Reprogramming of the LXRα Transcriptome Sustains Macrophage Secondary Inflammatory Responses.

Macrophages regulate essential aspects of innate immunity against pathogens. In response to microbial components, macrophages activate primary and secondary inflammatory gene programs crucial for host defense. The liver X receptors (LXRα, LXRß) are ligand-dependent nuclear receptors that direct gene expression important for cholesterol metabolism and inflammation, but little is known about the individual roles of LXRα and LXRß in antimicrobial responses. Here, the results demonstrate that induction of LXRα transcription by prolonged exposure to lipopolysaccharide (LPS) supports inflammatory gene expression in macrophages. LXRα transcription is induced by NF-κB and type-I interferon downstream of TLR4 activation. Moreover, LPS triggers a reprogramming of the LXRα cistrome that promotes cytokine and chemokine gene expression through direct LXRα binding to DNA consensus sequences within cis-regulatory regions including enhancers. LXRα-deficient macrophages present fewer binding of p65 NF-κB and reduced histone H3K27 acetylation at enhancers of secondary inflammatory response genes. Mice lacking LXRα in the hematopoietic compartment show impaired responses to bacterial endotoxin in peritonitis models, exhibiting reduced neutrophil infiltration and decreased expansion and inflammatory activation of recruited F4/80lo-MHC-IIhi peritoneal macrophages. Together, these results uncover a previously unrecognized function for LXRα-dependent transcriptional cis-activation of secondary inflammatory gene expression in macrophages and the host response to microbial ligands.

JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a hematological malignancy that highly depends on the BCR-ABL1/STAT5 signaling pathway for cell survival. First-line treatments for CML consist of tyrosine kinase inhibitors that efficiently target BCR-ABL1 activity. However, drug resistance and intolerance are still therapeutic limitations in Ph+ cells. Therefore, the development of new anti-CML drugs that exhibit alternative mechanisms to overcome these limitations is a desirable goal. In this work, the antitumoral activity of JKST6, a naphthoquinone-pyrone hybrid, was assessed in imatinib-sensitive and imatinib-resistant human CML cells. Live-cell imaging analysis revealed JKST6 potent antiproliferative activity in 2D and 3D CML cultures. JKST6 provoked cell increase in the subG1 phase along with a reduction in the G0/G1 phase and altered the expression of key proteins involved in the control of mitosis and DNA damage. Rapid increases in Annexin V staining and activation/cleavage of caspases 8, 9 and 3 were observed after JKST6 treatment in CML cells. Of interest, JKST6 inhibited BCR-ABL1/STAT5 signaling through oncokinase downregulation that was preceded by rapid polyubiquitination. In addition, JKST6 caused a transient increase in JNK and AKT phosphorylation, whereas the phosphorylation of P38-MAPK and Src was reduced. Combinatory treatment unveiled synergistic effects between imatinib and JKST6. Notably, JKST6 maintained its antitumor efficacy in BCR-ABL1-T315I-positive cells and CML cells that overexpress BCR-ABL and even restored imatinib efficacy after a short exposure time. These findings, together with the observed low toxicity of JKST6, reveal a novel multikinase modulator that might overcome the limitations of BCR-ABL1 inhibitors in CML therapy.

Paralytic shellfish toxins in Peruvian scallops associated with blooms of Alexandrium ostenfeldii (Paulsen) Balech & Tangen in Paracas Bay, Peru.

In recent years, dense Alexandrium ostenfeldii blooms have been reported in different coastal areas. In this study, we report for the first time the occurrence of A. ostenfeldii blooms associated with the detection of paralytic shellfish toxins (PSTs) in the Peruvian scallop (Argopecten purpuratus) from Paracas Bay. Alexandrium ostenfeldii blooms occurred at the end of summer and early fall, after the increase of riverine input and under stratified conditions following a decrease in wind velocity. The highest abundances occurred during warm sea surface temperatures (18-27 °C). High PST concentrations that exceed the maximum permissible level (800 µg STX eq. kg-1) occurred even under low A. ostenfeldii abundances (20 × 103 cells l-1). Our results contribute to a better understanding of the dynamics of A. ostenfeldii in coastal systems influenced by riverine inputs and upwelling and can be used to improve monitoring programs and allow the implementation of mitigation measures along the Peruvian coast.

From Ugi Multicomponent Reaction to Linkers for Bioconjugation.

