Top PDF Studies on the role of histones in the structure and function of chromatin

Studies on the role of histones in the structure and function of chromatin

Studies on the role of histones in the structure and function of chromatin

Thus, the template activity of chromatin samples partially dehistonized by increasing concentrations of sodium deoxycholate DOC or sodium chloride NaC1increeses from the template activit[r]

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The Structure of Universities’ Function and Performance, and Their Role in Iran’s Sustainable Development

The Structure of Universities’ Function and Performance, and Their Role in Iran’s Sustainable Development

Firstly, the university is considered as a member of nation-country. Secondly, it fulfills the local, national as well as economic requirements. University has global and international dimensions and has to be accountable about subjects like: justice and sustainable development. Graduates of the university should be citizens of the earth; the higher education system should prepare the society with citizens who have perspectives and commitments. On this basis, the university should not have abstract attitude; and its courses and researches should not have little role and relationship with the related society. In the meantime, university has to be responsive to the global issues (Stilphen 2010, 56). Seifullahi’s Attitude and the Performance of the Country’s Higher Education The country’s higher education system, with a long academic background, high statistics of specialized academic studies and number of students in all academic subjects, quantitative development of educational and research institutes, their interest in development, and despite the fundamental attention of the high authorities of the society to education in the Islamic Republic of Iran, has been unable to have a productive and appropriate performance. This doesn’t mean that the carried out efforts and struggles in the society are overlooked or they were ineffective, and that achievements of universities as well as governmental and non-governmental educational centers were useless, but the expectations and prospects of people, experts and the social planners from the higher education system are so.
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Studies on the structure and function of a mammalian sugar transport protein

Studies on the structure and function of a mammalian sugar transport protein

topologies of these isoforms are essentially identical to that proposed for GLUT1 (Mueckler at ai, 1985) in which the protein spans the plasma membrane twelve times, with its N- and C-termini cytoplasmically oriented (see Section 1.3). The greatest sequence divergences are found in the cytoplasmic domains at the N- and C-termini, the hydrophilic central loop, and the extracellular loop between the first two putative transmembrane regions, implying that these regions may contribute to the unique features of these proteins including their intrinsic activities and subcellular localisation. With the exception of human GLUT5, which has been shown to transport fructose (Burant at ai, 1992), each of the transporter isoforms has been shown to be capable of transporting D-glucose following their expression in heterologous systems (discussed in Section 1.5). Furthermore, in each case glucose transport has been found to be inhibited by the fungal metabolite cytochalasin B. It is noteworthy that in addition to functioning as sugar carriers, the facilitative glucose transporters may play a role in transport of nicotinamide (Sofue at ai, 1992) and vitamin C (Vera at ai, 1993), and may also serve as membrane water channels (Fischbarg at ai, 1990).
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Insights from structure-function studies of variant fibrinogen

Insights from structure-function studies of variant fibrinogen

In addition to the knob-hole binding, other interactions like the end-to-end associations mediated by the D:D interface stabilize fibrin polymerization. Unlike knob-hole interactions, D:D interfacial interactions are not well-studied. In Chapter 4, we examined the role of D:D interactions in fibrin polymerization using a variant recombinant fibrinogen, γN308K, patterned after a naturally occurring dysfibrinogen. Previous studies of this variant showed impaired polymerization that was not improved by increasing calcium ion concentrations (9). We combined biochemical and structural data to provide the molecular basis for the impairment seen in γN308K. Plasmin protection assays showed γN308K require higher concentration of the knob “A” peptide mimic (GPRP) to achieve partial protection from digestion suggesting that γN308K has slightly impaired “A:a” interactions. Calcium ions imparted protection to γN308K similar to normal fibrinogen suggesting calcium ion binding was not altered in the variant. However, modeling the D:D interactions seen in normal crosslinked fibrin for γN308K showed potential steric and charge repulsion between γ308Lys and γ321Lys that may destabilize the γ1 calcium binding loop. Analysis of the electrostatic potential in the area where D:D interactions normally occur showed increased positive charge in γN308K suggesting possible repulsion between abutting fibrin molecules. Indeed, molecular packing in rfD-γN308K+GP crystals showed symmetric D:D contacts involving residues different from those observed in all previously reported fragment D and naturally crosslinked double D structures. In conclusion, analysis of γN308K fibrinogen suggests that γ308Asn is critical not only for charge complementarity of the D:D interface during end-to-
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Chromatin structure and DNA damage repair

