1,721,054 research outputs found
Corporate Governance and Security-based Crowdfunding: From a Platform-level to a Firm-level Analysis
No full textThis research has the focus to carry out an in-depth analysis of corporate governance in security-based crowdfunding. Prior studies have often compared security-based crowdfunding with initial public offerings or with other types of early-stage finance providers. However, in security-based crowdfunding, small investors invest alongside professional early-stage investors. People from almost every country around the world have access to crowdfunding platforms and invest in promising campaigns or seek for capital to finance their businesses. The research work aims to answer the following research question “Do corporate governance matter in security-based crowdfunding?”. We address our research question by investigating corporate governance both at the platform and firm level. First, we investigate the relationship between financial literacy and the survival profile of security-based crowdfunding platforms, and how governance structures moderate such relationships. Second, we study the relationship between ESG criteria and the development of security-based crowdfunding platforms. Last, we focus on differences between family and non-family firms, providing new insights into the uniqueness of family firms relative to non-family firms in the delivery of voting rights and post-offering outcomes
Effects of Presenilin 2 mutations associated with Familial Alzheimer's Disease on mitochondrial bioenergetics
Full text linkAlzheimer’s Disease (AD) is a neurodegenerative disorder of the central nervous system. It is mainly sporadic, however, a little percentage of cases is inherited (Familial AD, FAD) and due to autosomal dominant mutations on three different genes, coding for Amyloid Precursor Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2). Presenilins, mainly localized at Endoplasmic Reticulum (ER) membranes, are the catalytic core of the ɣ-secretase complex, although several ɣ-secretase-independent activities of PSs, such as modulation of neurites outgrowth, apoptosis, autophagy, synaptic functions and regulation of Ca2+ homeostasis, have been described.
Ca2+, a key intracellular second messenger, is involved in multiple cellular functionalities. Interestingly, alterations in Ca2+ homeostasis have been proposed as an early event in different neurodegenerative diseases, including AD. Notably, FAD-PS mutants have been reported to be directly involved in these dysregulations. In our lab, it has been previously showed that PS2 expression, both WT and, more potently, FAD mutants (such as PS2-T122R), but not PS1, decreases the ER Ca2+ content, mainly by inhibiting SERCA pump activity. Moreover, PS2 increases ER-mitochondria physical and functional coupling, favouring the process of ER to mitochondria Ca2+ transfer. However, due to its effect on ER [Ca2+], which results in a lower amount of available Ca2+ within the ER, its expression dampens mitochondrial Ca2+ rises upon cell stimulation.
Based on the well-established role of Ca2+ on mitochondrial metabolism, here we investigate the possible effects on mitochondrial functionalities of the complex balance between alterations in ER Ca2+ content and increased ER-mitochondria coupling, induced by FAD-PS2 mutants expression. A neuroblastoma cell line (SH-SY5Y) grown in a medium containing galactose, as a substitute of glucose, has been used. This growth condition enhances mitochondrial metabolism and results in an excellent experimental protocol to visualize possible mitochondrial defects.
Lower total cellular ATP levels were measured in FAD-PS2-T122R expressing cells, grown either in glucose- or galactose-containing medium, with the reduction more evident in the latter condition, thus suggesting possible mitochondrial defects induced by PS2 expression.
In order to investigate how Ca2+ dysregulation induced by PS2 could influence mitochondrial metabolism, we stimulated mitochondrial ATP production inducing ER Ca2+ release, followed by mitochondria Ca2+ uptake, using both bradykinin, as a maximal IP3R stimulation, and Fetal Calf Serum (FCS), as a more physiological stimulus. In both conditions, a reduction in mitochondrial ATP production, measured by a mitochondrial luciferase-based ATP probe, has been observed in cells expressing FAD-PS2, but not PS1. The defects in ATP synthesis were observed in SH-SY5Y, MEF, HT22 cells and in cortical neurons from PS2-N141I transgenic (Tg) mice (PS2.30H), by employing FRET-based ATP probes (ATeam 1.03) specifically targeted to the mitochondrial matrix or the nucleus. We also evaluated the glycolytic flux in these cells, by both employing a cytosolic luciferase-based ATP probe and measuring the extracellular medium acidification, but we did not observed any difference in these two parameters in FAD-PS2 expressing cells, compared to controls.
