Disposition of Federally Owned Surpluses

PDZ domains are scaffolding modules in protein-protein interactions that mediate numerous physiological functions by interacting canonically with the C-terminus or non-canonically with an internal motif of protein ligands. A conserved carboxylate-binding site in the PDZ domain facilitates binding via backbone hydrogen bonds; however, little is known about the role of these hydrogen bonds due to experimental challenges with backbone mutations. Here we address this interaction by generating semisynthetic PDZ domains containing backbone amide-to-ester mutations and evaluating the importance of individual hydrogen bonds for ligand binding. We observe substantial and differential effects upon amide-to-ester mutation in PDZ2 of postsynaptic density protein 95 and other PDZ domains, suggesting that hydrogen bonding at the carboxylate-binding site contributes to both affinity and selectivity. In particular, the hydrogen-bonding pattern is surprisingly different between the non-canonical and canonical interaction. Our data provide a detailed understanding of the role of hydrogen bonds in protein-protein interactions

Effects of a contoured articular prosthetic device on tibiofemoral peak contact pressure: a biomechanical study

Many middle-aged patients are affected by localized cartilage defects that are neither appropriate for primary, nor repeat biological repair methods, nor for conventional arthroplasty. This in vitro study aims to determine the peak contact pressure in the tibiofemoral joint with a partial femoral resurfacing device (HemiCAP®, Arthrosurface Inc., Franklin, MA, USA). Peak contact pressure was determined in eight fresh-frozen cadaveric specimens using a Tekscan sensor placed in the medial compartment above the menisci. A closed loop robotic knee simulator was used to test each knee in static stance positions (5°/15°/30°/45°) with body weight ground reaction force (GRF), 30° flexion with twice the body weight (2tBW) GRF and dynamic knee-bending cycles with body weight GRF. The ground reaction force was adjusted to the living body weight of the cadaver donor and maintained throughout all cycles. Each specimen was tested under four different conditions: Untreated, flush HemiCAP® implantation, 1-mm proud implantation and 20-mm defect. A paired sampled t test to compare means (significance, P ≤ 0.05) was used for statistical analysis. On average, no statistically significant differences were found in any testing condition comparing the normal knee with flush device implantation. With the 1-mm proud implant, statistically significant increase of peak contact pressures of 217% (5° stance), 99% (dynamic knee bending) and 90% (30° stance with 2tBW) compared to the untreated condition was seen. No significant increase of peak contact pressure was evaluated with the 20-mm defect. The data suggests that resurfacing with the HemiCAP® does not lead to increased peak contact pressure with flush implantation. However, elevated implantation results in increased peak contact pressure and might be biomechanically disadvantageous in an in vivo application

The Extinction of Dengue through Natural Vulnerability of Its Vectors

Dengue transmission has not always been confined to tropical areas. In some cases, this has been due to a reduced geographic range of the mosquitoes that are able to carry dengue viruses. In Australia, Aedes aegypti mosquitoes once occurred throughout temperate, drier parts of the country but are now restricted to the wet tropics. We used a computer modelling approach to determine whether these mosquitoes could inhabit their former range. This was done by simulating dengue mosquito populations in virtual environments that experienced 10 years of actual daily weather conditions (1998–2007) obtained for 13 locations inside and outside the current tropical range. We discovered that in areas outside the Australian wet tropics, Ae. aegypti often becomes extinct, particularly when conditions are too cool for year-round egg-laying activity, and/or too dry for eggs to hatch. Thus, despite being a global pest and disease vector, Ae. aegypti mosquitoes are naturally vulnerable to extinction in certain conditions. Such vulnerability should be exploited in vector control programs

