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L-3,4-dihydroxyphenylalanine (L-DOPA) has been successfully used in the treatment of Parkinson’s disease (PD) for more than 50 years. It fulfilled the criteria to cross the blood–brain barrier and counteract the biochemical defect of dopamine (DA). It remarkably worked after some adjustments in line with the initial hypothesis, leaving a poor place to the plethora of mechanisms involving other neurotransmitters or mechanisms of action beyond newly synthesized DA itself. Yet, its mechanism of action is far from clear. It involves numerous distinct cell populations and does not mimic the mechanism of action of dopaminergic agonists. L-DOPA-derived DA is mainly released by serotonergic neurons as a false neurotransmitter, and serotonergic neurons are involved in L-DOPA-induced dyskinesia. The brain pattern and magnitude of DA extracellular levels together with this status of false neurotransmitters suggest that the striatal effects of DA via this mechanism would be minimal. Other metabolic products coming from newly formed DA or through the metabolism of L-DOPA itself could be involved. These compounds can be trace amines and derivatives. They could accumulate within the terminals of the remaining monoaminergic neurons. These “false neurotransmitters,” also known for some of them as inducing an “amphetamine-like” mechanism, could reduce the content of biogenic amines in terminals of monoaminergic neurons, thereby impairing the exocytotic process of monoamines including L-DOPA-induced DA extracellular outflow. The aim of this review is to present the mechanism of action of L-DOPA with a specific attention to “false neurotransmission.”

We introduce the notion of weighted limit in an arbitrary quasi-category, suitably generalizing ordinary limits in a quasi-category, and classical weighted limits in an ordinary category. This is accomplished by generalizing Joyal’s approach: we identify a meaningful construction for the quasi-category of weighted cones over a diagram in a quasi-category, whose terminal object is the weighted limit of the considered diagram. We then show that each weighted limit can be expressed as an ordinary limit. When the quasi-category arises as the homotopy coherent nerve of a category enriched over Kan complexes, we generalize an argument by Riehl-Verity to show that the weighted limit agrees with the homotopy weighted limit in the sense of enriched category theory, for which explicit constructions are available. When the quasi-category is complete, tensored and cotensored over the quasi-category of spaces, we discuss a possible comparison of our definition of weighted limit with the approach by Gepner-Haugseng-Nikolaus.

Over the past ten years, smart city research and application have grown in popularity. A thorough analysis of the literature evaluations that have already been published on SCs reveals a dearth of studies that categorize the literature into different themes and determine which topics are more and less popular based on the quantity of peer-reviewed research articles that fall under each subject. Therefore, the primary goal of this study is to determine the key advantages and difficulties of smart cities as well as the most productive phase of building projects. The results show that while topics like the social impact, governance and policy, performance indicators and standards, and citizens’ involvement in the design and development of SCs have received moderate attention, themes like innovation and technology, SC services design and management, and citizens’ involvement have been thoroughly researched. Less well-liked topics include the SC approach and implementation obstacles, nevertheless.

The JAK family, particularly JAK3, plays a crucial role in immune signaling and inflammatory responses. Dysregulated JAK3 activation in SARS-CoV-2 infections has been associated with severe inflammation and respiratory complications, making JAK inhibitors a viable therapeutic option. However, their use raises concerns regarding immunosuppression, which could increase susceptibility to secondary infections. While long-term adverse effects are less of a concern in acute COVID-19 treatment, patient selection and monitoring remain critical. Furthermore, adverse effects associated with oral JAK3 inhibitors necessitate the exploration of alternative strategies to optimize therapeutic efficacy while minimizing risks. This review highlights the role of JAK3 in immune and epithelial cells, examines the adverse effects of oral JAK3 inhibitors in COVID-19 and other treatments, and discusses alternative therapeutic strategies for improving patient outcomes.

Hyperlipidemia is a chronic disorder that plays an important role in the development of cardiovascular diseases, type II diabetes, atherosclerosis, hypertension, and non-alcoholic fatty liver disease. Hyperlipidemias have created a worldwide health crisis and impose a substantial burden not only on personal health but also on societies and economies. Transcription factors in the sterol regulatory element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. SREBPs regulate lipid homeostasis by controlling the expression of a range of enzymes required for the synthesis of endogenous cholesterol, fatty acids, triacylglycerol, and phospholipids. Thereby, SREBPs have been considered as targets for the treatment of metabolic diseases. The aim of this study was to investigate the beneficial functions and the possible underlying molecular mechanisms of SREBP decoy ODN, which is a novel inhibitor of SREBPs, in high-fat diet (HFD)-fed hyperlipidemic mice. Our studies using HFD-induced hyperlipidemia animal model revealed that SREBB decoy ODN inhibited the increased expression of fatty acid synthetic pathway, such as SREBP-1c, FAS, SCD-1, ACC1, and HMGCR. In addition, SREBP decoy ODN decreased pro-inflammatory cytokines, including TNF-α, IL-1β, IL-8, and IL-6 expression. These results suggest that SREBP decoy ODN exerts its anti-hyperlipidemia effects in HFD-induced hyperlipidemia mice by regulating their lipid metabolism and inhibiting lipogenesis through inactivation of the SREPB pathway.

The influence of the forced convection rate on the chemical structure of a polymethyl methacrylate (PMMA) flame in an oxidizer flow under microgravity conditions was studied using numerical modeling. Gas flow around a solid sphere was simulated using the full Navier–Stokes equations for a multicomponent mixture. A multistep chemical kinetic mechanism was considered in the gas phase. The heat transfer and radiation in both the condensed and gas phases were considered in the modeling. On the PMMA surface, the pyrolysis reaction leading to the transformation of fuel from the condensed phase to the gas phase is specified. The forced convection speed varied in the range from 3 to 20 cm/s. Analysis of CO2 concentration fields near the burning surface under microgravity conditions showed that the maximum CO2 concentration is observed in the downstream zone. The width of the flame zone and its chemical structure depend on the intensity of forced convection. The width of the flame against the flow decreases, and the maximum CO concentration increases as the forced convection rate increases. Analysis of the rates of fuel consumption reactions showed that at a low convection speed (vst=3 cm/s), the reaction with the H radical, which has the highest diffusion coefficient, plays a crucial role in MMA oxidation.

