Central Core Region Research Articles

DEAD-box helicases: Posttranslational regulation and function

Helicases are enzymes that can separate duplex oligonucleotides in a NTP-dependent fashion and are essential in all aspects of DNA and RNA metabolism. Amino acid sequence analysis identified several conserved sequence motifs in DNA and RNA helicases allowing their classification into 5 major groups (Super families SF1–SF5) [1]. DExD/H helicases share eight conserved sequence motifs, whereas the DEAD box helicase subgroup has an additional ninth conserved sequence motif [2]. These sequence motifs encompass an approximately 300–400 amino acid core region involved in ATP-binding/hydrolysis and RNA binding (Part 2: Figure 1A). Structural analyses of several DEAD-box proteins show this core region forms two RecA-like globular domains [2]. Open in a separate window Figure 1 Human DEAD-box protein (DDX) posttranslational modifications and protein-protein interactions A schematic representation of the DDX protein domain architecture features the conserved central DEAD-box core region along with the unique flanking N-terminal and C-terminal regions. Above shows the number of posttranslational documented in Table 1 with respect to their location within the DDX protein. Below lists known DDX-binding proteins, as well as where the interaction occurs on their respective DDX open reading frame.

FOUR HIGHLY LUMINOUS MASSIVE STAR-FORMING REGIONS IN THE NORMA SPIRAL ARM. I. MOLECULAR GAS AND DUST OBSERVATIONS

We report molecular line and dust continuum observations, made with the SEST telescope, towards four young high-mass star forming regions associated with highly luminous (L> 6x10^5 Lsun) IRAS sources (15290-5546, 15502-5302, 15567-5236 and 16060-5146). Molecular emission was mapped in lines of CS (J=2-1, 3-2 and 5-4), SiO (J=2-1 and 3-2), CH3OH (Jk=3k-2k and 2k-1k), and C34S (J=3-2). In addition, single spectra at the peak position were taken in the CO, 13CO and C18O (J=1-0) lines. We find that the luminous star forming regions are associated with molecular gas and dust structures with radii of typically 0.5 pc, masses of ~5x10^3 Msun, column densities of ~5x10^{23} cm^{-2}, molecular hydrogen densities of typically ~2x10^5 cm^{-3} and dust temperatures of ~40 K. The 1.2 mm dust continuum observations further indicate that the cores are centrally condensed, having radial density profiles with power-law indices in the range 1.6-1.9. We find that under these conditions dynamical friction by the gas plays an important role in the migration of high-mass stars towards the central core region, providing an explanation for the observed stellar mass segregation within the cores.

Increased right amygdala volume in lithium‐treated patients with bipolar I disorder

The amygdala plays a major role in processing emotional stimuli. Fourteen studies using structural magnetic resonance imaging (MRI) have examined the amygdala volume in paediatric and adult patients with bipolar disorder (BD) compared with healthy controls (HC) and reported inconsistent findings. Lithium has been found to increase grey matter volume, and first evidence points towards an effect on regional brain volume such as the amygdala. We examined the amygdala volume of euthymic patients with BD treated with lithium (n = 15), without lithium (n = 24) and HC (n = 41) using structural MRI. Patients treated with lithium exhibited in comparison to HC a larger right absolute (+17.9%, P = 0.015) and relative (+18%, P = 0.017) amygdala volume. There was no significant difference in amygdala volume between patients without lithium treatment and HC. Lithium appears to have a sustained effect on a central core region of emotional processing and should therefore be considered in studies examining BD.

Effect of swirl on the turbulent behaviour of a dump combustor flow

This article reports an experimental investigation of non-reacting flow in a low aspect ratio dump combustor with a tapered exit. The length of this combustor was less than the separated flow reattachment length. The turbulent intensity variation inside the combustor without swirl was found to be axi-symmetric. The turbulent intensity increases in the shear layer between the potential core and the recirculation eddy. The intensity in the core region increases as one moves along the centre-line in the axial direction. The turbulence behaviour significantly changed with the use of a swirler at the inlet of the combustor. The average turbulent intensity increased inside the combustor and the differences in the magnitude of the intensity along the axial and radial directions were less compared to the non-swirling flow. For a high swirl number (( SN) = 1.48), the intensity in the core region was higher compared to other regions inside the combustor. The intensity variation inside the combustor was more uniform than in the case of the low swirl number flow. The r.m.s. velocity studies also suggest more turbulence generation due to swirl. The presence of the swirler increased the turbulence kinetic energy and dissipation rate in the central vortex core region. The power spectral density distribution shows the alteration of the frequency content of the power spectrum, which can be attributed to the forced recirculation due to swirl. The effect of a high swirl number and Re on the frequency peak shows similar behaviour. Therefore, turbulence inside the combustor increased due to the swirler; hence, better mixing of the fuel and air and efficient and stable combustion is expected to be achieved.

