We use an attributional life cycle assessment (LCA) and simulation modelling to assess the effect of improved feeding practices and increased yields of feed crops on milk productivity and GHG ...emissions from the dairy sector of Tanzania's southern highlands region. We calculated direct non-CO
emissions from dairy production and the CO
emissions resulting from the demand for croplands and grasslands using a land footprint indicator. Baseline GHG emissions intensities ranged between 19.8 and 27.8 and 5.8-5.9 kg CO
eq kg
fat and protein corrected milk for the Traditional (local cattle) and Modern (improved cattle) sectors. Land use change contributed 45.8-65.8% of the total carbon footprint of dairy. Better feeding increased milk yields by up to 60.1% and reduced emissions intensities by up to 52.4 and 38.0% for the Traditional and Modern sectors, respectively. Avoided land use change was the predominant cause of reductions in GHG emissions under all the scenarios. Reducing yield gaps of concentrate feed crops lowered emissions further by 11.4-34.9% despite increasing N
O and CO
emissions from soils management and input use. This study demonstrates that feed intensification has potential to increase LUC emissions from dairy production, but that fertilizer-dependent yield gains can offset this increase in emissions through avoided emissions from land use change.
Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births; the incidence of CHD is up to tenfold higher in human fetuses. A genetic contribution is ...strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk. Here we report findings from a recessive forward genetic screen in fetal mice, showing that cilia and cilia-transduced cell signalling have important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signalling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signalling. Surprisingly, many CHD genes encoded interacting proteins, suggesting that an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note that the pathways identified show overlap with CHD candidate genes recovered in CHD patients, suggesting that they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations have been sperm archived, creating a rich public resource for human disease modelling.
•Cilia and cilia transduced cell signaling have key roles in congenital heart disease.•Disturbance in left-right patterning closely linked to congenital heart disease.•Shh signaling coordinates ...left-right patterning with heart development.•Negative regulation of Shh critical for left-right patterning and heart development.•Cilia defects also contribute to valve disease prevalent in adults.
An essential role for cilia in the pathogenesis of congenital heart disease (CHD) has emerged from findings of a large-scale mouse forward genetic screen. High throughput screening with fetal ultrasound imaging followed by whole exome sequencing analysis recovered a preponderance of cilia related genes and cilia transduced cell signaling genes among mutations identified to cause CHD. The perturbation of left-right patterning in CHD pathogenesis is suggested by the association of CHD with heterotaxy, but also by the finding of the co-occurrence of laterality defects with CHD in birth defect registries. Many of the cilia and cilia cell signaling genes recovered were found to be related to Hedgehog signaling. Studies in mice showed cilia transduced hedgehog signaling coordinates left-right patterning with heart looping and differentiation of the heart tube. Cilia transduced Shh signaling also regulates later events in heart development, including outflow tract septation and formation of the atrioventricular septum. More recent work has shown mutations in cilia related genes may also contribute to valve disease that largely manifest in adult life. Overall, these and other findings show cilia play an important role in CHD and also in more common valve diseases.
Congenital heart disease (CHD) affects up to 1% of live births. Although a genetic etiology is indicated by an increased recurrence risk, sporadic occurrence suggests that CHD genetics is complex. ...Here, we show that hypoplastic left heart syndrome (HLHS), a severe CHD, is multigenic and genetically heterogeneous. Using mouse forward genetics, we report what is, to our knowledge, the first isolation of HLHS mutant mice and identification of genes causing HLHS. Mutations from seven HLHS mouse lines showed multigenic enrichment in ten human chromosome regions linked to HLHS. Mutations in Sap130 and Pcdha9, genes not previously associated with CHD, were validated by CRISPR-Cas9 genome editing in mice as being digenic causes of HLHS. We also identified one subject with HLHS with SAP130 and PCDHA13 mutations. Mouse and zebrafish modeling showed that Sap130 mediates left ventricular hypoplasia, whereas Pcdha9 increases penetrance of aortic valve abnormalities, both signature HLHS defects. These findings show that HLHS can arise genetically in a combinatorial fashion, thus providing a new paradigm for the complex genetics of CHD.
Congenital heart disease (CHD) can affect up to 1% of live births, and despite abundant evidence of a genetic etiology, the genetic landscape of CHD is still not well understood. A large-scale mouse ...chemical mutagenesis screen for mutations causing CHD yielded a preponderance of cilia-related genes, pointing to a central role for cilia in CHD pathogenesis. The genes uncovered by the screen included genes that regulate ciliogenesis and cilia-transduced cell signaling as well as many that mediate endocytic trafficking, a cell process critical for both ciliogenesis and cell signaling. The clinical relevance of these findings is supported by whole-exome sequencing analysis of CHD patients that showed enrichment for pathogenic variants in ciliome genes. Surprisingly, among the ciliome CHD genes recovered were many that encoded direct protein-protein interactors. Assembly of the CHD genes into a protein-protein interaction network yielded a tight interactome that suggested this protein-protein interaction may have functional importance and that its disruption could contribute to the pathogenesis of CHD. In light of these and other findings, we propose that an interactome enriched for ciliome genes may provide the genomic context for the complex genetics of CHD and its often-observed incomplete penetrance and variable expressivity.
