Research needs for Chagas disease prevention.

We present an overview of the two main strategies for the primary (vector control) and secondary (patient care) prevention of Chagas disease (CD). We identify major advances, knowledge gaps, and key research needs in both areas. Improved specific chemotherapy, including more practical formulations (e.g., paediatric) or combinations of existing drugs, and a better understanding of pathogenesis, including the relative weights of parasite and host genetic makeup, are clearly needed. Regarding CD vectors, we find that only about 10-20% of published papers on triatomines deal directly with disease control. We pinpoint the pitfalls of the current consensus on triatomine systematics, particularly within the Triatomini, and suggest how some straightforward sampling and analytical strategies would improve research on vector ecology, naturally leading to sounder control-surveillance schemes. We conclude that sustained research on CD prevention is still crucial. In the past, it provided not only the know-how, but also the critical mass of scientists needed to foster and consolidate CD prevention programmes; in the future, both patient care and long-term vector control would nonetheless benefit from more sharply focused, problem-oriented research

Phylogenetics and sequence analysis--some problems for the unwary.

DNA sequence comparisons can provide deep insight into phylogenetic relationships, but can also present problems for the unwary. Alignment comparisons are not always as straightforward as they might seem, and comparative models applied to deduce relationships need to be carefully chosen with full regard to the assumptions on which they are based. Most importantly perhaps, genes are not organisms, so some sequence analyses can be poorly informative about relationships - especially if evolution of those organisms has involved significant epigenetic factors, for example, in controlling gene expression. This review highlights some of the most prevalent problems in sequence-based phylogenetic studies of parasite systems

Hypoxia-dependent sequestration of an oxygen sensor by a widespread structural motif can shape the hypoxic response - a predictive kinetic model

<p>Abstract</p> <p>Background</p> <p>The activity of the heterodimeric transcription factor hypoxia inducible factor (HIF) is regulated by the post-translational, oxygen-dependent hydroxylation of its α-subunit by members of the prolyl hydroxylase domain (PHD or EGLN)-family and by factor inhibiting HIF (FIH). PHD-dependent hydroxylation targets HIFα for rapid proteasomal degradation; FIH-catalysed asparaginyl-hydroxylation of the <it>C</it>-terminal transactivation domain (CAD) of HIFα suppresses the CAD-dependent subset of the extensive transcriptional responses induced by HIF. FIH can also hydroxylate ankyrin-repeat domain (ARD) proteins, a large group of proteins which are functionally unrelated but share common structural features. Competition by ARD proteins for FIH is hypothesised to affect FIH activity towards HIFα; however the extent of this competition and its effect on the HIF-dependent hypoxic response are unknown.</p> <p>Results</p> <p>To analyse if and in which way the FIH/ARD protein interaction affects HIF-activity, we created a rate equation model. Our model predicts that an oxygen-regulated sequestration of FIH by ARD proteins significantly shapes the input/output characteristics of the HIF system. The FIH/ARD protein interaction is predicted to create an oxygen threshold for HIFα CAD-hydroxylation and to significantly sharpen the signal/response curves, which not only focuses HIFα CAD-hydroxylation into a defined range of oxygen tensions, but also makes the response ultrasensitive to varying oxygen tensions. Our model further suggests that the hydroxylation status of the ARD protein pool can encode the strength and the duration of a hypoxic episode, which may allow cells to memorise these features for a certain time period after reoxygenation.</p> <p>Conclusions</p> <p>The FIH/ARD protein interaction has the potential to contribute to oxygen-range finding, can sensitise the response to changes in oxygen levels, and can provide a memory of the strength and the duration of a hypoxic episode. These emergent properties are predicted to significantly shape the characteristics of HIF activity in animal cells. We argue that the FIH/ARD interaction should be taken into account in studies of the effect of pharmacological inhibition of the HIF-hydroxylases and propose that the interaction of a signalling sensor with a large group of proteins might be a general mechanism for the regulation of signalling pathways.</p

Methyl 6-amino-6-oxohexanoate

The title compound, C7H13NO3, adopts an approximately planar conformation. The torsion angles in the aliphatic chain between the carbonyl group C atoms range from 172.97 (14) to 179.38 (14)° and the r.m.s. deviation of all non-H atoms is 0.059 Å. The crystal packing is dominated by two strong N—H⋯O hydrogen bonds involving the amide groups and forming R 2 2(8) rings and C(4) chains. Overall, a two-dimensional network parallel to (100) is formed. A weak inter­molecular C—H⋯O inter­action is also present

