Search

Parkinson's Disease (PD) is a prevalent and escalating neurodegenerative disorder with significant societal implications. Despite being considered a proteinopathy, in which the aggregation of α-synuclein is the main pathological change, the intricacies of PD initiation remain elusive. Recent evidence suggests a potential link between gut microbiota and PD initiation, emphasizing the need to explore the effects of microbiota-derived molecules on neuronal cells. In this study, we exposed dopaminergic-differentiated SH-SY5Y cells to microbial molecules such as lipopolysaccharide (LPS), rhamnolipid, curli CsgA and phenol soluble modulin α-1 (PSMα1). We assessed cellular viability, cytotoxicity, growth curves and α-synuclein levels by performing MTS, LDH, real-time impedance readings, qRT-PCR and Western Blot assays respectively. Statistical analysis revealed that rhamnolipid exhibited concentration-dependent effects, reducing viability and inducing cytotoxicity at higher concentrations, increasing α-synuclein mRNA and protein levels with negative effects on cell morphology and adhesion. Furthermore, LPS exposure also increased α-synuclein levels. Curli CsgA and PSMα-1 showed minimal or no changes. Our findings suggest that microbiota-derived molecules, particularly rhamnolipid and LPS, impact dopaminergic neurons by increasing α-synuclein levels. This study highlights the potential involvement of gut microbiota in initiating the upregulation of α-synuclein that may further initiate PD, indicating the complex interplay between microbiota and neuronal cells., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Well integrity is currently defined through the concept of well barriers, in which one or more barriers are used to prevent unwanted fluid flow. Many papers have highlighted that the casing-cement interfacial bonding is critical for well integrity, but many discrepancies between laboratory experiments and field data have been noticed. The use of finite element analysis is now established as an alternative to complex in situ tests, but these simulations are sensitive to the input parameters, which results in many discrepancies across published works. Currently, the cohesive zone material (CZM) method is considered to offer good results if the correct parameters are selected or experimentally determined. The novelty of this paper lies in the development of a better workflow that enables the simulation of three processes that are acting on the laboratory-scale casing-cement system: temperature changes, debonding, and post-debonding behavior. The aim of this paper is to fully understand the debonding process within laboratory-scale samples, and thus to eventually enable upscaling in the near future. The paper presents a new workflow generated using FEM that allows us to determine the contact stresses at the casing-cement interface during temperature changes at the moment of debonding and post-debonding. The results presented within this paper show that temperature samples tested according to the push-down setup will provide similar interfacial bonding shear strength values; however, post-debonding, there is a remaining frictional force slightly higher than that of the room-temperature samples. In this case, the results are within a 5% error of the average field data, which is slightly higher than in our previous experiments, where only room temperature data were considered. A major outcome of our paper is the demonstration of the existence of friction forces after debonding, which are a result of radial stresses induced during the debonding process.

Although they are considered rare disorders, muscular dystrophies have a strong impact on people's health. Increased disease severity with age, frequently accompanied by the loss of ability to walk in some people, and the lack of treatment, have directed the researchers towards the development of more effective therapeutic strategies aimed to improve the quality of life and life expectancy, slow down the progression, and delay the onset or convert a severe phenotype into a milder one. Improved understanding of the complex pathology of these diseases together with the tremendous advances in molecular biology technologies has led to personalized therapeutic procedures. Different approaches that are currently under extensive investigation require more efficient, sensitive, and less invasive methods. Due to its remarkable analytical sensitivity, droplet digital PCR has become a promising tool for accurate measurement of biomarkers that monitor disease progression and quantification of various therapeutic efficiency and can be considered a tool for non-invasive prenatal diagnosis and newborn screening. Here, we summarize the recent applications of droplet digital PCR in muscular dystrophy research and discuss the factors that should be considered to get the best performance with this technology.

Well integrity is of high importance during the entire well life span especially when renewable energy resources such as geothermal are designed to cover the increasing world energy demand. Many studies have documented the importance of the casing-cement interfacial bonding to ensure critical well integrity achievements; however, laboratory experiments and field data are not always aligned. Furthermore, Finite Element Analysis shows relatively high discrepancies compared with the results of various scholarly published works. The limitations in the FEA are most probably generated by the casing-cement interaction modeling parameters. Typically, the contact between casing and cement is modeled using the so-called CZM method, which includes the shear debonding process into the FEA. Several setups have been used in the past to determine the interfacial casing-cement bonding shear strength. Some of these setups are briefly summarized herein. The novelty of this paper consists in the combination of a relatively simple experimental setup with the finite element modeling of the experiment itself to demonstrate that it is important to acquire accurate laboratory data for debonding simulations and, thus, to improve the well integrity prediction. The aim of this paper is to better understand the limitations of the finite element method when modeling shear bonding of the cement and, in the same, to verify that the proposed experimental setup can be modelled using numerical approaches. The successful numerical simulation can later be used for upscaled models. The results confirm the experimental push down setup and aid engineers to further understand and validate CZM models and optimize the well design to achieve maximum well integrity potential. Our results are within 1% error from the average field data.

Neuroendocrine tumors (NETs) represent a large and heterogeneous group of malignancies with various biological and clinical characteristics, depending on the site of origin and the grade of tumor proliferation. In NETs, as in other cancer types, molecularly targeted therapies have radically changed the therapeutic landscape. Recently two targeted agents, the mammalian target of rapamycin inhibitor everolimus and the tyrosine kinase inhibitor sunitinib, have both demonstrated significantly prolonged progression free survival in patients with advanced pancreatic NETs. Despite these important therapeutic developments, there are still significant limitations to the use of these agents due to the lack of accurate biomarkers for predicting tumor response and efficacy of therapy. In this review, we provide an overview of the current clinical data for the evaluation of predictive factors of response to/efficacy of everolimus and sunitinib in advanced pancreatic NETs. Surrogate indicators discussed include circulating and tissue markers, as well as non-invasive imaging techniques.

Metronomic therapy is characterized by the administration of regular low doses of certain drugs with very low toxicity. There have been numerous debates over the empirical approach of this regimen, but fewest side effects are always something to consider in order to improve patients' quality of life. Neuroendocrine tumors (NETs) are rare malignancies relatively slow-growing; therefore their treatment is often chronic, involving several different therapies for tumor growth control. Knowing that these tumors are highly vascularized, the anti-angiogenic aspect is highly regarded as something to be targeted in all patients harboring NETs. Additionally the metronomic schedule has proved to be effective on an immunological level, rendering this approach as a multi-targeted therapy. Rationalizing that advanced NETs are in many cases a chronic disease, with which patients can live for as long as possible, a systemic therapy with regular low doses and a very low toxicity is in many cases a judicious manner of pursuing stabilization. Metronomic schedule is usually correlated with chemotherapy in oncology, but other therapies, such as radiotherapy and biotherapy can be delivered in a metronomic like manner. This review describes clinical trials and case series involving metronomic therapies alone or in combination in patients with advanced NETs. Nowadays level of evidence about metronomic therapy in NETs is quite low, therefore future prospective clinical studies are needed to validate the metronomic approach in specific clinical settings., (Copyright © 2017 Elsevier Ltd. All rights reserved.)