Chromatin structure and DNA damage repair

Genome function depends for a large part on the accessi- bility of the DNA template. Above, several mechanisms are summarized that provide more plasticity to the dense chromatin structure. However, long-range transactions on the DNA helix require more than simply increasing acces- sibility. During transcription, elongation and replication, polymerases progress over long distances on DNA and extended nucleoprotein filaments (involving RPA and RAD51) are formed in homologous recombination, which involves large-scale nucleosomal rearrangements. Although it is likely that the discussed chromatin remod- ellers provide sufficient space to allow these elongations, displaced nucleosomes need to be repositioned after ter- mination of these reactions. While some ATP-dependent chromatin remodellers are able to (re)deposit histones onto DNA, it is likely that for these more robust chroma- tin changes specialized activities exist to restore the chro- matin structure. These specialized enzymes are referred to as histone chaperones. Histone chaperones deposit core histones onto DNA in an ATP-independent manner [113]. ASF1 is a histone chaperone that works together with either CAF1 or HIRA to deposit H3/H4 dimers or tetram- ers. Throughout the cell cycle, ASF1-HIRA is responsible for the incorporation of H3 and H4, whereas ASF1-CAF1 is involved in replication-dependent histone deposition [114-116]. Upon UV damage induction, ASF1 promotes nucleosome assembly together with CAF1 in a NER- dependent manner [117-119]. CAF1 knockdown does not inhibit NER in mammalian cells, suggesting that this H3.1 deposition is part of a chromatin restoration step after damage has been repaired which likely has no or limited influence on the repair rate itself.
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Methods for analyzing the role of DNA methylation and chromatin structure in regulating T lymphocyte gene expression

Methods for analyzing the role of DNA methylation and chromatin structure in regulating T lymphocyte gene expression

Several strategies have been devised for the quantitative assessment of total genomic deoxycytosine (dC) and deoxymethylcytosine content, as well as the methylation status of specific sequences. These are the subject of a recent review (5). At present, the most precise and generally applicable techniques for sequence-specific methylation analysis rely on bisulfite modification of DNA. Treating DNA with bisulfite deaminates cytosine bases to form uracil, but does not affect methylcytosine. Thus, PCR amplification and sequencing of bisulfite treated DNA allows precise quantitation of the methylation status of any desired CG pair (6). This approach, coupled with regional methylation of dC bases in promoter reporter constructs and DNaseI hypersensitivity analysis of chromatin structure in the region, provides information regarding both the presence and functional significance of the methylation patterns. Further confirmation may be obtained by demethylating DNA with the irreversible DNA methyltransferase inhibitor 5-azacytidine (5-azaC), then comparing effects on gene expression and methylation patterns. In this report we describe the methods utilized to compare the methylation patterns of the ITGAL (CD11a) promoter in T cells and fibroblasts, and of the PRF1 (perforin) promoters in T cells, an NK cell line and in fibroblasts, and how cassette or “patch” methylation may be used to test the effects of regional methylation on ITGAL and PRF1 promoter function. We also describe the use of DNaseI hypersensitivity assays to probe the chromatin structure around the same genes in representative cells with differential CD11a and perforin expression, and the use of DNA methyltransferase inhibition to confirm transcriptionally relevant changes in DNA methylation patterns.
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Dynamic Nuclear Architecture and Chromatin Function (EuroDYNA)

Dynamic Nuclear Architecture and Chromatin Function (EuroDYNA)

