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El artículo examina las principales amenazas que surgen de los procesos de globalización. La validez y confiabilidad de los resultados del estudio la proporciona el estudio teórico del conocimiento acumulado en la ciencia, un estudio en profundidad de la literatura científica. Los autores concluyen que, a pesar de las medidas tomadas en las condiciones modernas, existen muchos desafíos y amenazas globales que pueden tener el impacto más negativo en la seguridad económica nacional a corto plazo. En este sentido, el desarrollo de la economía está directamente relacionado con la seguridad del país y debe actuar como el factor más importante que la proporciona.

Although it is well-known that limited local mutations of enzymes, such as matrix metalloproteinases (MMPs), may change enzyme activity by orders of magnitude as well as its stability, the completely rational design of proteins is still challenging. These local changes alter the electrostatic potential and thus local electrostatic fields, which impacts the dynamics of water molecules close the protein surface. Here we show by a combined computational design, experimental, and molecular dynamics (MD) study that local mutations have not only a local but also a global effect on the solvent: In the specific case of the matrix metalloprotease MMP14, we found that the nature of local mutations, coupled with surface morphology, have the ability to influence large patches of the water hydrogen-bonding network at the protein surface, which is correlated with stability. The solvent contribution can be experimentally probed via terahertz (THz) spectroscopy, thus opening the door to the exciting perspective of rational protein design in which a systematic tuning of hydration water properties allows manipulation of protein stability and enzymatic activity.

Simple Summary Extracellular matrix remodeling enzymes are dysregulated in several pathologies. Our aim was to generate a unique function blocking monoclonal antibody against one such cancer-associated enzyme, matrix metalloproteinase 7 (MMP-7). We generated GSM-192, with high affinity and specificity towards active MMP-7, utilizing a sequential immunization strategy. GSM-192 induced pancreatic cancer cell apoptosis, reduced migration and increased sensitivity to chemotherapeutics. Our study highlights the use of GSM-192 as a valuable therapeutic, diagnostic and research tool. Abstract Matrix metalloproteases (MMPs) undergo post-translational modifications including pro-domain shedding. The activated forms of these enzymes are effective drug targets, but generating potent biological inhibitors against them remains challenging. We report the generation of anti-MMP-7 inhibitory monoclonal antibody (GSM-192), using an alternating immunization strategy with an active site mimicry antigen and the activated enzyme. Our protocol yielded highly selective anti-MMP-7 monoclonal antibody, which specifically inhibits MMP-7′s enzyme activity with high affinity (IC50 = 132 ± 10 nM). The atomic model of the MMP-7-GSM-192 Fab complex exhibited antibody binding to unique epitopes at the rim of the enzyme active site, sterically preventing entry of substrates into the catalytic cleft. In human PDAC biopsies, tissue staining with GSM-192 showed characteristic spatial distribution of activated MMP-7. Treatment with GSM-192 in vitro induced apoptosis via stabilization of cell surface Fas ligand and retarded cell migration. Co-treatment with GSM-192 and chemotherapeutics, gemcitabine and oxaliplatin elicited a synergistic effect. Our data illustrate the advantage of precisely targeting catalytic MMP-7 mediated disease specific activity.

Dysregulated activity of A Disintegrin And Metalloproteinase 17 (ADAM17)/TNFα Converting Enzyme (TACE) is associated with inflammatory disorders and cancer progression by releasing regulatory membrane-tethered proteins like TNFα, IL6R and EGFR ligands. Although specific inhibition of TACE is thought to be a viable strategy for inflammatory disorders and for malignancies treatment, the generation of effective inhibitors in vivo has been proven to be challenging. Here we report on the development of a protein inhibitor that leverages the endogenous modulator of TACE. We have generated a stable form of the auto-inhibitory TACE prodomain (TPD), which specifically inhibits in vitro and cell-surface TACE, but not the related ADAM10, and effectively modulated TNFα secretion in cells. TPD significantly attenuated TACE-mediated disease models of sepsis, rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and reduced TNFα in synovial fluids from RA patients. Our results demonstrate that intervening with endogenous ADAM sheddase modulatory mechanisms holds potential as a general strategy for the design of ADAM inhibitors.

Multi-specific proteins located at the heart of complex protein–protein interaction (PPI) networks play essential roles in the survival and fitness of the cell. In addition, multi-specific or promiscuous enzymes exhibit activity toward a wide range of substrates so as to increase cell evolvability and robustness. However, despite their high importance, investigating the in vivo function of these proteins is difficult, due to their complex nature. Typically, deletion of these proteins leads to the abolishment of large PPI networks, highlighting the difficulty in examining the contributions of specific interactions/activities to complex biological processes and cell phenotypes. Protein engineering approaches, including directed evolution and computational protein design, allow for the generation of multi-specific proteins in which certain activities remain intact while others are abolished. The generation and examination of these mutants both in vitro and in vivo can provide high-resolution analysis of biological processes and cell phenotypes and provide new insight into the evolution and molecular function of this important protein family.

The magnetosome, a biomineralizing organelle within magnetotactic bacteria, allows their navigation along geomagnetic fields. Magnetosomes are membrane-bound compartments containing magnetic nanoparticles and organized into a chain within the cell, the assembly and biomineralization of magnetosomes are controlled by magnetosome-associated proteins. Here, we describe the crystal structures of the magnetosome-associated protein, MamA, from Magnetospirillum magneticum AMB-1 and Magnetospirillum gryphiswaldense MSR-1. MamA folds as a sequential tetra-trico-peptide repeat (TPR) protein with a unique hook-like shape. Analysis of the MamA structures indicates two distinct domains that can undergo conformational changes. Furthermore, structural analysis of seven crystal forms verified that the core of MamA is not affected by crystallization conditions and identified three protein–protein interaction sites, namely a concave site, a convex site, and a putative TPR repeat. Additionally, relying on transmission electron microscopy and size exclusion chromatography, we show that highly stable complexes form upon MamA homooligomerization. Disruption of the MamA putative TPR motif or N-terminal domain led to protein mislocalization in vivo and prevented MamA oligomerization in vitro. We, therefore, propose that MamA self-assembles through its putative TPR motif and its concave site to create a large homooligomeric scaffold which can interact with other magnetosome-associated proteins via the MamA convex site. We discuss the structural basis for TPR homooligomerization that allows the proper function of a prokaryotic organelle.