Renal urate excretion in patients with Wilson's disease

Renal urate excretion in patients with Wilson's disease. Because many patients with Wilson's disease have hypouricemia, a study was made of 10 patients and 10 control persons to determine the nature of the renal excretory defect. Uric acid excretion was studied before and after the administration of pyrazinamidem—an agent which is postulated to selectively block urate secretion. Urate excretion was also correlated with the quantity of various types of amino acids excreted. In the presence of pyrazinamide, total urate excretion is decreased markedly just as in normal individuals. It appears that proximal reabsorption of urate may not be impaired. There is a positive correlation between excessive urate excretion and that of serine, arginine, valine, and glutamine.Excrétion rénale des urates chez les malades atteints de maladie de Wilson. Du fait que beaucoup de malades atteints de maladie de Wilson ont une hypouricémie une étude a été réalisée chez dix malades et dix sujets témoins afin de déterminer la nature du trouble de l'excrétion des urates. L'excrétion d'acide urique a été étudiée avant et après l'administration de pyrazinamide, agent dont on suppose qu'il bloque électivement la secrétion d'urate. L'excrétion d'urate a été aussi corrélée avec la quantité de divers acides aminés excrétés. En présence de pyrazinamide l'excrétion totale d'urate est notablement diminuée, comme chez les témoins. Il apparaît que la réabsorption proximale des urates n'est probablement pas diminuée. Il existe une corrélation positive entre l'excrétion excessive d'urate et l'excrétion de sérine, d'arginine, de valine et de glutamine

The Midpoint Rule as a Variational--Symplectic Integrator. I. Hamiltonian Systems

Numerical algorithms based on variational and symplectic integrators exhibit special features that make them promising candidates for application to general relativity and other constrained Hamiltonian systems. This paper lays part of the foundation for such applications. The midpoint rule for Hamilton's equations is examined from the perspectives of variational and symplectic integrators. It is shown that the midpoint rule preserves the symplectic form, conserves Noether charges, and exhibits excellent long--term energy behavior. The energy behavior is explained by the result, shown here, that the midpoint rule exactly conserves a phase space function that is close to the Hamiltonian. The presentation includes several examples.Comment: 11 pages, 8 figures, REVTe

Assessing the Accuracy of Ancestral Protein Reconstruction Methods

The phylogenetic inference of ancestral protein sequences is a powerful technique for the study of molecular evolution, but any conclusions drawn from such studies are only as good as the accuracy of the reconstruction method. Every inference method leads to errors in the ancestral protein sequence, resulting in potentially misleading estimates of the ancestral protein's properties. To assess the accuracy of ancestral protein reconstruction methods, we performed computational population evolution simulations featuring near-neutral evolution under purifying selection, speciation, and divergence using an off-lattice protein model where fitness depends on the ability to be stable in a specified target structure. We were thus able to compare the thermodynamic properties of the true ancestral sequences with the properties of “ancestral sequences” inferred by maximum parsimony, maximum likelihood, and Bayesian methods. Surprisingly, we found that methods such as maximum parsimony and maximum likelihood that reconstruct a “best guess” amino acid at each position overestimate thermostability, while a Bayesian method that sometimes chooses less-probable residues from the posterior probability distribution does not. Maximum likelihood and maximum parsimony apparently tend to eliminate variants at a position that are slightly detrimental to structural stability simply because such detrimental variants are less frequent. Other properties of ancestral proteins might be similarly overestimated. This suggests that ancestral reconstruction studies require greater care to come to credible conclusions regarding functional evolution. Inferred functional patterns that mimic reconstruction bias should be reevaluated