Effect of acetylation and dual modification on physico-chemical, rheological and morphological characteristics of sweet potato ( Ipomoea batatas) starch

Chemical modification of sweet potato ( Ipomoea batatas) was carried out by acetylation using vinyl acetate ranging from 4% to 10% and dual modification using propylene oxide at specific level of 7% followed by adipic acid anhydride at levels ranging from 0.05% to 0.12%. Degree of substitution ranges between 0.018–0.058% and 0.020–0.034% for acetylated and dual-modified starch samples, respectively. There was significant increase in water binding and oil-binding capacities, solubility, paste clarity, gel strength due to modification, however, rupture strength, gel elasticity and adhesiveness decrease in both modified starches. Analysis of SEM revealed that the modification altered starch morphology. Acetylation brought about slight aggregation or cluster formation of granules with deep groove in the central core region whereas in dual-modified starches there were present a number of aggregates of starch granules with development of few blister like appearances along with protuberances on their surfaces.

X-ray structure of Pur-alpha reveals a Whirly-like fold and an unusual nucleic-acid binding surface.

The PUR protein family is a distinct and highly conserved class that is characterized by its sequence-specific RNA- and DNA-binding. Its best-studied family member, Pur-alpha, acts as a transcriptional regulator, as host factor for viral replication, and as cofactor for mRNP localization in dendrites. Pur-alpha-deficient mice show severe neurologic defects and die after birth. Nucleic-acid binding by Pur-alpha is mediated by its central core region, for which no structural information is available. We determined the x-ray structure of residues 40 to 185 from Drosophila melanogaster Pur-alpha, which constitutes a major part of the core region. We found that this region contains two almost identical structural motifs, termed "PUR repeats," which interact with each other to form a PUR domain. DNA- and RNA-binding studies confirmed that PUR domains are indeed functional nucleic-acid binding domains. Database analysis show that PUR domains share a fold with the Whirly class of nucleic-acid binding proteins. Structural analysis combined with mutational studies suggest that a PUR domain binds nucleic acids through two independent surface regions involving concave beta-sheets. Structure-based sequence alignment revealed that the core region harbors a third PUR repeat at its C terminus. Subsequent characterization by small-angle x-ray scattering (SAXS) and size-exclusion chromatography indicated that PUR repeat III mediates dimerization of Pur-alpha. Surface envelopes calculated from SAXS data show that the Pur-alpha dimer consisting of repeats I to III is arranged in a Z-like shape. This unexpected domain organization of the entire core domain of Pur-alpha has direct implications for ssDNA/ssRNA and dsDNA binding.

Synergistic Interplay between Promoter Recognition and CBP/p300 Coactivator Recruitment by FOXO3a

FOXO3a is a transcription factor belonging to the forkhead box O-Class (FOXO) subfamily, and it regulates metabolism, cell-cycle arrest, cell differentiation, and apoptosis through activating or suppressing gene transcription. FOXO3a contains a well-folded DNA-binding forkhead (FH) domain, but a large portion of the remaining protein sequence (75% of the total) is predicted to comprise intrinsically disordered regions (IDRs). Within the IDRs, there are three conserved regions (CR1-CR3), and it has been shown that CR3 (residues D610-N650) is a transactivation domain that recruits the coactivator histone acetyltransferase (HAT) CBP/p300, through binding to its KIX domain. In a previous study, we determined the solution structure of the FH domain and identified an intramolecular interaction between FH and CR3 domains of FOXO3a. Here we illustrate that the KIX domain of CBP interacts with the central core region (L620-A635) of CR3, which also internally interacts with the FH domain. In this heterotypic interplay, FH prevents CR3 from binding to KIX; however, upon binding to the Forkhead response element (FRE) DNA, the FH domain releases the CR3 domain, allowing it to interact with KIX. While previous studies have shown that the transactivation domains of c-Myb and MLL bind to distinct sites on KIX, our results indicate that FOXO3a CR3 has an ability to bind to both of these sites. These results suggest a model of FOXO3a-dependent coactivator recruitment in which the dynamic interplay between KIX and FH domains for binding to CR3 plays a key regulatory role in gene transcription activation.

