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Background and Purpose: Metabotropic glutamate receptor 1 (mGlu1) is a promising therapeutic target for neurodegenerative CNS disorders including spinocerebellar ataxias (SCAs). Clinical reports have identified naturally‐occurring mGlu1 mutations in rare SCA subtypes and linked symptoms to mGlu1 mutations. However, how mutations alter mGlu1 function remains unknown, as does amenability of receptor function to pharmacological rescue. Here, we explored SCA‐associated mutation effects on mGlu1 cell surface expression, canonical signal transduction and allosteric ligand pharmacology. Experimental Approach: Orthosteric agonists, positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) were assessed at two functional endpoints (iCa2+ mobilisation and inositol 1‐phosphate [IP1] accumulation) in FlpIn Trex HEK293A cell lines expressing five mutant mGlu1 subtypes. Key pharmacological parameters including ligand potency, affinity and cooperativity were derived using operational models of agonism and allostery. Key Results: mGlu1 mutants exhibited differential impacts on mGlu1 expression, with a C‐terminus truncation significantly reducing surface expression. Mutations differentially influenced orthosteric ligand affinity, efficacy and functional cooperativity between allosteric and orthosteric ligands. Loss‐of‐function mutations L454F and N885del reduced orthosteric affinity and efficacy, respectively. A gain‐of‐function Y792C mutant mGlu1 displayed enhanced constitutive activity in IP1 assays, which manifested as reduced orthosteric agonist activity. The mGlu1 PAMs restored glutamate potency in iCa2+ mobilisation for loss‐of‐function mutations and mGlu1 NAMs displayed enhanced inverse agonist activity at Y792C relative to wild‐type mGlu1. Conclusion and Implications: Collectively, these data highlight distinct mechanisms by which mGlu1 mutations affect receptor function and show allosteric modulators may present a therapeutic strategy to restore aberrant mGlu1 function in rare SCA subtypes. [ABSTRACT FROM AUTHOR]

The suprachiasmatic nucleus of the hypothalamus (SCN) houses the central circadian oscillator of mammals. The main neurotransmitters produced in the SCN are γ‐amino‐butyric acid, arginine‐vasopressin (AVP), vasoactive intestinal peptide (VIP), pituitary‐derived adenylate cyclase‐activating peptide (PACAP), prokineticin 2, neuromedin S, and gastrin‐releasing peptide (GRP). Apart from these, catecholamines and their receptors were detected in the SCN as well. In this study, we confirmed the presence of β‐adrenergic receptors in SCN and a mouse SCN‐derived immortalized cell line by immunohistochemical, immuno‐cytochemical, and pharmacological techniques. We then characterized the effects of β‐adrenergic agonists and antagonists on cAMP‐regulated element (CRE) signaling. Moreover, we investigated the interaction of β‐adrenergic signaling with substances influencing parallel signaling pathways. Our findings have potential implications on the role of stress (elevated adrenaline) on the biological clock and may explain some of the side effects of β‐blockers applied as anti‐hypertensive drugs. [ABSTRACT FROM AUTHOR]

Preadolescence is a critical period, characterised by changes in physical, hormonal, cognitive, behavioural, and emotional development, as well as by changes in social and school relationships. These changes are accompanied by the transition from elementary school to middle school. The literature shows that this transition is one of the most stressful events for preadolescents, which can have a negative impact on their well-being. The main objectives of this review, focused on the school context, were to identify protective and risk factors influencing the well-being of preadolescent students and to describe the interventions implemented. A systematic search of peer-reviewed papers published between 2011 and 2021 was conducted following the PRISMA reporting guidelines. A total of 36 full-text articles met the inclusion criteria. Studies converge in identifying risk factors that may affect student well-being in this age group: individual factors (levels of emotional awareness and self-esteem) and relational factors (friendship, teachers’ and parents’ supporting actions and roles). Intervention programs are mainly focused on improving emotional and social regulation skills that also influence academic achievement. Our findings have important implications for both research and intervention in school settings.

The goal of radiotherapy is to cover a target area with a desired radiation dose while keeping the exposition of non-target areas as low as possible in order to reduce radiation side effects. In the case of Intensity Modulated Proton Therapy (IMPT), the dose distribution is typically designed via a treatment planning optimisation process based on classical optimisation algorithms on some objective functions.We investigate the planning optimisation problem under the point of view of the Theory of Complexity in general and, in particular, of the Combinatorial Optimisation Theory. We firstly give a formal definition of a simplified version of the problem that is in the complexity class NPO.We prove that above version is computationally hard, i.e. it belongs to the class NPO$\setminus$PTAS if $\mathbb{NP}\neq \mathbb{P}$.We show how Combinatorial Optimisation Theory can give valuable tools, both conceptual and practical, in treatment plan definition, opening the way for new deterministic algorithms with bounded time complexity which have to support the technological evolution up to adaptive plans exploiting near real time solutions.

Bacteria classification has been deeply investigated with different tools for many purposes,such as early diagnosis, metagenomics, phylogenetics. Classification methods based on ribosomalDNA sequences are considered a reference in this area. We present a new classificatier for bacteriaspecies based on a dissimilarity measure of purely combinatorial nature. This measure is based onthe notion of Minimal Absent Words, a combinatorial definition that recently found applications inbioinformatics. We can therefore incorporate this measure into a probabilistic neural network in orderto classify bacteria species. Our approach is motivated by the fact that there is a vast literature on thecombinatorics of Minimal Absent Words in relation with the degree of repetitiveness of a sequence.We ran our experiments on a public dataset of Ribosomal RNA Sequences from the complex 16S. Ourapproach showed a very high score in the accuracy of the classification, proving hence that our methodis comparable with the standard tools available for the automatic classification of bacteria species.

The incidence of self-reported cognitive failures among older adults may be an index of successful cognitive aging. However, self-reported cognitive failures are biased by variation in depressive symptomatology. This study examined age-related and socio-cultural context effects on cognitive failures while controlling for depressive symptoms. Both overall and specific factors of cognitive failures were determined. A further goal was to investigate the relationship between working memory and cognitive efficiency measures and cognitive failures. One hundred and thirty-nine cognitively healthy adults were recruited from two populations known to differ in their dispositions toward cognitive failures and depressive symptoms (Sardinia and northern Italy). The participants were assigned to Young Old (65-74 years old), Old (75-84 years of age) or Oldest Old (≥85 years of age) groups, and individually presented with a test battery including the Cognitive Failures Questionnaire, the Centre for Epidemiological Studies of Depression Scale, and Forward and Backward Digit Span tests. Specific factors of cognitive failures were differentially associated with measures of depression and working memory. While age had no impact on any aspect of cognitive failures, overall and specific dispositions varied between the two populations. The overall liability to cognitive failure was lower in participants from Sardinia, however, this group also had a higher liability to lapses of action (Blunders factor). Overall, these findings highlight that richer information about cognitive failures may be revealed through the investigation of specific factors of cognitive failures. They also confirm that the absence of changes in cognitive failures across old age is independent of variation in depressive symptoms, at least among cognitively healthy elders.