Genome sequence of the progenitor of the wheat D genome Aegilops tauschii.

Aegilops tauschii is the diploid progenitor of the D genome of hexaploid wheat (Triticum aestivum, genomes AABBDD) and an important genetic resource for wheat. The large size and highly repetitive nature of the Ae. tauschii genome has until now precluded the development of a reference-quality genome sequence. Here we use an array of advanced technologies, including ordered-clone genome sequencing, whole-genome shotgun sequencing, and BioNano optical genome mapping, to generate a reference-quality genome sequence for Ae. tauschii ssp. strangulata accession AL8/78, which is closely related to the wheat D genome. We show that compared to other sequenced plant genomes, including a much larger conifer genome, the Ae. tauschii genome contains unprecedented amounts of very similar repeated sequences. Our genome comparisons reveal that the Ae. tauschii genome has a greater number of dispersed duplicated genes than other sequenced genomes and its chromosomes have been structurally evolving an order of magnitude faster than those of other grass genomes. The decay of colinearity with other grass genomes correlates with recombination rates along chromosomes. We propose that the vast amounts of very similar repeated sequences cause frequent errors in recombination and lead to gene duplications and structural chromosome changes that drive fast genome evolution.

Homoleptic Complexes of Heterocyclic Curcuminoids with Mg(II) and Cu(II): First Conformationally Heteroleptic Case, Crystal Structures, and Biological Properties.

We report herein the synthesis and characterization of three heterocyclic curcuminoid ligands and their homoleptic metal complexes with magnesium and copper. Thus, N-methyl-2-pyrrolecarboxaldehyde, Furan-2-carboxaldehyde, and 2-Thiophenecarboxaldehyde were condensed with 2,4-pentanedione-boron trioxide complex. The first N-methyl-2-pyrrole curcuminoid and its Mg(II) complex are reported. All curcuminoid ligands and their corresponding metal complexes were characterized by infrared spectroscopy (IR), liquid state nuclear magnetic resonance (LSNMR), electron paramagnetic resonance (EPR), mass spectrometry (MS) and single crystal X-ray diffraction (SCXRD). The ThiopheneCurc-Cu (9) constitutes the first case of a "conformationally-heteroleptic" complex. The unique six-peaks star arrangement for the ThiopheneCurc ligand derived from the supramolecular description is reported. The metal complexes of FuranCurc-Mg (5) and ThiopheneCurc-Cu (9) have a good antioxidant effect (IC50 = 11.26 ± 1.73 and 10.30 ± 0.59 µM), three and two times higher than their free ligands respectively. Additionally, (5) shows remarkable cytotoxicity against colon cancer adenocarcinoma cell line HCT-15, comparable to that of cisplatin, with a negligible toxic effect in vitro towards a healthy monkey kidney cell line (COS-7).

[Guidelines on atopic dermatitis for Mexico (GUIDAMEX): using the ADAPTE methodology]. / Guía de dermatitis atópica para México (GUIDAMEX): lineamientos usando metodología ADAPTE.

With the advancement of knowledge in relation to the physiopathogenesis of atopic dermatitis (AD), several new therapeutic forms have been developed. There are also new guidelines for self-care. On the other hand, there is still an underdiagnosis of AD in Mexico. Thus, the need was seen to develop a national guide, with a broad base among the different medical groups that care for patients with AD. The Atopic Dermatitis Guidelines for Mexico (GUIDAMEX) was developed with the ADAPTE methodology, with the endorsement and participation of ten national medical societies, from physicians in Primary Healthcare to allergists and dermatologists. Throughout the manuscript, key clinical questions are answered that lead to recommendations and suggestions for the diagnosis of AD (including differential diagnosis with immunodeficiency syndromes), the recognition of comorbidities and complications, non-pharmacological treatment including therapeutic education, treatment of flares and maintenance therapy. The latter encompasses general measures to avoid triggering factors, first-line treatment focussed on repair of the skin barrier, second-line treatment (topical proactive therapy), and third-line phototherapy or systemic treatment, including dupilumab and JAK inhibitors.

