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The most common form of genetic heart disease is hypertrophic cardiomyopathy (HCM), which is caused by variants in cardiac sarcomeric genes and leads to abnormal heart muscle thickening. Complications of HCM include heart failure, arrhythmia and sudden cardiac death. The dominant-negative c.1208G>A (p.R403Q) pathogenic variant (PV) in β-myosin ( MYH7 ) is a common and well-studied PV that leads to increased cardiac contractility and HCM onset. In this study we identify an adenine base editor and single-guide RNA system that can efficiently correct this human PV with minimal bystander editing and off-target editing at selected sites. We show that delivery of base editing components rescues pathological manifestations of HCM in induced pluripotent stem cell cardiomyocytes derived from patients with HCM and in a humanized mouse model of HCM. Our findings demonstrate the potential of base editing to treat inherited cardiac diseases and prompt the further development of adenine base editor-based therapies to correct monogenic variants causing cardiac disease. Adenine base editing successfully corrected a MYH7 pathogenic variant that causes hypertrophic cardiomyopathy in human cardiomyocytes and a mouse model of the disease, highlighting the potential of the approach to correct monogenic variants causing cardiac disease.

Engel curves describe how household expenditure on particular goods or services depends on household income. German statistician Ernst Engel (1821–1896) was the first to investigate this relationship systematically in an article published about 150 years ago. The best-known single result from the article is “Engel's law,” which states that the poorer a family is, the larger the budget share it spends on nourishment. We revisit Engel's article, including its context and the mechanics of the argument. Because the article was completed a few decades before linear regression techniques were established and income effects were incorporated into standard consumer theory, Engel was forced to develop his own approach to analyzing household expenditure patterns. We find his work contains some interesting features in juxtaposition to both the modern and classical literature. For example, Engel's way of estimating the expenditure–income relationship resembles a data-fitting technique called the “regressogram” that is nonparametric—in that no functional form is specified before the estimation. Moreover, Engel introduced a way of categorizing household expenditures in which expenditures on commodities that served the same purpose by satisfying the same underlying “want” were grouped together. This procedure enabled Engel to discuss the welfare implications of his results in terms of the Smithian notion that individual welfare is related to the satisfaction of wants. At the same time, he avoided making a priori assumptions about which specific goods were necessities, assumptions which were made by many classical economists like Adam Smith. Finally, we offer a few thoughts about some modern literature that builds on Engel's research.

Skeletal muscle fibers contain hundreds of nuclei, which increase the overall transcriptional activity of the tissue and perform specialized functions. Multinucleation occurs through myoblast fusion, mediated by the muscle fusogens Myomaker (MYMK) and Myomixer (MYMX). We describe a human pedigree harboring a recessive truncating variant of the MYMX gene that eliminates an evolutionarily conserved extracellular hydrophobic domain of MYMX, thereby impairing fusogenic activity. Homozygosity of this human variant resulted in a spectrum of abnormalities that mimicked the clinical presentation of Carey-Fineman-Ziter syndrome (CFZS), caused by hypomorphic MYMK variants. Myoblasts generated from patient-derived induced pluripotent stem cells displayed defective fusion, and mice bearing the human MYMX variant died perinatally due to muscle abnormalities. In vitro assays showed that the human MYMX variant conferred minimal cell-cell fusogenicity, which could be restored with CRISPR/Cas9-mediated base editing, thus providing therapeutic potential for this disorder. Our findings identify MYMX as a recessive, monogenic human disease gene involved in CFZS, and provide new insights into the contribution of myoblast fusion to neuromuscular diseases.

The challenge of predicting which patients with breast cancer will develop metastases leads to the overtreatment of patients with benign disease and to the inadequate treatment of aggressive cancers. Here, we report the development and testing of a microfluidic assay that quantifies the abundance and proliferative index of migratory cells in breast cancer specimens, for the assessment of their metastatic propensity and for the rapid screening of potential antimetastatic therapeutics. On the basis of the key roles of cell motility and proliferation in cancer metastasis, the device accurately predicts the metastatic potential of breast cancer cell lines and of patient-derived xenografts. Compared with unsorted cancer cells, highly motile cells isolated by the device exhibited similar tumourigenic potential but markedly increased metastatic propensity in vivo. RNA sequencing of the highly motile cells revealed an enrichment of motility-related and survival-related genes. The approach might be developed into a companion assay for the prediction of metastasis in patients and for the selection of effective therapeutic regimens. A microfluidic assay predicts the metastatic potential of breast cancer specimens by quantifying the abundance and proliferative index of the migratory cells within them.

