Biogenesis of secretory granules Implications arising from the immature secretory granule in the regulated pathway of secretion

AbstractIn endocrine cells the regulated secretion of hormones, peptides, enzymes and neurotransmitters into the external medium occurs when mature secretory granules fuse with the plasma membrane. Secretory granules form at the trans-Golgi network (TGN) by envelopment of the dense-core aggregate of regulated secretory proteins by a specific membrane. The secretory granules initially formed at the TGN, referred to here as immature secretory granules, are morphologically and biochemically distinct from mature secretory granules. The functional similarities and differences between the immature secretory granule and the mature secretory granule, and the events involved in the maturation of the secretory granules are briefly discussed

Tobacco Farmer Interest and Success in Income Diversification

As farm income from tobacco production has declined in recent years, there has been increasing interest in identifying alternative sources of income for tobacco farmers in the southern United States The recent termination of the tobacco quota program has accelerated the exit of tobacco farmers and has heightened concern regarding the availability of substitutes for tobacco production. In this study, we examine factors influencing tobacco farmers’ attempts to identify profitable alternatives to tobacco, their off-farm employment behavior, and changes in acres of tobacco cultivated using survey data collected from a panel of North Carolina tobacco farmers combined with market datadiversification, farm programs, farmer survey, quota buyout, tobacco, Crop Production/Industries, Farm Management, Financial Economics, C33, Q12, Q18,

The Cutting Edge of Modernity: Machine Tools in the United States and Germany 1930-1945

This paper aims to examine the difference between US and European manufacturing before and during the World War II, focusing on the key technology in the metal-working sector: machine tools. We present a new data set covering the installed capacity of metal-working tools in the United States and Germany for the period 1930-1945. The existing literature is heavily dependent on assumptions about the different type of machine tools in use on either side of the Atlantic. So far, systematic comparison has been limited to case studies. This is the first attempt to quantify the differences in this key technology for the entirety of metal-working in both economies. The enormous detail of the statistical sources we have uncovered allows us to combine aggregation and a degree of specificity, which exceeds that of any previous case study. In the German case, the original data is divided into well over a hundred sub-categories. For comparative purposes, we have identified 19 major classes of machines, which aggregate over 50 sub-categories. Our results suggest the need for a far more nuanced understanding of metal-working than the dichotomous picture of American mass manufacture, reliant on special-purpose tools, and European craft manufacturing employing general-purpose machinery. For 1930, we find a remarkable similarity in machine to worker ratios between Germany and the United States. There are differences in certain key areas. However, the US stock of metal-working tools is not yet distinguished by a clear commitment to mass production technology. For the period after 1935, until the early 1940s, our data suggest a remarkable degree of convergence. The American stock stagnated. In some areas, there was disinvestment. And the average age of machinery rose dramatically. By contrast, Germany entered a period of rapid catch-up, which appears to have continued into the early years of the war. By 1940, German metal-working came close to matching its American counterpart in terms of the number of workers employed and the quantity and types of machines installed. German machines were, on average, far younger. This process of catching-up, however, was dramatically reversed during World War II. Over a period of no more than four years the American stock expanded by over eighty percent and growth was markedly concentrated in key categories of mass production equipment. It appears that it was only in this period that mass production machinery came to truly dominate US metal-working. German investment, albeit moving in the same direction, failed to match the new intensity of American commitment to mass production in some key machinery classe

Membrane supply and remodeling during autophagosome biogenesis

The de novo generation of double-membrane autophagosomes is the hallmark of autophagy. The initial membranous precursor cisterna, the phagophore, is very likely generated by the fusion of vesicles and acts as a membrane seed for the subsequent expansion into an autophagosome. This latter step requires a massive convoy of lipids into the phagophore. In this review, we present recent advances in our understanding of the intracellular membrane sources and lipid delivery mechanisms, which principally rely on vesicular transport and membrane contact sites that contribute to autophagosome biogenesis. In this context, we discuss lipid biosynthesis and lipid remodeling events that play a crucial role in both phagophore nucleation and expansion

Lessons of Keynes’s Economic Consequences in a Turbulent Century

Just over a century old, John Maynard Keynes’s The Economic Consequences of the Peace (1919) remains a seminal document of the twentieth century. At the time, the book was a prescient analysis of political events to come. In the decades that followed, this still controversial text became an essential ingredient in the unfolding of history. In this essay, we review the arc of experience since 1919 from the perspective of Keynes’s influence and his changing understanding of economics, politics, and geopolitics. We identify how he, his ideas, and this text became key reference points during times of turbulence as actors sought to manage a range of shocks. Near the end of his life, Keynes would play a central role in planning the world economy’s reconstruction after World War II. We argue that the “global order” that evolved since then, marked by increasingly polarized societies, leaves the community of nations ill prepared to provide key global public goods or to counter critical collective threats

The puzzling origin of the autophagosomal membrane

Autophagy is one of the newest and fastest emerging research areas in biomedical life sciences. Autophagosomes, large double-membrane vesicles enclosing cytoplasmic components targeted for degradation, are the hallmark of this catabolic pathway. The origin of the lipid bilayers composing these transport carriers has been the central enigma of the field since the discovery of autophagy. A series of recent studies has implicated several cellular organelles as the possible source of the autophagosomal membranes, if anything further clouding our view. In this compendium, we will discuss these apparently contradictory results and briefly emphasize the relevance of determining the lipid source used for autophagy for future translational research, for example in drug discovery programs

Synaptotagmin IV is necessary for the maturation of secretory granules in PC12 cells

In neuroendocrine PC12 cells, immature secretory granules (ISGs) mature through homotypic fusion and membrane remodeling. We present evidence that the ISG-localized synaptotagmin IV (Syt IV) is involved in ISG maturation. Using an in vitro homotypic fusion assay, we show that the cytoplasmic domain (CD) of Syt IV, but not of Syt I, VII, or IX, inhibits ISG homotypic fusion. Moreover, Syt IV CD binds specifically to ISGs and not to mature secretory granules (MSGs), and Syt IV binds to syntaxin 6, a SNARE protein that is involved in ISG maturation. ISG homotypic fusion was inhibited in vivo by small interfering RNA–mediated depletion of Syt IV. Furthermore, the Syt IV CD, as well as Syt IV depletion, reduces secretogranin II (SgII) processing by prohormone convertase 2 (PC2). PC2 is found mostly in the proform, suggesting that activation of PC2 is also inhibited. Granule formation, and the sorting of SgII and PC2 from the trans-Golgi network into ISGs and MSGs, however, is not affected. We conclude that Syt IV is an essential component for secretory granule maturation

Trimeric G-proteins of the trans-Golgi network are involved in the formation of constitutive secretory vesicles and immature secretory granules

AbstractNon-hydrolysable analogues of GTP, such as GTPγS and GMP-PNP, have previously been shown to inhibit the formation of constitutive secretory vesicles (CSVs) and immature secretory granules (ISGs) from the trans-Golgi network (TGN). Using a cell-free system, we show here that the formation of these vesicles is also inhibited by [AIF4], a compound known to act on trimeric G-proteins. Addition of highly purified G-protein βγ subunits stimulated, in a differential manner, the cell-free formation of both CSVs and ISGs. ADP-ribosylation experiments revealed the presence of a pertussis toxin-sensitive G-protein α subunit in the TGN. We conclude that trimeric G-proteins regulate the formation of secretory vesicles from the TGN