Cryptic enzymatic assembly of peptides armed with ß-lactone warheads.

Nature has evolved biosynthetic pathways to molecules possessing reactive warheads that inspired the development of many therapeutic agents, including penicillin antibiotics. Peptides armed with electrophilic warheads have proven to be particularly effective covalent inhibitors, providing essential antimicrobial, antiviral and anticancer agents. Here we provide a full characterization of the pathways that nature deploys to assemble peptides with ß-lactone warheads, which are potent proteasome inhibitors with promising anticancer activity. Warhead assembly involves a three-step cryptic methylation sequence, which is likely required to reduce unfavorable electrostatic interactions during the sterically demanding ß-lactonization. Amide-bond synthetase and adenosine triphosphate (ATP)-grasp enzymes couple amino acids to the ß-lactone warhead, generating the bioactive peptide products. After reconstituting the entire pathway to ß-lactone peptides in vitro, we go on to deliver a diverse range of analogs through enzymatic cascade reactions. Our approach is more efficient and cleaner than the synthetic methods currently used to produce clinically important warhead-containing peptides.

Seguridad de la endoscopia y biopsia esofágica en un paciente con esofagitis eosinofílica y enfermedad de Von Willebrand / Safety of esophageal endoscopy and biopsy in a patient with eosinophilic esophagitis and Von Willebrand disease

La esofagitis eosinofílica (EoE) es una enfermedad causada por una respuesta inmune frente a antígenos alimentarios en contacto con la mucosa esofágica; por su parte, la enfermedad de Von Willebrand (EVW) es el trastorno hemorrágico hereditario más común en los seres humanos. La característica central de todos los tipos de EVW, es la presencia de cantidades reducidas o de formas anormales del factor de Von Willebrand (FVW) en el torrente sanguíneo. Debido a que no se han reportado casos previos de EVW tipo 2A asociada a EoE, se describe este caso clínico con el objetivo principal de dar a conocer el hallazgo casual de estas dos patologías, la seguridad de la evaluación por endoscopia de vías digestivas altas y el pronóstico de posibles complicaciones

Eosinophilic esophagitis (EoE) is a disease caused by an immune response against food antigens in contact with the esophageal mucosa; alternatively, Von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans. The central characteristic of all types of VWD is the presence of reduced amounts or abnormal forms of VWF in the bloodstream. Since no previous cases of VWD type 2A associated to EoE have been reported, this clinical case is described with the main objective to present the coincidental finding of these two pathologies, the safety of the evaluation by upper gastrointestinal endoscopy, and the prognosis of possible complications

Systemic paracoccidioidomycosis in a patient with enzymatic myeloperoxidase deficiency and acute lymphoblastic leukemia: case report.

Background: Paracoccidioidomycosis is a systemic fungal infection that is potentially fatal, and the most prevalent of its kind in Latin America. The predisposition to infection appears to be related to abnormalities in cellular immunity, given its low prevalence in endemic regions. The role of myeloperoxidase deficiency has not been elucidated. Case presentation: We present a case of 48-year-old female patient with acute lymphoblastic leukemia, stem cell transplant candidate, who developed a fever with lymphadenopathy and lung nodules, consistent with paracoccidioidomycosis infection, in whom a myeloperoxidase deficiency was later discovered. The treatment of the hematologic malignancy had a good impact solving the enzymatic deficiency and antifungal therapy achieve controlling the infection. Conclusions: This case lays out the possible association between acute leukemia, an alteration in neutrophil function (needed to fight fungal infections) and an infection due to Paracoccidioides brasiliensis.

Corn kernel hardness, drying temperature and amylase supplementation affect live performance and nutrient utilization of broilers.

