Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides.

Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on- and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort. Here, we demonstrate a method to identify promising screening directions via simple and scalable computational and linear regression tools that leads to a substantial improvement in hit rate, enabling the use of smaller screens to find new ligands. The application of this approach to a particular example of Ni-catalyzed cross-electrophile coupling of aryl halides with alkyl halides revealed a previously overlooked trend: reactions with more electron-poor amidine ligands result in a higher yield. Focused screens utilizing this trend were more successful than serendipity-based screening and led to the discovery of two new types of ligands, pyridyl oxadiazoles and pyridyl oximes. These ligands are especially effective for couplings of bromo- and chloroquinolines and isoquinolines, where they are now the state of the art. The simplicity of these models with parameters derived from metal-free ligand structures should make this approach scalable and widely accessible.

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling.

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)-C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2'-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parameterization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational ligand library, correlation of observed reaction outcomes with features of the ligands, and the in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a 5-fold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt.

Immunogenicity and cross-reactivity against Mycobacterium tuberculosis of proteoliposomes derived from Mycobacterium bovis BCG.

The only currently available vaccine against tuberculosis (TB) is Mycobacterium bovis Bacille Calmette-Guerin (BCG), which has inconsistent efficacy to protect against the disease in adults. M. tuberculosis (MTB) cell wall components have been implicated in the pathogenicity of TB and therefore have been a prime target for the identification and characterization of cell wall proteins with potential application in vaccine development. In this regard, proteoliposomes (PLs) derived from mycobacteria containing lipids and cell wall proteins could be potential vaccine candidates against TB. In the present study PLs derived from BCG were prepared. These homogeneous population of spherical microparticles was then immunized into Balb/c mice. Sera of immunized animals showed high IgG response and strong cross-reactivity against different MTB antigens.These results showed that BCG PLs could be potential vaccine candidates against TB.

Estado periodontal de niños de 5 a 12 años del internado «Marta Abreu¼, Santa Clara / Periodontal status of children aged 5 to 12 years from" Marta Abreu" boarding school in Santa Clara

RESUMEN Los estudios poblacionales muestran que la gingivitis es frecuente en la niñez; esta afección es más prevalente en la adolescencia y tiende a estabilizarse en edades más avanzadas. Se realizó un estudio descriptivo de corte epidemiológico transversal, en una población de 313 escolares, comprendidos en las edades de 5 a 12 años, pertenecientes al internado «Marta Abreu de Estévez¼, de la ciudad de Santa Clara, de septiembre de 2017 a junio de 2018, para caracterizar su estado periodontal. Prevaleció la gingivitis leve y se estableció la relación ascendente entre higiene bucal y gravedad de la enfermedad periodontal.

ABSTRACT Population studies show that gingivitis is common in childhood; this condition is more prevalent in adolescence and tends to stabilize at older ages. A descriptive, cross-sectional and epidemiological study was carried out in a population of 313 school children aged 5 to 12 years, belonging to "Marta Abreu de Estévez" boarding school, in Santa Clara city, from September 2017 to June of 2018, in order to characterize their periodontal status. Mild gingivitis prevailed and an ascending relationship between oral hygiene and severity of periodontal disease was established.

Relación orto-periodontal / Interrelationship between Orthodontics and Periodontics

RESUMEN El periodonto es el conjunto de tejidos que protegen y soportan los dientes, los cuales están relacionados en su desarrollo, topografía y funciones. Entre ellos se encuentra el ligamento periodontal: estructura de tejido conectivo que rodea la raíz del diente uniéndola al hueso alveolar. El ortodoncista mueve los dientes a expensas de esta estructura, por lo tanto, el éxito de un tratamiento ortodóncico depende en parte de la integridad y la salud de los tejidos periodontales. En esta investigación se presentó una paciente adulta que recibió un tratamiento fruto de la cooperación interdisciplinaria entre especialistas de Periodoncia y Ortodoncia. La paciente tenía diagnósticos establecidos y presentaba factores etiológicos involucrados en afecciones comunes de ambas especialidades. Se estableció una planificación del tratamiento adecuado, según el caso, para garantizar la salud bucal y estética de la paciente.

ABSTRACT The periodontium is the group of tissues that protect and support the teeth, which are related in their development, topography and functions. The periodontal ligament is one of them: that is a structure of connective tissue surrounding the root of the tooth and joining it to the alveolar bone. The orthodontist moves the teeth at the expense of this structure, so the success of orthodontic treatment depends in part on the integrity and health of the periodontal tissues. In this research, we present an adult patient who received treatment as a result of the interdisciplinary cooperation between specialists in Periodontics and Orthodontics. The patient had established diagnoses and presented etiological factors involved in common conditions of both specialties. An adequate treatment planning was established, according to the case, to guarantee her aesthetics and oral health.

Fibroma de encía: a propósito de un paciente / Fibroid of gum: apropos of a patient

Los tumores benignos son neoplasias que pueden presentarse en cualquier parte de la cavidad oral y ulcerarse, sangrar o interferir con la masticación y presentan un desarrollo lento y una superficie mucosa conservada. El fibroma de encía es una neoplasia benigna de tejido conjuntivo (la más común de la cavidad bucal) ocasionada por un aumento en la proliferación de fibras colágenas, es poco frecuente, se puede presentar en cualquier etapa de la vida, no tiene predilección por el sexo y aparece en mayor cuantía en el maxilar superior. Se presenta un caso clínico de este tumor en el que se analizaron las características clínicas e histológicas y la actitud terapéutica seguida(AU)

Proteoliposomes from Mycobacterium smegmatis induce immune cross-reactivity against Mycobacterium tuberculosis antigens in mice.

