Pathological vascular wall remodeling refers to the structural and functional changes of the vessel wall that occur in response to injury that eventually leads to cardiovascular disease (CVD). Vessel ...wall are composed of two major primary cells types, endothelial cells (EC) and vascular smooth muscle cells (VSMCs). The physiological communications between these two cell types (EC-VSMCs) are crucial in the development of the vasculature and in the homeostasis of mature vessels. Moreover, aberrant EC-VSMCs communication has been associated to the promotor of various disease states including vascular wall remodeling. Paracrine regulations by bioactive molecules, communication via direct contact (junctions) or information transfer via extracellular vesicles or extracellular matrix are main crosstalk mechanisms. Identification of the nature of this EC-VSMCs crosstalk may offer strategies to develop new insights for prevention and treatment of disease that curse with vascular remodeling. Here, we will review the molecular mechanisms underlying the interplay between EC and VSMCs. Additionally, we highlight the potential applicable methodologies of the co-culture systems to identify cellular and molecular mechanisms involved in pathological vascular wall remodeling, opening questions about the future research directions.
In budding yeast, the integrity of both the nuclear and mitochondrial genomes relies on dual-targeted isoforms of the conserved Pif1 helicase, generated by alternative translation initiation (ATI) of ...PIF1 mRNA from two consecutive AUG codons flanking a mitochondrial targeting signal. Here, we demonstrate that ribosomal leaky scanning is the specific ATI mechanism that produces not only these, but also novel, previously uncharacterized Pif1 isoforms. Both in-frame, downstream AUGs as well as near-cognate start codons contribute to the generation of these alternative isoforms. This has crucial implications for the rational design of genuine separation-of-function alleles and provides an explanation for the suboptimal behaviour of the widely employed mitochondrial- (pif1-m1) and nuclear-deficient (pif1-m2) alleles, with mutations in the first or second AUG codon, respectively. We have taken advantage of this refined model to develop improved versions of these alleles, which will serve as valuable tools to elucidate novel functions of this helicase and to disambiguate previously described genetic interactions of PIF1 in the context of nuclear and mitochondrial genome stability.
The efficient and timely resolution of DNA recombination intermediates is essential for bipolar chromosome segregation. Here, we show that the specialized chromosome segregation patterns of meiosis ...and mitosis, which require the coordination of recombination with cell-cycle progression, are achieved by regulating the timing of activation of two crossover-promoting endonucleases. In yeast meiosis, Mus81-Mms4 and Yen1 are controlled by phosphorylation events that lead to their sequential activation. Mus81-Mms4 is hyperactivated by Cdc5-mediated phosphorylation in meiosis I, generating the crossovers necessary for chromosome segregation. Yen1 is also tightly regulated and is activated in meiosis II to resolve persistent Holliday junctions. In yeast and human mitotic cells, a similar regulatory network restrains these nuclease activities until mitosis, biasing the outcome of recombination toward noncrossover products while also ensuring the elimination of any persistent joint molecules. Mitotic regulation thereby facilitates chromosome segregation while limiting the potential for loss of heterozygosity and sister-chromatid exchanges.
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► Mus81-Mms4 and Yen1 endonucleases collaboratively resolve DNA joint molecules in meiosis ► Cdc5 activates Mus81-Mms4 during meiosis I through the phosphorylation of Mms4 ► Phosphorylation inhibits Yen1 until the onset of meiosis II ► Yen1/GEN1 and Mus81-Mms4/EME1 are specifically activated during M phase of mitosis
Endonucleases resolve DNA recombination intermediates at different stages to promote and prevent crossing over in meiosis and mitosis, respectively.
The careful orchestration of cellular events such as DNA replication, repair, and segregation is essential for equal distribution of the duplicated genome into two daughter cells. To ensure that ...persistent recombination intermediates are resolved prior to cell division, the Yen1 Holliday junction resolvase is activated at anaphase. Here, we show that the master cell-cycle regulators, cyclin-dependent kinase (Cdk) and Cdc14 phosphatase, control the actions of Yen1. During S phase, Cdk-mediated phosphorylation of Yen1 promotes its nuclear exclusion and inhibits catalytic activity by reducing the efficiency of DNA binding. Later in the cell cycle, at anaphase, Cdc14 drives Yen1 dephosphorylation, leading to its nuclear relocalization and enzymatic activation. Using a constitutively activated form of Yen1, we show that uncontrolled Yen1 activity is detrimental to the cell: spatial and temporal restriction of Yen1 protects against genotoxic stress and, by avoiding competition with the noncrossover-promoting repair pathways, prevents loss of heterozygosity.
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•Yen1 undergoes a dual mode of regulation: activity and subcellular localization•Cdk phosphorylation inhibits Yen1 at S phase by reducing its DNA binding affinity•Yen1 activation at anaphase is driven by the Cdc14 phosphatase•Premature activation of Yen1 leads to loss of heterozygosity and genome instability
The complete elimination of DNA recombination intermediates is essential for chromosome segregation. Blanco et al. show that the master cell-cycle regulators Cdk and Cdc14 control both the localization and nuclease activation of the Holliday junction resolvase Yen1. Cdk/Cdc14 therefore control the final wave of joint molecule resolution at anaphase.