“Thanks to EuroDYNA, nine research projects were funded that may otherwise not have been funded. Therefore, European research in the area of nuclear dynamics and architecture has been stimulated. Without EuroDYNA I would not have been able to perform the research I have carried out over the last three years. One aspect of EuroDYNA that I like a lot is the lack of bureaucratic burden compared to other research programmes. Another very important aspect is that the EUROCORES programmes are suggested by the scientists themselves (bottom-up approach). Finally, a great added value is the willingness at ESF to stimulate discussion among scientists, by organizing conferences, workshops and brainstorm meetings. As a EuroDYNA member I have benefited enormously from this valuable resource,” said Niels Galjart, Department of Cell Biology and Genetics, Erasmus University, Rotterdam and the Project Leader of “Role of multi zinc finger proteins CTCF and BORIS in the dynamic change of the nuclear architecture and chromatin function during cell cycle and differentiation”. There is no doubt that EuroDYNA has achieved some great results and many of these results stem directly from the EUROCORES Programmes’ focus on networking and collaboration. David Shore, University of Geneva and the Project Leader of “Environmental stress-induced dynamic modulation of chromatin structure, gene expression and nuclear architecture in yeast” commented, “My project recently entered into collaboration with a lab in Vienna. This wouldn’t have happened if it weren’t for EuroDYNA. The Vienna group is interested in understanding how arsenic affects cells and of course this has important global health implications. Arsenic is a pollutant in drinking water in many places in the world. Our collaboration began at a EuroDYNA meeting in Brno; we presented a gene we were working on that’s involved in growth regulation in yeast cells and also in the cellular response to stress (which is what our project is aimed at understanding) when we were approached by a researcher from the Vienna group. The Vienna researcher noticed that this gene had also come up in his studies as a regulator of the cellular response to arsenic poisoning. As a result, we got together and did some more work which has now led to a manuscript ready for submission”.
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The conserved role of sirtuins in chromatin regulation

The conserved role of sirtuins in chromatin regulation

ABSTRACT The members of the Sir2 family, or Sirtuins, have garnered considerable attention because of their key roles as metabolic sensors and mediators of cell survival under stress. Sirtuins may play roles in myriad human pathologies such as cancer, neurological diseases, malaria, leishmaniasis and hormone-related disorders. They are present from prokaryotes to humans and show a high degree of functional diversification that has led to two different enzymatic activities, a wide range of substrates and a highly diversified pattern of cellular localization. Throughout chromatin evolution, Sirtuins have maintained an intimate functional relationship in regulating its structure and function via their targeting of histones, particularly H4K16Ac, as well as other non- histone chromatin proteins. This link permitted fast communication from metabolic fluctuations to chromatin allowing efficient adaptation to environmental stimuli. Therefore, understanding the common path of Sirtuins and chromatin development over the course of evolution might be important for understanding not only the remarkable diversity of functions of these proteins in mammals, but also the path followed by chromatin evolution. Herein is provided an overview of current knowledge of Sirtuin function, from bacteria to humans, including a discussion on its implications for chromatin dynamics, organization and integrity.
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Multifaceted role of tocotrienols in cardioprotection supports their structure: function relation

Multifaceted role of tocotrienols in cardioprotection supports their structure: function relation

Nuclear magnetic resonance studies have indicated that a-tocotrienol is located closer to the membrane surface, which may facilitate recycling. Furthermore, a-tocotrienol has a stronger disordering effect on membranes than a-tocopherol and is distributed more uniformly within the membrane. These properties likely enhance the interaction of chromanols with lipid radicals (Serbinova et al. 1993; Suzuki et al. 1993). Tocotrienols show significant inhibi- tion of lipid peroxidation in several model systems and for many years, a-tocotrienol was generally considered as the most potent antioxidant against lipid peroxidation in the vitamin E group. In vivo antioxidant effects of vitamin E compounds have been studied employing methods such as formation of thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxide (LOOH) (Watkins et al. 1993). Whether antioxidant activity is measured in vitro or in vivo, it is evident that tocotrienols have stronger anti- oxidant activity than tocopherols (Nesaretnam et al. 1993; Serbinova et al. 1993; Suzuki et al. 1993). Kamat and Devasagayam (1995) in the same study observed, a-toco- trienol to be 40 times more effective than a-tocopherol in protecting rat liver microsomal membranes against lipid peroxidation and 6.5 times more efficient in protecting cytochrome P-450 from oxidative damage. In the same study, observed similar results in rat brain mitochondria and noted a stronger effect with a-tocotrienol. In an elab- orate study, a number of mechanisms were shown to con- tribute to a-tocotrienol higher antioxidant activity compared to a-tocopherol, including: (a) a more uniform distribution in the membrane lipid bilayer, (b) a more efficient interaction of the chromanol ring with lipid radi- cals, and (c) a higher recycling efficiency from chroman- oxyl radicals (Serbinova et al. 1992).
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Local structure studies using the pair distribution function

