摘要 :
DNA replication is central to cell proliferation. Studies in the past six decades since the proposal of a semiconservative mode of DNA replication have confirmed the high degree of conservation of the basic machinery of DNA replic...
展开
DNA replication is central to cell proliferation. Studies in the past six decades since the proposal of a semiconservative mode of DNA replication have confirmed the high degree of conservation of the basic machinery of DNA replication from prokaryotes to eukaryotes. However, the need for replication of a substantially longer segment of DNA in coordination with various internal and external signals in eukaryotic cells has led to more complex and versatile regulatory strategies. The replication program in higher eukaryotes is under a dynamic and plastic regulation within a single cell, or within the cell population, or during development. We review here various regulatory mechanisms that control the replication program in eukaryotes and discuss future directions in this dynamic field. [References: 312]
收起
摘要 :
In an attempt to discover anti-HIV agents with much reduced cytotoxicity from the currently available HIV-reverse transcriptase inhibitors, AZT conjugates of cholanic acids, 2-imidazolidone-4-carboxylic acid and its derivatives, a...
展开
In an attempt to discover anti-HIV agents with much reduced cytotoxicity from the currently available HIV-reverse transcriptase inhibitors, AZT conjugates of cholanic acids, 2-imidazolidone-4-carboxylic acid and its derivatives, and N,N'-disubstituted 5-hydroxy-tetrahydropyrimidin-2-ones have been synthesized and their anti-HIV profiles determined with CEM-SS cell line. The AZT conjugates with 2-imidazolidone-4-carboxylic acid and 2-pyrrolidone-5-carboxylic acid through an ester linkage, and with N,N'-diphenyl-5-hydroxy-tetrahydropyrimidin-2-one through a succinate tether showed significantly higher therapeutic indexes than AZT while they also retained or enhanced AZT's anti-HIV activity. Thus, structural features that favor the desired therapeutic profile of the conjugates appear to include a five-membered ring cyclic urea or lactam, and six-membered ring cyclic urea with N,N'-diphenyl substitution.
收起
摘要 :
Endovascular aneurysm repair (EVAR) has quickly gained popularity for infrarenal abdominal aortic aneurysm repair during the last two decades. The improvement of available EVAR devices is critical for the advancement of patient ca...
展开
Endovascular aneurysm repair (EVAR) has quickly gained popularity for infrarenal abdominal aortic aneurysm repair during the last two decades. The improvement of available EVAR devices is critical for the advancement of patient care in vascular surgery. Problems are still associated with the grafts, many of which can necessitate the conversion of the patient to open repair, or even result in rupture of the aneurysm. This review attempts to address these problems, by highlighting why they occur and what the failings of the currently available stent grafts are, respectively. In addition, the review gives critical appraisal as to the novel methods required for dealing with these problems and identifies the new generation of stent grafts that are being or need to be designed and constructed in order to overcome the issues that are associated with the existing first- and second-generation devices.
收起
摘要 :
This paper presents a method of building large mobile assemblies using the Bennett linkage. The method is based on a, basic single-layer layout consisting of overlapping 4R loops, each of which is a Bennett linkage. The assemblies...
展开
This paper presents a method of building large mobile assemblies using the Bennett linkage. The method is based on a, basic single-layer layout consisting of overlapping 4R loops, each of which is a Bennett linkage. The assemblies created have a single degree of freedom, and are overconstrained and scaleable, allowing unlimited extension by repetition. In general, they deploy into a circular or non-circular cylindrical profile. The joints of the assemblies move spirally on the surface during deployment. Under some particular geometrical conditions, the profiles of the assemblies can become arch-like or flat. Moreover, the single-layer assemblies can be extended to form multi-layer mechanisms, even mobile masts. The paper shows the great versatility of the Bennett linkage and demonstrates that the century-old invention can play an important role in the construction of deployable structures.
收起
摘要 :
Backgrounds: Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in th...
展开
Backgrounds: Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in the cholangiocyte pathology of cholestatic liver diseases. Methods: We studied humans with primary biliary cholangitis (PBC) and Primary sclerosing cholangitis (PSC), P4HA2-/-mice injured by DDC, and P4HA2-/-/MDR2-/-double knockout mice. A parallel study was performed in patients with PBC, PSC, and controls using immunohistochemistry and immunofluorescence. In the murine model, the level of ductular reaction and biliary fibrosis were monitored by histology, qPCR, immunohistochemistry, and Western blotting. Expression of Yes1 Associated Transcriptional Regulator (YAP) phosphorylation was measured in isolated mouse cholangiocytes. The mechanism of P4HA2 was explored in RBE and 293T cell lines by using qPCR, Western blot, immunofluorescence, and co-immunoprecipitation. Results: The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. Cholestatic patients with more severe liver injury correlated with levels of P4HA2 in the liver. In P4HA2-/-mice, there was a significantly reduced level of ductular reaction and fibrosis compared with controls in the DDC-induced chronic cholestasis. Decreased liver fibrosis and ductular reaction were observed in P4HA2-/-/MDR2-/-mice compared with MDR2-/-mice. Cholangiocytes isolated from P4HA2-/-/MDR2-/-mice displayed a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cell proliferation by inducing SAV1 degradation, eventually resulting in the activation of YAP. Conclusions: P4HA2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC. ? 2023 John Wiley and Sons Inc.. All rights reserved.
收起
摘要 :
In response to DNA double-strand breaks (DSBs), cells sense the DNA lesions and then activate the protein kinase ATM. Subsequent DSB resection produces RPA-coated ssDNA that is essential for activation of the DNA damage checkpoint...