Con el avance de los conocimientos en relación con la fisiopatogenia de la dermatitis atópica (DA) se han desarrollado varias formas terapéuticas nuevas. Asimismo, existen nuevos lineamientos para el autocuidado. Por otro lado, aún existe un subdiagnóstico de la DA en México. Así, se vio la necesidad de desarrollar una guía nacional, con base amplia entre las diferentes agrupaciones médicos que atienden pacientes con DA. Se desarrolló la Guía de DA para México (GUIDAMEX) con la metodología ADAPTE, con el aval y la participación de diez sociedades médicas nacionales, desde médicos del primer contacto hasta alergólogos y dermatólogos. A lo largo del escrito se contestan preguntas clínicas clave que llevan a recomendaciones y sugerencias para el diagnóstico de la DA (incluyendo diagnóstico diferencial con síndromes de inmunodeficiencia), el reconocer de las comorbilidades y complicaciones, las medidas generales (tratamiento no farmacológico) incluyendo la educación terapéutica, el tratamiento de los brotes y el tratamiento de mantenimiento. Este último abarca las medidas generales de evitar agravantes, el tratamiento de primera línea reparador de la barrera cutánea, de segunda línea (manejo proactivo tópico), hasta la fototerapia y el tratamiento sistémico de la tercera línea, incluyendo dupilumab y los inhibidores de la cinasa de Jano.

Optical maps refine the bread wheat Triticum aestivum cv. Chinese Spring genome assembly.

Until recently, achieving a reference-quality genome sequence for bread wheat was long thought beyond the limits of genome sequencing and assembly technology, primarily due to the large genome size and > 80% repetitive sequence content. The release of the chromosome scale 14.5-Gb IWGSC RefSeq v1.0 genome sequence of bread wheat cv. Chinese Spring (CS) was, therefore, a milestone. Here, we used a direct label and stain (DLS) optical map of the CS genome together with a prior nick, label, repair and stain (NLRS) optical map, and sequence contigs assembled with Pacific Biosciences long reads, to refine the v1.0 assembly. Inconsistencies between the sequence and maps were reconciled and gaps were closed. Gap filling and anchoring of 279 unplaced scaffolds increased the total length of pseudomolecules by 168 Mb (excluding Ns). Positions and orientations were corrected for 233 and 354 scaffolds, respectively, representing 10% of the genome sequence. The accuracy of the remaining 90% of the assembly was validated. As a result of the increased contiguity, the numbers of transposable elements (TEs) and intact TEs have increased in IWGSC RefSeq v2.1 compared with v1.0. In total, 98% of the gene models identified in v1.0 were mapped onto this new assembly through development of a dedicated approach implemented in the MAGAAT pipeline. The numbers of high-confidence genes on pseudomolecules have increased from 105 319 to 105 534. The reconciled assembly enhances the utility of the sequence for genetic mapping, comparative genomics, gene annotation and isolation, and more general studies on the biology of wheat.

IDH1 p.R132H ctDNA and D-2-hydroxyglutarate as CSF biomarkers in patients with IDH-mutant gliomas.

INTRODUCTION: We aimed to evaluate IDH1 p.R132H mutation and 2-hydroxyglutarate (2HG) in cerebrospinal fluid (CSF) as biomarkers for patients with IDH-mutant gliomas. METHODS: CSF was collected from patients with infiltrating glioma, and 2HG levels were measured by liquid chromatography-mass spectrometry. IDH1 p.R132H mutant allele frequency (MAF) in CSF-ctDNA was measured by digital droplet PCR (ddPCR). Tumor volume was measured from standard-of-care magnetic resonance images. RESULTS: The study included 48 patients, 6 with IDH-mutant and 42 with IDH-wildtype gliomas, and 57 samples, 9 from the patients with IDH-mutant and 48 from the patients with IDH-wildtype gliomas. ctDNA was detected in 7 of the 9 samples from patients with IDH-mutant glioma, and IDH1 p.R132H mutation was detected in 5 of the 7 samples. The MAF ranged from 0.3 to 39.95%. Total 2HG level, D-2HG level, and D/L-2HG ratio in CSF were significantly higher in patients with IDH-mutant gliomas than in patients with IDH-wildtype gliomas. D-2HG level and D/L-2HG ratio correlated with total tumor volume in patients with IDH-mutant gliomas but not in patients with IDH-wildtype gliomas. CONCLUSION: Our results suggest that detection of IDH1 p.R132H mutation by ddPCR and increased D-2HG level in CSF may help identify IDH-mutant gliomas. Our results also suggest that D-2HG level and D/L-2HG ratio correlate with tumor volume in patients with IDH-mutant gliomas. Further prospective studies with larger cohorts are needed to validate these findings.

