Dynamics of Lamin-A Processing Following Precursor Accumulation

Lamin A (LaA) is a component of the nuclear lamina, an intermediate filament meshwork that underlies the inner nuclear membrane (INM) of the nuclear envelope (NE). Newly synthesized prelamin A (PreA) undergoes extensive processing involving C-terminal farnesylation followed by proteolysis yielding non-farnesylated mature lamin A. Different inhibitors of these processing events are currently used therapeutically. Hutchinson-Gilford Progeria Syndrome (HGPS) is most commonly caused by mutations leading to an accumulation of a farnesylated LaA isoform, prompting a clinical trial using farnesyltransferase inhibitors (FTI) to reduce this modification. At therapeutic levels, HIV protease inhibitors (PI) can unexpectedly inhibit the final processing step in PreA maturation. We have examined the dynamics of LaA processing and associated cellular effects during PI or FTI treatment and following inhibitor washout. While PI reversibility was rapid, with respect to both LaA maturation and associated cellular phenotype, recovery from FTI treatment was more gradual. FTI reversibility is influenced by both cell type and rate of proliferation. These results suggest a less static lamin network than has previously been observed

The search for the 'next' euphoric non-fentanil novel synthetic opioids on the illicit drugs market: current status and horizon scanning

Purpose: A detailed review on the chemistry and pharmacology of non-fentanil novel synthetic opioid receptor agonists, particularly N-substituted benzamides and acetamides (known colloquially as U-drugs) and 4-aminocyclohexanols, developed at the Upjohn Company in the 1970s and 1980s is presentedMethod: Peer-reviewed literature, patents, professional literature, data from international early warning systems and drug user fora discussion threads have been used to track their emergence as substances of abuse.Results: In terms of impact on drug markets, prevalence and harm, the most significant compound of this class to date has been U-47700 (trans-3,4-dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide), reported by users to give short-lasting euphoric effects and a desire to re-dose. Since U-47700 was internationally controlled in 2017, a range of related compounds with similar chemical structures, adapted from the original patented compounds, have appeared on the illicit drugs market. Interest in a structurally unrelated opioid developed by the Upjohn Company and now known as BDPC/bromadol appears to be increasing and should be closely monitored.Conclusions: International early warning systems are an essential part of tracking emerging psychoactive substances and allow responsive action to be taken to facilitate the gathering of relevant data for detailed risk assessments. Pre-emptive research on the most likely compounds to emerge next, so providing drug metabolism and pharmacokinetic data to ensure that new substances are detected early in toxicological samples is recommended. As these compounds are chiral compounds and stereochemistry has a large effect on their potency, it is recommended that detection methods consider the determination of configuration

Towards reconciling structure and function in the nuclear pore complex

The spatial separation between the cytoplasm and the cell nucleus necessitates the continuous exchange of macromolecular cargo across the double-membraned nuclear envelope. Being the only passageway in and out of the nucleus, the nuclear pore complex (NPC) has the principal function of regulating the high throughput of nucleocytoplasmic transport in a highly selective manner so as to maintain cellular order and function. Here, we present a retrospective review of the evidence that has led to the current understanding of both NPC structure and function. Looking towards the future, we contemplate on how various outstanding effects and nanoscopic characteristics ought to be addressed, with the goal of reconciling structure and function into a single unified picture of the NPC

The disruption of proteostasis in neurodegenerative diseases

Cells count on surveillance systems to monitor and protect the cellular proteome which, besides being highly heterogeneous, is constantly being challenged by intrinsic and environmental factors. In this context, the proteostasis network (PN) is essential to achieve a stable and functional proteome. Disruption of the PN is associated with aging and can lead to and/or potentiate the occurrence of many neurodegenerative diseases (ND). This not only emphasizes the importance of the PN in health span and aging but also how its modulation can be a potential target for intervention and treatment of human diseases.info:eu-repo/semantics/publishedVersio

One size fits all? High frequency trading, tick size changes and the implications for exchanges: market quality and market structure considerations

This paper offers a systematic review of the empirical literature on the implications of tick size changes for exchanges. Our focus is twofold: first, we are concerned with the market quality implications of a change in the minimum tick size. Second, we are interested in the implications of changes in the minimum tick size on market structure. We show that there is a large body of empirical literature that documents a decrease in transaction costs following a decrease in the minimum tick size. However, even though market liquidity increases, the incentive to provide market making activities decreases. We document a strong link between the minimum tick size regulations and the recent increase in high frequency trading activity. A smaller tick enhances the price discovery process. However, the question of how multiple tick size regimes affect market liquidity in a fragmented market remains to be answered. Finally, we identify topics for future research; we discuss the empirical literature on the minimum trade unit and the recent calls for a minimum resting time for quotes

The effect of diversification on capital structure

Previously, empirical financial studies paid little attention to the role of diversification strategy on financial choices. The aim of the present study is to analyze the financing strategies of multibusiness firms, suggesting the relevance of sorting the diversification phenomena into its related and unrelated components. The implications of our findings are very relevant in that they explain earlier contradictory results on capital-structure determinants. The degree of product specialization/diversification and the direction of diversification (related or unrelated) translate into different corporate financial behaviours. In particular, the two types of diversification- related or unrelated, had opposite effects on debt. Specifically, a related-diversification strategy, which is associated with lower debt ratios, has a negative influence on leverage. By contrast, unrelated diversity, which is associated with higher debt usage, has a positive effect on debt. According to the coinsurance effect and the transaction-cost hypothesis, unrelated-diversified firms have a higher debt capacity and can assume more debt as a source of finance. Moreover, the capital-structure decisions of unrelated-diversified firms seem to be strictly aimed at reaching their target optimal debt level—a behaviour that is consistent with the trade-off hypothesis. On the other hand, related-diversified firms adjust more slowly towards their target capital structur

A Survey of the Relation Between Capital Structure and Corporate Strategy

This paper responds to the general call for integration between finance and strategy researchby examining how financial decisions are related to corporate strategy. In particular, the paperfocuses on the link between capital structure and strategy. Corporate strategies complementtraditional finance paradigms and extend our insight into a firm’s decisions regarding capitalstructure. Equity and debt must be considered as financial instruments as well as strategicinstruments of corporate governance (Williamson 1988). Debt subordinates governanceactivities to stricter management, while equity allows for greater flexibility and decisionmakingpower.The literature on finance and strategy analyzes how the strategic actions of key players(managers, shareholders, debtholders, competitors, workers, suppliers, etc) affect firm valueand the allocation of value between claimholders. Specifically, financing decisions canconcern value creation process (1) influencing efficient investments decisions according to theexistence of conflict of interest between managers and firm’s financial stakeholders(shareholders and debtholders) and (2) affecting the relationship with non-financialstakeholders, as suppliers, competitors, customers.To summarize, the potential interaction between managers, financial stakeholders, and nonfinancialstakeholders influences capital structure, corporate governance activities, and valuecreation processes. These in turn, may give rise to inefficient managerial decisions or theymay shape the industry’s competitive dynamics to achieve a competitive advantage. A goodintegration between strategy and finance dimensions can be tantamount to a competitiveweapon