展开
In response to DNA double-strand breaks (DSBs), cells sense the DNA lesions and then activate the protein kinase ATM. Subsequent DSB resection produces RPA-coated ssDNA that is essential for activation of the DNA damage checkpoint and DNA repair by homologous recombination (HR). However, the biochemical mechanism underlying the transition from DSB sensing to resection remains unclear. Using Xenopus egg extracts and human cells, we show that the tumor suppressor protein CtIP plays a critical role in this transition. We find that CtIP translocates to DSBs, a process dependent on the DSB sensor complex Mre11-Rad50-NBS1, the kinase activity of ATM, and a direct DNA-binding motif in CtIP, and then promotes DSB resection. Thus, CtIP facilitates the transition from DSB sensing to processing: it does so by binding to the DNA at DSBs after DSB sensing and ATM activation and then promoting DNA resection, leading to checkpoint activation and HR.
收起
摘要 :
In response to DNA double-strand breaks (DSBs), cells sense the DNA lesions and then activate the protein kinase ATM. Subsequent DSB resection produces RPA-coated ssDNA that is essential for activation of the DNA damage checkpoint...
展开
In response to DNA double-strand breaks (DSBs), cells sense the DNA lesions and then activate the protein kinase ATM. Subsequent DSB resection produces RPA-coated ssDNA that is essential for activation of the DNA damage checkpoint and DNA repair by homologous recombination (HR). However, the biochemical mechanism underlying the transition from DSB sensing to resection remains unclear. Using Xenopus egg extracts and human cells, we show that the tumor suppressor protein CtIP plays a critical role in this transition. We find that CtIP translocates to DSBs, a process dependent on the DSB sensor complex Mre11-Rad50-NBS1, the kinase activity of ATM, and a direct DNA-binding motif in CtIP, and then promotes DSB resection. Thus, CtIP facilitates the transition from DSB sensing to processing: it does so by binding to the DNA at DSBs after DSB sensing and ATM activation and then promoting DNA resection, leading to checkpoint activation and HR.
收起
摘要 :
Cell death after traumatic brain injury (TBI) evolves over days to weeks. Despite advances in understanding biochemical mechanisms that contribute to posttraumatic brain cell death, the time course of cell injury, death, and remov...
展开
Cell death after traumatic brain injury (TBI) evolves over days to weeks. Despite advances in understanding biochemical mechanisms that contribute to posttraumatic brain cell death, the time course of cell injury, death, and removal remains incompletely characterized in experimental TBI models. In a mouse controlled cortical impact (CCI) model, plasmalemma permeability to propidium iodide (PI) was an early and persistent feature of posttraumatic cellular injury in cortex and hippocampus. In cortical and hippocampal brain regions known to be vulnerable to traumatic cell death, the number of PI+ cells peaked early after CCI, and increased with increasing injury severity in hippocampus but not cortex (P<0.05). Propidium iodide labeling correlated strongly with hematoxylin and eosin staining in injured cells (r=0.99, P<0.001), suggesting that plasmalemma damage portends fatal cellular injury. Using PI pulse labeling to identify and follow the fate of a cohort of injured cells, we found that many PI+ cells recovered plasmalemma integrity by 24 h and were terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling negative, but nonetheless disappeared from injured brain by 7 days. Propidium iodide-positive cells in dentate gyrus showed significant ultrastructural damage, including plasmalemma and nuclear membrane damage or overt membrane loss, in all cells when examined by laser capture microdissection and transmission electron microscopy 1 to 24 h after CCI. The data suggest that plasmalemma damage is a fundamental marker of cellular injury after CCI; some injured cells might have an extended window for potential rescue by neuroprotective strategies.
收起
摘要 :
The radially retractable plate structures (RPS) are a family of new retractable structures consisting of a set of cover plates connected by revolute hinges. The concept evolves from the foldable bar structures (FBS) by replacing t...
展开
The radially retractable plate structures (RPS) are a family of new retractable structures consisting of a set of cover plates connected by revolute hinges. The concept evolves from the foldable bar structures (FBS) by replacing the beams in an FBS with cover plates. With a single degree of freedom, the structures close to form a covered enclosure and expand to reveal a large central opening space, which makes them ideal for use as retractable roofs. In designing the plates of an RPS, two primary requirements have to be met. First, the boundary of these plates must be designed such that they form an enclosure without any gaps or overlaps in both closed and open configurations, and the plates do not interfere with each other during deployment. Second, all of the pivots of a beam must remain within the boundary of its corresponding RPS plate. This paper tackles the second problem. To meet the requirement, an analytical method is proposed. A feasible design area, defined by closed and open angles of the corresponding FBS, can be identified under this approach. The designers are no longer limited to use the empirical or numerical means to determine whether all of the pivots of a multi-angulated beam are within its corresponding plate. The analytical approach can be used regardless of the boundary's profile. The approach can be extended into both symmetrical and non-symmetrical structures. Physical models built to validate our approach have shown that the analysis is correct. (c) 2006 Elsevier Ltd. All rights reserved.
收起
摘要 :
A closed-loop overconstrained spatial mechanism composed of six hinge-jointed bars, which has three planes of symmetry in any position, is called a threefold-symmetric Bricard linkage. In this paper a kinematic analysis of these l...
展开
A closed-loop overconstrained spatial mechanism composed of six hinge-jointed bars, which has three planes of symmetry in any position, is called a threefold-symmetric Bricard linkage. In this paper a kinematic analysis of these linkages is presented. It is pointed out that for particular parameter values, kinematic bifurcation of the linkages can occur. Features of the kinematic bifurcation are discussed in detail. The applicability of threefold-symmetric Bricard linkages and of their alternative forms to deployable structures is investigated. In addition, by using the theory of kinematic bifurcation, a snap-through phenomenon appearing in a deployable hexagonal ring is explained. (C) 2004 Elsevier Ltd. All rights reserved.
收起
原文获取