Fibronectin is a smart adhesive that both influences and responds to the mechanics of early spinal column development.

An extracellular matrix of Fibronectin adheres the neural tube to the two flanking columns of paraxial mesoderm and is required for normal vertebrate development. Here, we find that the bilaterally symmetric interfaces between the zebrafish neural tube and paraxial mesoderm function as optimally engineered adhesive lap joints with rounded edges, graded Fibronectin 'adhesive' and an arced adhesive spew filet. Fibronectin is a 'smart adhesive' that remodels to the lateral edges of the neural tube-paraxial mesoderm interfaces where shear stress is highest. Fibronectin remodeling is mechanically responsive to contralateral variation morphogenesis, and Fibronectin-mediated inter-tissue adhesion is required for bilaterally symmetric morphogenesis of the paraxial mesoderm. Strikingly, however, perturbation of the Fibronectin matrix rescues the neural tube convergence defect of cadherin 2 mutants. Therefore, Fibronectin-mediated inter-tissue adhesion dynamically coordinates bilaterally symmetric morphogenesis of the vertebrate trunk but predisposes the neural tube to convergence defects that lead to spina bifida.

In embryos, the spinal cord starts out as a flat sheet of cells that curls up to form a closed cylinder called the neural tube. The folding tube is attached to the surrounding tissues through an extracellular matrix of proteins and sugars. Overlapping strands of a protein from the extracellular matrix called Fibronectin connect the neural tube to adjacent tissues, like a kind of biological glue. However, it remained unclear what effect this attachment had on the embryonic development of the spinal cord. Connecting two overlapping objects with glue to form what is known as an 'adhesive lap joint' is common in fields such as woodworking and aeronautical engineering. The glue in these joints comes under shearing stress whenever the two objects it connects try to pull apart. But, thanks to work in engineering, it is possible to predict how different joints will perform under tension. Now, Guillon et al. have deployed these engineering principles to shed light on neural tube development. Using zebrafish embryos and computational models, Guillon et al. investigated what happens when the strength of the adhesive lap joints in the developing spine changes. This revealed that Fibronectin works like a smart adhesive: rather than staying in one place like a conventional glue, it moves around. As the neural tube closes, cells remodel the Fibronectin, concentrating it on the areas under the highest stress. This seemed to both help and hinder neural tube development. On the one hand, by anchoring the tube equally to the left and right sides of the embryo, the Fibronectin glue helped the spine to develop symmetrically. On the other hand, the strength of the adhesive lap joints made it harder for the neural tube to curl up and close. If the neural tube fails to close properly, it can lead to birth defects like spina bifida. One of the best-known causes of these birth defects in humans is a lack of a vitamin known as folic acid. Cell culture experiments suggest that this might have something to do with the mechanics of the cells during development. It may be that faulty neural tubes could close more easily if they were able to unglue themselves from the surrounding tissues. Further use of engineering principles could shed more light on this idea in the future.

Synthesis of novel naphthalene-heterocycle hybrids with potent antitumor, anti-inflammatory and antituberculosis activities.

Multitarget-directed drugs (hybrid drugs) constitute an efficient avenue for the treatment of multifactorial diseases. In this work, novel naphthalene hybrids with different heterocyclic scaffolds such as nicotinonitrile, pyran, pyranopyrazole, pyrazole, pyrazolopyridine, and azepine were efficiently synthesized via tandem reactions of 3-formyl-4H-benzo[h]chromen-4-one 1 with different nucleophilic reagents. Analysis of these hybrids using PASS online software indicated different predicted biological activities such as anticancer, antimicrobial, antiviral, antiprotozoal, anti-inflammatory, etc. By focusing on antitumor, anti-inflammatory, and antituberculosis activities, many compounds revealed remarkable activities. While 3c, 3e, and 3h were more potent than doxorubicin in the case of HepG-2 cell lines, 3a-e, 3i, 6, 8, 10, 11, and 12b were more potent in the case of MCF-7. Moreover, compounds 3c, 3h, 8, 10, 3d, and 12b manifested superior activity and COX-2 selectivity to the reference anti-inflammatory Celecoxib. Regarding antituberculosis activity, 3c, 3d, and 3i were found to be the most promising with MIC less than 1 µg mL-1. The molecular docking studies showed strong polar and hydrophobic interactions with the novel naphthalene-heterocycle hybrids that were compatible with experimental evaluations to a great extent.