Turing Instabilities and Rotating Spiral Waves in Glycolytic Processes.

We study single-frequency oscillations and pattern formation in the glycolytic process modeled by a reduction in the well-known Sel'kov's equations (Sel'kov in Eur J Biochem 4:79, 1968), which describe, in the whole cell, the phosphofructokinase enzyme reaction. By using averaging theory, we establish the existence conditions for limit cycles and their limiting average radius in the kinetic reaction equations. We analytically establish conditions on the model parameters for the appearance of unstable nonlinear modes seeding the formation of two-dimensional patterns in the form of classical spots and stripes. We also establish the existence of a Hopf bifurcation, which characterizes the reaction dynamics, producing glycolytic rotating spiral waves. We numerically establish parameter regions for the existence of these spiral waves and address their linear stability. We show that as the model tends toward a suppression of the relative source rate, the spiral wave solution loses stability. All our findings are validated by full numerical simulations of the model equations. Finally, we discuss in vitro evidence of spatiotemporal activity patterns found in glycolytic experiments, and propose plausible biological implications of our model results.

Molecular dissection of the membrane aggregation mechanisms induced by monomeric annexin A2.

Annexins are a multigene family of proteins involved in aggregation and fusion processes of biological membranes. One of its best-known members is annexin A2 (or p36), capable of binding to acidic phospholipids in a calcium-dependent manner, as occurs with other members of the same family. In its heterotetrameric form, especially with protein S100A10 (p11), annexin A2 has been involved as a determinant factor in innumerable biological processes like tumor development or anticoagulation. However, the subcellular coexistence of different pools of the protein, in which the monomeric form of annexin A2 is growing in functional relevance, is to date poorly described. In this work we present an exhaustive structural and functional characterization of monomeric human annexin A2 by using different recombinant mutants. The important role of the amphipathic N-terminal α-helix in membrane binding and aggregation has been analyzed. We have also studied the potential implication of lateral "antiparallel" protein dimers in membrane aggregation. In contrast to what was previously suggested, formation of these dimers negatively regulate aggregation. We have also confirmed the essential role of three lysine residues located in the convex surface of the molecule in calcium-free and calcium-dependent membrane binding and aggregation. Finally, we propose models for annexin A2-mediated vesicle aggregation mechanisms.

Massive integrative gene set analysis enables functional characterization of breast cancer subtypes.

The availability of large-scale repositories and integrated cancer genome efforts have created unprecedented opportunities to study and describe cancer biology. In this sense, the aim of translational researchers is the integration of multiple omics data to achieve a better identification of homogeneous subgroups of patients in order to develop adequate diagnostic and treatment strategies from the personalized medicine perspective. So far, existing integrative methods have grouped together omics data information, leaving out individual omics data phenotypic interpretation. Here, we present the Massive and Integrative Gene Set Analysis (MIGSA) R package. This tool can analyze several high throughput experiments in a comprehensive way through a functional analysis strategy, relating a phenotype to its biological function counterpart defined by means of gene sets. By simultaneously querying different multiple omics data from the same or different groups of patients, common and specific functional patterns for each studied phenotype can be obtained. The usefulness of MIGSA was demonstrated by applying the package to functionally characterize the intrinsic breast cancer PAM50 subtypes. For each subtype, specific functional transcriptomic profiles and gene sets enriched by transcriptomic and proteomic data were identified. To achieve this, transcriptomic and proteomic data from 28 datasets were analyzed using MIGSA. As a result, enriched gene sets and important genes were consistently found as related to a specific subtype across experiments or data types and thus can be used as molecular signature biomarkers.

A New Family of Homoleptic Copper Complexes of Curcuminoids: Synthesis, Characterization and Biological Properties.

