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Thinking outside the box: non-canonical targets in multiple sclerosis.

ABSTRACT: Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system that causes demyelination, axonal degeneration and astrogliosis, resulting in progressive neurological disability. Fuelled by an evolving understanding of MS immunopathogenesis, the range of available immunotherapies for clinical use has expanded over the past two decades. However, MS remains an incurable disease and even targeted immunotherapies often fail to control insidious disease progression, indicating the need for new and exceptional therapeutic options beyond the established immunological landscape. In this Review, we highlight such non-canonical targets in preclinical MS research with a focus on five highly promising areas: oligodendrocytes; the blood-brain barrier; metabolites and cellular metabolism; the coagulation system; and tolerance induction. Recent findings in these areas may guide the field towards novel targets for future therapeutic approaches in MS.

SUBMITTER: Bierhansl L

PROVIDER: S-EPMC9169033 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Thinking outside the Ischemia Box: Advancements in the Use of Multiple Sclerosis Drugs in Ischemic Stroke.

Project description:Ischemic stroke (IS) is a major cause of death and disability, despite early intervention. Thrombo-inflammation, the inflammatory process triggered by ischemia, is a concept that ties IS with multiple sclerosis (MS), under the wider 'umbrella' of neuroinflammation, i.e., the inflammation of the nervous tissue. Drawing from this, numerous studies have explored the potential of MS disease-modifying drugs in the setting of IS. In this review, we present the available studies and discuss their potential in ameliorating IS outcomes. Based on our search, the vast majority of the studies have been conducted on animals, yielding mostly positive results. Two clinical trials involving natalizumab showed that it does not confer any benefits, but four human studies regarding fingolimod have showcased its potential in improving recovery prospects. However, concerns on safety and other issues are raised, and basic questions still need to be answered.

| S-EPMC7914575 | biostudies-literature

The PCNA interaction motifs revisited: thinking outside the PIP-box.

Project description:Proliferating cell nuclear antigen (PCNA) is a cellular hub in DNA metabolism and a potential drug target. Its binding partners carry a short linear motif (SLiM) known as the PCNA-interacting protein-box (PIP-box), but sequence-divergent motifs have been reported to bind to the same binding pocket. To investigate how PCNA accommodates motif diversity, we assembled a set of 77 experimentally confirmed PCNA-binding proteins and analyzed features underlying their binding affinity. Combining NMR spectroscopy, affinity measurements and computational analyses, we corroborate that most PCNA-binding motifs reside in intrinsically disordered regions, that structure preformation is unrelated to affinity, and that the sequence-patterns that encode binding affinity extend substantially beyond the boundaries of the PIP-box. Our systematic multidisciplinary approach expands current views on PCNA interactions and reveals that the PIP-box affinity can be modulated over four orders of magnitude by positive charges in the flanking regions. Including the flanking regions as part of the motif is expected to have broad implications, particularly for interpretation of disease-causing mutations and drug-design, targeting DNA-replication and -repair.

| S-EPMC6881253 | biostudies-literature

Thinking outside the CaaX-box: an unusual reversible prenylation on ALDH9A1

Project description:Protein lipidation is a post-translational modification that confers hydrophobicity on protein substrates to control their cellular localization, mediate protein trafficking, and regulate protein function. In particular, protein prenylation is a C-terminal modification on proteins bearing canonical motifs catalyzed by prenyltransferases. Prenylated proteins have been of interest due to their numerous associations with various diseases. Chemical proteomic approaches have been pursued over the last decade to define prenylated proteomes (prenylome) and probe their responses to perturbations in various cellular systems. Here, we describe the discovery of prenylation of a non-canonical prenylated protein, ALDH9A1, which lacks any apparent prenylation motif. This enzyme was initially identified through chemical proteomic profiling of prenylomes in various cell lines. Metabolic labeling with an isoprenoid probe using overexpressed ALDH9A1 revealed that this enzyme can be prenylated inside cells but does not respond to inhibition by prenyltransferase inhibitors. Site-directed mutagenesis of the key residues involved in ALDH9A1 activity indicates that the catalytic C288 bears the isoprenoid modification likely through an NAD+-dependent mechanism. Furthermore, the isoprenoid modification is also susceptible to hydrolysis, indicating a reversible modification. We hypothesize that this modification originates from endogenous farnesal or geranygeranial, the established degradation products of prenylated proteins and results in a thioester form that accumulates. This novel reversible prenoyl modification on ALDH9A1 expands the current paradigm of protein prenylation by illustrating a potentially new type of protein–lipid modification that may also serve as a novel mechanism for controlling enzyme function

2023-11-06 | PXD036365 | Pride

Thinking outside the "Blue Box": from molecular to supramolecular pH-responsiveness.

Project description:We present herein the development of a new polycationic cyclophane: the "red box", second in a series of hydrazone-based analogues of the well-known organic receptor cyclobis(paraquat-p-phenylene)cyclophane ("blue box"). The macrocycle has been prepared in an excellent yield in aqueous media, and shows both a remarkable pH-responsiveness and unusual hydrolytic stability of the two hydrazone C[double bond, length as m-dash]N bonds, associated with charge delocalization of the amine lone pair. Whilst in aqueous media the "red box" is able to complex a variety of aromatic substrates, both in its acidic and basic form, in organic media the cyclophane is only able to capture those in the acidic form, resulting in supramolecular pH-responsiveness.

| S-EPMC7069232 | biostudies-literature

Antifungal drug screening: thinking outside the box to identify novel antifungal scaffolds.