Drying temperature (DT) of corn can influence its nutritional quality, but whether this is influenced by endosperm hardness is not clear. Two parallel experiments were conducted to investigate the effects of 2 yellow dent corn hybrids with average and hard kernel hardness, dried at 3 temperatures (35, 80, and 120°C), and 2 supplementation levels of an exogenous amylase (0, 133 g/ton of feed) on live performance, starch and protein digestibility, and energy utilization of Ross 708 male broilers. Twelve dietary treatments consisting of a 2 × 3 × 2 factorial arrangement were evaluated using 3-way ANOVA in a randomized complete block design. In Experiment 1, a total of 1,920 male-chicks were randomly allocated to 96 floor pens, whereas 480 day-old chicks were distributed among 96 cages for Experiment 2. At 40 d, interaction effects (P < 0.05) were detected on BWG, FCR, and flock uniformity. Supplementation with exogenous amylase resulted in heavier broilers, better FCR and flock uniformity, only in the diets based on corn dried at 35°C. Additionally, interaction effects were observed on FCR due to kernel hardness and DT (P < 0.01), kernel hardness and amylase supplementation (P < 0.001), and DT and amylase supplementation (P < 0.05). Exogenous amylase addition to the diets based on corn with an average hardness improved FCR up to 2 points (1.49 vs. 1.51 g:g) whereas there was no effect of amylase on FCR of broilers fed diets based on corn with hard endosperm. Total tract retention of starch was increased (P < 0.05) in broilers fed diets based on corn with average kernel hardness compared to hard kernel. Corn dried at 80 and 120°C had up to 1.21% points less starch total tract retention than the one dried at 35°C. Supplementing alpha-amylase resulted in beneficial effects for broiler live performance, energy utilization, and starch total tract digestibility results. Treatment effects on starch characteristics were explored. Corn endosperm hardness, DT and exogenous amylase can influence the live performance of broilers. However, these factors are not independent and so must be manipulated strategically to improve broiler performance.

Corn drying temperature, particle size, and amylase supplementation influence growth performance, digestive tract development, and nutrient utilization of broilers.

Broiler live performance may be influenced by postharvest corn drying temperature, and results could depend on particle size after grinding. The supplementation with an exogenous amylase may improve performance parameters, but responses to enzymes are also affected by particle size. Two parallel experiments were conducted to evaluate the effects of hard-kernel corn dried at 2 temperatures (35°C and 120°C), ground at 2 particle sizes (coarse or fine), and 3 supplementation levels (0, 133, and 266 g ton-1) of an exogenous amylase on live performance, gastrointestinal organ development, energy utilization, and nutrient digestibility. Twelve dietary treatments resulting from a 2 × 2 × 3 factorial arrangement of drying temperature, particle size, and amylase supplementation were evaluated in both experiments. A total of 1,920 day-old male chicks were randomly allocated to 96 floor pens, while 480 chicks were distributed among 4 battery brooder units. Ileal and fecal samples were collected to determine energy utilization and nutrient digestibility using titanium dioxide as inert marker. At 42 D, organs were collected, and relative weight or length was determined. Data were analyzed using a three-way ANOVA in a randomized complete block design. Feeding fine corn-based diets showed improvements on live performance for both studies. At 40 D, supplementing 266 g ton-1 of amylase improved feed conversion ratio (P < 0.05) by 1 point compared to chickens that consumed nonsupplemented diets and feed with amylase at 133 g ton-1. Broilers fed coarse corn-based diets had heavier gizzard (P < 0.001) and liver (P < 0.05) than chickens that consumed fine corn-based diets. In addition, starch digestibility was improved by amylase (P < 0.05) at 133 g ton-1 and by feeding coarse corn-based diets (P = 0.06). For chicks raised in cages (16 D), AMEn was increased (P < 0.01) by amylase supplementation regardless of its inclusion level. In conclusion, drying temperature and particle size interactions influenced broiler live performance, gastrointestinal organ development, nutrient digestibility, and energy utilization, and these parameters were improved by supplementing amylase.

Haloterrigena sp. Strain SGH1, a Bacterioruberin-Rich, Perchlorate-Tolerant Halophilic Archaeon Isolated From Halite Microbial Communities, Atacama Desert, Chile.

