestine of the rodent Euryoryzomys russatus (Cricetidae, Sigmodontinae) from the Atlantic Forest of Northeast Brazil. This study aims to characterize the new species and its prevalence in host populations. METHODS: A total of 43 Euryoryzomys russatus individuals were collected and analyzed for parasitic infections. Morphological features of Stilestrongylus magnumspiculum n. sp. were examined, focusing on the number of ridges, synlophe characteristics, caudal bursa type, lobe hypertrophy, and the spicule length to body length ratio. RESULTS: The new species exhibited a prevalence of 21% among the sampled hosts. Distinctive morphological features were observed, including:the synlophe structure exhibited specific ridge patterns that differentiate it from other species within the genus; the caudal bursa was identified as a type 2-2-1; hypertrophy of the right lobe was observed, indicating notable morphological adaptation; rays 4 and 5 were found to be equivalent in size and diverged at the distal end; the spicule length to body length ratio (SpL/BL) was measured at 30-36%, representing the largest ratio recorded for the genus. In comparison, other Stilestrongylus species displayed the following ratios: S. rolandoi (21-33%), S. lanfrediae (25-29%), S. kaaguyporai (20-24%), S. inexpectatus (20-23%), and S. stilesi (26-28%). CONCLUSIONS: This report presents Stilestrongylus magnumspiculum n. sp. as a new species of nematode, contributing to the diversity of the genus Stilestrongylus. The findings underscore the importance of studying host-parasite interactions within the Atlantic Forest ecosystem and provide a basis for future ecological and parasitological research.

Assessment of aortic dissection remodeling with patient-specific fluid-structure interaction models.

Aortic dissection leads to late complications due to chronic degeneration and dilatation of the false lumen. However, the interaction between hemodynamics and microstructural remodeling driving long-term changes is not fully understood. This study examines the progression of a patient's aortic dissection, tracked from pre-dissection to the chronic phase using computed tomography angiography. Fluid-structure interaction models that account for tissue prestress, external support, and anisotropic properties were used to analyze hemodynamic markers. Each aortic wall layer had distinct thicknesses and material properties. The boundary conditions were guided by in vitro 4D-flow MRI and the patient's blood pressure. Quantitative measurements during routine clinical care showed that aortic dilatation was most significant distal to the left subclavian artery, reaching 6cm in the chronic phase. Simulations resulted in a flow jet velocity through the entry tear that peaked at 185cm/s in the subacute phase and decreased to 123 to 133 cm/s in the chronic phase, corresponding to an increased entry tear size. Flow jet impingement on the false lumen resulted in a localized pressure increase of 11 and 2mmHg in the subacute and chronic phases, with the wall shear stress reaching 4,Pa. These hemodynamic changes appear to be the main drivers of aortic growth and morphological changes. Despite moderate overall flap movement, in-plane displacement increased from 0.6 to 1.8mm as disease progressed, which was associated with an overall increase in aortic diameter. Additional simulations with a significant reduction in flap stiffness during the subacute phase resulted in increased flap motion up to 9.5mm. Although these results are based on a single patient, they suggest a strong relationship between hemodynamics and aortic growth.

StratosPHere 2: study protocol for a response-adaptive randomised placebo-controlled phase II trial to evaluate hydroxychloroquine and phenylbutyrate in pulmonary arterial hypertension caused by mutations in BMPR2.

BACKGROUND: Pulmonary arterial hypertension is a life-threatening progressive disorder characterised by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery). Although treatable, there is no known cure for this rare disorder, and its exact cause is unknown. Mutations in the bone morphogenetic protein receptor type-2 (BMPR2) are the most common genetic cause of familial pulmonary arterial hypertension. This study represents the first-ever trial of treatments aimed at directly rescuing the BMPR2 pathway, repurposing two drugs that have shown promise at restoring levels of BMPR2 signalling: hydroxychloroquine and phenylbutyrate. METHODS: This three-armed phase II precision medicine study will investigate BMPR2 target engagement and explore the efficacy of two repurposed therapies in pulmonary arterial hypertension patients with BMPR2 mutations. Patients will be stratified based on two BMPR2 mutation classes: missense and haploinsufficient mutations. Eligible subjects will be randomised to one of the three arms (two active therapy arms and a placebo arm, all plus standard of care) following a Bayesian response-adaptive design implemented independently in each stratum and updated in response to a novel panel of primary biomarkers designed to assess biological modification of the disease. DISCUSSION: The results of this trial will provide the first randomised evidence of the efficacy of these therapies to rescue BMPR2 function and will efficiently explore the potential for a differential response of these therapies per mutation class to address causes rather than consequences of this rare disease. TRIAL REGISTRATION: The study has been registered with ISRCTN (ISRCTN10304915, 22/09/2023).