Local structure studies using the pair distribution function

Although in principle the PDF can be obtained with X-rays and neutrons, the latter have seen a strong development in the recent years and present some advantages. High Q data can readily be obtained at neutron spallation sources, (for example at ISIS, in England) or at hot sources in neutrons reactors and dedicated instruments such as NPDF at LANL, USA, are now available. The characteristic of nuclear neutron scattering play an important role in calculating and measuring the PDF. We have seen that the PDF peak height is proportional to the product of the scattering powers of the atoms forming the pair. It is well-known that for neutrons the scattering power due to the nuclear interaction between the neutron and the atom nucleus, varies in a very different way than that of X-rays, coming from the electromagnetic interaction between X-rays and the electron cloud. Two consequences are that for X-rays, the scattering power – the so-called atomic form factor – is mainly proportional to Z and decays rapidly with increasing Q, whereas for neutrons the scattering power – the Fermi length – varies in a seemingly erratic manner with Z and is constant as function of Q. This is used in diffraction studies to increase scattering contrast between atoms of neighboring Z’s and two detect low Z atoms (typically H or O) which have a large fermi length. The same is true for the PDF. Figure 6 shows the comparison of the PDFs calculated for LaMnO 3 up to 10 Å for X-rays (black non continuous line) and neutrons (blue line). The first peak
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Chromatin Remodeling Factors Isw2 and Ino80 Regulate Checkpoint Activity and Chromatin Structure in S Phase

Chromatin Remodeling Factors Isw2 and Ino80 Regulate Checkpoint Activity and Chromatin Structure in S Phase

previously that chromatin accessibility increases around replica- tion forks to promote replication (Rodriguez and Tsukiyama 2013). Therefore, one possibility is that Isw2 and Ino80 may attenuate checkpoint activity by changing the way checkpoint protein(s) interact with chromatin at stalled forks, which, in turn, affects replication progression and checkpoint dynamics. Because we found that Isw2 and Ino80 likely do not function through their known biochemical activities, we speculate that Isw2 and Ino80 function in a currently unknown manner. This can be either by modifying how DNA and core histones interact or by changing histone turnover rate, which may influence other factors to bind and potentially affect checkpoint factor localiza- tion or activity. For example, weakening histone-DNA interac- tions around stalled replication forks could cause an increase in accessibility to recruit checkpoint repressors to facilitate removal of checkpoint factor(s) and promote resumption of DNA repli- cation. Indeed, another ATP-dependent chromatin remodeling factor, Fun30, and its mammalian counterpart, SMARCAD1, were both found to be recruited to sites of DSBs to promote resection presumably by removing Rad9 from DSB ends (Chen et al. 2012; Costelloe et al. 2012). Alternatively, checkpoint hyperactivation in the chromatin-remodeling-factor mutant may be the cause of the observed decrease in chromatin acces- sibility. Interestingly, we have shown previously that a mutation in mec1 also results in decreased chromatin accessibility at rep- licating regions in S phase in HU (Rodriguez and Tsukiyama 2013). However, because Mec1 facilitates chromatin accessibility around stalled replication forks (Rodriguez and Tsukiyama 2013), it is difficult to explain the increased checkpoint activity in isw2 nhp10 cells as the direct cause of the decreased chroma- tin accessibility in the mutant. Whether these changes in chro- matin structure are related to the phenotypes of isw2 nhp10 cells in MMS remains to be explored and will be investigated in future work. Finally, it is also possible that the changes in chro- matin accessibility are separable from checkpoint activation.
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PIP5K: Role in Plant Nuclear Function and Characterization of MORN Domain Structure.

PIP5K: Role in Plant Nuclear Function and Characterization of MORN Domain Structure.