Salvage of failed free flaps used in head and neck reconstruction

Free flap success rates are in excess of 95%. Vascular occlusion (thrombosis) remains the primary reason for flap loss, with venous thrombosis being more common than arterial occlusion. The majority of flap failures occur within the first 48 hours. With early recognition and intervention of flap compromise salvage is possible. Successful salvage rates range from 28% to over 90%. Rapid re-exploration in this clinical setting is crucial to maximise the chances of flap salvage. If salvage is not feasible or unsuccessful then non-surgical methods of salvage may be employed with some possibility of success. The purpose of this article is to review the causes of free flap failure and to highlight the available options for salvage

Fully automated synthesis of (phospho)peptide arrays in microtiter plate wells provides efficient access to protein tyrosine kinase characterization

BACKGROUND: Synthetic peptides have played a useful role in studies of protein kinase substrates and interaction domains. Synthetic peptide arrays and libraries, in particular, have accelerated the process. Several factors have hindered or limited the applicability of various techniques, such as the need for deconvolution of combinatorial libraries, the inability or impracticality of achieving full automation using two-dimensional or pin solid phases, the lack of convenient interfacing with standard analytical platforms, or the difficulty of compartmentalization of a planar surface when contact between assay components needs to be avoided. This paper describes a process for synthesis of peptides and phosphopeptides on microtiter plate wells that overcomes previous limitations and demonstrates utility in determination of the epitope of an autophosphorylation site phospho-motif antibody and utility in substrate utilization assays of the protein tyrosine kinase, p60(c-src). RESULTS: The overall reproducibility of phospho-peptide synthesis and multiplexed EGF receptor (EGFR) autophosphorylation site (pY1173) antibody ELISA (9H2) was within 5.5 to 8.0%. Mass spectrometric analyses of the released (phospho)peptides showed homogeneous peaks of the expected molecular weights. An overlapping peptide array of the complete EGFR cytoplasmic sequence revealed a high redundancy of 9H2 reactive sites. The eight reactive phospopeptides were structurally related and interestingly, the most conserved antibody reactive peptide motif coincided with a subset of other known EGFR autophosphorylation and SH2 binding motifs and an EGFR optimal substrate motif. Finally, peptides based on known substrate specificities of c-src and related enzymes were synthesized in microtiter plate array format and were phosphorylated by c-Src with the predicted specificities. The level of phosphorylation was proportional to c-Src concentration with sensitivities below 0.1 Units of enzyme. CONCLUSIONS: The ability of this method to interface with various robotics and instrumentation is highly flexible since the microtiter plate is an industry standard. It is highly scalable by increasing the surface area within the well or the number of wells and does not require specialized robotics. The microtiter plate array system is well suited to the study of protein kinase substrates, antigens, binding molecules, and inhibitors since these all can be quantitatively studied at a single uniform, reproducible interface

Variation in Emission and Absorption Lines and Continuum Flux by Orbital Phase in Vela X-1

High resolution spectral studies were undertaken at orbital phases 0, 0.25 and 0.5 on the high-mass X-ray binary (HMXB) Vela X-1 using archival Chandra data. We present (a) the first detailed analysis of the multiple strong narrow emission lines present in phase 0.5 (b) an analysis of the absorption of the continuum in phase 0.5, and (c) the first detection of narrow emission and absorption lines in phase 0.25. Multiple fluorescent and H-and He-like emission lines in the band 1.6 - 20 Angstrom in eclipse are partially obscured at phase 0.25 by the X-ray continuum. The phase 0.25 spectrum displays 3 triplets, 2 with a blue-shifted resonance (r) line in absorption and the intercombination (i) and forbidden (f) lines in emission, and shows in absorption other blue-shifted lines seen in emission in eclipse. At phase 0.5 the soft X-ray continuum diminishes revealing an "eclipse-like" spectrum, however line flux values are around 13-fold those in eclipse. We conclude the narrow emission lines in Vela X-1 become apparent when the continuum is blocked from line of sight, either by eclipse or by scattering and/or absorption from a wake or cloud. The H-and He-like lines arise in warm photoionised regions in the stellar wind, while the fluorescent lines (including a Ni K alpha line) are produced in cooler clumps of gas outside these regions. Absorption of the 5-13 Angstrom continuum at phase 0.5 may be caused by an accretion wake comprised of dense stagnant photoionized plasma inside a Stromgren zone. Multiple fluorescent emission lines may be a common feature of the supergiant category of HMXBs.Comment: 29 pages, 7 figures, accepted for publication in the Astronomical Journa