An extreme halophilic archaeon, strain SGH1, is a novel microorganism isolated from endolithic microbial communities colonizing halites at Salar Grande, Atacama Desert, in northern Chile. Our study provides structural, biochemical, genomic, and physiological information on this new isolate living at the edge of the physical and chemical extremes at the Atacama Desert. SGH1 is a Gram-negative, red-pigmented, non-motile unicellular coccoid organism. Under the transmission electron microscope, strain SGH1 showed an abundant electro-dense material surrounding electron-lucent globular structures resembling gas vacuoles. Strain SGH1 showed a 16S rRNA gene sequence with a close phylogenetic relationship to the extreme halophilic archaea Haloterrigena turkmenica and Haloterrigena salina and has been denominated Haloterrigena sp. strain SGH1. Strain SGH1 grew at 20-40°C (optimum 37°C), at salinities between 15 and 30% (w/v) NaCl (optimum 25%) and growth was improved by addition of 50 mM KCl and 0.5% w/v casamino acids. Growth was severely restricted at salinities below 15% NaCl and cell lysis is avoided at a minimal 10% NaCl. Maximal concentrations of magnesium chloride and sodium or magnesium perchlorates that supported SGH1 growth were 0.5 and 0.15M, respectively. Haloterrigena sp. strain SGH1 accumulates bacterioruberin (BR), a C50 xanthophyll, as the major carotenoid. Total carotenoids in strain SGH1 amounted to nearly 400 µg BR per gram of dry biomass. Nearly 80% of total carotenoids accumulated as geometric isomers of BR: all-trans-BR (50%), 5-cis-BR (15%), 9-cis-BR (10%), 13-cis-BR (4%); other carotenoids were dehydrated derivatives of BR. Carotenogenesis in SGH1 was a reversible and salt-dependent process; transferring BR-rich cells grown in 25% (w/v) NaCl to 15% (w/v) NaCl medium resulted in depigmentation, and BR content was recovered after transference and growth of unpigmented cells to high salinity medium. Methanol extracts and purified BR isomers showed an 8-9-fold higher antioxidant activity than Trolox or ß-carotene. Both, plasma membrane integrity and mitochondrial membrane potential measurements under acute 18-h assays showed that purified BR isomers were non-toxic to cultured human THP-1 cells.

Kalman-Based Real-Time Functional Decomposition for the Spectral Calibration in Swept Source Optical Coherence Tomography.

This paper presents a real-time functional decomposition adaptive algorithm for the optimal sampling of the interferometric signal in Swept-Source Optical Coherence Tomography imaging systems, which completely eliminates the input signal dependent nonlinearities that are problematic in current state-of-the-art OCT realizations that use interpolation and resampling. The proposed adaptive calibration algorithm uses the Kalman approach to estimate the wavenumber index parameter k from the Mach-Zender Interferometer signal which is then applied to an adaptive level crossing sampler to generate a sampling clock that k-linearizes the data on real-time during the sampling process. Such a system implements an artifact-free realization of the technology removing the need for classical interpolation and resampling. The new real-time linearization scheme has the additional capability of increasing the imaging acquisition speed by 10X while providing robustness to noise, properties that are demonstrated through mathematical analysis and simulation results throughout the paper.

Asynchronous compressed beamformer for portable diagnostic ultrasound systems.

State-of-the-art portable ultrasound imaging systems employ a small transducer array and a low carrier frequency to fit stringent constraints on power and form factor, and this tends to compromise the ultrasound imaging quality. In this paper, we present a low-complexity low-power asynchronous compressed beamformer (ACB) for portable diagnostic ultrasound. The proposed ACB integrates asynchronous sampling and compressive sensing (CS), and is capable of reducing data conversion power and handling a large data volume at the mixed-signal interface. A high-rate continuoustime ternary encoding (CT-TE) scheme eliminates the need for interpolation filters and coordinate rotation digital computer (CORDIC) units typically used in a conventional architecture. A split-projection least squares (SPLS) signal reconstruction algorithm is applied that replaces high-cost nonlinear signal recovery with a series of low-complexity and independent linear problems. Experiments with measured ultrasound data demonstrate the proposed ACB architecture, and the SPLS reconstruction algorithm achieves 9-fold data compression compared with Nyquist sampling.