We report herein the synthesis and crystal structures of five new homoleptic copper complexes of curcuminoids. The scarcity of reports of homoleptic complex structures of curcuminoids is attributed to the lack of crystallinity of such derivatives, and therefore, their characterization by single crystal X-ray diffraction is rare. The ligand design suppressing the phenolic interaction by esterification or etherification has afforded a significant increase in the number of known crystal structures of homoleptic metal complexes of curcuminoids revealing more favorable crystallinity. The crystal structures of the present new copper complexes show four-fold coordination with a square planar geometry. Two polymorphs were found for DiBncOC-Cu when crystallized from DMF. The characterization of these new complexes was carried out using infrared radiation (IR), nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and single crystal X-ray diffraction (SCXRD) and the antioxidant and cytotoxic activity of the obtained complexes was evaluated.

Analysis of Brachypodium genomes with genome-wide optical maps.

Brachypodium distachyon (n = 5) is a diploid and has been widely used as a genetic model. Brachypodium stacei (n = 10) and B. hybridum (n = 15) are species that are related to B. distachyon, leading to an hypothesis that they are part of a polyploid series based on x = 5. Several lines of evidence suggest that this hypothesis is incorrect and that the genomes of the three taxa may have evolved by a more complex process. We constructed an optical whole-genome BioNano genome (BNG) map for each species and did pairwise alignment of the BNG maps. The maps showed that B. distachyon and B. stacei are both diploid, in spite of B. stacei having twice as many chromosomes as B. distachyon, and that B. hybridum is an allopolyploid formed from hybridization between B. distachyon and B. stacei. This study also demonstrated the use of BNG maps in the detection and quantification of structural variants among the genomes.

Prospective validation of right ventricular role in primary graft dysfunction after lung transplantation.

Primary graft dysfunction is a significant cause of lung transplant morbidity and mortality, but its underlying mechanisms are not completely understood. The aims of the present study were: 1) to confirm that right ventricular function is a risk factor for severe primary graft dysfunction; and 2) to propose a clinical model for predicting the development of severe primary graft dysfunction.A prospective cohort study was performed over 14 months. The primary outcome was development of primary graft dysfunction grade 3. An echocardiogram was performed immediately before transplantation, measuring conventional and speckle-tracking parameters. Pulmonary artery catheter data were also measured. A classification and regression tree was made to identify prognostic models for the development of severe graft dysfunction.70 lung transplant recipients were included. Patients who developed severe primary graft dysfunction had better right ventricular function, as estimated by cardiac index (3.5±0.8 versus 2.6±0.7 L·min-1·m-2, p<0.01) and basal longitudinal strain (-25.7±7.3% versus -19.5±6.6%, p<0.01). Regression tree analysis provided an algorithm based on the combined use of three variables (basal longitudinal strain, pulmonary fibrosis disease and ischaemia time), allowing accurate preoperative discrimination of three distinct subgroups with low (11-20%), intermediate (54%) and high (75%) risk of severe primary graft dysfunction (area under the receiver operating characteristic curve 0.81).Better right ventricular function is a risk factor for the development of severe primary graft dysfunction. Preoperative estimation of right ventricular function could allow early identification of recipients at increased risk, who would benefit the most from careful perioperative management in order to limit pulmonary overflow.

Surface Activity as a Crucial Factor of the Biological Actions of Ole e 1, the Main Aeroallergen of Olive Tree (Olea europaea) Pollen.

Aeroallergens are airborne substances-mainly proteins-capable of triggering Th2-immune responses in respiratory allergies. They enter into the body through the upper airways, reaching the mucosa afterward. Mucosae lining at the luminal side consists of an epithelial barrier completely covered by mucus and pulmonary surfactant. Both pulmonary surfactant and plasma membrane of the epithelial cells represent two physiological phospholipid-based barriers where allergens first impact before triggering their biological effects. The interaction of allergens with lipids at relevant physiological surfaces could promote structural changes on the molecule, resulting on a potential modification of its allergenic properties. In this work, we have first described the surface and phospholipid interaction capabilities of the clinically relevant aeroallergen Ole e 1, the main allergen of olive tree pollen. By using epifluorescence microscopy of Langmuir transferred films, we observed that lipid-packed ordered domains may function as a preferential location for allergen to accumulate at the air-liquid interface, an effect that is abolished in the presence of cholestenone. The possible implications of phospholipid-interfacial effects in the modification of allergen structural and functional properties will be discussed.