Stimulated C2C12 Myotube Headspace Volatile Organic Compound Analysis.

Understanding exercise metabolism and the relationship with volatile organic compounds (VOCs) holds potential in both health care and sports performance. Exercise metabolism can be investigated using whole body exercise testing (in vivo) or through the culture and subsequent electrical pulse stimulation (EPS) of myotubes (in vitro). This research investigates the novel headspace (HS) analysis of EPS skeletal muscle myotubes. An in vitro system was built to investigate the effect of EPS on the volatile constituents in the HS above EPS skeletal muscle. The C2C12 immortalised cell line was chosen. EPS was applied to the system to induce myotube contraction. The in vitro system was applied to the analysis of VOCs using thermal desorption (TD) sampling. Samples were collected under four conditions: environmental samples (enviro), acellular media HS samples (blank), skeletal muscle myotubes without stimulation HS samples (baseline) and EPS of skeletal muscle myotube HS samples (stim). TD sampling combined with gas-chromatography mass spectrometry (GC-MS) detected two compounds that, after multivariate and univariate statistical analysis, were identified as changing due to EPS (p < 0.05). These compounds were tentatively assigned as 1,4-Dioxane-2,5-dione, 3,6-dimethyl- and 1-pentene. The former is a known lactide and the latter has been reported as a marker of oxidative stress. Further research should focus on improvements to the EPS system, including the use of more relevant cell lines, quantification of myotube contractions, and the application of targeted analysis, metabolic assays and media analysis.

N-[4-(Benzyloxy)-3-methoxybenzyl)]adamantane-1-amine (DZH2), a dual CCR5 and CXCR4 inhibitor as a potential agent against triple negative breast cancer.

DZH2, a dual inhibitor of the chemokine receptors CCR5 and CXCR4, was discovered from virtual screening for CCR5 antagonists. In specific Ca2+ chemokine signaling assays, DZH2 displayed low micromolar IC50 values at both chemokine receptors. Its binding to intracellular allosteric binding sites of CCR5 and CXCR4 was confirmed by MD simulations and binding free-energy calculations. DZH2 is superior to the CCR5 antagonist maraviroc in terms of its inhibitory activity on the growth of two breast cancer cell lines. In MCF7 and MDA-MB-231 cells, DZH2 was a >100-fold more potent inhibitor of cell viability compared to maraviroc. DZH2 (6.7 µM) reduced migration of MDA-MB-231 cells to 4% compared to 50% inhibition of migration caused by maraviroc (780 µM). Also, DZH2 was a significantly more potent inhibitor of colony formation in MDA-MB-231 cells than maraviroc. In MCF10 cells, DZH2 caused no alteration in the gene expression with respect to cellular pathways mediating cell death, indicating its selectivity to breast cancer cells.

APOL1 Bi- and Monoallelic Variants and Chronic Kidney Disease in West Africans.

BACKGROUND: Apolipoprotein L1 gene (APOL1) variants are risk factors for chronic kidney disease (CKD) among Black Americans. Data are sparse on the genetic epidemiology of CKD and the clinical association of APOL1 variants with CKD in West Africans, a major group in the Black population. METHODS: We conducted a case-control study involving participants from Ghana and Nigeria who had CKD stages 2 through 5, biopsy-proven glomerular disease, or no kidney disease. We analyzed the association of CKD with APOL1 variants among participants with high-risk genotypes (two APOL1 risk alleles) and those with low-risk genotypes (fewer than two APOL1 risk alleles) by fitting logistic-regression models that controlled for covariates, including clinical site, age, and sex. RESULTS: Among 8355 participants (4712 with CKD stages 2 through 5, 866 with glomerular diseases, and 2777 with no kidney disease), the prevalence of monoallelic APOL1 variants was 43.0% and that of biallelic APOL1 variants was 29.7%. Participants with two APOL1 risk alleles had higher odds of having CKD than those with one risk allele or no risk alleles (adjusted odds ratio, 1.25; 95% confidence interval [CI], 1.11 to 1.40), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.84; 95% CI, 1.30 to 2.61). Participants with one APOL1 risk allele had higher odds of having CKD than those with no risk alleles (adjusted odds ratio, 1.18; 95% CI, 1.04 to 1.33), as well as higher odds of focal segmental glomerulosclerosis (adjusted odds ratio, 1.61; 95% CI, 1.04 to 2.48). The inclusion of covariates did not modify the association of monoallelic and biallelic APOL1 variants with CKD or focal segmental glomerulosclerosis. CONCLUSIONS: In this study, monoallelic APOL1 variants were associated with 18% higher odds of CKD and 61% higher odds of focal segmental glomerulosclerosis; biallelic APOL1 variants were associated with 25% higher odds of CKD and 84% higher odds of focal segmental glomerulosclerosis. (Funded by the National Human Genome Research Institute and others.).