In order to understand the mechanism through which PS2 causes the observed mitochondrial dysfunction, we firstly considered the marked Ca2+ dysregulation induced by PS2 expression. We thus decided to modulate Ca 2+ handling in control cells, to mimic the ER Ca2+ depletion caused by PS2 expression. We used two different approaches: i) treating control cells with a SERCA pump inhibitor (Cyclopiazonic acid, CPA), to partially reduce the ER Ca2+ content, or ii) overexpressing a mutated-MICU1 (MICU1mut), a component of the mitochondrial Ca2+ uniporter complex. Although both approaches were able to reduce the capacity of control cells to produce ATP, for similar mitochondrial Ca2+ uptake in control and PS2-expressing cells, a lower mitochondrial ATP production in FAD-PS2 expressing-cells compared to CPA-treated or MICU1mut expressing controls was still observed. Taken together, these results suggest that part of the FAD-PS2-induced defects in mitochondrial metabolism is due to a reduced ER Ca2+ content and, consequently, mitochondrial Ca2+ uptake, negatively regulating the Ca2+-dependent mitochondrial metabolism. However, additional mechanisms, induced by FAD-PS2, are likely involved in mitochondrial dysfunctions. We thus evaluated the respiratory chain activity measuring the oxygen consumption rate (OCR): both basal and maximal OCR were reduced in FAD-PS2, but not in FAD-PS1, expressing cells. Moreover, a reduced mitochondrial ATP-linked respiration was measured in PS2-T122R expressing cells, while no difference was found in the proton leak.
Since the expression levels of the ATP synthase and the respiratory chain complexes were not affected by FAD-PS2 expression, and isolated mitochondria from WT and PS2-N141I Tg mice did not reveal substantial differences in mitochondrial respiratory activity, we reasoned that the impairment in ATP production observed in intact cells is not due to defective mitochondria per se, but likely depends on the cellular environment.
Importantly, for a proper mitochondrial metabolism, the right amount of substrates produced through glycolysis in the cytosol has to reach the mitochondrial matrix to support the TCA cycle and the respiratory chain activity. Hexokinase1 (HK1), the enzyme that catalyses the first step of glycolysis converting glucose to glucose 6-phosphate, seems to be involved in the modulation of the mitochondrial substrates import, since HK1 interaction/detachment with/from mitochondria can modulate mitochondrial substrates permeability. Firstly, we measured a reduced HK1-mitochondria co-localization in FAD-PS2 expressing SH-SY5Y cells, in FAD-PS2 patient-derived fibroblasts and in primary cortical neurons from FAD-PS2-N141I Tg mice, compared to controls. By mimicking the FAD-PS2 effect on HK1-mitochondria interaction treating control cells with Clotrimazole, a drug capable to detach HK1 from mitochondria, a reduced mitochondrial ATP production was measured; however, the impairment on ATP production induced by clotrimazole was less marked than that caused by FAD-PS2 expression. These results indicate that, although the detachment of HK1 from mitochondria plays a pivotal role in causing mitochondrial defects upon FAD-PS2 expression, the PS2-induced Ca2+ dysregulation, described above, may additionally contribute to the overall mitochondrial impairment. These results have been confirmed also by a genetic approach. We down-regulated the expression of endogenous HK1, by specific siRNAs, and we rescued HK1 protein level by over-expressing siRNA-resistant full-length- (FL-HK1) or truncated- (Tr-HK1) HK1. This latter protein lacks the mitochondrial binding domain, but still conserves the catalytic activity. We found that, upon endogenous HK1 silencing, mitochondrial ATP production is strongly reduced. Interestingly, while the re-expression of FL-HK1 was able to completely rescue the reduced ATP production, the Tr-HK1 was unable to do it, again confirming that the detachment of HK1 from mitochondria is involved in the mitochondrial impairment caused by FAD-PS2.