Plants and animals both have a complex nuclear structure (reviewed in Cheung and Reddy, 2012) and each structural component of the nucleus is potentially a site for diverse PIs and PI pathway-mediated signaling. The structural components include outer and inner nuclear envelopes (which create a double membrane between the cytoplasm and nucleoplasm generating an intramembrane space around the nucleus, reviewed in Meier and Brkljacic, 2009, Boruc et al. 2012), nuclear pore complexes (the site of active transport between the nucleoplasm and the cytoplasm, reviewed in Boruc et al., 2012), nucleoplasm (similar to cytoplasm), nuclear matrix (structural scaffold for nuclear content, reviewed in Hancock, 2000), chromatin (DNA, protein and metabolites that hold together the tertiary structure of DNA), and nucleoplasmic reticulum (invaginations of the endoplasmic reticulum in the nucleus, reviewed in Malhas et al., 2011). Current studies of the nuclear membrane in plants and animals suggest a similar mechanism for breakdown and reformation during nuclear division (reviewed in Rose et al., 2004; Lloyd and Chan, 2006), suggesting a common origin of the nuclear division. Considering the conservation in nuclear structure, it is not surprising to find that many plant nuclear functions are potential targets of PI pathway regulation, and evidence is mounting for a nuclear PI pathway in plants similar to animal and yeast systems.
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ROLE OF RNAi IN HETEROCHROMATIN FORMATION AND CHROMATIN REMODELLING

ROLE OF RNAi IN HETEROCHROMATIN FORMATION AND CHROMATIN REMODELLING

Small RNA pathways are vital mechanisms for genome regulation at the epigenetic level. Per se epigenetic regulation is a phenomenon that is responsible for generating and maintaining diversity of cell types during development and stability of the genome. Epigenetics basically involves modifications at the DNA and Histone level. Changes in packaging of genomic DNA along with histone proteins leads to the remodeling of chromatin structure (Van Holde K 1998). The majority of nucleosomes in the cell are composed of the same four types of core histones, but tremendous diversity in the histone/nucleosome structures is generated by a variety of post- translational modifications, such as acetylation, phosphorylation, methylation, and ubiquitination (Iizuka M and Smith MM 2003) Modifications of the core histones H2A, H2B, H3, H4 and histone variants such as H2A.Z and H3.3, are implicated in gene regulation. These modifications are collectively referred to as the histone code (Jenuwein et al 2001). Histone methylation and histone variants have a major role in heterochromatin assembly and the maintenance of the boundaries between heterochromatin and euchromatin. Many of these modifications are specific for heterochromatin such as methylation of histone H3 lysine 9 and histone H3 lysine 27 (Silva et al 2003) and for euchromatin, it is histone H3 lysine 4. (Lachner et al, 2002) Chromatin associated proteins such as HP1, Pc, Swi6 identify these specific histone tail modifications and initiate the formation and maintenance of heterochromatin.
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Kinetochore Function and Chromosome Segregation Rely on Critical Residues in Histones H3 and H4 in Budding Yeast

Kinetochore Function and Chromosome Segregation Rely on Critical Residues in Histones H3 and H4 in Budding Yeast

Our work identified the H3 residues Q5, R40, G44, R53, N108, and L109 and the H4 residues K44, V81, and Y98 as important for segregation and biorientation. While it is unclear how all of the residues that we identified contribute to these processes, five of the mutants reside near the nucleosome entry/exit site and can be suppressed by increasing the dosage of SGO1, consistent with the Sgo1- binding site spanning this region of the nucleosome. An attractive hypothesis is that the DNA at the entry/exit site of the nucleosome may come under tension when kineto- chores biorient, thus signaling to the cell that the kineto- chores have achieved biorientation. Consistent with this, tension-dependent changes in budding yeast pericentro- meric chromatin structure have been observed by micros- copy (Haase et al. 2012; Verdaasdonk et al. 2012). The localization of Sgo1 to this region may therefore be coupled to its ability to trigger the spindle checkpoint when the peri- centromeric chromatin is not under tension. Sgo1 and Bub1 modulate pericentromeric chromatin structure in response to microtubule dynamics (Haase et al. 2012), so it is possible that the histone mutations that we have identified alter a specific structural property associated with pericentro- meres. We attempted to analyze chromatin structure in the pericentromere region in the absence of tension and Sgo1, but the resolution of the assay that we used was not sensitive enough to detect any changes (data not shown). In addition, we were not able to detect significant changes in Sgo1 localization to pericentromeres by ChIP (data not shown). An important future direction will be to determine how the interaction between Sgo1 and nucleosomes mech- anistically contributes to biorientation. It will also be impor- tant to understand how the other histone mutants that we identified contribute to chromosome segregation and thus
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Crosstalk between chromatin structure, cohesin activity and transcription