Outcomes of Distal Rectal Cancer Patients Who Did Not Qualify for Watch-and-Wait: Comparison of Intersphincteric Resection Versus Abdominoperineal Resection.

INTRODUCTION: Total mesorectal excision (TME) with intersphincteric resection and handsewn coloanal anastomosis (ISR-CAA) has been shown to be oncologically safe in patients with distal rectal cancer treated with preoperative chemoradiation. The introduction of the watch-and-wait (WW) strategy for rectal cancer patients with a clinical complete response to neoadjuvant therapy is changing the profile of patients undergoing TME surgery immediately following neoadjuvant treatment. The outcomes of ISR-CAA for patients with locally advanced rectal cancers not qualifying for WW have not been investigated. METHODS: We conducted a retrospective analysis comparing the outcomes of ISR-CAA and abdominoperineal resection (APR) in patients with distal rectal cancer treated with neoadjuvant therapy and not qualifying for WW, at a comprehensive cancer center with an established WW program. The primary outcome was local recurrence-free survival. RESULTS: Sixty-seven patients had ISR-CAA and 79 had APR. Median follow-up was 61.1 months. The two groups were similar in sex, tumor stage, grade, and distance from the anal verge, but patients in the APR group were older on average. An R0 resection was achieved in 94% of ISR-CAA patients and 91% of APR patients. Patients in the ISR-CAA group had a lower 5-year rate of local recurrence-free survival (79% vs. 93%; p = 0.038) compared with the APR group; however, 5-year disease-free survival did not differ significantly between groups (67% for ISR-CAA and 64% for APR; p = 0.19). CONCLUSIONS: The local recurrence rate after ISR-CAA may be higher than after APR for patients without a clinical complete response to neoadjuvant therapy requiring TME surgery.

Natural History and Clinicopathological Associations of TRPC6-Associated Podocytopathy.

BACKGROUND: Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6, in order to help define the specific features of disease and further facilitate drug development and clinical trials design. METHODS: the study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their impact on protein function. In depth re-analysis of light and electron microscopy specimens for 9 available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP. RESULTS: Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. The majority of patients presented in adolescence or early adulthood but with ample variation (average 22, SD ± 14 years), with frequent progression to kidney failure but with variability in time between presentation and ESKD. CONCLUSIONS: This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.

Burden of selenium deficiency and cost-effectiveness of selenium agronomic biofortification of staple cereals in Ethiopia.

Selenium (Se) deficiency among populations in Ethiopia is consistent with low concentrations of Se in soil and crops that could be addressed partly by Se-enriched fertilisers. This study examines the disease burden of Se deficiency in Ethiopia and evaluates the cost-effectiveness of Se agronomic biofortification. A disability-adjusted life years (DALY) framework was used, considering goiter, anaemia, and cognitive dysfunction among children and women. The potential efficiency of Se agronomic biofortification was calculated from baseline crop composition and response to Se fertilisers based on an application of 10 g/ha Se fertiliser under optimistic and pessimistic scenarios. The calculated cost per DALY was compared against gross domestic product (GDP; below 1-3 times national GDP) to consider as a cost-effective intervention. The existing national food basket supplies a total of 28·2 µg of Se for adults and 11·3 µg of Se for children, where the risk of inadequate dietary Se reaches 99·1 %-100 %. Cereals account for 61 % of the dietary Se supply. Human Se deficiency contributes to 0·164 million DALYs among children and women. Hence, 52 %, 43 %, and 5 % of the DALYs lost are attributed to anaemia, goiter, and cognitive dysfunction, respectively. Application of Se fertilisers to soils could avert an estimated 21·2-67·1 %, 26·6-67·5 % and 19·9-66·1 % of DALY via maize, teff and wheat at a cost of US$129·6-226·0, US$149·6-209·1 and US$99·3-181·6, respectively. Soil Se fertilisation of cereals could therefore be a cost-effective strategy to help alleviate Se deficiency in Ethiopia, with precedents in Finland.

MSH6-proficient crypt foci in MSH6 constitutional mismatch repair deficiency: reversion of a frameshifted coding microsatellite to its wild-type sequence.