Background The glycosylphosphatidylinositol-anchored extracellular membrane serine protease prostasin is expressed in normal bladder urothelial cells. Bladder inflammation reduces prostasin expression and a loss of prostasin expression is associated with epithelial-mesenchymal transition (EMT) in human bladder transitional cell carcinomas. Non-steroidal anti-inflammatory drugs (NSAIDs) decrease the incidence of various cancers including bladder cancer, but the molecular mechanisms underlying the anticancer effect of NSAIDs are not fully understood. Methods The normal human bladder urothelial cell line UROtsa, the normal human trophoblast cell line B6Tert-1, human bladder transitional cell carcinoma cell lines UM-UC-5 and UM-UC-9, and the human breast cancer cell line JIMT-1 were used for the study. Expression changes of the serine proteases prostasin and matriptase, and cyclooxygenases (COX-1 and COX-2) in these cells following ibuprofen treatments were analyzed by means of reverse-transcription/quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. The functional role of the ibuprofen-regulated prostasin in epithelial tight junction formation and maintenance was assessed by measuring the transepithelial electrical resistance (TEER) and epithelial permeability in the B6Tert-1 cells. Prostasin’s effects on tight junctions were also evaluated in B6Tert-1 cells over-expressing a recombinant human prostasin, silenced for prostasin expression, or treated with a functionally-blocking prostasin antibody. Matriptase zymogen activation was examined in cells over-expressing prostasin. Results Ibuprofen increased prostasin expression in the UROtsa and the B6Tert-1 cells. Cyclooxygenase-2 (COX-2) expression was up-regulated at both the mRNA and the protein levels in the UROtsa cells by ibuprofen in a dose-dependent manner, but was not a requisite for up-regulating prostasin expression. The ibuprofen-induced prostasin contributed to the formation and maintenance of the epithelial tight junctions in the B6Tert-1 cells. The matriptase zymogen was down-regulated in the UROtsa cells by ibuprofen possibly as a result of the increased prostasin expression because over-expressing prostasin leads to matriptase activation and zymogen down-regulation in the UROtsa, JIMT-1, and B6Tert-1 cells. The expression of prostasin and matriptase was differentially regulated by ibuprofen in the bladder cancer cells. Conclusions Ibuprofen has been suggested for use in treating bladder cancer. Our results bring the epithelial extracellular membrane serine proteases prostasin and matriptase into the potential molecular mechanisms of the anticancer effect of NSAIDs.

Two centuries of continuous economic growth since the industrial revolution have fundamentally transformed consumer lifestyles. Here Keynes raised an important question: will consumption always continue to expand in the same manner as it has in the previous two centuries? If so, how? This paper critically reviews a body of work that has adopted the Learning To Consume (LTC) approach to study the long run growth of consumption (Witt 2001 ). By borrowing certain established insights from psychology and biology about how consumers learn and what motivates them to consume, it highlights how rising income, new technologies and market competition have combined to trigger important changes in both the underlying set of needs possessed by consumers and how they learn to satisfy these needs. Methodological issues and open questions are discussed.

In the Economic Possibilities of our Grandchildren (Keynes 1933), John Maynard Keynes recognized that the extent to which economic growth delivers better living conditions in the long run is mediated by how the character of demand evolves as households become more affluent. If consumer needs are indeed insatiable, there is little reason to doubt that any extra income generated by economic growth will continuously be converted into increases in demand ad infinitum (Stiglitz 2008). This is the position adopted by much of the growth literature that typically does not consider the possibility of non-homothetic preferences. In contrast, Keynes started to outline a more nuanced approach in this essay. In line with other scholars preceding him (e.g. Menger 1871) Keynes considered the nature of the underlying needs that motivate consumption and how rising affluence may impact their satisfaction. He conjectured that there are two types of needs: absolute and relative needs. Absolute needs are satiable and Keynes argued that within a hundred years, these needs would be sufficiently satisfied to the extent that further energies could be devoted to non-economic purposes (Keynes 1933; Pecchi and Piga 2008). However, relative needs are insatiable because their satisfaction is linked to a desire for superiority over others. Thus, the character of the needs that are the ultimate ends of economics activity must be taken into account in order to take proper stock of the extent to which long run economic growth translates into rising human welfare. Moreover, the possibility that the economy has shifted from satisfying absolute needs towards satisfying relative needs also raises deeper questions concerning the extent to which further increases in per capita consumption levels are desirable (Easterlin 2001; Frank 2001; Van den Bergh 2011) and what behavioural processes and social institutions are responsible for shaping the evolving character of demand (Scitovsky 1976; Pasinetti 1981; Bowles 1998; Witt 2001; Bisin and Verdier 2001; Earl and Potts 2004).

Using UK household expenditure data spanning over four decades (1960–2000), this paper employs Engel’s needs-based approach to analyzing household expenditure patterns and finds evidence for the existence of a stable hierarchy of expenditure patterns at low levels of household income. Second, we investigate how rising household income influences the manner in which total expenditure is distributed across Engel’s expenditure categories. Our results suggest that i) total household expenditure is distributed across Engel’s expenditure categories in an increasingly even manner as household income increases and ii) over time, there has been an acceleration in the rate at which household expenditure patterns become diversified as household income rises. Finally, we consider how the shape of Engel Curves may help shed light on the relationship between goods and the underlying needs they serve.

Information represents an essential input in social processes influencing human sentiment, attitudes, and behavior. With the rise of internet, information consumption habits have changed. The standard process of consuming news via traditional mass media (such as newspapers, radio and television) is now substituted, or complemented by news consumption via online sources. We study the effects of this behavioral change on environmental attitudes in Europe. More precisely, we ask whether this change has contributed to increased polarisation in environmental attitudes. We utilize a large-scale survey data across multiple European countries in the period from 2002 to 2010. We find evidence that traditional media (television, radio and newspapers) consumption, as well as internet use is associated with pro-environmental attitudes. Importantly, we also show that political preferences of an individual moderate the manner in which internet use is related to environmental attitudes. Among progressive and green voters, greater internet use is positively correlated with environmental attitudes. Among conservative voters, internet use appears to be negatively related to environmental attitudes. The pattern is similar, but much weaker, for TV consumption which constitutes a similar high-choice environment (compared to radio and newspapers). These results support the notion that internet use tends to strengthen people’s pre-existing beliefs (measured by voting behavior), much beyond the effect of TV viewership.