Crosstalk between chromatin structure, cohesin activity and transcription

In budding yeast, cohesins are loaded at chromatin by the cohesin loader complex Scc2/Scc4 during G1 and early S phase in a non-stable conformation that promotes topological and non-topological interactions (depending on whether or not cohesin entraps chromosomal DNA inside its ring) through dynamic turnover [8–10]. After loading, cohesins are moved away by the transcriptional machinery and accumulate preferentially at intergenic regions (IGRs) [11–14]. A fraction of cohesins becomes cohesive during S phase by topologically entrapping the two sister chromatids [15–18] and remains stably bound until its degradation in mitosis [19] (reviewed in [20, 21]). Although essential, sister chromatid cohesion is not the only function of cohesins, and multiple roles in DNA compaction, transcription regulation, DNA repair and DNA replication have been revealed in the past few years [22–25]. Remarkably, Scc2/Scc4 has been reported to have a role in RSC-mediated chromatin remodeling and transcription [26]. Specifically, the chromatin remodeling complex RSC recruits Scc2/Scc4 to specific promoters, where the cohesin loader helps to maintain the nucle- osome-free region (NFR) for transcription activation [26]. RSC also interacts with and is required for cohesin loading [27] through a mechanism that involves direct interactions between RSC and both cohesin and Scc2/ Scc4 [28]. However, cohesins and cohesin loaders accu- mulate at non-overlapping peaks along the genome after their loading [12]. Therefore, it is unclear whether or not cohesins take part in chromatin remodeling and/or tran- scription in yeast.
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Genome Wide Transcription Studies on Infection Structure Formation and Function in Magnaporthe grisea

Genome Wide Transcription Studies on Infection Structure Formation and Function in Magnaporthe grisea

To evaluate the function of Mgd1 in M. grisea, we generated 4 independent targeted deletion mutants. Mutants lacked aerial hyphae when grown on complete media (Figure 7). In addition, growth was severely reduced on poor carbon sources such as Tween 20 and PEG compared to ectopic and wild type strains. The mutants also grow more poorly than ectopic and wild type strains on glucose limiting conditions in the presence of glutamate and glutamine. To determine the role of Mgd1 in virulence we evaluated mutants for appressorium formation and the ability to cause disease. Mutants had a reduced ability to form mature appressoria (45%) on an inductive surface, others produced appressorium that appeared immature (41%) or were abnormal and highly swollen (4%) (Figure 6). When inoculated onto susceptible barley and rice plants, the mutants exhibited highly reduced virulence and produced many fewer and smaller lesions (Figure 6). Thus, Mgd1 appears to be required for efficient metabolism of carbon and/or nitrogen from the break down of proteins under nutrient limiting conditions as experienced when cells are attempting to form appressoria.
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Structure-Function Studies of Nicotinic Acetylcholine Receptors Using Unnatural Amino Acids

Structure-Function Studies of Nicotinic Acetylcholine Receptors Using Unnatural Amino Acids

First, I would like to thank my advisor, Professor Dennis Dougherty. I was determined to join Dennis’ lab from the start and as such, I sat in his lab as if I was already a member for several months (a tactic encouraged by Katie McMenimen and Ariele Hanek). I remember feeling so victorious when Dennis eventually caved in and let me join his lab. Dennis is an awesome advisor and has played a huge role in making my time in graduate school a rewarding and positive experience. I really appreciate his mentoring style, which fosters scientific and personal growth through giving his students the flexibility to pursue multiple projects while keeping us focused on the end goal.
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The role of heterogeneity in asthma: a structure-to-function perspective

The role of heterogeneity in asthma: a structure-to-function perspective

inclusive of their branching angles obtained from previ- ous morphometric studies with human airways [68, 85]. A stack-based algorithm traverses the airway tree and determines the highest branch to designate for closure to reproduce the ventilation defect in precise anatomic locations of the model that correspond to the anatomic locations of the image. Each branch within the airway tree is modeled assuming laminar flow in a compliant walled tube and hence requires a distinct flow resistance and inertance partitioned via a shunt airway wall compli- ance with each parameter for an airway branch a func- tion of its length, diameter and wall material properties (Eq.  13). The terminal airways are then connected to a gas compression associated with the alveolar gas in par- allel with a constant-phase tissue model all scaled to the appropriate volume. Impedance of the entire tree as well as ventilation distribution to all alveolar regions can be calculated by the appropriate series and parallel calcula- tions also through a stack-based algorithm. All airway diameters are scaled to FRC, and the subsequent lung volume at FRC is distributed evenly among the terminal alveolar units.
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Human linker histones: interplay between phosphorylation and O-β-GlcNAc to mediate chromatin structural modifications

