A new multistage lattice vector quantization with adaptive subband thresholding for image compression

Lattice vector quantization (LVQ) reduces coding complexity and computation due to its regular structure. A new multistage LVQ (MLVQ) using an adaptive subband thresholding technique is presented and applied to image compression. The technique concentrates on reducing the quantization error of the quantized vectors by "blowing out" the residual quantization errors with an LVQ scale factor. The significant coefficients of each subband are identified using an optimum adaptive thresholding scheme for each subband. A variable length coding procedure using Golomb codes is used to compress the codebook index which produces a very efficient and fast technique for entropy coding. Experimental results using the MLVQ are shown to be significantly better than JPEG 2000 and the recent VQ techniques for various test images

Advancing Tests of Relativistic Gravity via Laser Ranging to Phobos

Phobos Laser Ranging (PLR) is a concept for a space mission designed to advance tests of relativistic gravity in the solar system. PLR's primary objective is to measure the curvature of space around the Sun, represented by the Eddington parameter $\gamma$, with an accuracy of two parts in $10^7$, thereby improving today's best result by two orders of magnitude. Other mission goals include measurements of the time-rate-of-change of the gravitational constant, $G$ and of the gravitational inverse square law at 1.5 AU distances--with up to two orders-of-magnitude improvement for each. The science parameters will be estimated using laser ranging measurements of the distance between an Earth station and an active laser transponder on Phobos capable of reaching mm-level range resolution. A transponder on Phobos sending 0.25 mJ, 10 ps pulses at 1 kHz, and receiving asynchronous 1 kHz pulses from earth via a 12 cm aperture will permit links that even at maximum range will exceed a photon per second. A total measurement precision of 50 ps demands a few hundred photons to average to 1 mm (3.3 ps) range precision. Existing satellite laser ranging (SLR) facilities--with appropriate augmentation--may be able to participate in PLR. Since Phobos' orbital period is about 8 hours, each observatory is guaranteed visibility of the Phobos instrument every Earth day. Given the current technology readiness level, PLR could be started in 2011 for launch in 2016 for 3 years of science operations. We discuss the PLR's science objectives, instrument, and mission design. We also present the details of science simulations performed to support the mission's primary objectives.Comment: 25 pages, 10 figures, 9 table

The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo

Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol. We now show that while TPI is a prominent target of the antibody response to infection, there is little antibody-mediated inhibition of catalytic activity by polyclonal sera. We generated a panel of twenty-three anti-TPI monoclonal antibodies and found only two were able to block TPI enzymatic activity. Immunisation of jirds with B. malayi TPI, or mice with the homologous protein from the rodent filaria Litomosoides sigmodontis, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult B. malayi resulted in 60–70% reductions in microfilarial levels in vivo and both oocyte and microfilarial production by individual adult females. The loss of fecundity was accompanied by reduced IFNγ expression by CD4+ T cells and a higher proportion of macrophages at the site of infection. Thus, enzymatically active TPI plays an important role in the transmission cycle of B. malayi filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections

Plate-based diversity subset screening generation 2: An improved paradigm for high throughput screening of large compound files

High throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time-consuming and costly and the use of subsets as an efficient alternative to screening these large collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity, or biological target focus. Previously we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Purpose: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases. Methods: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46, XY DSD. Additional cases with 46, XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-beta (ER-beta) was performed in an 8-week-old human male embryo. Results: We identified a homozygous ESR2 variant, c.541_543del p. (Asn181del), located in the highly conserved DNA-binding domain of ER-beta, in an individual with syndromic 46, XY DSD. Two additional heterozygous missense variants, c.251G>T p.(Gly84Val) and c.1277T>G p.(Leu426Arg), located in the N-terminus and the ligand-binding domain of ER-beta, were found in unrelated, nonsyndromic 46, XY DSD cases. Significantly increased transcriptional activation and an impact on protein conformation were shown for the p.(Asn181del) and p.(Leu426Arg) variants. Testicular ESR2 expression was previously documented and ER-beta immunostaining was positive in the developing intestine and eyes. Conclusion: Our study supports a role for ESR2 as a novel candidate gene for 46, XY DSD

Interaction of Imidazole Containing Hydroxamic Acids with Fe(III): Hydroxamate Versus Imidazole Coordination of the Ligands

Solution equilibrium studies on Fe(III) complexes formed with imidazole-4-carbohydroxamic acid (Im-4-Cha), N-Me-imidazole-4-carbohydroxamic acid (N-Me-Im-4-Cha), imidazole-4-acetohydroxamic acid (Im-4-Aha), and histidinehydroxamic acid (Hisha) have been performed by using pH-potentiometry, UV-visible spectrophotometry, EPR, ESI-MS, and H1-NMR methods. All of the obtained results demonstrate that the imidazole moiety is able to play an important role very often in the interaction with Fe(III), even if this metal ion prefers the hydroxamate chelates very much. If the imidazole moiety is in α-position to the hydroxamic one (Im-4-Cha and N-Me-Im-4-Cha) its coordination to the metal ion is indicated unambiguously by our results. Interestingly, parallel formation of (Nimidazole, Ohydroxamate), and (Ohydroxamate, Ohydroxamate) type chelates seems probable with N-Me-Im-4-Cha. The imidazole is in β-position to the hydroxamic moiety in Im-4-Aha and an intermolecular noncovalent (mainly H-bonding) interaction seems to organize the intermediate-protonated molecules in this system. Following the formation of mono- and bishydroxamato mononuclear complexes, only EPR silent species exists in the Fe(III)-Hisha system above pH 4, what suggests the rather significant “assembler activity” of the imidazole (perhaps together with the ammonium moiety)