Treatment of isoniazid-resistant pulmonary tuberculosis

<p>Abstract</p> <p>Background</p> <p>Although resistance to isoniazid (INH) is the most common form of drug resistance seen among <it>Mycobacterium tuberculosis </it>isolates, there have been few studies on the efficacy and optimal duration of treatment for patients with INH-resistant tuberculosis (TB).</p> <p>Methods</p> <p>We evaluated retrospectively the treatment outcomes of 39 patients who were treated for INH-resistant pulmonary TB. The treatment regimens consisted of a 12-month regimen of rifampin (RIF) and ethambutol (EMB), with pyrazinamide (PZA) given during the first 2 months (2HREZ/10RE) (<it>n </it>= 21), a 9-month regimen of RIF and EMB with PZA during the first 2 months (2HREZ/7RE) (<it>n </it>= 5), and a 6-month regimen of RIF, EMB, and PZA (2HREZ/4REZ) (<it>n </it>= 13). After drug susceptibility testing confirmed the INH-resistance of the isolated <it>M. tuberculosis </it>strains, INH was discontinued for all the patients.</p> <p>Results</p> <p>Among the 39 patients, treatment was successfully completed by 36 patients (92%). However, treatment failure occurred, and acquired resistance to other first-line drugs, such as RIF, developed in three patients (8%). Cavitary and bilateral extensive lesions were commonly found in the chest radiographs of the patients who exhibited treatment failure.</p> <p>Conclusion</p> <p>These findings underline the seriousness of concerns regarding treatment failure and the development of multidrug-resistant TB in patients with INH-resistant TB following treatment with recommended regimens.</p

Defending the genome from the enemy within:mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline

Divergence exists in the subcellular distribution of intramuscular triglyceride in human skeletal muscle dependent on the choice of lipid dye.

Despite over 50 years of research, a comprehensive understanding of how intramuscular triglyceride (IMTG) is stored in skeletal muscle and its contribution as a fuel during exercise is lacking. Immunohistochemical techniques provide information on IMTG content and lipid droplet (LD) morphology on a fibre type and subcellular-specific basis, and the lipid dye Oil Red O (ORO) is commonly used to achieve this. BODIPY 493/503 (BODIPY) is an alternative lipid dye with lower background staining and narrower emission spectra. Here we provide the first quantitative comparison of BODIPY and ORO for investigating exercise-induced changes in IMTG content and LD morphology on a fibre type and subcellular-specific basis. Estimates of IMTG content were greater when using BODIPY, which was predominantly due to BODIPY detecting a larger number of LDs, compared to ORO. The subcellular distribution of intramuscular lipid was also dependent on the lipid dye used; ORO detects a greater proportion of IMTG in the periphery (5 μm below cell membrane) of the fibre, whereas IMTG content was higher in the central region using BODIPY. In response to 60 min moderate-intensity cycling exercise, IMTG content was reduced in both the peripheral (- 24%) and central region (- 29%) of type I fibres (P < 0.05) using BODIPY, whereas using ORO, IMTG content was only reduced in the peripheral region of type I fibres (- 31%; P < 0.05). As well as highlighting some methodological considerations herein, our investigation demonstrates that important differences exist between BODIPY and ORO for detecting and quantifying IMTG on a fibre type and subcellular-specific basis

Icariside II Induces Apoptosis in U937 Acute Myeloid Leukemia Cells: Role of Inactivation of STAT3-Related Signaling

Background: The aim of this study is to determine anti-cancer effect of Icariside II purified from the root of Epimedium koreanum Nakai on human acute myeloid leukemia (AML) cell line U937. Methodology/Principal Findings Icariside II blocked the growth U937 cells in a dose- and time-dependent manner. In this anti-proliferation process, this herb compound rendered the cells susceptible to apoptosis, manifested by enhanced accumulation of sub-G1 cell population and increased the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells. Icariside II was able to activate caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP) in a time-dependent manner. Concurrently, the anti-apoptotic proteins, such as bcl-xL and survivin in U937 cells, were downregulated by Icariside II. In addition, Icariside II could inhibit STAT3 phosphorylation and function and subsequently suppress the activation of Janus activated kinase 2 (JAK2), the upstream activators of STAT3, in a dose- and time-dependent manner. Icariside II also enhanced the expression of protein tyrosine phosphatase (PTP) SH2 domain-containing phosphatase (SHP)-1, and the addition of sodium pervanadate (a PTP inhibitor) prevented Icariside II-induced apoptosis as well as STAT3 inactivation in STAT3 positive U937 cells. Furthermore, silencing SHP-1 using its specific siRNA significantly blocked STAT3 inactivation and apoptosis induced by Icariside II in U937 cells. Conclusions/Significance: Our results demonstrated that via targeting STAT3-related signaling, Icariside II sensitizes U937 cells to apoptosis and perhaps serves as a potent chemotherapeutic agent for AML

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012