Fluorenylidene-pyrroline Biomimetic Light-driven Molecular Switches

A new family of biomimetic photoactivated molecular switches based in the retinal chromophore is described. Expedient synthesis allows a library of compounds with a different substitution pattern, including chiral substituents, to be obtained. The effect of substitution, solvent, and light source on the photoisomerization step has been assessed. The absorption maximum has been red-shifted ca. 50 nm with respect to related systems and rotation is now easily achieved by using visible light

TRPA1 mediates aromatase inhibitor-evoked pain by the aromatase substrate androstenedione

Aromatase inhibitors (AI) induce painful musculoskeletal symptoms (AIMSS), which are dependent upon the pain transducing receptor TRPA1. However, as the AI concentrations required to engage TRPA1 in mice are higher than those found in the plasma of patients, we hypothesized that additional factors may cooperate to induce AIMSS. Here we report that the aromatase substrate androstenedione, unique among several steroid hormones, targeted TRPA1 in peptidergic primary sensory neurons in rodent and human cells expressing the native or recombinant channel. Androstenedione dramatically lowered the concentration of letrozole required to engage TRPA1. Notably, addition of a minimal dose of androstenedione to physiologically ineffective doses of letrozole and oxidative stress byproducts produces AIMSS-like behaviors and neurogenic inflammatory responses in mice. Elevated androstenedione levels cooperated with low letrozole concentrations and inflammatory mediators were sufficient to provoke AIMSS-like behaviors. The generation of such painful conditions by small quantities of simultaneously administered TRPA1 agonists justifies previous failure to identify a precise link between AIs and AIMSS, underscoring the potential of channel antagonists to treat AIMSS

Fibroblast autofluorescence in connective tissue disorders: a future tool for clinical and differential diagnosis?

Marfan syndrome (MFS) is an inherited disorder of connective tissue due to mutations in FBN1 (90%) and TGFBR1 and TGFBR2 (5 to 10%) genes. Clinical and differential diagnosis is difficult because of the inter- and intrafamiliar marked heterogeneity and the variable onset age of clinical manifestations. Among the disorders, in differential diagnosis, thoracic aortic aneurysm (TAA) and Ullrich scleroatonic muscular dystrophy (UCMD) are reported. We evaluate the possibility of utilizing autofluorescence (AF) analysis as a diagnostic tool in the clinical and/or differential diagnosis of MFS and related disorders and in the investigation of the molecular mechanisms involved. Both multispectral imaging autofluorescence microscopy (MIAM) and autofluorescence microspectroscopy (AMS) have been used to characterize AF emission of fibroblasts from patients affected by inherited connective tissue disorders. Our preliminary results show significant differences in AF emission between normal and pathological fibroblasts, suggesting possible improvement in diagnostics of connective tissue disorders by AF analysis

Transcriptomic indices of fast and slow disease progression in two mouse models of amyotrophic lateral sclerosis

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Divergent thinking abilities in frontotemporal dementia: A mini-review

A large number of studies, including single case and case series studies, have shown that patients with different types of frontotemporal dementia (FTD) are characterized by the emergence of artistic abilities. This led to the hypothesis of enhanced creative thinking skills as a function of these pathological conditions. However, in the last years, it has been argued that these brain pathologies lead only to an augmented \u201cdrive to produce\u201d rather than to the emergence of creativity. Moreover, only a few studies analyzed specific creative skills, such as divergent thinking (DT), by standardized tests. This Mini-Review aimed to examine the extent to which DT abilities are preserved in patients affected by FTD. Results showed that DT abilities (both verbal and figural) are altered in different ways according to the specific anatomical and functional changes associated with the diverse forms of FTD. On the one hand, patients affected by the behavioral form of FTD can produce many ideas because of unimpaired access to memory stores (i.e., episodic and semantic), but are not able to recombine flexibly the information to produce original ideas because of damages in the pre-frontal cortex. On the other hand, patients affected by the semantic variant are impaired also in terms of fluency because of the degradation of their semantic memory store. Potential implications, limitations, and future research directions are discussed