Bioconjugation is a key approach for the development of novel molecular entities with clinical applications. The biocompatibility and specificity of biomolecules such as peptides, proteins, and antibodies make these macromolecules ideal carriers for selective targeted therapies. In this context, there is a need to develop new molecular units that cover the requirements of the next generation of targeted pharmaceuticals. Here, we present the design and development of a versatile and stable linker based on a N-alkylated α,α-dialkyl dipeptide for bioconjugation, with a particular focus on antibody-drug conjugates (ADCs). Starting with the well-known Ugi multicomponent reaction, the convenient chemical modification of the prepared adducts allowed us the obtention of versatile bifunctional linkers for bioconjugation. A conjugation strategy was tested to demonstrate the efficiency of the linker. In addition, a novel cytotoxic anti-HER2 ADC was prepared using the Ugi-linker approach.

Idiopathic multicentric Castleman's disease, infrequent cause of Lupus-like: case report

Castleman's disease (CD) or angiofollicular lymph node hyperplasia includes a heterogeneous mix of reactive lymphoproliferative processes with well-defined histological features. However, they differ in their localization patterns, clinical expression and etiopathogenesis. There are 4 types, one of them is the multicentric CD that is not associated with any viruses and has re-cently been called idiopathic MCD (iMCD). iMCD is a lymphoproliferative disorder with specific histopathological characteristics, more than one region of affected lymph nodes and absence of infection associated to human herpesvirus 8 and human immunodeficiency virus (HIV). iMCD covers multiple differential diagnoses and might simulate autoimmune diseases such as syste-mic lupus erythematosus. The aim of this article is to report the case of a patient with Castle-man's disease and lupus-like presentation. We present the case of a 38-year-old man without morbid history, who presented lumbago, fever, diaphoresis and asthenia with two months of evolution, associated to bilateral cervical adenopathies. General examinations result negative, antinuclear antibodies at a dilution of 1/640 were positive, and extractable nuclear antigens were positive suggesting moderate Systemic Lupus Erythematosus (SLE) plus secondary Sjö-gren's. Methylprednisolone and Hydroxycloroquine boli were thus initiated. The patient evolved with anasarca, severe anemia, acidosis, polyserositis and multiple mediastinal adenopathies. Immunoglobulin and cyclophosphamide were thus initiated. He later presented fever, throm-bocytopenia and nephrotic syndrome. Biopsy of cervical lymph node reported lymphadenitis with polyclonal plasmacytosis and concentric lymphoid hyperplasia, in agreement with iMCD. Treatment with Rituximab was initiated, which led to the favorable evolution of the patient. iMCD is a systemic inflammatory disease, its presentation corresponds to a constitutional syndrome resulting in a wide differential diagnosis. Every time suspicious adenopathies appear, they must be biopsied since this might lead to a definitive diagnosis

Bioconjugation through Mesitylene Thiol Alkylation.

The design and generation of complex multifunctional macromolecular structures by bioconjugation is a hot topic due to increasing interest in conjugates with therapeutic applications. In this regard, the development of efficient, selective, and safe conjugation methods is a major objective. In this report, we describe the use of the bis(bromomethyl)benzene scaffold as a linker for bioconjugation with special emphasis on antibody conjugation. We first performed the monothioalkylation of 1,3,5-tris(bromomethyl)benzene, which rendered the reactive dibromotrimethylbenzyl derivatives to be used in thiol bis-alkylation. Next, we introduced into the linker either a bis(Cys)-containing peptide or anti-CD4 and -CD13 monoclonal antibodies, previously subjected to partial reduction of disulfide bonds. Mass spectrometry, UV-vis spectra, and SDS-PAGE experiments revealed that this bis-alkylating agent for bioconjugation preserved both antibody integrity and antibody-antigen binding affinity, as assessed by flow cytometry. Taken together, our results show that the mesitylene scaffold is a suitable linker for thiol-based bioconjugation reactions. This linker could be applicable in the near future for the preparation of antibody drug conjugates.

DISEÑO DE MATERIAL EDUCATIVO PARA LA ENSEÑANZA DE LA CONSERVACIÓN DEL CÓNDOR DE LOS ANDES (Vultur gryphus) / DESIGN OF EDUCATIVE MATERIAL FOR THE CONSERVATION TEACHING OF THE ANDEAN CONDOR (Vultur gryphus)