Background/Objectives: Identifying treatment failure at earlier time points to could spare cancer patients from ineffective treatment and side effects. In this study, circulating tumor DNA (ctDNA) and [18F]FDG-PET/CT were investigated during the first cycle of anticancer therapy in patients with advanced non-small cell lung cancer (NSCLC) to explore their potential for early response evaluation. Methods: Patients with advanced NSCLC receiving first-line therapy with immune checkpoint inhibitors and/or chemotherapy were included. CtDNA and [18F]FDG-PET/CT assessments were conducted before treatment and at weeks 1 and 3 during the first cycle of therapy. ctDNA quantification was performed using a targeted next-generation sequencing (NGS) panel, and the least favorable change in any mutated allele frequency at a given time was used for analysis. [18F]FDG-PET/CT was quantified using sumSULpeak and metabolic tumor volume (MTV4.0). Early changes in ctDNA levels and [18F]FDG-PET parameters were compared with final treatment response, measured by RECIST after 12 weeks, as well as progression-free survival and overall survival. Results: Of the sixteen included patients, eight were non-responders. ctDNA mutations were detected in baseline blood samples in eight patients. Changes in ctDNA level, MTV4.0, and sumSULpeak at week 3 indicated response in 7 out of 8 patients, 13 out of 15 patients, and 9 out of 15 patients, respectively. At week 3, no false increases were seen with ctDNA and MTV4.0. Conclusions: These results suggest that early changes in ctDNA and [18F]FDG-PET/CT at 3 weeks of treatment could be used to early assess treatment response. Increased levels of ctDNA and MTV4.0 at week 3 were only observed in patients with treatment failure.

Technology is part of education. The example that can use is a smartphone that contains Google translate application in supporting students translate a text form descriptive. This study intends to define the use of English Dictionary in the form of Google translate impact on English speaking capability as well as discover the importance of student interest in learning English, especially in speaking skill. The method of this research is descriptive analysis where the data settled from the students' speaking test then explained into descriptive. The target of this research was the students of Informatics Engineering and Information System second term. The outcome of this research is that the speaking test in the previous discussion found that the average value of Informatics Technique 1 experienced an addition of 4.89 points; in the Informatics Engineering 2 class encountered a change of 6.4 points, and Information System class progressed by 4.4 points. This number indicates there is an increase in the ability of students in speaking skills through the use of Automatic Dictionary applications such as Google Translate. Means that the use of Automatic dictionary media in the form of google translate can improve students' speaking skill as well as using google translate media as a tool in helping students to speak in English because it can be their means in translating the language either from English to Indonesian or from the language Indonesia to English.

In this study, a framework to monitor the volumetric fluctuation of the inland water body by the combination of a bathymetry map, an optical satellite imagery & multiple satellite altimetry measurements is presented. In spite of the recent studies in monitoring water level changes in lakes using satellite altimetry & optical satellite imagery, it’s still evident that these methods are limited to the water level, surface area and volume changes. However, to effectively study the lakes, it’s important to quantify the total lake volume. This hasn’t been possible as the existing satellite methods cannot estimate the bathymetry depth. The methodology was developed over Lake Victoria during 1993–2016. The results indicate that the water level, area, and volume of Lake Victoria decreased over the past 23 years. The water level shows a slight decrease (−0.005 m/year) of a total of −0.115 m from 1993 to 2016. The changes in water level translates to a reduction in lake area (−100 km 2 ) and volume (−5 km 3 ). Despite the inconsistent changes in area and volume, significant reduction occurred between 1998 and 2006 where (3484 km 2 ) and (122.87 km 3 ) reduction in area and volumes respectively were observed.

Introduction: The aim of this study was to determine the role of Notch in indoxyl sulfate (IS)-induced vascular calcification (VC). Materials and methods: VC and expression of Notch-related and osteogenic molecules were examined in Dahl salt-sensitive (DS), DS hypertensive (DH), and DH IS-treated rats (DH+IS). The effects of IS on expression of Notch receptors, apoptotic activity, and calcification were examined in cultured aortic smooth muscle cells (SMCs). Results: Medial calcification was noted only in aortas and coronary arteries of DH+IS rats. Notch1, Notch3, and Hes-1 were expressed in aortic SMCs of all rats, but only weakly in the central areas of the media and around the calcified lesions in DH+IS rats. RT-PCR and western blotting of DH+IS rat aortas showed downregulation of Notch ligands, Notch1 and Notch3, downstream transcriptional factors, and SM22, and conversely, overexpression of osteogenic markers. Expression of Notch1 and Notch3 in aortic SMCs was highest in incubation under 500 μM IS for 24hrs, and then decreased time- and dose-dependently. Coupled with this decrease, IS increased caspase 3/7 activity and TUNEL-positive aortic SMCs. In addition, pharmacological Notch signal inhibition with DAPT induced apoptosis in aortic SMCs. ZVAD, a caspase inhibitor abrogated IS-induced and DAPT-induced in vitro vascular calcification. Knockdown of Notch1 and Notch3 cooperatively increased expression of osteogenic transcriptional factors and decreased expression of SM22. Conclusion: Our results suggested that IS-induced VC is mediated through suppression of Notch activity in aortic SMCs, induction of osteogenic differentiation and apoptosis.