Related to HK1 and its role in the regulation of mitochondrial substrates permeability, an increase in the cytosolic amount of pyruvate was measured in FAD-PS2 expressing cells, compared to controls, employing a cytosolic FRET-based pyruvate probe, Pyronic. Importantly, by pharmacologically blocking mitochondrial pyruvate carrier (MPC), the protein responsible for mitochondrial pyruvate uptake, with two different drugs, UK5099 and Pioglitazone, no differences were anymore detected between control and FAD-PS2 expressing cells, suggesting that FAD-PS2 is acting on this pathway.
Overall, we have showed that FAD-PS2 mutants decrease cellular ATP levels, in particular mitochondrial ATP production, by two different mechanisms: 1) causing Ca2+ dysregulation, mainly decreasing the ER Ca2+ content, and thus the amount of Ca2+ available for mitochondrial Ca2+ uptake; 2) inducing the detachment of HK1 from mitochondria, likely affecting the availability of substrates (i.e., pyruvate) for mitochondria. Further experiments will be aimed at: i) evaluate the impact of the PS2-dependent strengthened ER-mitochondria coupling on the reported mitochondrial defects; ii) defining the molecular mechanism through which FAD- PS2 mutants affect HK1 intracellular distribution; iii) evaluate the impact of these alterations on the onset/progression of the AD phenotype
Governo d'impresa e security-based crowdfunding: da un'analisi a livello di piattaforma ad un'analisi a livello d'impresa
No full textUnsuccessful Equity Crowdfunding Offerings and the Persistence in Equity Fundraising of Family Business Start-Ups
No full textLittle is known about what happens after an unsuccessful equity crowdfunding campaign. Taking a socioemotional wealth perspective, we hypothesize that family business start-ups are more likely to eventually still raise equity financing relative to nonfamily business start-ups. Moreover, while family business start-ups are initially less likely to provide voting rights, we hypothesize that they are more likely to offer shares with voting rights after an unsuccessful campaign. Using data on the UK equity crowdfunding market, we find support for our hypotheses. This study adds novel insights into the nexus between equity crowdfunding and family business literature
Voting rights delivery in investment-based crowdfunding : a cross-platform analysis
No full textThis is one of the first studies to investigate corporate governance in investment-based crowdfunding. Our cross-platform analysis reveals a large variety in corporate governance mechanisms, in particular with regard to voting rights delivery. Some platforms assign voting rights to individual investors, some work under a nominee structure, and some require the involvement of accredited investors to list offerings. Using a sample of 185 investment-based crowdfunding portals based in Australia, Austria, Canada, France, Germany, Italy, New Zealand, the UK and the US, we find that the delivery of individual voting rights is associated with lower chances of success of the platforms, whereas the delivery of pooled voting rights is not significant. Fewer offerings are listed in syndicate-like platforms
Calcium, mitochondria and cell metabolism: A functional triangle in bioenergetics
No full textThe versatility of mitochondrial metabolism and its fine adjustments to specific physiological or pathological conditions regulate fundamental cell pathways, ranging from proliferation to apoptosis. In particular, Ca 2+ signalling has emerged as a key player exploited by mitochondria to tune their activity according with cell demand. The functional interaction between mitochondria and endoplasmic reticulum (ER) deeply impacts on the correct mitochondrial Ca 2+ signal, thus modulating cell bioenergetics and functionality. Indeed, Ca 2+ released by the ER is taken up by mitochondria where, both in the intermembrane space and in the matrix, it regulates the activity of transporters, enzymes and proteins involved in organelles' metabolism. In this review, we will briefly summarize Ca 2+ -dependent mechanisms involved in the regulation of mitochondrial activity. Moreover, we will discuss some recent reports, in which alterations in mitochondrial Ca 2+ signalling have been associated with specific pathological conditions, such as neurodegeneration and cancer
ESG and crowdfunding platforms
Full text linkWe hypothesize that environmental, social, and governance (ESG) goals enable crowdfunding platforms to attract more investors and thus survive longer. Using data on the population of 508 security-based platforms established in the 38 OECD countries between 2007 and 2020, we document that platforms with higher levels of ESG selection criteria are more likely to survive over time. The importance of ESG criteria is more pronounced for platforms operating in countries with lower power distance. In decomposing ESG, we find that governance is the most significant component of the three, while environmental criteria have increased in importance for
platform survival in recent years
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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