Tubulysins are among the most recent antimitotic compounds to enter into antibody/peptide-drug conjugate (ADC/PDC) development. Thus far, the design of the most promising tubulysin payloads relied on ...simplifying their structures, e.g., by using small tertiary amide N-substituents (Me, Et, Pr) on tubuvaline residue. Cumbersome solution-phase approaches are typically used for both syntheses and functionalization with cleavable linkers. p-Aminobenzyl quaternary ammonium (PABQ) linkers were a remarkable advancement for targeted delivery, but the procedures to incorporate them into tubulysins are only of moderate efficiency. Here we describe a novel all-on-resin strategy permitting a loss-free resin linkage and an improved access to super potent tubulysin analogs showing close resemblance to the natural compounds. For the first time, a protocol enables the integration of on-resin tubulysin derivatization with, e.g., a maleimido-Val-Cit-PABQ linker, which is a notable progress for the payload-PABQ-linker technology. The strategy also allows tubulysin diversification of the internal amide N-substituent, thus enabling to screen a tubulysin library for the discovery of new potent analogs. This work provides ADC/PDC developers with new tools for both rapid access to new derivatives and easier linker-attachment and functionalization.
World Health Organization (WHO) identified twenty tropical disease categories as neglected tropical diseases (NTDs). Chagas' disease (also known as American trypanosomiasis) and leishmaniasis are two ...major classes of NTDs. The total number of mortality, morbidity, and disability attributed each year due to these two categories of diseases in magnitudes is much higher than the so-called elite diseases like cancer, diabetes, AIDS, cardiovascular and neurodegenerative diseases. Impoverished communities around the world are the major victim of NTDs. The development of new and novel drugs in the battle against Chagas' disease and leishmaniasis is highly anticipated. An easy and straightforward on-water green access to synthesize benzopyrazines is reported. This ultrasound-assisted procedure does not require any catalyst/support/additive/hazardous solvents and maintains a high atom economy. A series of eleven benzopyrazines has been synthesized, and most of the synthesized compounds possess the drug-likeness following Lipinski's "Rule of 5". Benzopyrazines
and
demonstrated moderate leishmanicidal activity against
(M378) strain. The selective lead compound
showed good leishmanicidal, and trypanocidal activities (
) against both
(M378) and
(NINOA) strains compared to the standard controls. The
trypanocidal and leishmanicidal activities of the lead compound
have been validated by molecular docking studies against four biomolecular drug targets
histidyl-tRNA synthetase,
-sialidase, leishmanial rRNA A-site, and leishmania major
-myristoyl transferase.
Introduction: Barrett's esophagus (BE) is the main precursor of esophageal adenocarcinoma (EAC). This study aimed to identify the risk factors associated with BE progression to dysplasia or EAC in a ...Latin population.Methods: The study is a retrospective analysis of a single-center cohort of patients with BE, evaluated from 2002 to 2012.Results: We identified 420 patients with BE; 281 (66.9%) of them were men with a mean age of 57.2 ± 15.3 years. Among all BE patients evaluated, 81 (19.3%) had progression to some degree of dysplasia/EAC. The mean follow-up was 5.6 years. Multivariate analysis showed that age (OR = 1.03), cigarette smoking (OR = 3.05), long-segment BE (OR = 4.81), and a visible lesion on BE (OR = 6.94) were associated with progression to dysplasia/EAC.Conclusion: In Latin patients with BE, age, cigarette smoking, long-segment BE, and the presence of lesions were associated with the presence of dysplasia/EAC.
Epigenetic modifications such as DNA methylation have been shown to participate in plastic responses to environmental change in a wide range of organisms, including scleractinian corals. ...Unfortunately, the current understanding of the links between environmental signals, epigenetic modifications, and the subsequent consequences for acclimatory phenotypic changes remain obscure. Such a knowledge gap extends also to the dynamic nature of epigenetic changes, hampering our ability to ascertain the magnitude and extent of these responses under natural conditions. The present work aims to shed light on these subjects by examining temporal changes in genome-wide patterns of DNA methylation in the staghorn coral Acropora cervicornis in the island of Culebra, PR. During a 17-month period, a total of 162 polymorphic loci were identified using Methylation-Sensitive Amplified Polymorphism (MSAP). Among them, 83 of these fragments displayed changes in DNA methylation changes that were significantly correlated to seasonal variation as determined mostly by changes in sea water temperature. Remarkably, the observed time-dependent change in DNA methylation patterns is consistent across coral genets, coral source sites and site-specific conditions studied. Overall, these results are consistent with a conserved epigenetic response to seasonal environmental variation. These findings highlight the importance of including seasonal variability into experimental designs investigating the role of epigenetic mechanisms such as DNA methylation in responses to stress.
Borehole resistivity measurements are routinely inverted in real-time during geosteering operations. The inversion process can be efficiently performed with the help of advanced artificial ...intelligence algorithms such as deep learning. These methods require a massive dataset that relates multiple Earth models with the corresponding borehole resistivity measurements. In here, we propose to use an advanced numerical method — refined isogeometric analysis (rIGA) — to perform rapid and accurate 2.5D simulations and generate databases when considering arbitrary 2D Earth models. Numerical results show that we can generate a meaningful synthetic database composed of 100,000 Earth models with the corresponding measurements in 56 h using a workstation equipped with two CPUs.
•We use rIGA discretizations for simulating 2.5D borehole electromagnetic measurements.•We generate a synthetic database as a preliminary stage for deep learning inversion.•Computational cost of rIGA is compared to that of IGA and FEA discretizations.•rIGA generates the database O(p) times faster than high-continuity IGA discretization.
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The antigenic epitope regions of pathogens (e.g., viruses) are recognized by antibodies (Abs) and subsequently cleared by the host immune system, thereby protecting us from disease. ...Some of these epitopes are conserved among different variants or subgroups of pathogens (e.g., Influenza (FLU) viruses, Coronaviruses), hence can be targeted for potential broad-neutralization. Here we report a web-based tool, Epitope Analyzer (EA), that rapidly identifies conformational epitope and paratope residues in an antigen–antibody complex structure. Furthermore, the tool provides the ways and means to analyze broadly neutralizing epitopes by comparing the equivalent epitope residues in similar antigen structures. The similarity in the epitope residues between (multiple) pairs of similar antigen molecules suggest the presence of conserved epitopes that can be targeted by broadly neutralizing antibodies. These details can be used as a guide in developing effective treatments, such as the design of novel vaccines and formulation of cocktail of broadly neutralizing antibodies, against multiple variants or subgroups of viruses. The web application can be freely accessed from the URL, http://viperdb.scripps.edu/ea.php.
Daniel García Rivera se graduó en la Universidad de La Habana como Licenciado en Química en 2002, realizó la Maestría en Química Orgánica en esta universidad en ese mismo año y obtuvo el grado de ...Doctor en Ciencias Químicas en 2007 en la Universidad Martin-Luther Halle-Wittenberg. Es Profesor Adjunto del Departamento de Química Orgánica y Jefe del Grupo de Química Bioorgánica del Centro de Estudios de Productos Naturales, colectivo de trabajo con el que realiza investigaciones en el campo de la Química Orgánica y Biológica. Se ha especializado en la síntesis química de análogos de productos naturales biológicamente activos, especialmente, de naturaleza esteroidal, peptídica y glicolípida. Sus proyectos de investigación están dirigidos al desarrollo de nuevas metodologías sintéticas que permitan la obtención eficiente de estas moléculas de gran importancia por su aplicación en el desarrollo de fármacos, vacunas y otros agentes terapéuticos
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