Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors.

Wnt Signaling in Periodontal Disease

Periodontitis is a multifactorial and chronic condition associated with the formation of a dysbiotic biofilm, leading to a pro-inflammatory environment that can modulate cell signaling. The Wnt pathway plays fundamental roles during homeostasis and disease, and emerging evidence suggests its involvement in the maintenance of the periodontium and the development of periodontitis. Here, we summarize the role of the Wnt/β-catenin and non-canonical Wnt signaling pathways in periodontitis. The accumulated data suggests specific roles for each branch of the Wnt pathway. Wnt5a emerges as a critical player promoting periodontal ligament remodeling and impairing regenerative responses modulated by the Wnt/β-catenin pathway, such as alveolar bone formation. Collectively, the evidence suggests that achieving a proper balance between the Wnt/β-catenin and non-canonical pathways, rather than their independent modulation, might contribute to controlling the progression and severity of the periodontal disease.

Culture in the State Reporting Procedure of the UN Human Rights Treaty Bodies

Ever since the adoption of the Universal Declaration of Human Rights in 1948 there has been a debate on the issue of universality and cultural diversity. The UN human rights treaty bodies have an important role to play in ensuring a proper balance between safeguarding the universality of the rights, while at the same time leaving room for cultural particularities. This book examines how the UN treaty bodies, in particular the Human Rights Committee, the Committee on Economic, Social and Cultural Rights and the Committee on the Elimination of Discrimination against Women, fulfil this role.

Urban Sustainability Deficits: The Urban Non-Sustainability Index (UNSI) as a Tool for Urban Policy

Urban sustainability has been revealed as one of the key elements in achieving global sustainability. There is a wide range of indicators in this field; however, sustainability indicators have not been exempt from criticism, in both their formal aspects and practical usefulness. If measuring sustainability is “measuring the immeasurable”, then the objective of this article is to propose a composite indicator that evaluates only the deficits of sustainability or, which is the same thing, the unsustainability of cities. This focus has the advantage of showing up the particular deficiencies and thus the priorities that each city must attend to. For this purpose, only unsustainability, defined as the distance to a sustainability target, was considered. Aggregation was carried out through generalized means, which lead to a proper balance between compensatory and non-compensatory aggregation. The results emerging from the application of our methodology to a sample of fifty different cities suggest that all cities should attend to some aspect concerning sustainability, and that no city is sustainable, but only less unsustainable, showing both significant differences between cities in terms of the degree of unsustainability and a common underlying structure of unsustainability in which the environmental dimension contributes the most.

Informed Forms and Matters

After sufficient consideration for the proper balance between material and formal constraints, this chapter describes a pedagogical approach that transforms the education of future architects through a 'form-finding' method, allowing the material to accommodate itself to form and celebrate its own nature. To enhance pedagogical improvement of foundational studies in architecture and further explore this pedagogy based on form-finding in early design education, this chapter also presents the challenges to integrating materiality within the design process, as derived from the incorporation of experimental form-finding methods into early-stage design.

Literature Review on Siddha Medicine for the Management of Neerkana Maantham with Utthamani Kudineer- A Drug Review

Siddha medicine is an ancient and traditional system of medicine.. When the three humors (Vatham, Pitham, Kabam) are in proper balance then the person experiences good health; any imbalance of three humors leads to disease. Acute Nasopharyngitis defines an inflammation of the mucous membrane of the naso pharynx. It is characterized by rhinorrhea, nasal obstruction, sneezing, malaise, fever, headache, & myalgia. It may be correlated with Neerkana maantham, one of the 31 types of Maantham in children mentioned in Siddha literature Balavagadam. The symptoms of Neerkana mantham can be managed by Siddha herbal formulation Utthamani kudineer. The main ingredients of the Utthamani kudineer are Chukku, Milagu, Thippili, Omam, Sutta Vasambu, Utthamani leaf, Velai ver, Nochi thulir, Murungai eerku, Nuna eerku. The ingredients of this formulation possess anti-inflammatory, antiviral, anti microbial, antipyretic activities. All the ingredients of trial drug are purely herbals only. It is easily prepared, palatable, assimilates quickly and also safe for pediatric usage in the treatment of Neerkana maantham. Hence, this article gives an insight on the efficacy of Utthamani kudineer for Neerkana maantham (Acute Nasopharyngitis) based on review of various literatures and scientific studies. This review further focuses to improve the research on Siddha herbal medicines.

Rawls’ traces in contemporary philosophy of education

This article examines the many traces of John Rawls’ theory of justice in contemporary philosophy of education. Beyond work that directly explores the educational implications of justice as fairness and political liberalism, there are many interesting debates in philosophy of education that make use of Rawlsian concepts to defend views that go well beyond those advocated in justice as fairness. There have also been methodological debates on Rawls’ distinction between ideal and non-ideal theory which concern the proper balance between empirically informed discussion and fruitful normative reflection.

A graph-based data quality analysis in distributed telemedicine systems

Telemedicine is one of the most rapidly developing areas of healthcare and it plays an increasing role in modern medicine. As the amount of data and demand for features increase, the data paths are becoming ever-more complex. Owing to this, it is vital in telemedicine to find a proper balance between consistency and availability under any given circumstances. However, making a trade-off can significantly influence the quality of the data. This study seeks to get an in-depth view of the problem by considering a real-world telemedicine use-case and elaborating the formal system specification of the scenario. After evaluating the specification, the constructed state graph is examined using graph coloring and other graph algorithms.

Non-Ceruloplasmin Copper as a Stratification Biomarker of Alzheimer’s Disease Patients: How to Measure and Use It

: Alzheimer’s disease (AD) is a type of dementia very common in the elderly. A growing body of recent evidence has linked AD pathogenesis to copper (Cu) dysmetabolism in the body. In fact, a subset of patients affected either by AD or by its prodromal form known as Mild Cognitive Impairment (MCI) have been observed to be unable to maintain a proper balance of Cu metabolism and distribution and are characterized by the presence in their serum of increased levels of Cu not bound to ceruloplasmin (non-ceruloplasmin Cu). Since serum non-ceruloplasmin Cu is a biomark- er of Wilson's disease (WD), a well-known condition of Cu-driven toxicosis, in this review, we pro- pose that in close analogy with WD, the assessment of non-ceruloplasmin Cu levels can be exploit- ed as a cost-effective stratification and susceptibility/risk biomarker for the identification of some AD/MCI individuals. The approach can also be used as an eligibility criterion for clinical trials aim- ing at investigating Cu-related interventions against AD/MCI.

Radically Hopeful Thinking for a Wicked Covid-19 Pandemic Problem

This paper explores the prospects of radical hope for addressing the devastation of the Covid-19 pandemic. Hope is useful for conceptualizing the proper balance between too much fear and too little about our uncertain future. First, I describe the ethical challenge of the pandemic as a wicked problem. Because accepted ethical theories fail to motivate solutions, wicked problems pressure us to develop our value systems, exercise moral imaginations, and discover creative solutions. Second, I develop an Aristotelian account of radical hope, drawing from ancient philosophy, virtue ethics, and recent climate ethics. Radical hope is a novel form of courage, which balances the goal of external success, that something good will emerge from the tragedy, against the goal of living well for its own sake through practical wisdom. I conclude by applying some lessons to our present situation.