3-Meth­oxy-3-oxopropanaminium chloride

In the title compound, C4H10NO2 +·Cl−, the central ethyl­ene bond of the cation adopts a gauche conformation. The three H atoms of the –NH3 + group are engaged in strong and highly directional inter­molecular N—H⋯Cl hydrogen bonds, which result in a tape-like arrangement along [010] of the respective ion pairs. In addition, weak inter­molecular C—H⋯Cl and C—H⋯O inter­actions are present

Conformational studies on substituted ε-caprolactams by X-ray crystallography and NMR spectroscopy

The synthesis and conformational analysis of ε-caprolactams containing a -COOMe group at the C-6 position is described. The influence of different C-2, C-6 and N substituents on ring conformation was studied using X-ray crystallography and NMR spectroscopy. The results provide evidence that all the analysed caprolactams adopt a chair type conformation with a planar lactam. In the 6-substituted caprolactam, the -COOMe residue prefers to reside in an equatorial position, but can be induced to occupy an axial orientation by the introduction of a bulky tert-butyloxycarbonyl (BOC) group on the lactam nitrogen or by C-2/C-3 ring desaturation. The BOC protected caprolactam was found to undergo exchange between two chair forms as detected by solution NMR, one with the C-6 ester equatorial (30%) and the other with it in the axial position (70%); the latter was observed by X-ray crystallography. For the C-2 dithiocarbamate substituted C-6 methyl ester seven-membered rings, a single chair form is observed for cis-isomers with both substituents equatorial. The analogous trans-isomers, however, exist as two chair forms in a 1 : 1 equilibrium ratio of 1,NC4 and 4C1,N conformers, where either substituent can occupy axial or equatorial positions. This journal i

Kinetic and inhibition studies on human Jumonji-C (JmjC) domain-containing protein 5

Jumonji-C (JmjC) domain-containing protein 5 (JMJD5) is a human 2-oxoglutarate (2OG) and Fe(II)-dependent oxygenase which catalyses the post-translational C3 hydroxylation of arginyl-residues and which is linked to the circadian rhythm and to cancer biology through as yet unidentified mechanisms. We report robust solid phase extraction coupled to mass spectrometry (SPE-MS)-based JMJD5 assays which enable kinetic and high-throughput inhibition studies. The kinetic studies reveal that some synthetic 2OG derivatives, notably including a 2OG derivative with a cyclic carbon backbone (i.e. (1R)-3-(carboxycarbonyl)cyclopentane-1-carboxylic acid), are efficient alternative cosubstrates of JMJD5 and of factor inhibiting hypoxia-inducible transcription factor HIF-α (FIH), but not of the Jumonji-C (JmjC) histone Nε-methyl lysine demethylase KDM4E, apparently reflecting the closer structural similarity of JMJD5 and FIH. The JMJD5 inhibition assays were validated by investigating the effect of reported 2OG oxygenase inhibitors on JMJD5 catalysis; the results reveal that broad-spectrum 2OG oxygenase inhibitors are also efficient JMJD5 inhibitors (e.g. N-oxalylglycine, pyridine-2,4-dicarboxylic acid, ebselen) whereas most 2OG oxygenase inhibitors that are in clinical use (e.g. roxadustat) do not inhibit JMJD5. The SPE-MS assays will help enable the development of efficient and selective JMJD5 inhibitors for investigating the biochemical functions of JMJD5 in cellular studies

Symmetric Grothendieck polynomials, skew Cauchy identities, and dual filtered Young graphs

Symmetric Grothendieck polynomials are analogues of Schur polynomials in the K-theory of Grassmannians. We build dual families of symmetric Grothendieck polynomials using Schur operators. With this approach we prove skew Cauchy identity and then derive various applications: skew Pieri rules, dual filtrations of Young's lattice, generating series and enumerative identities. We also give a new explanation of the finite expansion property for products of Grothendieck polynomials

Cyclic boronates as versatile scaffolds for KPC-2 β-lactamase inhibition

Klebsiella pneumoniae carbapenemase-2 (KPC-2) is a serine-β-lactamase (SBL) capable of hydrolysing almost all β-lactam antibiotics. We compare KPC-2 inhibition by vaborbactam, a clinically-approved monocyclic boronate, and VNRX-5133 (taniborbactam), a bicyclic boronate in late-stage clinical development. Vaborbactam inhibition is slowly reversible, whereas taniborbactam has an off-rate indicating essentially irreversible complex formation and a 15-fold higher on-rate, although both potentiate β-lactam activity against KPC-2-expressing K. pneumoniae. High resolution X-ray crystal structures reveal closely related binding modes for both inhibitors to KPC-2, with differences apparent only in positioning of the endocyclic boronate ester oxygen. The results indicate the bicyclic boronate scaffold as both an efficient, long-lasting, KPC-2 inhibitor and capable of supporting further iterations that may improve potency against specific enzyme targets and pre empt the emergence of inhibitor resistant KPC-2 variants