Project description:Invasive fungal infections are responsible for a significant disease burden worldwide. Drugs to treat these infections are limited to only four unique classes, and despite these available treatments, mortality rates remain unacceptably high. In this review, we will discuss antifungal drug screening and how the approach to identifying novel compounds needs move away from traditional growth-based assays in order to meet the demand for new drugs. We highlight specific examples of creative screening strategies that increase the likelihood of identifying compounds with desired activities and provide perspective to inspire development of novel screens for the identification of first-in-class antifungals.

| S-EPMC7652037 | biostudies-literature

Bicaval Valve Implantation for Severe Tricuspid Regurgitation: Thinking Outside the Valve Box.

Project description: Not available

| S-EPMC8289099 | biostudies-literature

Thinking Outside the Box: Developing Dynamic Data Visualizations for Psychology with Shiny.

Project description:The study of human perception has helped psychologists effectively communicate data rich stories by converting numbers into graphical illustrations and data visualization remains a powerful means for psychology to discover, understand, and present results to others. However, despite an exponential rise in computing power, the World Wide Web, and ever more complex data sets, psychologists often limit themselves to static visualizations. While these are often adequate, their application across professional psychology remains limited. This is surprising as it is now possible to build dynamic representations based around simple or complex psychological data sets. Previously, knowledge of HTML, CSS, or Java was essential, but here we develop several interactive visualizations using a simple web application framework that runs under the R statistical platform: Shiny. Shiny can help researchers quickly produce interactive data visualizations that will supplement and support current and future publications. This has clear benefits for researchers, the wider academic community, students, practitioners, and interested members of the public.

| S-EPMC4664644 | biostudies-literature

Thinking Outside the Euclidean Box: Riemannian Geometry and Inter-Temporal Decision-Making.

Project description:Inter-temporal decisions involves assigning values to various payoffs occurring at different temporal distances. Past research has used different approaches to study these decisions made by humans and animals. For instance, considering that people discount future payoffs at a constant rate (e.g., exponential discounting) or at variable rate (e.g., hyperbolic discounting). In this research, we question the widely assumed, but seldom questioned, notion across many of the existing approaches that the decision space, where the decision-maker perceives time and monetary payoffs, is a Euclidean space. By relaxing the rigid assumption of Euclidean space, we propose that the decision space is a more flexible Riemannian space of Constant Negative Curvature. We test our proposal by deriving a discount function, which uses the distance in the Negative Curvature space instead of Euclidean temporal distance. The distance function includes both perceived values of time as well as money, unlike past work which has considered just time. By doing so we are able to explain many of the empirical findings in inter-temporal decision-making literature. We provide converging evidence for our proposal by estimating the curvature of the decision space utilizing manifold learning algorithm and showing that the characteristics (i.e., metric properties) of the decision space resembles those of the Negative Curvature space rather than the Euclidean space. We conclude by presenting new theoretical predictions derived from our proposal and implications for how non-normative behavior is defined.

| S-EPMC4809573 | biostudies-literature

'Thinking outside the box': advanced geriatric nursing in primary health care in Scandinavia.

Project description:BackgroundOlder people are frequent users of primary health care (PHC) services. PHC services have been critiqued, mainly regarding limited accessibility and continuity of care. In many countries, investment in nurse practitioners (NPs) has been one strategy to improve PHC services. In the North of Europe, the NP role is still in its infancy. The aim of this study was to explore the feasibility of introducing geriatric nurse practitioners (GNPs) in PHC in Scandinavia, from multiprofessional and older persons' perspectives.MethodsThe study had a qualitative design, including 25 semi-structured interviews with nurses, nurse leaders, physicians, politicians and older persons from several communities in Scandinavia. The material was analysed by means of qualitative content analysis.ResultsThe results highlight current challenges in health services for the older population, i.e. comorbid older patients with complex care needs aging in place, lack of competent staff, and organisational challenges. The results present an envisioned GNP scope of practice in health services for the older population, including bringing advanced competence closer to the patient, an autonomous role including task-shifting, and a linking role. The results also present factors influencing implementation of the GNP role, i.e. GNP competence level, unclear role and scope of practice, and openness to reorganisation.ConclusionsThe results indicate that it is feasible to implement the GNP role in primary health care in Scandinavia. Notwithstanding, there are factors influencing implementation of the GNP role that should be considered.

| S-EPMC6604267 | biostudies-literature

Thinking outside the box: students positive about visionary elective curricula in medical school.

Project description:Objective: Space for personality development as well as for the development of critical, creative and interdisciplinary thinking is rarely found in medical curricula in Germany. To be prepared for the challenges of modern medicine, future physicians need a visionary mindset. The aim of this study is to determine the need for teaching such content among medical students in the context of visionary elective curricula and to examine these with regard to the desired topics and organizational structure. Methods: This is a cross-sectional study with 236 medical students from all semesters of the Ludwig-Maximilians-University Munich. The survey consists of 50 questions and includes single choice, multiple choice, matrix questions, open-ended questions and Likert scales. Responses were examined using descriptive statistics and compared parametrically in sub-aspects. Results: Three-quarters of respondents would like to see curricular content on interdisciplinary interfaces with other disciplines. A suitable framework for this is seen by 87% of the respondents in a visionary elective curriculum. Students would like to see a broad range of specific content such as global health, politics, business, and computer science. The majority of respondents would like to see 1 unit of instruction per week and would participate in an appropriate program. Such an offering would promote creative (53.6%), critical (63.7%), and interdisciplinary thinking (69.0%) and train to become better physicians (87%). Conclusion: Participants in this study are positive toward the introduction of visionary content in medical school. Faculties should build visionary elective curricula according to the graduate profile requirements of the new NKLM 2.0 to make medical education sustainable.

| S-EPMC8675382 | biostudies-literature

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