Replacing the axial ligand tyrosine 75 or its hydrogen bond partner histidine 83 minimally affects hemin acquisition by the hemophore HasAp from Pseudomonas aeruginosa.

Hemophores from Pseudomonas aeruginosa (HasAp), Serratia marcescens (HasAsm), and Yersinia pestis (HasAyp) bind hemin between two loops. One of the loops harbors conserved axial ligand Tyr75 (Y75 loop) in all three structures, whereas the second loop (H32 loop) contains axial ligand His32 in HasAp and HasAsm, but a noncoordinating Gln32 in HasAyp. Binding of hemin to the Y75 loop of HasAp or HasAsm causes a large rearrangement of the H32 loop that allows His32 coordination. The Q32 loop in apo-HasAyp is already in the closed conformation, such that binding of hemin to the conserved Y75 loop occurs with minimal structural rearrangement and without coordinative interaction with the Q32 loop. In this study, structural and spectroscopic investigations of the hemophore HasAp were conducted to probe (i) the role of the conserved Tyr75 loop in hemin binding and (ii) the proposed requirement of the His83-Tyr75 hydrogen bond to allow the coordination of hemin by Tyr75. High-resolution crystal structures of H83A holo-HasAp obtained at pH 6.5 (0.89 Å) and pH 5.4 (1.25 Å) show that Tyr75 remains coordinated to the heme iron, and that a water molecule can substitute for Nδ of His83 to interact with the Oη atom of Tyr75, likely stabilizing the Tyr75-Fe interaction. Nuclear magnetic resonance spectroscopy revealed that in apo-Y75A and apo-H83A HasAp, the Y75 loop is disordered, and that disorder propagates to nearby elements of secondary structure, suggesting that His83 Nδ-Tyr75 Oη interaction is important to the organization of the Y75 loop in apo-HasA. Kinetic analysis of hemin loading conducted via stopped-flow UV-vis and rapid-freeze-quench resonance Raman shows that both mutants load hemin with biphasic kinetic parameters that are not significantly dissimilar from those previously observed for wild-type HasAp. When the structural and kinetic data are taken together, a tentative model emerges, which suggests that HasA hemophores utilize hydrophobic, π-π stacking, and van der Waals interactions to load hemin efficiently, while axial ligation likely functions to slow hemin release, thus allowing the hemophore to meet the challenge of capturing hemin under inhospitable conditions and delivering it selectively to its cognate receptor.

Antitumor efficacy, pharmacokinetic and biodistribution studies of the anticancer peptide CIGB-552 in mouse models.

Accumulation of the COMMD1 protein as a druggable pharmacology event to target cancer cells has not been evaluated so far in cancer animal models. We have previously demonstrated that a second-generation peptide, with cell-penetrating capacity, termed CIGB-552, was able to induce apoptosis mediated by stabilization of COMMD1. Here, we explore the antitumor effect by subcutaneous administration of CIGB-552 in a therapeutic schedule. Outstandingly, a significant delay of tumor growth was observed at 0.2 and 0.7 mg/kg (p < 0.01) or 1.4 mg/kg (p < 0.001) after CIGB-552 administration in both syngeneic murine tumors and patient-derived xenograft models. Furthermore, we evidenced that (131)I-CIGB-552 peptide was actually accumulated in the tumors after administration by subcutaneous route. A typical serine-proteases degradation pattern for CIGB-552 in BALB/c mice serum was identified. Further, biological characterization of the main metabolites of the peptide CIGB-552 suggests that the cell-penetrating capacity plays an important role in the cytotoxic activity. This report is the first in describing the antitumor effect induced by systemic administration of a peptide that targets COMMD1 for stabilization. Moreover, our data reinforce the perspectives of CIGB-552 for cancer targeted therapy.

Implants for orthodontic anchorage: success rates and reasons of failures.