Describing the Diffusion of Guest Molecules Inside Porous Structures

The design and development of many emerging separation and catalytic process technologies require a proper quantitative description of diffusion of mixtures of guest molecules within meso- and microporous structures. In mesoporous materials with pore sizes 2 nm < dp < 50 nm, there is a central core region where the influence of interactions of the molecules with the pore wall is either small or negligible; mesopore diffusion is governed by a combination of molecule−molecule and molecule−pore wall interactions. Within micropores with dp < 2 nm, the guest molecules are always within the influence of the force field exerted with the wall; we have to reckon with the motion of adsorbed molecules, and there is no “bulk” fluid region. This article presents a unified, phenomenological, description of diffusion inside meso- and microporous structures using concepts and ideas that originate from James Clerk Maxwell and Josef Stefan. With the aid of extensive data sets of molecular dynamic simulations of unary and mixture diffusion in a wide variety of materials such as zeolites, metal-organic frameworks, covalent organic frameworks, carbon nanotubes, and cylindrical silica pores with a diverse range of pore topologies and pore sizes, we derive a molecular-level understanding of the various coefficients that arise in the phenomenological Maxwell−Stefan diffusion formulation. This understanding helps us to explain and describe a variety of experimental data and observations. We also demonstrate how a molecular level understanding aids separation and reaction process development.

Influence of the drawing process on the defect generation in multistep-index germanium-doped optical fibers

Variation of germanium lone pair center (GLPC) concentration in germanosilicate multistep-index optical fibers and preforms was studied using confocal microscopy luminescence technique. The experimental results provide evidence that in the central core region ([Ge] approximately 11 wt.%) of our specific canonical samples the ratio [GLPC]/[Ge] is five times larger in fiber than in preforms. The relative influence of the glass composition and of the drawing process on the generation efficiency of the GLPC defects that drive the glass photosensitivity is discussed. The radial distribution of these defects suggests a possible enhancement of the defect creation related to the internal stress of the fiber core.

The kinematics and spatial distribution of stellar populations in E+A galaxies

We have used the Gemini Multi–Object Spectragraph (GMOS) instrument on the 8.1–m Gemini–South Telescope to obtain spatially resolved two–colour imaging and integral field unit (IFU) spectroscopy of a sample of 10 nearby (z= 0.04–0.20)‘E+A’ galaxies selected from the Two Degree Field Galaxy Redshift Survey. These galaxies have been selected to lie in a variety of environments from isolated systems to rich clusters. Surface brightness profiles measured using our imaging data show the isophotal profiles of our sample are generally r1/4–like, consistent with a sample dominated by early–type galaxies. Only one galaxy in our sample has an obvious exponential (‘disc–like’) component in the isophotal profile. This is further underscored by all galaxies having early Hubble–type morphological classifications, and showing a behaviour in the central velocity dispersion–absolute magnitude plane that is consistent with the Faber–Jackson relation, once the transitory brightening that occurs in the E+A phase is corrected for. In addition, two–thirds of our sample shows clear evidence of either ongoing or recent tidal interactions/mergers, as evidenced by the presence of tidal tails and disturbed morphologies. While all the galaxies in our sample have total integrated colours that are relatively blue (in keeping with their E+A status), they show a diversity of colour gradients, possessing central core regions that are either redder, bluer or indistinct in colour relative to their outer regions. The E+A spectra are well fitted by that of a young stellar population, the light from which is so dominant that it is impossible to quantify the presence of the underlying old stellar population. Consistent with other recent findings, there is little evidence for radial gradients in the Balmer absorption line equivalent widths over the central few kiloparsecs (<4 kpc), although we are unable to search for the previously reported radial gradients at larger galactocentric radii due to the limited spatial extent of our IFU data. Kinematically, the most striking property is the significant and unambiguous rotation that is seen in all our E+A galaxies, with it being generally aligned close to the photometric major axis. This is contrary to the findings of Norton et al., who found little or no evidence for rotation in a very similar sample of nearby E+A galaxies. We also clearly demonstrate that our E+A galaxies are, in all but one case, consistent with being ‘fast rotators’, based on their internal angular momentum per unit mass measured as a function of radius and ellipticity. We argue that the combination of disturbed morphologies and significant rotation in these galaxies supports their production via gas–rich galaxy mergers and interactions. The large fraction of fast rotators argues against equal mass mergers being the dominant progenitor to the E+A population.

A Nonlinear Switch Based on Irregular Structures and Nonuniformity in Doped Photonic Crystal Fibers

We propose a novel nonlinear switch-based on the irregularity in a three-core-doped photonic crystal fiber (PCF). We numerically investigate the proposed structure, which consists of air holes arranged in a triangular lattice around two defects separated by a single Er-Yb doped core. Its switching operation is based on the gain change in the doped core due to the nonuniformity and irregular structure around it. It is shown that by adjusting the gain in the doped core, the light is entirely transferred from the central core to the upper and lower ones. We have employed the full vectorial finite-element method and the finite-difference time domain to investigate and optimize the optical modes, nonlinear parameter, and gain effects on the switching operation. It is found that an optimum gain is essential to allow either a periodic exchange of the light between the upper and lower cores or independent core propagation. Possible nonuniformity in the hole diameters and irregularity problems of the proposed PCF design during the fabrication process have been predicted. The waveguide dispersion with respect to the doped central core region has been thoroughly investigated.

Radial distribution of the contributions to band broadening of a silica‐based semi‐preparative monolithic column

Using an on-column local electrochemical microdetector operated in the amperometric mode, band elution profiles were recorded at different radial locations at the exit of a 10 mm id, 100 mm long silica-based monolithic column. HETP plots were then acquired at each of these locations, and all these results were fitted to the Knox equation. This provided a spatial distribution of the values of the eddy diffusion (A), the molecular diffusion (B), and the resistance to the kinetics of mass transfer (C) terms. Results obtained indicate that the wall region yields higher A values and smaller C values than the central core region. Significant radial fluctuations of these contributions to band broadening occur throughout the exit column cross-section. This phenomenon is due to the structural radial heterogeneity of the column.

Intramolecular Activation Mechanism of the Dictyostelium LRRK2 Homolog Roco Protein GbpC

GbpC is a large multidomain protein involved in cGMP-mediated chemotaxis in the cellular slime mold Dictyostelium discoideum. GbpC belongs to the Roco family of proteins that often share a central core region, consisting of leucine-rich repeats, a Ras domain (Roc), a Cor domain, and a MAPKKKinase domain. In addition to this core, GbpC contains a RasGEF domain and two cGMP-binding domains. Here, we report on an intramolecular signaling cascade of GbpC. In vitro, the RasGEF domain of GbpC specifically accelerates the GDP/GTP exchange of the Roc domain. Moreover, cGMP binding to GbpC strongly stimulates the binding of GbpC to GTP-agarose, suggesting cGMP-stimulated GDP/GTP exchange at the Roc domain. The function of the protein in vivo was investigated by rescue analysis of the chemotactic defect of gbpC null cells. Mutants that lack a functional guanine exchange factor (GEF), Roc, or kinase domain are inactive in vivo. Together, the results suggest a four-step intramolecular activation mechanism of the Roco protein GbpC: cGMP binding to the cyclic nucleotide-binding domains, activation of the GEF domain, GDP/GTP exchange of Roc, and activation of the MAPKKK domain.

The Diaphanous-related Formin FHOD1 Associates with ROCK1 and Promotes Src-dependent Plasma Membrane Blebbing

Diaphanous-related formins (DRFs) mediate GTPase-triggered actin rearrangements to regulate central cellular processes, such as cell motility and cytokinesis. The DRF FHOD1 interacts with the Rho-GTPase Rac1 and mediates formation of actin stress fibers in its deregulated form; the physiologically relevant activities and molecular mechanisms of endogenous FHOD1, however, are still unknown. Here we report that FHOD1 physically associates via the N-terminal part of its FH2 domain with the central domain of ROCK1. Although FHOD1 does not affect the kinase activity of ROCK1, the DRF is an efficient substrate for phosphorylation by ROCK1. Co-expression of FHOD1 and ROCK1 results in the generation of nonapoptotic plasma membrane (PM) blebs, to which the DRF is efficiently recruited. Blebbing induced by FHOD1 and ROCK1 depends on F-actin integrity, the Rho-ROCK cascade, and Src activity and is reminiscent of the recently described PM blebs triggered by expression of Src homology 4 (SH4) domain PM targeting signals. Consistently, endogenous FHOD1 is required in SH4 domain expressing cells for efficient PM blebbing and rounded cell morphology in two-dimensional cultures or three-dimensional matrices, respectively. Efficient association of FHOD1 with ROCK1, as well as recruitment of the DRF to blebs, depends on Src activity, suggesting that the functional interaction between both proteins is regulated by Src. These results define a role for endogenous FHOD1 in SH4 domain-induced blebbing and suggest that its activity is regulated by ROCK1 in a Src-dependent manner.

Photonic crystal fiber for fundamental mode operation of multicore fiber lasers and amplifiers

A mode-selection method based on a single-mode photonic crystal fiber (PCF) in the multicore fiber (MCF) lasers is presented. The designed PCF has a central core region formed by a missing air-hole, and three air-hole rings. With an appropriate choice of the design parameters of the PCF, the power coupling between the fundamental mode (FM) of the PCF and the fundamental MCF mode can be much higher than those between the FM and the other supermodes. As a result, the fundamental MCF mode has the maximum power reflection coefficient on the right-hand side of the MCF laser cavity, and dominates the output laser power. Since the maximum power of the fundamental MCF mode will lead to the desired laser beam profile, higher the fraction of the fundamental MCF mode power contained in the total output power contributes to higher beam quality. The numerical simulations show that the effectiveness of the fundamental MCF mode-selection is higher in the MCF lasers with the PCF as a mode-selection component than in the MCF lasers based on the free-space Talbot cavity method. Additionally, for the MCF amplifiers, an approach is presented to decrease the sensitivity of the amplifier performance to the variation of Gaussian beam waist utilizing the coupling between the Gaussian beam and the FM of the PCF. The numerical results show that this method can effectively increase the design flexibility for a broad range of the Gaussian beam waist.

Crystal structure of a putative lysostaphin peptidase from Vibrio cholerae.

Peptidoglycan (PGN) constitutes the cell walls of virtually all bacteria, making it a target of the innate immune system. PGN is a polymer of alternating {Beta} (1{yields}4) linked N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc), crossbridged by oligopeptide stems. Lysotaphin type enzymes are believed to cleave the glycl-glycine and glycyl-alanine bonds that occur in glycine-rich cross-bridges. Lysostaphins represent potential anti staphylococcal agents. Specifically, they can eradicate S.aureus nasal colonization in the rat model and are effective in treating methicillin-resistant S. aureus endophthalmitis in rabbits. These enzymes belong to the metalloendopeptidase family and possess a conserved HXH active site motif.

Comparative Molecular Dynamics Studies of Wild-Type and Oxidized Forms of Full-Length Alzheimer Amyloid β-Peptides Aβ(1−40) and Aβ(1−42)

In this study, all-atom 50 ns molecular dynamics simulations are performed on the full-length amyloid beta (Abeta) monomers (WT-Abeta(1-40) and WT-Abeta(1-42)) and their oxidized forms (Met35(O)-Abeta(1-40) and Met35(O)-Abeta(1-42)) in aqueous solution. The effects of the oxidation state of Met35 and the presence of dipeptide (Ile41-Ala42) on the secondary structures of the three distinct regions (the central hydrophobic core region 17-21 (LVFFA), the loop 23-28 (DVGSNK), and the second hydrophobic domain 29-35 (GAIIGLM)) of all monomers have been analyzed in detail, and results are compared with the available experimental information. Our simulations indicate that the WT-Abeta(1-40) monomer adopts an overall beta-hairpin-like structure, which is promoted by the turn region (24-27). This turn region is stabilized through salt-bridge formation between the Asp23 and Lys28 residues. In contrast, the overall structure of the oxidized (Met35(O)-Abeta(1-40)) monomer can be divided into three well-defined bend regions separated by coil segments. These structural differences may be critical for the measured decrease in the rate of aggregation of Met35(O)-Abeta(1-40) peptide. In the WT-Abeta(1-42) monomer, in comparison to the WT-Abeta(1-40), the Asp23-Lys28 salt bridge is absent, and consequently, the turn in the middle (24-27) region has a smaller curvature. The observed difference in the aggregation rates of these two peptides may be related to the opening of the turn (24-27) stabilized by the Asp23-Lys28 salt bridge. For WT-Abeta(1-42), in the absence of this salt bridge, the unfolding and aggregation events may be more favorable than for WT-Abeta(1-40).