En este trabajo se diseñó un material educativo para la enseñanza de la conservación del Cóndor de los Andes (Vultur gryphus) en el Parque Nacional Natural Los Nevados, localizado en la Cordillera Central de Colombia con alturas comprendidas entre 2600 y 5300 metros sobre el nivel del mar. Para la realización de este material se tomó como referentes teóricos el modelo educativo Escuela Nueva, los estándares para la educación en Colombia y los conceptos de lúdica y creatividad. Se realizó una selección de los estándares por grados y por área, y se procedió a estructurar actividades lúdico-creativas de acuerdo con los parámetros establecidos en el modelo educativo Escuela Nueva. El material educativo está compuesto por un texto guía que contiene actividades desde cuatro áreas del conocimiento como lo son las ciencias sociales, las matemáticas, las ciencias naturales y la lengua castellana; y una cartilla que es necesaria para el desarrollo de las actividades que se proponen en el texto guía y contiene la información sobre los aspectos biológicos, ecológicos, literarios y de conservación referentes al cóndor. Se obtuvo un texto guía que contiene seis unidades y 11 guías; y se obtuvo una cartilla con 13 puntos generales sobre el Cóndor de los Andes (Vultur gryphus). El texto guía diseñado ofrece un gran número y variedad de actividades de tipo flexible, lúdicas y creativas que se dinamiza con la cartilla de la especie objeto de conservación. El material educativo diseñado está dirigido a docentes de los centros educativos, facilitadores y promotores ambientales, guías del parque, turistas y a la comunidad en general.

In this work, an educative material was designed for the conservation teaching of the Andean Condor (Vultur gryphus) in the Parque Nacional Natural Los Nevados, located in the Central Cordillera of Colombia, with heights ranging between 2600 and 5300 m. There were taken as theoretical referring the Escuela Nueva educational model, the standards for education in Colombia, and the concepts of playful and creativity. We performed a selection of standards by grade and by area and proceeded to organize the activities in accordance with the parameters established in the Escuela Nueva educational model. The educative material consists of a guide text which contains activities from four areas of knowledge such as social sciences, mathematics, natural sciences and the castilian language, and a handbook that is necessary for the development of the activities proposed in the guide text and contains information about biological, ecological, literature and conservation concerning to the condor. The result was a guide text that contains six units and 11 guides, and a handbook with 13 general points of the Andean Condor (Vultur gryphus). The guide text designed offers a great number and variety of flexible, playful and creative activities that is invigorated with the handbook of the specie object of conservation. The educational material designed is aimed at teachers of schools, facilitators and environmental promoters, park guides, tourists and the community in general.

DETERMINACIÓN DE LA PRODUCCIÓN DE FOLLAJE VERDE DE LA Acacia decurrens EN EL PRIMER AÑO DE SIEMBRA / PRODUCTION OF FOLIAGE AT Acacia decurrens IN THE FIRST PLANTING YEAR

La determinación de la producción de follaje verde en el primer año de siembra de la Acacia decurrens se realizó en la finca La Ramada, Quindío, a 4° 31' 41" de latitud norte y 75° 32' 41'' de longitud oeste, con una temperatura promedio de 16 °C. Las plantas fueron establecidas con un mes de edad, en surcos paralelos a la pendiente, podadas al alcanzar 1,8 m de altura y defoliadas manualmente simulando el ramoneo que realiza el ganado. Las densidades de siembra fueron: alta, media y baja: 1664, 832 y 416 acacias/hectárea, respectivamente; se realizaron defoliaciones por periodos a los 6, 9 y 12 meses de siembra. Las variables a medir fueron: peso en gramos de follaje verde por árbol e incremento en gramos de follaje verde/árbol/día. Todos los datos fueron analizados por ANOVA. No fue encontrada diferencia significativa (P>0,05) entre las variables analizadas al estudiar las diferentes densidades de siembra. Se evidenció diferencia significativa (P<0,05) entre periodos de defoliación, al analizar la variable de incremento en gramos de follaje verde por día, esto indica, que la producción de gramos de follaje verde fue mejor en el tercer periodo. La producción de follaje verde de la acacia en el primer año no se ve afectada por las diferentes densidades de siembra y hay un incremento de la producción de follaje verde a medida que las acacias incrementan su edad.

The determination of green foliage production of Acacia decurrens in the first planting year, was in La Ramada farm, Quindío, located 4° 31' 41'' of latitude north and 75° 32' 41'' longitude west, an average temperature 16 °C. The age for planting was one month, in parallel rows to the slope, pruning to 1,5 m of high and the acacia's browsing was simulated by manual defoliation; The planting densities were high, medium, and low: 1664, 832 and 416 acacias/hectare, respectively; and the periods o frequency of defoliation was to 6, 9 and 12 months of planting. The variables were grams/tree of foliage production and grams/tree/day of foliage increment. All data were analyzed by ANOVA. In this trial, the planting densities were not significantly (P>0.05), however, between periods the grams/tree/day of foliage increment were significantly (P<0.05), because the better production was in the third defoliation period. Acacia foliage production is similar in the first planting year with three different densities, and the foliage production increment improves with the time.