Flow-volume loops derived from three-dimensional echocardiography: a novel approach to the assessment of left ventricular hemodynamics

BACKGROUND: This study explores the feasibility of non-invasive evaluation of left ventricular (LV) flow-volume dynamics using 3-dimensional (3D) echocardiography, and the capacity of such an approach to identify altered LV hemodynamic states caused by valvular abnormalities. METHODS: Thirty-one patients with moderate-severe aortic (AS) and mitral (MS) stenoses (21 and 10 patients, respectively) and 10 healthy volunteers underwent 3D echocardiography with full volume acquisition using Philips Sonos 7500 equipment. The digital 3D data were post- processed using TomTec software. LV flow-volume loops were subsequently constructed for each subject by plotting instantaneous LV volume data sampled throughout the cardiac cycle vs. their first derivative representing LV flow. After correction for body surface area, an average flow-volume loop was calculated for each subject group. RESULTS: Flow-volume loops were obtainable in all subjects, except 3 patients with AS. The flow-volume diagrams displayed clear differences in the form and position of the loops between normal individuals and the respective patient groups. In patients with AS, an "obstructive" pattern was observed, with lower flow values during early systole and larger end-systolic volume. On the other hand, patients with MS displayed a "restrictive" flow-volume pattern, with reduced diastolic filling and smaller end-diastolic volume. CONCLUSION: Non-invasive evaluation of LV flow-volume dynamics using 3D-echocardiographic data is technically possible and the approach has a capacity to identify certain specific types of alteration of LV flow-volume pattern caused by valvular abnormalities, thus reflecting underlying hemodynamic states specific for these abnormalities

Preference of Small Molecules for Local Minimum Conformations when Binding to Proteins

It is well known that small molecules (ligands) do not necessarily adopt their lowest potential energy conformations when binding to proteins. Analyses of protein-bound ligand crystal structures have reportedly shown that many of them do not even adopt the conformations at local minima of their potential energy surfaces (local minimum conformations). The results of these analyses raise a concern regarding the validity of virtual screening methods that use ligands in local minimum conformations. Here we report a normal-mode-analysis (NMA) study of 100 crystal structures of protein-bound ligands. Our data show that the energy minimization of a ligand alone does not automatically stop at a local minimum conformation if the minimum of the potential energy surface is shallow, thus leading to the folding of the ligand. Furthermore, our data show that all 100 ligand conformations in their protein-bound ligand crystal structures are nearly identical to their local minimum conformations obtained from NMA-monitored energy minimization, suggesting that ligands prefer to adopt local minimum conformations when binding to proteins. These results both support virtual screening methods that use ligands in local minimum conformations and caution about possible adverse effect of excessive energy minimization when generating a database of ligand conformations for virtual screening

Normal-Mode-Analysis–Monitored Energy Minimization Procedure for Generating Small–Molecule Bound Conformations

The energy minimization of a small molecule alone does not automatically stop at a local minimum of the potential energy surface of the molecule if the minimum is shallow, thus leading to folding of the molecule and consequently hampering the generation of the bound conformation of a guest in the absence of its host. This questions the practicality of virtual screening methods that use conformations at local minima of their potential energy surfaces (local minimum conformations) as potential bound conformations. Here we report a normal-mode-analysis–monitored energy minimization (NEM) procedure that generates local minimum conformations as potential bound conformations. Of 22 selected guest–host complex crystal structures with guest structures possessing up to four rotatable bonds, all complexes were reproduced, with guest mass–weighted root mean square deviations of <1.0 Å, through docking with the NEM–generated guest local minimum conformations. An analysis of the potential energies of these local minimum conformations showed that 22 (100%), 18 (82%), 16 (73%), and 12 (55%) of the 22 guest bound conformations in the crystal structures had conformational strain energies of less than or equal to 3.8, 2.0, 0.6, and 0.0 kcal/mol, respectively. These results suggest that (1) the NEM procedure can generate small–molecule bound conformations, and (2) guests adopt low-strain–energy conformations for complexation, thus supporting the virtual screening methods that use local minimum conformations

Detailed Regulatory Mechanism of the Interaction between ZO-1 PDZ2 and Connexin43 Revealed by MD Simulations

The gap junction protein connexin43 (Cx43) binds to the second PDZ domain of Zonula occludens-1 (ZO-1) through its C-terminal tail, mediating the regulation of gap junction plaque size and dynamics. Biochemical study demonstrated that the very C-terminal 12 residues of Cx43 are necessary and sufficient for ZO-1 PDZ2 binding and phosphorylation at residues Ser (-9) and Ser (-10) of the peptide can disrupt the association. However, only a crystal structure of ZO-1 PDZ2 in complex with a shorter 9 aa peptide of connexin43 was solved experimentally. Here, the interactions between ZO-1 PDZ2 and the short, long and phosphorylated Cx43 peptides were studied using molecular dynamics (MD) simulations and free energy calculation. The short peptide bound to PDZ2 exhibits large structural variations, while the extension of three upstream residues stabilizes the peptide conformation and enhanced the interaction. Phosphorylation at Ser(-9) significantly weakens the binding and results in conformational flexibility of the peptide. Glu210 of ZO-1 PDZ2 was found to be a key regulatory point in Cx43 binding and phosphorylation induced dissociation