IMPORTANCE: Unruptured intracranial aneurysms not undergoing preventive endovascular or neurosurgical treatment are often monitored radiologically to detect aneurysm growth, which is associated with ...an increase in risk of rupture. However, the absolute risk of aneurysm rupture after detection of growth remains unclear. OBJECTIVE: To determine the absolute risk of rupture of an aneurysm after detection of growth during follow-up and to develop a prediction model for rupture. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data were obtained from 15 international cohorts. Patients 18 years and older who had follow-up imaging for at least 1 untreated unruptured intracranial aneurysm with growth detected at follow-up imaging and with 1 day or longer of follow-up after growth were included. Fusiform or arteriovenous malformation-related aneurysms were excluded. Of the 5166 eligible patients who had follow-up imaging for intracranial aneurysms, 4827 were excluded because no aneurysm growth was detected, and 27 were excluded because they had less than 1 day follow-up after detection of growth. EXPOSURES: All included aneurysms had growth, defined as 1 mm or greater increase in 1 direction at follow-up imaging. MAIN OUTCOMES AND MEASURES: The primary outcome was aneurysm rupture. The absolute risk of rupture was measured with the Kaplan-Meier estimate at 3 time points (6 months, 1 year, and 2 years) after initial growth. Cox proportional hazards regression was used to identify predictors of rupture after growth detection. RESULTS: A total of 312 patients were included (223 71% were women; mean SD age, 61 12 years) with 329 aneurysms with growth. During 864 aneurysm-years of follow-up, 25 (7.6%) of these aneurysms ruptured. The absolute risk of rupture after growth was 2.9% (95% CI, 0.9-4.9) at 6 months, 4.3% (95% CI, 1.9-6.7) at 1 year, and 6.0% (95% CI, 2.9-9.1) at 2 years. In multivariable analyses, predictors of rupture were size (7 mm or larger hazard ratio, 3.1; 95% CI, 1.4-7.2), shape (irregular hazard ratio, 2.9; 95% CI, 1.3-6.5), and site (middle cerebral artery hazard ratio, 3.6; 95% CI, 0.8-16.3; anterior cerebral artery, posterior communicating artery, or posterior circulation hazard ratio, 2.8; 95% CI, 0.6-13.0). In the triple-S (size, site, shape) prediction model, the 1-year risk of rupture ranged from 2.1% to 10.6%. CONCLUSION AND RELEVANCE: Within 1 year after growth detection, rupture occurred in approximately 1 of 25 aneurysms. The triple-S risk prediction model can be used to estimate absolute risk of rupture for the initial period after detection of growth.
Congenital heart defect is one of the most common structural birth defects in the human population. It is highly associated with heterotaxy, a birth defect involving randomized left-right patterning ...of visceral organ situs. Large scale mouse forward genetics have led to the finding of a central role for cilia in CHD pathogenesis, with some cilia and non-cilia mutations causing CHD with heterotaxy. Interestingly, many of the mutations causing CHD with heterotaxy can give rise to three laterality outcomes comprising normal situs solitus, mirror symmetric situs inversus totalis, or randomized situs with heterotaxy. Given CHD is largely observed only with heterotaxy, this suggests a new paradigm is needed for investigating the genetics of CHD associated with heterotaxy. Furthermore, analysis of data from multiple large birth cohorts have independently confirmed a broader involvement of laterality disturbance in CHD. This was demonstrated by the common cooccurrence of rare laterality defects with CHD lesions of a wide spectrum. These findings suggest left-right patterning is tightly intertwined with the developmental processes that regulate cardiac morphogenesis and its disturbance may contribute to all types of CHD even in the absence of laterality defects.
Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE ...experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis-collectively this is referred to as central nervous system (CNS) lupus. In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies, promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab, a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.
Abstract
A growing body of evidence shows that more intensive dairy systems can be good for both nature and people. Little research considers whether such systems correspond with local priorities and ...preferences. Using a mixed methods approach, this study examined the effects of three intensification scenarios on milk yield and emission intensities in Kenya and Tanzania. Scenarios included (a) an incremental change to feed management; (b) adaptive change by replacing poor quality grass with nutrient-rich fodder crops; and (c) multiple change involving concurrent improvements to breeds, feeds and concentrate supplementation. These scenarios were co-constructed with diverse stakeholder groups to ensure these resonate with local preferences and priorities. Modelling these scenarios showed that milk yield could increase by 2%–15% with incremental changes to over 200% with multiple changes. Greenhouse gas emission intensities are lowest under the multiple change scenario, reducing by an estimated 44%. While raising yields, incremental change conversely raises emission intensities by 9%. Our results suggest that while future interventions that account for local priorities and preferences can enhance productivity and increase the uptake of practices, far-reaching shifts in practices are needed to reduce the climatic footprint of the dairy sector. Since top-down interventions does not align with local priorities and preferences in many situations, future low-emission development initiatives should place more emphasis on geographic and stakeholder heterogeneity when designing targeting and implementation strategies. This suggests that in low-income countries, bottom-up approaches may be more likely to improve dairy productivity and align with mitigation targets than one-size-fits-all approaches.
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