On the constraints violation in forward dynamics of multibody systems

It is known that the dynamic equations of motion for constrained mechanical multibody systems are frequently formulated using the Newton-Euler’s approach, which is augmented with the acceleration constraint equations. This formulation results in the establishment of a mixed set of partial differential and algebraic equations, which are solved in order to predict the dynamic behavior of general multibody systems. The classical resolution of the equations of motion is highly prone to constraints violation because the position and velocity constraint equations are not fulfilled. In this work, a general and comprehensive methodology to eliminate the constraints violation at the position and velocity levels is offered. The basic idea of the described approach is to add corrective terms to the position and velocity vectors with the intent to satisfy the corresponding kinematic constraint equations. These corrective terms are evaluated as function of the Moore-Penrose generalized inverse of the Jacobian matrix and of the kinematic constraint equations. The described methodology is embedded in the standard method to solve the equations of motion based on the technique of Lagrange multipliers. Finally, the effectiveness of the described methodology is demonstrated through the dynamic modeling and simulation of different planar and spatial multibody systems. The outcomes in terms of constraints violation at the position and velocity levels, conservation of the total energy and computational efficiency are analyzed and compared with those obtained with the standard Lagrange multipliers method, the Baumgarte stabilization method, the augmented Lagrangian formulation, the index-1 augmented Lagrangian and the coordinate partitioning method.The first author expresses his gratitude to the Portuguese Foundation for Science and Technology through the PhD grant (PD/BD/114154/2016). This work has been supported by the Portuguese Foundation for Science and Technology with the reference project UID/EEA/04436/2013, by FEDER funds through the COMPETE 2020 – Programa Operacional Competitividade e Internacionalização (POCI) with the reference project POCI-01-0145-FEDER-006941.info:eu-repo/semantics/publishedVersio

Polymorphism: an evaluation of the potential risk to the quality of drug products from the Farmácia Popular Rede Própria

Polymorphism in solids is a common phenomenon in drugs, which can lead to compromised quality due to changes in their physicochemical properties, particularly solubility, and, therefore, reduce bioavailability. Herein, a bibliographic survey was performed based on key issues and studies related to polymorphism in active pharmaceutical ingredient (APIs) present in medications from the Farmácia Popular Rede Própria. Polymorphism must be controlled to prevent possible ineffective therapy and/or improper dosage. Few mandatory tests for the identification and control of polymorphism in medications are currently available, which can result in serious public health concerns

Pharmacological inhibition of TFF3 enhances sensitivity of CMS4 colorectal carcinoma to 5-fluorouracil through inhibition of p44/42 MAPK

10.3390/ijms20246215International Journal of Molecular Sciences2024621

Inhibition of TFF3 enhances sensitivity—and overcomes acquired resistance—to doxorubicin in estrogen receptor-positive mammary carcinoma

10.3390/cancers11101528Cancers1110152

Integrating genetics with single-cell multiomic measurements across disease states identifies mechanisms of beta cell dysfunction in type 2 diabetes

Dysfunctional pancreatic islet beta cells are a hallmark of type 2 diabetes (T2D), but a comprehensive understanding of the underlying mechanisms, including gene dysregulation, is lacking. Here we integrate information from measurements of chromatin accessibility, gene expression and function in single beta cells with genetic association data to nominate disease-causal gene regulatory changes in T2D. Using machine learning on chromatin accessibility data from 34 nondiabetic, pre-T2D and T2D donors, we identify two transcriptionally and functionally distinct beta cell subtypes that undergo an abundance shift during T2D progression. Subtype-defining accessible chromatin is enriched for T2D risk variants, suggesting a causal contribution of subtype identity to T2D. Both beta cell subtypes exhibit activation of a stress-response transcriptional program and functional impairment in T2D, which is probably induced by the T2D-associated metabolic environment. Our findings demonstrate the power of multimodal single-cell measurements combined with machine learning for characterizing mechanisms of complex diseases

Neuroprotective effects of hesperetin in mouse primary neurones are independent of CREB activation

Dietary flavonoids, including the citrus flavanone hesperetin, may have stimulatory, effects on cytoprotective intracellular signalling pathways. In primary mouse cortical neurone cultures, but not SH-SY5Y human neuroblastoma cells or human primary dermal fibroblasts (Promocells), hesperetin (100-300 nM, 15 min) caused significant increases in the level of ERK1/2 phosphorylation, but did not increase CREB phosphorylation. Administration of hesperetin for 18 h did not alter gene expression driven by the cyclic AMP response element (CRE), assessed using a luciferase reporter system, but 300 nM hesperetin partially reversed staurosporine-induced cell death in primary neurones. Our data show that hesperetin is a neuroprotective compound at concentrations where antioxidant effects are unlikely to predominate. The effects of hesperetin are cell-type dependent and, unlike the flavanol (-)epicatechin, neuroprotection in vitro is not associated with enhanced CREB phosphorylation or CRE-mediated gene expression. (C) 2008 Elsevier Ireland Ltd. All rights reserved