Interplay Between the Persistent Random Walk and the Contact Inhibition of Locomotion Leads to Collective Cell Behaviors.

Cell migration plays an important role in physiology and pathophysiology. It was observed in the experiments that cells, such as fibroblast, leukocytes, and cancer cells, exhibit a wide variety of migratory behaviors, such as persistent random walk, contact inhibition of locomotion, and ordered behaviors. To identify biophysical mechanisms for these cellular behaviors, we developed a rigorous computational model of cell migration on a two-dimensional non-deformable substrate. Cells in the model undergo motion driven by mechanical interactions between cellular protrusions and the substrate via the balance of tensile forces. Properties of dynamic formation of lamellipodia induced the persistent random walk behavior of a migrating cell. When multiple cells are included in the simulation, the model recapitulated the contact inhibition of locomotion between cells at low density without any phenomenological assumptions or momentum transfer. Instead, the model showed that contact inhibition of locomotion can emerge via indirect interactions between the cells through their interactions with the underlying substrate. At high density, contact inhibition of locomotion between numerous cells gave rise to confined motions or ordered behaviors, depending on cell density and how likely lamellipodia turn over due to contact with other cells. Results in our study suggest that various collective migratory behaviors may emerge without more restrictive assumptions or direct cell-to-cell biomechanical interactions.

Unorthodox synthesis, biological activity and DFT studies of novel and multifunctionalized naphthoxocine derivatives.

A new promising protocol has been developed for the synthesis of scarce oxocine derivatives 3a-e and 6 through addition of amine-based nucleophiles such as hydroxylamine hydrochloride, primary amine and hydrazide to chromonylidene benzothiazol-2-ylacetonitrile 2 in refluxing dioxane under metal free reaction conditions in moderate to good yields. Other nitrogen nucleophiles such as piperidine, hydrazine and thiosemicarbazide failed to afford the corresponding oxocinols, and instead pyridine derivatives 7, 8 and 10 were obtained exclusively. Predictive study for the biological activities using PASS (prediction of activity spectra for biologically active substances) online software showed optimistic activities for oxocinols 3a-e in the treatment of cancer, influenza A and microbial infections. Additionally, DFT studies of oxocine derivatives 3a-e and 6 indicated the presence of required thermodynamics parameters for the application in dye-sensitized solar cells (DSSCs).

Mechanical Model for Durotactic Cell Migration.

Cell migration is a fundamental process in biological systems, playing an important role for diverse physiological processes. Cells often exhibit directed migration in a specific direction in response to various types of cues. In particular, cells are able to sense the rigidity of surrounding environments and then migrate toward stiffer regions. To understand this mechanosensitive behavior called durotaxis, several computational models have been developed. However, most of the models employed cell decision making to recapitulate durotactic behaviors, significantly limiting insights provided from these studies. In this study, we developed a computational biomechanical model without any cell decision making to illuminate intrinsic mechanisms of durotactic behaviors of cells migrating on a two-dimensional substrate. The model consists of a simplified cell generating contractile forces and a deformable substrate coarse-grained into an irregular triangulated mesh. Using the model, we demonstrated that durotactic behaviors emerge from purely mechanical interactions between the cell and the underlying substrate. We investigated how durotactic migration is regulated by biophysical properties of the substrate, including elasticity, viscosity, and stiffness profile.

Platelet function profile post-clopidogrel therapy in patients with type 2 diabetes undergoing coronary stent implantation.

Platelet dysfunction contributes to the increased risk of thromboischemic complications after percutaneous coronary intervention (PCI), particularly in type 2 diabetes. Little is known about the effects of glycemic control on platelet reactivity. We assessed adenosine diphosphate-induced platelet aggregation and flow cytometric expression of P-selectin in 90 patients (56 diabetic and 34 nondiabetic patients) undergoing coronary stent implantation after administration of clopidogrel as a potential predictor of poststent complications and its relation to glycemic control. Posttreatment platelet reactivity was significantly elevated in diabetic compared with nondiabetic participants and was associated with smoking, hypercholesterolemia, overweight, and cardiovascular ischemic events. A linear relationship was found between hemoglobin A1c in diabetic patients and platelet reactivity. Both methods (standard aggregometry and P-selectin expression) used for assessment of platelet function were positively correlated. Low responsiveness to clopidogrel detected by posttreatment platelet reactivity is a risk factor for ischemic events after PCI in diabetic patients.