Time-dependent quantum many-body theory of identical bosons in a double well: Early time ballistic interferences of fragmented and number entangled states

A time-dependent multiconfigurational self-consistent field theory is presented to describe the many-body dynamics of a gas of identical bosonic atoms confined to an external trapping potential at zero temperature from first principles. A set of generalized evolution equations are developed, through the time-dependent variational principle, which account for the complete and self-consistent coupling between the expansion coefficients of each configuration and the underlying one-body wave functions within a restricted two state Fock space basis that includes the full effects of the condensate's mean field as well as atomic correlation. The resulting dynamical equations are a classical Hamiltonian system and, by construction, form a well-defined initial value problem. They are implemented in an efficient numerical algorithm. An example is presented, highlighting the generality of the theory, in which the ballistic expansion of a fragmented condensate ground state is compared to that of a macroscopic quantum superposition state, taken here to be a highly entangled number state, upon releasing the external trapping potential. Strikingly different many-body matter-wave dynamics emerge in each case, accentuating the role of both atomic correlation and mean-field effects in the two condensate states.Comment: 16 pages, 5 figure

A solution to the zero-hamiltonian problem in 2-D gravity

The zero-hamiltonian problem, present in reparametrization invariant systems, is solved for the 2-D induced gravity model. Working with methods developed by Henneaux et al. we find systematically the reduced phase-space physics, generated by an {\it effective} hamiltonian obtained after complete gauge fixing.Comment: 5 pages, revte

Classification of lapses in smokers attempting to stop: A supervised machine learning approach using data from a popular smoking cessation smartphone app

Introduction Smoking lapses after the quit date often lead to full relapse. To inform the development of real-time, tailored lapse prevention support, we used observational data from a popular smoking cessation app to develop supervised machine learning algorithms to distinguish lapse from non-lapse reports. Methods We used data from app users with ≥20 unprompted data entries, which included information about craving severity, mood, activity, social context, and lapse incidence. A series of group-level supervised machine learning algorithms (e.g., Random Forest, XGBoost) were trained and tested. Their ability to classify lapses for out-of-sample i) observations and ii) individuals were evaluated. Next, a series of individual-level and hybrid algorithms were trained and tested. Results Participants (N=791) provided 37,002 data entries (7.6% lapses). The best-performing group-level algorithm had an area under the receiver operating characteristic curve (AUC) of 0.969 (95% CI= 0.961-0.978). Its ability to classify lapses for out-of-sample individuals ranged from poor to excellent (AUC=0.482-1.000). Individual-level algorithms could be constructed for 39/791 participants with sufficient data, with a median AUC of 0.938 (range: 0.518-1.000). Hybrid algorithms could be constructed for 184/791 participants and had a median AUC of 0.825 (range: 0.375-1.000). Discussion Using unprompted app data appeared feasible for constructing a high-performing group-level lapse classification algorithm but its performance was variable when applied to unseen individuals. Algorithms trained on each individual’s dataset, in addition to hybrid algorithms trained on the group plus a proportion of each individual’s data, had improved performance but could only be constructed for a minority of participants. Implications This study used routinely collected data from a popular smartphone app to train and test a series of supervised machine learning algorithms to distinguish lapse from non-lapse events. Although a high-performing group-level algorithm was developed, it had variable performance when applied to new, unseen individuals. Individual-level and hybrid algorithms had somewhat greater performance but could not be constructed for all participants due to lack of variability in the outcome measure. Triangulation of results with those from a prompted study design is recommended prior to intervention development, with real-world lapse prediction likely requiring a balance between unprompted and prompted app data