Towards a Standard Mixed-Signal Parallel Processing Architecture for Miniature and Microrobotics.

The conventional analog-to-digital conversion (ADC) and digital signal processing (DSP) architecture has led to major advances in miniature and micro-systems technology over the past several decades. The outlook for these systems is significantly enhanced by advances in sensing, signal processing, communications and control, and the combination of these technologies enables autonomous robotics on the miniature to micro scales. In this article we look at trends in the combination of analog and digital (mixed-signal) processing, and consider a generalized sampling architecture. Employing a parallel analog basis expansion of the input signal, this scalable approach is adaptable and reconfigurable, and is suitable for a large variety of current and future applications in networking, perception, cognition, and control.

Liver fibrosis secondary to bile duct injury: correlation of Smad7 with TGF-beta and extracellular matrix proteins.

BACKGROUND: Liver fibrosis is the result of continuous liver injury stemming from different etiological factors. Bile duct injury induces an altered expression of TGF-beta, which has an important role in liver fibrosis because this cytokine induces the expression of target genes such as collagens, PAI-1, TIMPs, and others that lead to extracellular matrix deposition. Smad7 is the principal inhibitor that regulates the target gene transcription of the TGF-beta signaling. The aim of the study was to determine whether Smad7 mRNA expression correlates with the gene expression of TGF-beta, Col I, Col III, Col IV, or PAI-1 in liver fibrosis secondary to bile duct injury (BDI). RESULTS: Serum TGF-beta concentration was higher in BDI patients (39 296 pg/ml) than in liver donors (9008 pg/ml). Morphometric analysis of liver sections showed 41.85% of tissue contained fibrotic deposits in BDI patients. mRNA expression of Smad7, Col I, and PAI-1 was also significantly higher (P < 0.05) in patients with BDI than in controls. Smad7 mRNA expression correlated significantly with TGF-beta concentration, Col I and Col III expression, and the amount of fibrosis. CONCLUSION: We found augmented serum concentration of TGF-beta and an increase in the percentage of fibrotic tissue in the liver of BDI patients. Contrary to expected results, the 6-fold increase in Smad7 expression did not inhibit the expression of TGF-beta, collagens, and PAI-1. We also observed greater expression of Col I and Col III mRNA in BDI patients and significant correlations between their expression and TGF-beta concentration and Smad7 mRNA expression.

[Gastrointestinal stromal tumors in the pediatric population. Report of two cases and a review of the literature]. / Tumores estromales del tracto gastrointestinal en población pediátrica. Informe de dos casos y revisión de la literatura.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are uncommon mesenchymal tumors of the gastrointestinal (GI) tract that occur predominantly in adults. GISTs in pediatric patients are rare and not well characterized. We reviewed the presentation, diagnostic work-up, pathological specimens, and outcomes of two children with GIST that originated from the stomach. Literature pertaining to pediatric GISTs was also reviewed. CLINICAL CASES: Both patients presented with upper GI bleeding from a gastric tumor. The first patient was a 10-year-old male who underwent partial gastrectomy but had recurrence 26 years later requiring surgical exploration due to extensive infiltration into the surrounding organs; the tumor was not resected. The patient is currently being treated with imatinib mesylate. The second patient was a 12-year-old female who had a pedunculated mass originating from the stomach and requiring resection. She subsequently had a local recurrence 2 years later requiring partial gastrectomy. Adjuvant imatinib mesylate was recommended because of the large size of the tumor (8 cm). CONCLUSIONS: Pediatric GISTs represent a distinct subset of sarcomas with a strong predominance for females and gastric location, with 56 cases reported in the English-language literature.