The discovery of "mismatch repair deficient (MMRd)-crypt foci" in non-neoplastic intestinal mucosa in Lynch syndrome (LS) has significantly enhanced our understanding of how tumors and tumor immunity form and evolve in LS. In this study, we report the frequent presence of "mismatch repair proficient (MMRp)-crypt foci" in both non-neoplastic and neoplastic intestinal mucosa in a patient with constitutional MMR deficiency (CMMRD), who carried a germline MSH6 pathogenic variant (c.3261dupC) in trans with an MSH6 likely pathogenic variant (c.3724_3726del) and whose tissues were otherwise deficient in MMR globally. The MMRp-crypts occurred at a rate of 1.1/100 crypts in non-neoplastic intestinal mucosa and were readily discernible in adenomas > 1 cm. Sequencing analysis revealed normalization of the MSH6c.3261dupC variant in MMRp-adenoma crypts, indicating reverse frameshifting of the exon 5 C8 microsatellite. Interestingly but not surprisingly, the MMRp-adenoma crypts remained microsatellite-instability-high (MSI-H), and shared oncogenic APC mutations with the background MMRd-adenoma. Contrasting with MSH6-CMMRD, no PMS2-CMMRD individuals (0/5) harbored MMRp-crypts. In conclusion, our study documents distinct MMRp-crypts in MSH6-CMMRD, a phenomenon in keeping with MSH6 being a frequent target of MSI-H due to its coding microsatellite and suggesting that MSH6-CMMRD can potentially serve as a unique model system to further our understanding of MSH6's role in MSI-H tumor formation and evolution. Our findings also bear diagnostic implications; when using MMR immunohistochemistry as an ancillary tool in detecting CMMRD, awareness of these MMRp crypts can help avoid diagnostic pitfalls.

Establishment of Translational Luciferase-Based Cancer Models to Evaluate Antitumoral Therapies.

Luciferase (luc) bioluminescence (BL) is the most used light-emitting protein that has been engineered to be expressed in multiple cancer cell lines, allowing for the detection of tumor nodules in vivo as it can penetrate most tissues. The goal of this study was to develop an oncolytic adenovirus (OAd)-resistant human triple-negative breast cancer (TNBC) that could express luciferase. Thus, when combining an OAd with chemotherapies or targeted therapies, we would be able to monitor the ability of these compounds to enhance OAd antitumor efficacy using BL in real time. The TNBC cell line HCC1937 was stably transfected with the plasmid pGL4.50[luc2/CMV/Hygro] (HCC1937/luc2). Once established, HCC1937/luc2 was orthotopically implanted in the 4th mammary gland fat pad of NSG (non-obese diabetic severe combined immunodeficiency disease gamma) female mice. Bioluminescence imaging (BLI) revealed that the HCC1937/luc2 cell line developed orthotopic breast tumor and lung metastasis over time. However, the integration of luc plasmid modified the HCC1937 phenotype, making HCC1937/luc2 more sensitive to OAdmCherry compared to the parental cell line and blunting the interferon (IFN) antiviral response. Testing two additional luc cell lines revealed that this was not a universal response; however, proper controls would need to be evaluated, as the integration of luciferase could affect the cells' response to different treatments.

FSGe: A fast and strongly-coupled 3D fluid-solid-growth interaction method.

Equilibrated fluid-solid-growth (FSGe) is a fast, open source, three-dimensional (3D) computational platform for simulating interactions between instantaneous hemodynamics and long-term vessel wall adaptation through mechanobiologically equilibrated growth and remodeling (G&R). Such models can capture evolving geometry, composition, and material properties in health and disease and following clinical interventions. In traditional G&R models, this feedback is modeled through highly simplified fluid solutions, neglecting local variations in blood pressure and wall shear stress (WSS). FSGe overcomes these inherent limitations by strongly coupling the 3D Navier-Stokes equations for blood flow with a 3D equilibrated constrained mixture model (CMMe) for vascular tissue G&R. CMMe allows one to predict long-term evolved mechanobiological equilibria from an original homeostatic state at a computational cost equivalent to that of a standard hyperelastic material model. In illustrative computational examples, we focus on the development of a stable aortic aneurysm in a mouse model to highlight key differences in growth patterns between FSGe and solid-only G&R models. We show that FSGe is especially important in blood vessels with asymmetric stimuli. Simulation results reveal greater local variation in fluid-derived WSS than in intramural stress (IMS). Thus, differences between FSGe and G&R models became more pronounced with the growing influence of WSS relative to pressure. Future applications in highly localized disease processes, such as for lesion formation in atherosclerosis, can now include spatial and temporal variations of WSS.

Sex-specific Genetic Determinants of Right Ventricular Structure and Function.