Human linker histones: interplay between phosphorylation and O-β-GlcNAc to mediate chromatin structural modifications

Post-translational modifications (PTMs) of linker his- tone H1 play very important role in regulation of chro- matin structure, transcriptional regulation, gene activity [17] and controlling the accessibility of transcription fac- tors to chromatin structure [20]. A working model of the cell cycle has slowly been constructed from the dis- covery of cyclins 22 years ago. This model is composed of protein phosphorylation, acetylation timed expression of cyclins, and well orchestrated cell division. Neverthe- less, a detailed mechanism of the cell cycle is still incomplete [21-23]. Transcriptional activation of genes starts with the dissociation of linker histone H1 from linker DNA [24]. Phosphorylation of linker histone is required for efficient cell cycle progression by enzyme CDK2 [25]. These kinases requires a consensus sequence (S/T)PXZ or (S/T)PXK for phosphorylation (where X is any amino acid and Z is a basic amino acid) and this consensus sequence is found in many linker histone H1 variants which become phosphorylated [26]. It is found that PKC is also involved in phosphorylation of linker histone variants during regulation of gene expression in cell cycle [27]. Phosphorylation of linker histone regulates transcription and gene expression by reducing the electrostatic binding of linker histone to DNA in chromatin [28]. In vivo phosphorylation of the linker histone tails influence both the binding to mono- nucleosomes and the aggregation of polynucleosomes [29]. The phosphorylation of linker histones at their N and C-terminal tails during the cell cycle influence its functions for enhancing decondensation which in turn regulate transcription and gene expression. This phos- phorylation and dephosphorylation is a common regula- tory mechanism for protein functions [30].
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ASF1 is required to load histones on the HIRA complex in preparation of paternal chromatin assembly at fertilization

ASF1 is required to load histones on the HIRA complex in preparation of paternal chromatin assembly at fertilization

chaperones form a heterogeneous group of proteins with various functions, such as storage, transport, modifica- tion or deposition of histones on DNA [4, 5]. Originally discovered in the budding yeast, Anti-Silencing Factor 1 (ASF1) is a small, conserved histone chaperone of the H3/H4 family that is involved in a variety of chromatin- related functions, such as nucleosome assembly and dis- assembly, chromatin remodeling, gene silencing or DNA damage checkpoint [6–9]. This diversity of functions reflects the implication of ASF1 in both Replication- Coupled (RC) and Replication-Independent (RI) histone deposition pathways. Studies in the budding yeast and metazoan have indeed established that ASF1 interacts with subunits of the Cac/CAF-1 (Chromatin Assembly Factor 1; RC) and Hir/HIRA (Histone Regulator-A; RI) complexes, respectively [10–14]. Structural studies have revealed that ASF1 interacts with H3 and H4 as dimers by binding the so-called tetramerization interface. This likely regulates the initiation of nucleosome assembly by preventing uncontrolled formation of heterotetram- ers [3, 9, 14–16]. During DNA replication in animal cells, ASF1 plays a pivotal role in controlling the flux of H3–H4 dimers to the CAF-1 complex, in close cooperation with the replicative helicase subunit MCM2 [17, 18]. Notably, ASF1 knock-down (KD) in Drosophila and human cells blocks the progression of DNA replication forks [8, 17]. On the other hand, the functional relationship between ASF1 and the HIRA complex has been essentially char- acterized in the context of transcriptional regulation. For instance, HIRA and ASF1 cooperate for the transcrip- tional activation of Mef2 target genes in a cell model of mouse muscle differentiation [19]. During the activation of hsp70 (heat-shock protein 70) genes on Drosophila polytene chromosomes, ASF1 presumably cooperates with HIRA and the dATRX/XNP chromatin remodeler to fill nucleosome gaps at these loci [20]. HIRA, UBN1 and ASF1a associate at different regulatory elements over the human genome to allow H3.3 deposition, including active or poised enhancers as well as the transcription start sites of highly transcribed genes [21]. Finally, ASF1 and HIRA cooperate for the transcriptional silencing of heterochromatin regions in fission yeast [22] and the for- mation of senescence-associated heterochromatin foci in human cells [13].
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