Proteoliposomes (PL) obtained from Mycobacterium smegmatis (Ms) were evaluated for their capacity to elicit cross-reactive responses against Mycobacterium tuberculosis (Mtb) antigens in BALB/c mice. Animals immunized with PL adjuvanted with alum (PL-AL) or Freund's Incomplete Adjuvant (PL-IFA) showed significant IgG responses against the PL as well as total Ms lipids. Both groups of animals also showed significant IgG responses against BCG, but only animals immunized with PL-AL produced significant IgG responses against soluble cell wall proteins (SCWP) or whole cell lysate (WCL) of Mtb. Significant DTH responses against WCL were observed in both groups of animals after 24 h, but only PL-AL-immunized mice showed significant DTH responses after 48 h and 72 h. PL-Ms are capable of eliciting cross-reactive humoral and cellular responses against Mtb antigens and thus may be a potential vaccine strategy against tuberculosis.

Anticuerpos IgY en ensayos de látex-aglutinación / IgY antibodies in latex-agglutination assay

Los anticuerpos aviares (IgY) presentan algunas ventajas con relación a los anticuerpos IgG de mamíferos, debido a su fácil obtención y purificación y su bajo costo de producción. El objetivo de este trabajo fue estudiar la factibilidad de acoplar anticuerpos IgY a partículas de poliestireno y evaluar su desempeño en ensayos de látex-aglutinación en lámina. Para este propósito se utilizó como modelo la detección del antígeno de superficie de la hepatitis B (HBsAg). Gallinas Leghorn se inmunizaron con el ingrediente farmacéutico activo que se utiliza en la elaboración de la vacuna recombinante cubana Heberbiovac-HB. Los anticuerpos obtenidos se purificaron y emplearon en la preparación de reactivos de látex-aglutinación (0,8 µm) para la detección del HBsAg, los cuales se evaluaron con 50 muestras de suero frente a un reactivo comercial similar. Los resultados se evaluaron de satisfactorios. Se demostró la factibilidad de acoplar anticuerpos aviares a partículas de látex y se abre una perspectiva al empleo de este tipo de ensayo para el diagnóstico rápido de diversas enfermedades(AU)

Avian antibodies (IgY) display some advantages in relation to the mammalian IgG antibodies due to its easy procedure for generation and purification and besides for its lower production cost. The objective of this work was to analyze the feasibility of binding IgY antibodies to polystyrene particles and to evaluate its performance in latex-agglutination tests in slide. For this purpose, the detection of hepatitis B surface antigen (HBsAg) was used as a model. Leghorn hens were immunized with the active pharmaceutical ingredient (MPA) used in the manufacturing of the Cuban recombinant vaccine Heberbiovac HB . The obtained antibodies were purified and used in the preparation of the latex particles (0.8 µm) for the detection of the HBsAg by agglutination. The performance of the test was evaluated with 50 serum samples against similar commercial reagent. The results obtained were satisfactory and demonstrated the feasibility of binding such avian antibodies to latex particles. These results open a perspective to the use of this type of assay for the rapid diagnostic of many diseases(AU)

Evaluación del potencial de Mycobacterium smegmatis como candidato vacunal contra la tuberculosis mediante estudios in sílico e in vivo / Evaluation of the potential of Mycobacterium smegmatis as vaccine Candidate against tuberculosis by in silico and in vivo studies

In this study, we scanned multiple published databases of gene expression in vivo of M tuberculosis at different phases of infection in animals and humans, to select 38 proteins that are highly expressed in the active, latent and reactivation phases. The selected proteins were predicted for T and B epitopes. For each proteins, the regions containing T and B epitopes were selected at the same time to look for identical epitopes on M smegmatis based on sequence alignments. Preliminary studies of humoral immunogenicity and cross-reactivity with M tuberculosis in mice using two M smegmatis-derived experimental vaccines were carried out, demonstrating the immunogenicity of M smegmatis proteoliposomes and the recognition of M tuberculosis proteins by the sera of animals immunized with this vaccine candidate. The conjunction of in silico and in vivo studies suggested the potential for future evaluation of M smegmatis as vaccine candidate against tuberculosis using different strategies.(AU)

En este estudio se revisaron múltiples bases de datos publicadas, relacionadas con experimentos de expresión de genes de M tuberculosis in vivo en diferentes estadios de la infeccción en humanos y animales. Se identificaron 38 proteínas con elevada expresión en las fases activa, latente y de reactivación de la infección. Se llevó a cabo la predicción de epítopes T y B en dichas proteínas. Las regiones de cada proteína que contenían simultàneamente epítopes T y B se seleccionaron y utilizaron para identificar regiones idénticas en M smegmatis mediante el alineamiento de secuencias. Se llevaron a cabo estudios de inmunogenicidad humoral y reactividad cruzada con M tuberculosis en ratones inmunizados con dos vacunas experimentales obtenidas a partir de M smegmatis, demostràndose la immunogenicidad de los proteoliposomas y el reconocimiento de proteínas de M tuberculosis por el suero de ratones vacunados con este candidato vacunal. Los resultados obtenidos con los estudios in sílico e in vivo sugieren la potencialidad para evaluación futura de candidatos vacunales obtenidos a partir de M smegmatis para la prevención de la tuberculosis(AU)