A Comparison of Divergent Thinking Abilities Between Healthy Elderly Subjects and MCI Patients: Preliminary Findings and Implications

Objective: Divergent thinking (DT) has attracted research interest because of its potential role in early diagnosis and rehabilitation programs for patients affected by neurodegenerative diseases. Recently, DT has received even more attention because of its proven relationship with cognitive reserve (CR) and the possibility of a standardized assessment. However, few studies have investigated this ability in dementia patients, and even less is known about patients affected by Mild Cognitive Impairment (MCI). Thus, this study aims to investigate DT abilities in MCI patients. Methods: A total of 25 MCI patients and 25 healthy controls subjects (HC; from a random selection of 50) matched for age, gender, and educational level were enrolled. General cognitive functioning was measured by the Montreal Cognitive Assessment (MoCA), while the Abbreviated Torrance Test for Adults (ATTA) was selected to measure DT. Results: MANOVA analysis did not reveal any significant differences in DT abilities between MCI patients and HC except for the figural indicator score. A logistic hierarchical regression analysis revealed that the figural indicator score added an 8% of accuracy in the prediction of the group variable over the general cognition measure (MoCA). Conclusion: MCI patients seem to perform significantly worse than HC only in the figural DT score and this evidence has significant practical implications. First, that figural DT seemed to decrease even earlier than verbal DT and could therefore be taken into account for early diagnosis of MCI patients. On the contrary, the sparing of all the other DT skills (such as verbal DT skills, fluency, flexibility, originality, and elaboration) may suggest that, given its relationship with CR, verbal DT could instead be considered a possible target for prevention or early cognitive stimulation interventions

A horizon scan of priorities for coastal marine microbiome research

Research into the microbiomes of natural environments is changing the way ecologists and evolutionary biologists view the importance of microbes in ecosystem function. This is particularly relevant in ocean environments, where microbes constitute the majority of biomass and control most of the major biogeochemical cycles, including those that regulate the Earth's climate. Coastal marine environments provide goods and services that are imperative to human survival and well-being (e.g. fisheries, water purification), and emerging evidence indicates that these ecosystem services often depend on complex relationships between communities of microorganisms (the ‘microbiome’) and their hosts or environment – termed the ‘holobiont’. Understanding of coastal ecosystem function must therefore be framed under the holobiont concept, whereby macroorganisms and their associated microbiomes are considered as a synergistic ecological unit. Here we evaluated the current state of knowledge on coastal marine microbiome research and identified key questions within this growing research area. Although the list of questions is broad and ambitious, progress in the field is increasing exponentially, and the emergence of large, international collaborative networks and well-executed manipulative experiments are rapidly advancing the field of coastal marine microbiome research

A horizon scan of priorities for coastal marine microbiome research

Research into the microbiomes of natural environments is changing the way ecologists and evolutionary biologists view the importance of microbes in ecosystem function. This is particularly relevant in ocean environments, where microbes constitute the majority of biomass and control most of the major biogeochemical cycles, including those that regulate the Earth's climate. Coastal marine environments provide goods and services that are imperative to human survival and well-being (e.g. fisheries, water purification), and emerging evidence indicates that these ecosystem services often depend on complex relationships between communities of microorganisms (the ‘microbiome’) and their hosts or environment – termed the ‘holobiont’. Understanding of coastal ecosystem function must therefore be framed under the holobiont concept, whereby macroorganisms and their associated microbiomes are considered as a synergistic ecological unit. Here we evaluated the current state of knowledge on coastal marine microbiome research and identified key questions within this growing research area. Although the list of questions is broad and ambitious, progress in the field is increasing exponentially, and the emergence of large, international collaborative networks and well-executed manipulative experiments are rapidly advancing the field of coastal marine microbiome research

Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma

SummaryBRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan-RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance