365 research outputs found
Localization of the regulatory particle subunit Semi in the 26S proteasome
No full textThe ubiquitin-proteasome system is responsible for regulated protein degradation in the cell with the 26S proteasome acting as its executive arm. The molecular architecture of this 2.5 MDa complex has been established recently, with the notable exception of the small acidic subunit Semi. Here, we localize the C-terminal helix of Semi binding to the PCI domain of the subunit Rpn7 using cryo-electron microscopy single particle reconstruction of proteasomes purified from yeast cells with semi deletion. The approximate position of the N-terminal region of Semi bridging the cleft between Rpn7 and Rpn3 was inferred based on site-specific cross-linking data of the 26S proteasome. Our structural studies indicate that Semi can assume different conformations in different contexts, which supports the idea that Semi functions as a molecular glue stabilizing the Rpn3/Rpn7 heterodimer. (C) 2013 Elsevier Inc. All rights reserved
Glucocorticoids enhance intestinal glucose uptake via the dimerized glucocorticoid receptor in enterocytes
No full textGlucocorticoid (GC) treatment of inflammatory disorders, such as inflammatory bowel disease, causes deranged metabolism, in part by enhanced intestinal resorption of glucose. However, the underlying molecular mechanism is poorly understood. Hence, we investigated transcriptional control of genes reported to be involved in glucose uptake in the small intestine after GC treatment and determined effects of GC on electrogenic glucose transport from transepithelial currents. GR(villinCre) mice lacking the GC receptor (GR) in enterocytes served to identify the target cell of GC treatment and the requirement of the GR itself; GR(dim) mice impaired in dimerization and DNA binding of the GR were used to determine the underlying molecular mechanism. Our findings revealed that oral administration of dexamethasone to wild-type mice for 3 d increased mRNA expression of serum- and GC-inducible kinase 1, sodium-coupled glucose transporter 1, and Na(+)/H(+) exchanger 3, as well as electrogenic glucose transport in the small intestine. In contrast, GR(villinCre) mice did not respond to GC treatment, neither with regard to gene activation nor to glucose transport. GR(dim) mice were also refractory to GC, because dexamethasone treatment failed to increase both, gene expression and electrogenic glucose transport. In addition, the rise in blood glucose levels normally observed after GC administration was attenuated in both mutant mouse strains. We conclude that enhanced glucose transport in vivo primarily depends on gene regulation by the dimerized GR in enterocytes, and that this mechanism contributes to GC-induced hyperglycemia
Unraveling new mechanisms of intestinal and renal ion transport : lessons from mouse models
No full textStructural and function analysis of the 19S regulatory particle from Drosophila melanogaster 26S proteasome
No full textStrukturelle und funktionelle Untersuchungen der 19S Untereinheiten regulatorischen Partikel aus dem 26S-Proteasome
No full textThe 26S proteasome executes targeted protein degradation, a process essential for
eukaryotic cells. It consists of proteolytic and regulatory subcomplexes, named CP and
RP, respectively. The latter provides poly-ubiquitin removal and substrate unfolding
activities. In the present thesis crystal structures of the Rpn6 subunit and the
Rpn8-Rpn11 heterodimer complex and their localization in the holocomplex are reported,
which provided crucial insights into the structure and function of the RP.Das 26S Proteasom dient dem gezielten Abbau zellulärer Proteine. Dieser Prozess ist
essentiell in eukaryotische Zellen. Es besteht aus proteolytischen und regulatorischen
Proteinkomplexen (CP und RP). Letztere spalten Polyubiquitinketten ab und entfalten die
Substrate. In der vorgelegten Arbeit werden Kristallstrukturen der Rpn6 Untereinheit und
des Rpn8-Rpn11-Heterodimers sowie deren Lage im Holokomplex beschrieben, welche
entscheidende Erkenntnisse zur Struktur und Funktion des RP lieferten
"More Societal than Generational": Examining the Construction and Resistance of Generational Messages in the Workplace
No full textAuthor email: [email protected] Millennial generation, those born between 1980-2000, have drawn vast, sometimes fanatical, criticism in popular media. Slated as narcissistic praise hounds, they are cast as demanding graduate divas who are about to attack the workplace and everything ‘you hold sacred’ (Clark, 2008; Safer, 2007). The abundance of such messages about this generation in formats ‘tailored, targeted, and consumed’ by the public is problematic given that generational constructs are by many perceived as sacrosanct (Myers et al, 2010).
The proliferation of such criticism is by no means innocuous given the very likely impact that they will have on Millennial work opportunities. For many scholars the field of Millennial research suffers from a lack of empirical and cross sectional data to establish more calculated and careful generational constructs, – instead relying on or reacting to popular negative stereotypes. While some Millennial scholarship has begun to move beyond criticisms of popular media, Millennial research is by many considered contradictory at best and confusing at worst (Kowske et al, 2010). Additional difficulties arise when the scramble to publish more research-based work has led to methodologies which are inherently flawed because they reinforce the very same monolithic generational categories they are supposed to assess.
This study, undertaken in New Zealand, explores critical approaches as a means of examining the construction of generational messages and the establishment of generational difference. As a starting point, this small-scale examination analyses the very way in which generational messages are constructed and resisted within the workplace through an analysis of interviews undertaken with 26 employees of a Small to Medium Enterprise (SME) in the information technology sector.
Unlike many generational studies, this project did not seek to draw conclusions by framing differences and measuring responses across generational lines, but rather took a bottom-up approach to understand how participants themselves constructed and resisted messages about generational difference. The project asked two research questions: First, how are generational messages constructed in the context of the workplace? And second, how are generational messages resisted in the workplace? Through axial coding this research categorized five themes under which participants constructed generational difference. These five themes are Technology, Voice, Fairness, Informality, and Stimulus. Broadly speaking, these themes were underpinned by a belief that Millennials have a great demand for respect, democratic process, and the reduction of power distances.
Given the critical approach, the study also observed resistance as a component of the discursive process. As such this research outlines the partiality of resistance and outlines strategies of resistance employed by employees. In line with the idea that construction and resistance are mutually implicated as negotiation, participants were frequently observed simultaneously constructing and resisting generational difference, both synchronically and diachronically. Through axial coding this study also categorized three strategies of resistance. These three strategies are established as Dismissal, the Third Person Effect, and the Decline Metaphor.
This research highlights the usefulness of adopting critical approaches by illustrating the way in which generational meaning is perpetually produced, reproduced, negotiated, and resisted by participants (Murphy, 1998). While there are several factors which are indicative of the Millennial generation, this thesis establishes the hegemonic character of most constructions of generational difference. Given the fragmented and complex state of society, this thesis posits that the usefulness of the monolithic birth-cohort generation has long since passed and we should instead look to understanding generations in terms of their consumption of similar cultural capital
The solute carrier SLC16A12 is critical for creatine and guanidinoacetate handling in the kidney
No full textA heterozygous mutation (c.643C.A; p.Q215X) in the creatine transporter SLC16A12 was proposed to cause a syndrome with juvenile cataracts, microcornea and glucosuria in humans. To further explore the role of SLC16A12 in renal physiology and decipher the mechanism underlying the phenotype of humans with the SLC16A12 mutation, we studied Slc16a12 knock-out (KO) rats. Slc16a12 KO rats had lower plasma levels and increased absolute and fractional urinary excretion of creatine and its precursor guanidinoacetate (GAA). Slc16a12 KO rats displayed lower plasma and urinary creatinine levels, but GFR was normal. The phenotype of heterozygous rats was indistinguishable from wild-type (WT) rats. Renal artery to vein (RAV) concentration differences in WT rats were negative for GAA and positive for creatinine. However, RAV differences for GAA were similar in Slc16a12 KO rats, indicating incomplete compensation of urinary GAA losses by renal GAA synthesis. Together, our results reveal that Slc16a12 in the basolateral membrane of the proximal tubule is critical for reabsorption of creatine and GAA. Our data suggest a dominant-negative mechanism underlying the phenotype of humans affected by the heterozygous SLC16A12 mutation. Furthermore, in the absence of Slc16a12, urinary losses of GAA are not adequately compensated by increased tubular synthesis, caused by feedback inhibition of the rate limiting enzyme L-arginine:glycine amidinotransferase by creatine in proximal tubular cells
Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC)
No full textAbstract Fibroblast growth factor 23 (FGF23) participates in the orchestration of mineral metabolism by inducing phosphaturia and decreasing the production of 1,25(OH)2D3. It is known that FGF23 release is stimulated by aldosterone and extracellular volume depletion. To characterize this effect further in a model of mild hypovolemia, we studied mice lacking the thiazide sensitive NaCl cotransporter (NCC). Our data indicate that NCC knockout mice (KO) have significantly higher FGF23, PTH and aldosterone concentrations than corresponding wild type (WT) mice. However, 1,25(OH)2D3, fractional phosphate excretion and renal brush border expression of the sodium/phosphate co-transporter 2a were not different between the two genotypes. In addition, renal expression of FGF23 receptor FGFR1 and the co-receptor Klotho were unaltered in NCC KO mice. FGF23 transcript was increased in the bone of NCC KO mice compared to WT mice, but treatment of primary murine osteoblasts with the NCC inhibitor hydrochlorothiazide did not elicit an increase of FGF23 transcription. In contrast, the mineralocorticoid receptor blocker eplerenone reversed excess FGF23 levels in KO mice but not in WT mice, indicating that FGF23 upregulation in NCC KO mice is primarily aldosterone-mediated. Together, our data reveal that lack of renal NCC causes an aldosterone-mediated upregulation of circulating FGF23
Journal Of The Nepal Medical Association
No full textNEW DIRECTOR
NEPAL MEDICAL COUNCIL
CONFERENCE AND SEMINARS
SYMPOSIUM
MEDICLA NEWS
BIRTHDAY AWARDS
CENTRAL BODY
KATHMANDU BRANCH
BIRATNAGAR BRANCH
AN ACKNOWLEDGEMENT
JORE GANESH PRESS Pvt. Ltd
Influence of geometric parameters on 3D periodic lattice effective properties
No full textLattice materials are generated by tessellating a unit cell, composed of a specific truss configurations, in an infinite periodicity to combine the effect of bulk material properties and geometric periodicity. They offer enhanced mechanical and dynamic properties per unit mass, and the ability to engineer the material response by optimizing the unit cell. Characterizing lattice properties through experiments can be a time consuming and costly process, so analytical and numerical methods are crucial. Specifically, the Bloch-wave homogenization approach allows one to characterize the effective static properties of the lattice unit cell while simultaneously analyzing wave propagation properties. While this analysis has been used for some time, a thorough study of this approach on 3D lattice materials with different symmetries and geometries is presented here. Using Bloch-wave homogenization, multiple periodic lattices with cubic, transversely isotropic, and tetragonal symmetry, including an auxetic geometry, over a wide range of relative densities are analyzed within a finite element framework. The effect of geometric parameters on lattice properties is discussed and a comparison between lattices based on their anisotropy index is presented. Method studied in this thesis can be extended for designing multifunctional metamaterials with optimized static and dynamic properties simultaneously. This work can also serve as the basis for nondestructive evaluation of metamaterials properties using ultrasonic velocity measurements.Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2021-05-01The student, Ganesh Patil, accepted the attached license on 2019-04-24 at 19:00.The student, Ganesh Patil, submitted this Thesis for approval on 2019-04-24 at 19:11.This Thesis was approved for publication on 2019-04-25 at 12:03.DSpace SAF Submission Ingestion Package generated from Vireo submission #13897 on 2019-08-22 at 15:08:33Made available in DSpace on 2019-08-23T20:36:11Z (GMT). No. of bitstreams: 2
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Previous issue date: 2019-04-25Embargo set by: Seth Robbins for item 112211
Lift date: 2021-08-23T20:36:18Z
Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD systemU of I Only Restriction Lifted for Item 112211 on 2021-08-24T09:15:10Z
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