An Experimental and Theoretical Study on the Novel Tetraphosphorus Triselenide Boron Triiodide (P<Subscript>4</Subscript>Se<Subscript>3</Subscript>)·(BI<Subscript>3</Subscript>) Adduct

Tetraphosphorus triselenide boron triiodide (P₄Se₃)·(BI₃) has been prepared. The product formed has been characterized by Raman and IR spectroscopy. Vibrational assignments for the normal modes of this Lewis acid-base adduct have been made on the basis of comparison between theoretically obtained and experimentally observed Raman and IR data. The geometries of several possible tetraphosphorus triselenide boron triiodide (P₄Se₃)·(BI₃) adducts have been calculated. The bonding and electron transfer from the tetraphosphorus triselenide P₄Se₃ unit to the Lewis acid BI₃ has been investigated by applying NBO analysis.     

Integrating Protein Homeostasis Strategies in Prokaryotes

Bacterial cells are frequently exposed to dramatic fluctuations in their environment, which cause perturbation in protein homeostasis and lead to protein misfolding. Bacteria have therefore evolved powerful quality control networks consisting of chaperones and proteases that cooperate to monitor the folding states of proteins and to remove misfolded conformers through either refolding or degradation. The levels of the quality control components are adjusted to the folding state of the cellular proteome through the induction of compartment specific stress responses. In addition, the activities of several quality control components are directly controlled by these stresses, allowing for fast activation. Severe stress can, however, overcome the protective function of the proteostasis network leading to the formation of protein aggregates, which are sequestered at the cell poles. Protein aggregates are either solubilized by AAA+ chaperones or eliminated through cell division, allowing for the generation of damage-free daughter cells.     

Comparison of the structure of human recombinant short form stromelysin by multidimensional heteronuclear NMR and X-ray crystallography

Summary Stromelysin-1 is a matrix metalloprotease that has been implicated in a number of degenerative diseases. Here we present the refined NMR solution structure of the catalytic domain of stromelysin-1 complexed with a small inhibitor and compare it to the X-ray crystal structure of the same complex. The structures are similar in global fold and show an unusual bottomless S1' subsite. There are differences, however, in the least well defined regions, Phe⁸³-Ile⁸⁹, His²²⁴-Phe²³² and Pro²⁴⁹-Pro²⁵⁰, reflecting the lack of NOE data and large B-factors. The region His²²⁴-Phe²³² contains residues of the Sl' subsite and, consequently, small differences are observed in this subsite. Hydrogen-bond data show that, in contrast to the crystal structure, the solution structure lacks a hydrogen bond between the amide of Tyr²²³ and the carbonyl of the P3' residue. Analysis of bound water shows two tightly bound water molecules both in the solution and the crystal structure; neither of these waters are in the inhibitor binding site.Abbreviations MMP matrix metalloendoprotease - HMQC heteronuclear multiple quantum coherence - HSQC heteronuclear single quantum coherence - NOE nuclear Overhauser enhancement - NOESY NOE spectroscopy - PFG pulsed field gradient - sfSTR stromelysin-1 (EC 3.4.24.17), truncated at residue 255 The coordinates of the NMR solution structure (file name 2SRT) and the X-ray crystal structure (file name 1SLN) have been deposited in the Brookhaven Protein Data Bank.     

Towards Raman spectroscopy of urine as screening tool

For the screening purposes urine is an especially attractive biofluid, since it offers easy and noninvasive sample collection and provides a snapshot of the whole metabolic status of the organism, which may change under different pathological conditions. Raman spectroscopy (RS) has the potential to monitor these changes and utilize them for disease diagnostics. The current study utilizes mouse models aiming to compare the feasibility of the urine based RS combined with chemometrics for diagnosing kidney diseases directly influencing urine composition and respiratory tract diseases having no direct connection to urine formation. The diagnostic models for included diseases were built using principal component analysis with linear discriminant analysis and validated with a leave‐one‐mouse‐out cross‐validation approach. Considering kidney disorders, the accuracy of 100% was obtained in discrimination between sick and healthy mice, as well as between two different kidney diseases. For asthma and invasive pulmonary aspergillosis achieved accuracies were noticeably lower, being, respectively, 77.27% and 78.57%. In conclusion, our results suggest that RS of urine samples not only provides a solution for a rapid, sensitive and noninvasive diagnosis of kidney disorders, but also holds some promises for the screening of nonurinary tract diseases.     

Phosphate inhibition of secondary metabolism in Streptomyces hygroscopicus and its reversal by cyclic AMP

Inorganic phosphate inhibited the biosynthesis of the macrolide antibiotic turimycin in different strains of Streptomyces hygroscopicus. In the wild type strain a depression was observed with increasing phosphate concentrations. A total inhibition was found at 0.1 M phosphate. In a high producing mutant a minimum of turimycin production occured when the phosphate concentration was between 5 mM and 10 mM. Above this concentration the antibiotic synthesis increased again but the production period shifted to a later period of cultivation. Addition of inorganic phosphate resulted in an initial increase of intracellular cyclic AMP content. But a second elevation characterizing the normal level of cyclic AMP throughout the growth phase was prevented by phosphate. Exogenous cyclic AMP as well as positive effectors of the adenylyl cyclase system were able to overcome the phosphate suppression. Cyclic AMP abolished the reduction of protein synthesis following phosphate addition and caused the reappearance of a protein band which may be responsible for the turimycin biosynthesis.     

Towards a Computable Data Corpus of Temporal Correlations between Drug Administration and Lab Value Changes

Background

The analysis of electronic health records for an automated detection of adverse drug reactions is an approach to solve the problems that arise from traditional methods like spontaneous reporting or manual chart review. Algorithms addressing this task should be modeled on the criteria for a standardized case causality assessment defined by the World Health Organization. One of these criteria is the temporal relationship between drug intake and the occurrence of a reaction or a laboratory test abnormality. Appropriate data that would allow for developing or validating related algorithms is not publicly available, though.

Methods

In order to provide such data, retrospective routine data of drug administrations and temporally corresponding laboratory observations from a university clinic were extracted, transformed and evaluated by experts in terms of a reasonable time relationship between drug administration and lab value alteration.

Result

The result is a data corpus of 400 episodes of normalized laboratory parameter values in temporal context with drug administrations. Each episode has been manually classified whether it contains data that might indicate a temporal correlation between the drug administration and the change of the lab value course, whether such a change is not observable or whether a decision between those two options is not possible due to the data. In addition, each episode has been assigned a concordance value which indicates how difficult it is to assess. This is the first open data corpus of a computable ground truth of temporal correlations between drug administration and lab value alterations.

Discussion

The main purpose of this data corpus is the provision of data for further research and the provision of a ground truth which allows for comparing the outcome of other assessments of this data with the outcome of assessments made by human experts. It can serve as a contribution towards systematic, computerized ADR detection in retrospective data. With this lab value curve data as a basis, algorithms for detecting temporal relationships can be developed, and with the classification made by human experts, these algorithms can immediately be validated. Due to the normalization of the lab value data, it allows for a generic approach rather than for specific or solitary drug/lab value combinations.