RATIONALE: While sex differences in right heart phenotypes have been observed, the molecular drivers remain unknown. OBJECTIVES: To provide biological insights into sex differences in the structure and function of the right ventricle (RV) using common genetic variation. METHODS: RV phenotypes were obtained from cardiac magnetic resonance imaging in 18,156 women and 16,171 men from the UK Biobank. Observational analyses and sex-stratified genome-wide association studies were performed. Candidate female-specific loci were evaluated against invasively measured cardiac performance in 479 female patients with idiopathic or heritable pulmonary arterial hypertension (PAH), recruited to the UK NIHR BioResource Rare Diseases study. MEASUREMENTS AND MAIN RESULTS: Sex was associated with differences in RV volumes and ejection fraction in models adjusting for left heart counterparts, blood pressure, lung function and sex hormone levels. Six genome-wide significant loci (13%) revealed heterogeneity of allelic effects between women and men, and significant sex-by-genotype interaction. These included two sex-specific candidate loci present in women only: a locus for RV ejection fraction in BMPR1A and a locus for RV end-systolic volume near DMRT2. Epigenetic data in RV tissue indicate that variation at the BMPR1A locus likely alters transcriptional regulation. In female patients with PAH, a variant located in the promoter of BMPR1A was significantly associated with cardiac index (effect size 0.16 l/min/m2), despite similar RV afterload. CONCLUSIONS: BMPR1A has emerged as a biologically plausible candidate gene for female-specific genetic determination of RV function, showing associations with cardiac performance under chronically increased afterload in female patients with PAH.

Effect of dietary fat source and concentration on feed intake, enteric methane and milk production in dairy cows.

Dietary fat can be used in dairy cow nutrition to reduce enteric methane (CH4), but studies with multiple dietary fat concentrations are scarce. Among fat sources, rapeseed is easily accessible in Europe and North America, and palm kernel fat has been shown to be a potent inhibitor of ruminal methanogenesis. Forty-eight cows (half primiparous and half multiparous) were used in a 6 × 6 Latin square design, with 6 periods of 21 d each. Six treatments were used: a control, 3 fat concentrations (low, medium and high) of rapeseed (RS), and 2 fat concentrations (low and medium) of palm kernel fatty acids (PK). The total crude fat concentrations ranged from 3 to 7% of DM. The cows were fed the treatments as partial mixed ration, and they received additional concentrate from GreenFeed units (1 unit for 12 cows) used to measure CH4 production. Increased dietary crude fat concentration of both RS and PK reduced DMI. The reduction in DMI was stronger in cows fed medium concentration of PK than for any RS concentration, which was comparable to previous studies for both RS and PK. Digestibility of OM was highest at low fat concentration of both fat sources, and lowest at high RS concentration. Digestibility of NDF was reduced by 2 percentage units when cows were fed medium PK concentration instead of the control treatment. Rapeseed supplementation with dietary crude fat up to 5.7% of DM increased milk and energy corrected milk (ECM) yields, but the equivalent PK concentration reduced ECM. Increased fat supplementation decreased CH4 yield (g CH4/kg of DMI) linearly when RS was used, and quadratically when PK was used. Medium PK concentration reduced CH4 yield more than medium RS concentration, but there was no difference for CH4 intensity (g CH4/kg of ECM). Rapeseed fat supplementation with dietary crude fat above 5.7% of DM could reduce further CH4 yield, but fat supplementation was not accompanied by an increase in productivity. The fat source has to be accounted for when considering enteric methane reduction, as the PK provided stronger effect than RS, but the associated reduction in milk production did not support the use of PK for methane reduction.

Axonal damage and inflammation response are biological correlates of decline in small-world values: a cohort study in autosomal dominant Alzheimer's disease.

The grey matter of the brain develops and declines in coordinated patterns during the lifespan. Such covariation patterns of grey matter structure can be quantified as grey matter networks, which can be measured with magnetic resonance imaging. In Alzheimer's disease, the global organization of grey matter networks becomes more random, which is captured by a decline in the small-world coefficient. Such decline in the small-world value has been robustly associated with cognitive decline across clinical stages of Alzheimer's disease. The biological mechanisms causing this decline in small-world values remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and small-world coefficient in mutation carriers (N = 219) and non-carriers (N = 136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Amyloid beta, Tau, synaptic (Synaptosome associated protein-25, Neurogranin) and neuronal calcium-sensor protein (Visinin-like protein-1) preceded loss of small-world coefficient by several years, while increased levels in CSF markers for inflammation (Chitinase-3-like protein 1) and axonal injury (Neurofilament light) co-occurred with decreasing small-world values. This suggests that axonal loss and inflammation play a role in structural grey matter network changes.