Diatoms in the desert: Plankton community response to a mesoscale eddy in the subtropical North Pacific

Abstract As part of the E-Flux project, we documented spatial variability and temporal changes in plankton community structure in a cold-core cyclonic eddy in the lee of the Hawaiian Islands. Cyclone Opal spanned 200 km in diameter, with sharply uplifted isopycnals (80–100 m relative to surrounding waters) and a strongly expressed deep chlorophyll a maximum (DCM) in its central core region of 40 km diameter. Microscopic and flow cytometric analyses of samples from across the eddy revealed dramatic transitions in phytoplankton community structure, reflecting Opal's well-developed physical structure. Upper mixed-layer populations in the eddy resembled those outside the eddy and were dominated by picophytoplankton. In contrast, the DCM was composed of large chain-forming diatoms dominated by Chaetoceros and Rhizosolenia spp. Diatoms attained unprecedented levels of biomass (nearly 90 μg C l−1) in the center of the eddy, accounting for 85% of photosynthetic biomass. Protozoan grazers displayed two- to three-fold higher biomass levels in the eddy center as well. We also found a distinct and persistent layer of senescent diatom cells overlying healthy populations, often separated by less than 10 m, indicating that we were sampling a bloom in a state of decline. Time-series sampling over 8 days showed a successional shift in community structure within the central diatom bloom, from the unexpected large chain-forming species to smaller forms more typical of the subtropical North Pacific. The diatom bloom of Cyclone Opal was a unique, and possibly extreme, example of biological response to physical forcing in the North Pacific subtropical gyre, and its detailed study may therefore help to improve our predictive understanding of environmental controls on plankton community structure.

Unique features of the structure and interactions of mycobacterial uracil-DNA glycosylase: structure of a complex of theMycobacterium tuberculosisenzyme in comparison with those from other sources

Uracil-DNA glycosylase (UNG), a repair enzyme involved in the excision of uracil from DNA, from mycobacteria differs from UNGs from other sources, particularly in the sequence in the catalytically important loops. The structure of the enzyme from Mycobacterium tuberculosis (MtUng) in complex with a proteinaceous inhibitor (Ugi) has been determined by X-ray analysis of a crystal containing seven crystallographically independent copies of the complex. This structure provides the first geometric characterization of a mycobacterial UNG. A comparison of the structure with those of other UNG proteins of known structure shows that a central core region of the molecule is relatively invariant in structure and sequence, while the N- and C-terminal tails exhibit high variability. The tails are probably important in folding and stability. The mycobacterial enzyme exhibits differences in UNG-Ugi interactions compared with those involving UNG from other sources. The MtUng-DNA complex modelled on the basis of the known structure of the complex involving the human enzyme indicates a domain closure in the enzyme when binding to DNA. The binding involves a larger burial of surface area than is observed in binding by human UNG. The DNA-binding site of MtUng is characterized by the presence of a higher proportion of arginyl residues than is found in the binding site of any other UNG of known structure. In addition to the electrostatic effects produced by the arginyl residues, the hydrogen bonds in which they are involved compensate for the loss of some interactions arising from changes in amino-acid residues, particularly in the catalytic loops. The results arising from the present investigation represent unique features of the structure and interaction of mycobacterial Ungs.

The first transport code simulations using the trapped gyro-Landau-fluid model

The first transport code simulations using the newly developed trapped gyro-Landau-fluid (TGLF) theory-based transport model are presented. TGLF has comprehensive physics to approximate the turbulent transport due to drift-ballooning modes in tokamaks. The TGLF model is a next generation gyro-Landau-fluid model that improves the accuracy of the trapped particle response and the finite Larmor radius effects compared to its predecessor, GLF23. The model solves for the linear eigenmodes of trapped ion and electron modes, ion and electron temperature gradient modes, and electromagnetic kinetic ballooning modes in either shifted circle or shaped geometry. A database of over 400 nonlinear gyrokinetic simulations using the GYRO code has been created. A subset of 83 simulations with shaped geometry has been used to find a model for the saturation levels. Using a simple quasilinear (QL) saturation rule, remarkable agreement with the energy and particle fluxes from a wide variety of GYRO simulations is found for both shaped or circular geometry and also for low aspect ratio. Using this new QL saturation rule along with a new E×B shear quench rule for shaped geometry, the density and temperature profiles have been predicted in over 500 transport code runs and the results compared against experimental data from 96 tokamak discharges. Compared to GLF23, the TGLF model demonstrates better agreement between the predicted and experimental temperature profiles. Surprisingly, TGLF predicts that the high-k modes are found to play an important role in the central core region of low and high confinement plasmas lacking transport barriers.