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We study the crack-tip fields in a three-dimensional (3D) plate with a V-shaped crack employing Rajagopal's theory of elasticity with the strain-limiting effect. The classical linear elastic fracture mechanics (LEFM) theory bears a well-documented inconsistency, i.e., for a static crack problem under the traction-free boundary condition, the LEFM theory predicts singular crack-tip strains. Such results are inconsistent with the constitutive relation derived using the assumption of uniform bound for the strain values. Instead, Rajagopal's recent theory of elasticity provides implicit constitutive relations between the linearized strain and Cauchy stress in which one can impose an a-priori upper bound for strains. We formulate the strain-limiting theory comprehensively in this article. The linearized strain is expressed as a nonlinear function of the Cauchy stress. The equation for the equilibrium of the linear momentum under a special type of nonlinear constitutive relation reduces to a second-order quasilinear elliptic boundary value problem (BVP). Using a Picard-type linearization and a continuous Galerkin-type finite element technique, we solve several BVPs with tensile and shear displacement loading. The numerical results for the strains, the stresses, the stress intensity factor (SIF), and strain energy density (SED) are obtained for different Poisson values, strain-limiting parametric values, and the V-shaped angles. The growth of the near-tip strains is far less than that of stresses, and the results for both the SIF and SED are also consistent with the results from LEFM. Our work demonstrates that the framework of Rajagopal's theory of elasticity can provide a basis for developing physically meaningful and mathematically well-posed BVPs to study evolution of cracks, damage, nucleation, or failure in elastic bodies. [ABSTRACT FROM AUTHOR]

We consider the truncated geometric distribution and analyze the condition under which a nontrivial maximum likelihood (ML) estimator of the parameter p exists. Additionally, the uniqueness criterion of such an ML estimator is also investigated. Our results indicate that in order to ensure the existence of a nontrivial ML estimator, the sample mean should be smaller than the midpoint of the two boundary positions. Without such a condition, the ML estimator will only exist trivially at p = 0. Finally, we demonstrate that the same condition is also required for the existence of the method of moments estimator. Our results lead to a rigorous understanding of the two estimators and aid in the interpretation of experimental designs that incorporate the truncated geometric distribution. [ABSTRACT FROM AUTHOR]

Growth is a significant factor that results in deformations of tubular organs, and particular deformations associated with growth enable tubular organs to perform certain physiological functions. Configuring growth profiles that achieve particular deformation patterns is critical for analyzing potential pathological conditions and for developing corresponding clinical treatments for tubular organ dysfunctions. However, deformation-targeted growth is rarely studied. In this article, the human cervix during pregnancy is studied as an example to show how cervical thinning and dilation are generated by growth. An advanced hyperelasticity theory called morphoelasticity is employed to model the deformations, and a growth tensor is used to represent growth in three principle directions. The computational results demonstrate that both negative radial growth and positive circumferential growth facilitate thinning and dilation. Modeling such mixed growth represents an advancement beyond commonly used uniform growth inside tissues to study tubular deformations. The results reveal that complex growth may occur inside tissues to achieve certain tubular deformations. Integration of further biochemical and cellular activities that initiate and mediate such complex growth remains to be explored. [ABSTRACT FROM AUTHOR]

Angioedema is a tissue-swelling pathology due to rapid change in soft tissue fluid content. Its occurrence in the trachea is predominantly localized to the soft mucous tissue that forms the innermost tracheal layer. The biomechanical consequences, such as airway constriction, are dependent upon the ensuing mechanical interactions between all of the various tissues that comprise the tracheal tube. We model the stress interactions by treating the trachea organ as a three-tissue system consisting of swellable mucous in conjunction with nonswelling cartilage and nonswelling trachealis musculature. Hyperelastic constitutive modeling is used by generalizing the standard anisotropic, incompressible soft tissue framework to incorporate the swelling effect. Finite element stress analysis then proceeds with swelling of the mucous layer providing the driving factor for the mechanical analysis. The amount of airway constriction is governed by the mechanical interaction between the three predominant tissue types. The detailed stress analysis indicates the presence of stress concentrations near the various tissue junctions. Because of the tissue's nonlinear mechanical behavior, this can lead to material stiffness fluctuations as a function of location on the trachea. Patient specific modeling is presented. The role of the modeling in the interpretation of diagnostic procedures and the assessment of therapies is discussed. [ABSTRACT FROM AUTHOR]