Tumores estromales del tracto gastrointestinal en población pediátrica: informe de dos casos y revisión de la literatura / Gastrointestinal stromal tumors in the pediatric population: report of two cases and a review of the literature

Introducción: El tumor estromal del tracto gastrointestinal es una neoplasia rara que se presentan por lo general en la quinta a séptima década de la vida; en pacientes pediátricos es menos frecuente que en adultos y no está bien caracterizado. En esta descripción se evalúa presentación, diagnóstico clínicopatológico y evolución de dos niños con tumor estromal del tracto gastrointestinal originado en el estómago; también se revisa la literatura respecto a la experiencia mundial que se tiene con este tipo de tumor en la población pediátrica. Casos clínicos: Ambos pacientes iniciaron con hematemesis debido a un tumor gástrico. El primer paciente tenía 10 años de edad cuando se le practicó gastrectomía parcial; después de 26 años experimentó recurrencia local de la enfermedad, por lo que se le practicó laparotomía exploradora que mostró neoplasia con extensa infiltración a órganos vecinos. La neoplasia fue irresecable; se prescribió tratamiento con mesilato de imatinib. El segundo caso correspondió a una niña quien a los 12 años de edad presentó una masa unida a la pared gástrica por un pedículo, la cual fue resecada. Dos años después por recurrencia local se le practicó gastrectomía parcial. Se recomendó mesilato de imatinib como tratamiento adyuvante debido a que el tumor tenía 8 cm de diámetro mayor. Conclusiones: El tumor estromal del tracto gastrointestinal de presentación en la edad pediátrica representa un subgrupo distintivo de sarcomas que predomina en niñas y que por lo general afecta el estómago. En una revisión de la literatura solo se encontraron 56 casos de dicha neoplasia. El pronóstico es variable y heterogéneo. La resección completa de la neoplasia es indispensable y el tratamiento adyuvante con mesilato de imatinib se recomienda para los casos con alto riesgo.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are uncommon mesenchymal tumors of the gastrointestinal (GI) tract that occur predominantly in adults. GISTs in pediatric patients are rare and not well characterized. We reviewed the presentation, diagnostic work-up, pathological specimens, and outcomes of two children with GIST that originated from the stomach. Literature pertaining to pediatric GISTs was also reviewed. CLINICAL CASES: Both patients presented with upper GI bleeding from a gastric tumor. The first patient was a 10-year-old male who underwent partial gastrectomy but had recurrence 26 years later requiring surgical exploration due to extensive infiltration into the surrounding organs; the tumor was not resected. The patient is currently being treated with imatinib mesylate. The second patient was a 12-year-old female who had a pedunculated mass originating from the stomach and requiring resection. She subsequently had a local recurrence 2 years later requiring partial gastrectomy. Adjuvant imatinib mesylate was recommended because of the large size of the tumor (8 cm). CONCLUSIONS: Pediatric GISTs represent a distinct subset of sarcomas with a strong predominance for females and gastric location, with 56 cases reported in the English-language literature.

[Histological evaluation of hepatic fibrosis in patients with post surgical bile duct injury]. / Evaluación histológica de la fibrosis hepática en pacientes con lesión posquirúrgica de vías biliares.

BACKGROUND: Bile duct injuries after cholecystectomy can produce fibrous and collagen deposit tissue. Our objective was to evaluate the liver fibrosis measured in histological tissue in patients with bile duct injury after cholecystectomy. METHODS: Three normal liver biopsies and 21 from patients with bile duct injuries were studied. Group I: with three normal liver biopsies. Group II: with external abdominal fistula alone in six patients. Group III with complete bile duct obstruction in 15 patients. The surgical biliary enteric reconstructions were performed 8 weeks after bile duct injury in all cases. The fibrosis and collagen deposits were studied by Masson's trichrome and Sirius red stains and they were measured by a digital program. RESULTS: Group I showed 2 % of fibrosis tissue and 1% of collagen deposit and was considered as normal. Group II showed unexpected 1 fold more liver fibrosis and 9 fold more collagen deposit in extracellular matrix macromolecule (p < 0.05, Anova) against group I. Patients in group III, had fibrous tissue increase 43 folds more and 14 collagen folds more (p < 0.0001, Bonferroni's post hoc) versus group I. CONCLUSIONS: The patients in groups II and III showed liver fibrosis, being this more important in group III.