INTRODUCTION: The aims of this study were to analyze the success rate of mini-implants and miniscrews and to report the reasons behind them. MATERIALS AND METHODS: An electronic literature search from PubMed databases and a hand search in implant- and orthodontic-related journals were performed until December 31, 2011. Human clinical studies in English that reported temporary anchorage devices used for orthodontic purpose with at least 6 months follow-up were included. In addition, the minimal number of implants had to be at least 10. Implants placed in maxilla, mandible, and hard palate were included. RESULTS: The initial search resulted in 847 articles, of which 46 were further evaluated. Finally, 29 studies were qualified and classified into 2 groups: implants placed in maxilla and mandible (group 1) and implants placed in hard palate (group 2). A meta-analysis performed for groups 1 and 2 showed 87.8% and 93.8% survival rate, respectively. In addition, the most common cause for implants failure was surgery-related factors. CONCLUSION: Mini-implant survival rate is location dependent, with those placed in the palate showing higher success rates. In addition, failures most commonly occur because of surgery-related factors.

Design, Manufacturing and Acoustic Assessment of Polymer Mouthpieces for Trombones.

Brass instruments mouthpieces have been historically built using metal materials, usually brass. With the auge of additive manufacturing technologies new possibilities have arisen, both for testing alternative designs and for using new materials. This work assesses the use of polymers for manufacturing trombone mouthpieces, specifically PLA and Nylon. The acoustical behavior of these two mouthpieces has been compared with the obtained from a third one, built from brass. Both additive and subtractive manufacturing techniques were used, and the whole manufacturing process is described. The mouthpieces were acoustically assessed in an anechoic chamber with the collaboration of a professional performer. The harmonic analysis confirmed that all the manufactured mouthpieces respect the harmonic behavior of the instrument. An energy analysis of the harmonics revealed slight differences between the mouthpieces, which implies differences in the timbre of the instrument. Although these subtle differences would not be acceptable when performing with the instrument in an orchestra, they could be perfectly valid for early learners, personal rehearsals or any kind of alternative performance.

Effectiveness and Safety of Secukinumab in Latin American Patients with Moderate to Severe Plaque Psoriasis: PURE Registry 12-Month Data.

BACKGROUND:  The efficacy and safety of secukinumab in patients with psoriasis has been established in randomised clinical trials. However, data on effectiveness and safety of secukinumab in Latin American real-world settings are scarce. OBJECTIVES: To evaluate the effectiveness and safety of secukinumab in real-world settings in patients with psoriasis in Latin America. METHODS: PURE is an ongoing multinational, prospective, observational study in patients with moderate-to-severe chronic plaque psoriasis in Canada and Latin America assessing the real-world safety and effectiveness of secukinumab and other approved therapies. The study enrolled (1:1) patients treated with secukinumab versus other approved therapies (other Tx) per local standard of care from 81 community- and hospital-based speciality sites (21 in Latin America). Here, we report effectiveness and safety outcomes with secukinumab and other Tx for plaque psoriasis for up to 12 months in a Latin American population. RESULTS: Overall, 187 patients were included in the analysis, 89 of whom initiated secukinumab treatment and 98 of whom received other Tx. At month 12, 84.4%, 71.1% and 53.3% of patients treated with secukinumab achieved Psoriasis Area and Severity Index (PASI) 75/90/100, respectively, compared with 66.7%, 47.9% and 29.2% of patients who received other Tx. Investigator Global Assessment (IGA) 0/1 responders in secukinumab versus other Tx were 78.3% versus 36.7% at month 3 and 81.8% versus 66.7% at month 12, respectively. Overall, the proportion of patients achieving Dermatology Life Quality Index (DLQI) 0/1 improved from 6.9% at baseline to 76.5% at month 12 in patients treated with secukinumab versus 5.6% at baseline to 54.5% at month 12 in patients on other Tx. No unexpected adverse events were reported during the 12-month observation period. CONCLUSION: Secukinumab demonstrated real-world effectiveness and improved dermatology quality-of-life in chronic plaque psoriasis patients from Latin America. TRIAL REGISTRATION: PURE: NCT02786186.

Contribution of interferon gamma release assays testing to the diagnosis of latent tuberculosis infection in HIV-infected patients: a comparison of QuantiFERON-TB Gold In Tube, T-SPOT.TB and tuberculin skin test.