We consider three different compressible versions of the conventional incompressible neo-Hookean material model. The different versions are not new and have been used in various model studies. They each give neo-Hookean behavior in an appropriate incompressible limit. The three versions each show some basic differences with respect to each other as regards the qualitative nature of the approach to the neo-Hookean limit. The purpose of this study is to exhibit these differences. [ABSTRACT FROM PUBLISHER]

The rate-limiting serine biogenesis enzyme PHGDH is overexpressed in cancers. Both serine withdrawal and genetic/pharmacological inhibition of PHGDH have demonstrated promising tumor-suppressing activities. However, the enzyme properties of PHGDH are not well understood and the discovery of PHGDH inhibitors is still in its infancy. Here, oridonin was identified from a natural product library as a new PHGDH inhibitor. The crystal structure of PHGDH in complex with oridonin revealed a new allosteric site. The binding of oridonin to this site reduced the activity of the enzyme by relocating R54, a residue involved in substrate binding. Mutagenesis studies showed that PHGDH activity was very sensitive to cysteine mutations, especially those in the substrate binding domain. Conjugation of oridonin and other reported covalent PHGDH inhibitors to these sites will therefore inhibit PHGDH. In addition to being inhibited enzymatically, PHGDH can also be inhibited by protein aggregation and proteasome-mediated degradation. Several tested PHGDH cancer mutants showed altered enzymatic activity, which can be explained by protein structure and stability. Overall, the above studies present new biophysical and biochemical insights into PHGDH and may facilitate the future design of PHGDH inhibitors. [ABSTRACT FROM AUTHOR]

As a key rate-limiting enzyme in the de novo synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase ( h DHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1 H -pyrazolo[3,4- b ]pyridine scaffold was identified as an h DHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1 H -pyrrolo[2,3- b ]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine ( w2) , which was found to be the most promising and drug-like compound with potent inhibitory activity against h DHODH (IC 50 = 173.4 nM). Compound w2 demonstrated acceptable pharmacokinetic characteristics and alleviated the severity of acute ulcerative colitis induced by dextran sulfate sodium in a dose-dependent manner. Notably, w2 exerted better therapeutic effects on ulcerative colitis than h DHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, w2 is a promising h DHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.

Lysine-specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cell-derived and patient-derived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damage-inducible gene 45beta ( GADD45B ) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B , a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, co-administration of ZY0511 and DTP3, which specifically enhanced the pro-apoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Human dihydroorotate dehydrogenase ( h DHODH), as the fourth and rate-limiting enzyme of the de novo pyrimidine synthesis pathway, is regarded as an attractive target for malignancy therapy. In the present study, a novel series of teriflunomide derivatives were designed, synthesized, and evaluated as h DHODH inhibitors. 13t was the optimal compound with promising enzymatic activity (IC 50 = 16.0 nM), potent antiproliferative activity against human lymphoma Raji cells (IC 50 = 7.7 nM), and excellent aqueous solubility (20.1 mg/mL). Mechanistically, 13t directly inhibited h DHODH and induced cell cycle S-phase arrest in Raji cells. The acute toxicity assay indicated a favorable safety profile of 13t . Notably, 13t displayed significant tumor growth inhibition activity with a tumor growth inhibition (TGI) rate of 81.4% at 30 mg/kg in a Raji xenograft model. Together, 13t is a promising inhibitor of h DHODH and a preclinical candidate for antitumor therapy, especially for lymphoma.

During pregnancy, the cervix experiences significant mechanical property change due to tissue swelling, and to ongoing changes in the collagen content. In this paper, we model how these two effects contribute to cervical deformation as the pressure load on top of the cervix increases. The cervix and its surrounding supporting ligaments are taken into consideration in the resulting mechanical analysis. The cervix itself is treated as a multilayered tube-like structure, with layer-specific collagen orientation. The cervical tissue in each layer is treated in terms of a collagen constituent that remodels with time within a ground substance matrix that experiences swelling. The load and swelling are taken to change sufficiently slowly so that the collagen properties at any instant can be regarded as being in a state of homeostasis. Among other things, the simulations show how the luminal cross-sectional area varies along its length as a function of pressure and swelling. In general, an increase in pressure causes an overall shortening of the lumen while an increase in swelling has the opposite effect., (Copyright © 2020 by ASME.)