While DNA replication and mitosis occur in a sequential manner, precisely how cells maintain their temporal separation and order remains elusive. Here, we unveil a double-negative feedback loop ...between replication intermediates and an M-phase-specific structure-selective endonuclease, MUS81-SLX4, which renders DNA replication and mitosis mutually exclusive. MUS81 nuclease is constitutively active throughout the cell cycle but requires association with SLX4 for efficient substrate targeting. To preclude toxic processing of replicating chromosomes, WEE1 kinase restrains CDK1 and PLK1-mediated MUS81-SLX4 assembly during S phase. Accordingly, WEE1 inhibition triggers widespread nucleolytic breakage of replication intermediates, halting DNA replication and leading to chromosome pulverization. Unexpectedly, premature entry into mitosis—licensed by unrestrained CDK1 activity during S phase—requires MUS81-SLX4, which inhibits DNA replication. This suggests that ongoing replication assists WEE1 in delaying entry into M phase and, indirectly, in preventing MUS81-SLX4 assembly. Conversely, MUS81-SLX4 activation during mitosis promotes targeted resolution of persistent replication intermediates, which safeguards chromosome segregation.
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•CDK1-dependent phosphorylation of SLX4 controls MUS81-SLX4 complex formation•CDK1 activation in S phase drives MUS81-SLX4-mediated chromosome pulverization•WEE1 inhibitors cause cell death partly by MUS81-SLX4-dependent chromosome breakage•DNA replication and WEE1 collaboratively suppress CDK1 activity during S phase
MUS81 nuclease resolves persistent replication intermediates at mitotic onset to safeguard chromosome segregation. Duda et al. uncover dynamic regulation of MUS81 function during the cell cycle to protect S-phase chromosomes from unscheduled breakage and pulverization. This regulation ensures that DNA replication and mitosis occur sequentially and in a mutually exclusive manner.
The propagation of the deformation front in foreland systems is typically accompanied by the incorporation of parts of the basin into wedge‐top piggy‐back basins, this process is likely producing ...considerable changes to sedimentation rates (SR). Here we investigate the spatial‐temporal evolution of SR for the Tremp–Jaca Basin in the Southern Pyrenees during its evolution from a wedge‐top, foreredeep, forebulge configuration to a wedge‐top stage. SR were controlled by a series of tectonic structures that influenced subsidence distribution and modified the sediment dispersal patterns. We compare the decompacted SR calculated from 12 magnetostratigraphic sections located throughout the Tremp–Jaca Basin represent the full range of depositional environment and times. While the derived long‐term SR range between 9.0 and 84.5 cm/kyr, compiled data at the scale of magnetozones (0.1–2.5 Myr) yield SR that range from 3.0 to 170 cm/kyr. From this analysis, three main types of depocenter are recognized: a regional depocenter in the foredeep depozone; depocenters related to both regional subsidence and salt tectonics in the wedge‐top depozone; and a depocenter related to clastic shelf building showing transgressive and regressive trends with graded and non‐graded episodes. From the evolution of SR we distinguish two stages. The Lutetian Stage (from 49.1–41.2 Ma) portrays a compartmentalized basin characterized by variable SR in dominantly underfilled accommodation areas. The markedly different advance of the deformation front between the Central and Western Pyrenees resulted in a complex distribution of the foreland depozones during this stage. The Bartonian–Priabonian Stage (41.2–36.9 Ma) represents the integration of the whole basin into the wedge‐top, showing a generalized reduction of SR in a mostly overfilled relatively uniform basin. The stacking of basement units in the hinterland during the whole period produced unusually high SR in the wedge‐top depozone.
The study of 10 Myr evolution of sedimentation rates on a Foreland Basin Systemhas demonstrated the effect of tectonic evolution and overfilled versus underfilled accommodation zones in the basin.
Bond Paths as Privileged Exchange Channels Pendás, A. Martín; Francisco, Evelio; Blanco, Miguel A. ...
Chemistry : a European journal,
01/2007, Letnik:
13, Številka:
33
Journal Article
Recenzirano
Evidence that the bond paths of the quantum theory of atoms‐in‐molecules (QTAIM) signal preferred quantum‐mechanical exchange channels is presented. We show how bond paths between an atom A and the ...atoms B in its environment appear to be determined by competition among the A–B exchange‐correlation energies that always contribute to stabilize the A–B interactions. These pairwise additive stabilizations depend neither on the attractive or repulsive nature of the classical electrostatic interaction between the atoms' charge densities, nor on the change in the self energies of the atoms involved. These other terms may well cause an overall molecular‐energy increase in spite of a possibly large A–B exchange‐correlation stabilization. After our proposal, bond paths, both at and out of equilibrium geometries, are endowed with a specific energetic meaning that should contribute to reconcile the orthodox QTAIM interpretation with other widely accepted views, and to settle recent controversies questioning the meaning of hydrogen–hydrogen bonding and the nature of the so‐called “steric interactions”, the role of bond paths in endohedral complexes, and the generality of the results provided by the QTAIM. Implications for the nature of more general closed‐shell interactions are also briefly discussed.
Bond paths signal preferred exchange channels: 1) They provide a stabilizing contribution to the interaction energy between a pair of quantum atoms A, B. 2) Total energy changes may still be positive owing to the increase in self energies of the A and B atoms (see graphic).
Abstract Homologous recombination involves the formation of branched DNA molecules that may interfere with chromosome segregation. To resolve these persistent joint molecules, cells rely on the ...activation of structure-selective endonucleases (SSEs) during the late stages of the cell cycle. However, the premature activation of SSEs compromises genome integrity, due to untimely processing of replication and/or recombination intermediates. Here, we used a biochemical approach to show that the budding yeast SSEs Mus81 and Yen1 possess the ability to cleave the central recombination intermediate known as the displacement loop or D-loop. Moreover, we demonstrate that, consistently with previous genetic data, the simultaneous action of Mus81 and Yen1, followed by ligation, is sufficient to recreate the formation of a half-crossover precursor in vitro. Our results provide not only mechanistic explanation for the formation of a half-crossover, but also highlight the critical importance for precise regulation of these SSEs to prevent chromosomal rearrangements.
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