BACKGROUND: Diagnosis and treatment of latent tuberculosis infection (LTBI) is the most effective strategy to control tuberculosis (TB) among patients with HIV infection. The tuberculin skin test (TST) was the only available method to identify LTBI. The aim of the present work was to evaluate the usefulness of the interferon-gamma release assays (IGRAs): QuantiFERON-tuberculosis (TB) Gold-In-Tube test (QFG) and T-SPOT.TB for the diagnosis of LTBI in a diverse cohort of HIV-infected patients. METHODS: A prospective study was carried out in consecutive patients cared for in a single institution in Spain from January 2009 to October 2010. IGRAs and TST were performed simultaneously. TST induration ≥ 5 mm was considered positive. RESULTS: QFG, T-SPOT.TB and TST were performed in 373 subjects. Median CD4 cell count was 470/µl with a median nadir of 150/µl. TST, QFG and T-SPOT.TB were positive in 13.3%, 7.5% and 18.5% cases respectively. Among 277 patients with neither past or current TB nor previous treatment for LTBI and who had TST results, a positive TST result was obtained in 20 (7.2%) cases. When adding QFG results to TST, there were a total of 26 (8.6%) diagnoses of LTBI. When the results of both IGRAs were added, the number of diagnoses increased to 54 (17.9%) (incremental difference: 10.7% [95% confidence interval [CI]:5.3-16.2%] [p < 0.001]), and when both IGRAs were added, the number of diagnoses reached 56 (18.5%) (incremental difference: 11.3% [95% CI:5.7%-16.9%] [p < 0.001]). Patients with a CD4 cell count greater than 500 cells/µl and prior stay in prison were more likely to have a diagnosis of LTBI by TST and/or QFG and/or T-SPOT.TB (adjusted odds ratio [aOR]: 3.8; 95% CI, 1.4 - 9.9; and aOR: 3.3; 95% CI, 1.3 - 8.3, respectively). CONCLUSIONS: IGRAs were more sensitive than TST for diagnosis of M. tuberculosis infection in HIV-infected patients. Dual sequential testing with TST and IGRAs may be the optimal approach for LTBI screening in this population.

Biosynthesis of Athmu, a α,γ-hydroxy-ß-amino acid of pahayokolides A-B.

Pahayokolides A-B are cyanobacteria derived non-ribosomal peptides which exhibit cytotoxicity against a number of cancer cell lines. The biosynthetic origin of the 3-amino-2,5,7,8-tetrahydroxy-10-methylundecanoic acid (Athmu) moiety has been investigated using stable isotope incorporation experiments. While α-ketoisocaproic acid (α-KIC), α-hydroxyisocaproic acid (α-HIC) and leucine all serve as precursors to Athmu, the feeding of [1-(13)C] α-KIC results in more than threefold greater (13)C enrichment than the other precursors. This result suggests that α-KIC is the immediate precursor which is selected and activated by the adenylation domain of the loading NRPS module and subsequently reduced in a fashion similar to that of the recently identified pathways for cryptophycins A-B, cereulide and valinomycin.

Chagas disease in Latin American pregnant immigrants: experience in a non-endemic country.

PURPOSE: Chagas disease is a systemic chronic parasitic infection by Trypanosoma cruzi endemic in Latin America. Migration of women of childbearing age from Latin America to developed countries may spread the disease to non-endemic areas through vertical transmission. METHODS: Prospective study of seroprevalence of T. cruzi infection in immigrant Latin American pregnant women during a 5-year period (from 2006 to 2010) in Spain. RESULTS: Seven out of 545 participants were seropositive for T. cruzi [prevalence 1.28%, 95% confidence interval (CI) 0.06-2.56]. Four (57%) were from Bolivia and three (43.%) from Paraguay. The seroprevalence in pregnant women from Bolivia was 10.26% (95% CI 4.06-23.58) and in participants from Paraguay was 6.52% (95% CI 2.24-17.5). No congenital transmission occurred. CONCLUSIONS: Seroprevalence of T. cruzi infection in Latin American pregnant women coming from Bolivia and Paraguay is high. Those women should be screened for T. cruzi to control mother-to-child transmission in non-endemic areas.