Cutaneous Ulcer Caused by Apixaban Treatment Is Resolved after Replacement with Dabigatran.

Nowadays, novel oral anticoagulants (NOACs) have shown improved safety profile and efficacy compared to vitamin K antagonists in the prevention of thromboembolic events occurring during different pathological conditions. However, there are concerns and safety issues, mostly related to adverse events following interactions with other drugs, in real-world practice. We report the case of an 83-year-old woman who developed a non-bleeding leg ulcer not caused by trauma or other evident pathological conditions after 10 days of treatment with apixaban 5 mg/q.d. She was switched from apixaban to dabigatran and the leg ulcer rapidly improved and completely cicatrized in 40 days. The resolution of the ulcer and the toleration of dabigatran therapy suggest an apixaban-specific reaction; however, the pathological mechanism of ulcer onset is currently unclear. Careful evaluation of hospital databases of Molise region (Southern Italy) hospitals identified two similar cases between 2019 and 2021. These cases underline the necessity of careful post-marketing surveillance, considering the rapidly increasing number of patients treated with NOACs and patient's risk factors such as old age, high polypharmacy rate, co-morbidities, and peculiar genetic background related to NOACs pharmacokinetic features.

Structure-activity relationships of fraxamoside as an unusual xanthine oxidase inhibitor.

Fraxamoside, a macrocyclic secoiridoid glucoside featuring a hydroxytyrosol group, was recently identified as a xanthine oxidase inhibitor (XOI) comparable in potency in vitro to the standard antigout drug allopurinol. However, this activity and its considerably higher value than its derivatives oleuropein, oleoside 11-methyl ester, and hydroxytyrosol are not explained by structure-activity relationships (SARs) of known XOIs. To exclude allosteric mechanisms, we first determined the inhibition kinetic of fraxamoside. The resulting competitive mechanism prompted a computational SAR characterization, combining molecular docking and dynamics, which fully explained the behavior of fraxamoside and its derivatives, attributed the higher activity of the former to conformational properties of its macrocycle, and showed a substantial contribution of the glycosidic moiety to binding, in striking contrast with glycoside derivatives of most other XOIs. Overall, fraxamoside emerged as a lead compound for a new class of XOIs potentially characterized by reduced interference with purine metabolism.

Native PAGE to study the interaction between the oncosuppressor p53 and its protein ligands.

In the present study, we investigated a new approach for studying the interaction between p53 and MDM2/X (where MDM is murine double minute protein). The method is based on the different mobility between the interacting domains of the oncosuppressor p53 and its protein ligands MDM2/X on polyacrylamide gels under native conditions. While the two proteins MDM2/X alone were able to enter the gel, the formation of a binary complex between p53 and MDM2/X prevented the gel entry. The novel technique is reliable for determining the different affinity elicited by MDM2 or MDMX toward p53, and can be useful for analyzing the dissociation power exerted by other molecules on the p53-MDM2/X complex.

Nondenaturing polyacrylamide gel electrophoresis to study the dissociation of the p53·MDM2/X complex by potentially anticancer compounds.

A new analytical method to study the dissociation of the complexes between the oncosuppressor p53 and its negative modulators murine double-minute protein 2 (MDM2) or MDMX, is proposed. This technique is reliable to determine the dissociative power exerted by small molecules on the complex taking advantage of the appearance of migrating MDM2 or MDMX in a native polyacrylamide gel, when inhibitors are added to the complex mixture. Therefore, we propose this new approach to easily screen library of compounds, with potential pharmacological anticancer activity.

Discriminative Power of Handwriting and Drawing Features in Depression.

This study contributes knowledge on the detection of depression through handwriting/drawing features, to identify quantitative and noninvasive indicators of the disorder for implementing algorithms for its automatic detection. For this purpose, an original online approach was adopted to provide a dynamic evaluation of handwriting/drawing performance of healthy participants with no history of any psychiatric disorders ([Formula: see text]), and patients with a clinical diagnosis of depression ([Formula: see text]). Both groups were asked to complete seven tasks requiring either the writing or drawing on a paper while five handwriting/drawing features' categories (i.e. pressure on the paper, time, ductus, space among characters, and pen inclination) were recorded by using a digitalized tablet. The collected records were statistically analyzed. Results showed that, except for pressure, all the considered features, successfully discriminate between depressed and nondepressed subjects. In addition, it was observed that depression affects different writing/drawing functionalities. These findings suggest the adoption of writing/drawing tasks in the clinical practice as tools to support the current depression detection methods. This would have important repercussions on reducing the diagnostic times and treatment formulation.

Visual and kinesthetic motor imagery in adults with different degrees of self-reported motor coordination difficulties.

Developmental Coordination Disorder (DCD) involves difficulties in performing coordinated movements with fine and/or gross motor skills deficits. Several studies showed that DCD is characterized by motor imagery deficits as well. Here we investigated in neurotypical adults (N = 334) the relationships between the ease of imaging two main motor imagery components, that is the visual and the kinesthetic one, self-reported motor coordination difficulties and handwriting speed. Self-reported motor difficulties were measured by the Adult Developmental Co-ordination Disorders/Dyspraxia Checklist (ADC) and scores were used to distinguish three groups: participants at risk of DCD (with both relevant childhood and current motor coordination difficulties); with motor coordination difficulties (relevant current but not childhood difficulties); without motor coordination difficulties (neither current nor childhood difficulties). The main results showed more kinesthetic and visual imagery difficulties in participants at risk of DCD than in those both with and without motor coordination difficulties. Interestingly, the relationships between the two imagery components and motor difficulties were different in the three groups, depending on: 1) the developmental phase (childhood or adulthood) to which motor coordination difficulties referred, and 2) the point of view (self or other), from which images were judged. Instead, no relationship was found between imagery abilities and handwriting speed. Thus, a nuanced pattern of the ease of imaging motor imagery emerged in adults with different degrees of self-reported motor coordination difficulties. These findings could be relevant for the assessment of people candidate to undergo a motor imagery training.

The Relationships between Self-Reported Motor Functioning and Autistic Traits: The Italian Version of the Adult Developmental Coordination Disorders/Dyspraxia Checklist (ADC).

BACKGROUND: We developed the Italian version of the adult developmental co-ordination disorders/dyspraxia checklist (ADC), providing reliability and concurrent validity data for the scale (Aim 1). In addition, we investigated the relationships between motor coordination difficulties and different autistic traits (Aim 2). METHODS: 498 participants (341 females; age range = 18-34) underwent the Italian version of the ADC, as well as a handwriting speed test, the autism spectrum quotient, the empathy quotient, and the systemizing quotient. RESULTS: The distinction between three main factors (A, B, and C) identified in the original version of the ADC was confirmed here. Internal consistency of the ADC subscales was adequate, as well as the correlation with the handwriting speed test used to assess concurrent validity. No substantial sex differences on the ADC scores were found. Furthermore, data revealed that poor autistic-related communication skills and lower levels of systemizing tendencies were, among all the investigated autistic traits, those more strongly associated with higher motor coordination difficulties. CONCLUSIONS: The Italian ADC seems a valuable tool for assessing motor coordination difficulties in adults and can reveal the nuanced impact exerted by different autistic traits on self-reported motor functioning.

Specific Global-Local Visual Processing Abilities Mediate the Influence of Non-social Autistic-like Traits on Mental Rotation.

Inconsistent data are available on mental rotation performance in neurotypicals with high autistic-like traits. Here, we tested whether global-local visual processing abilities mediate the influence of specific autistic-like trait domains (social skill, attention switching, attention-to-detail, communication, and imagination) on mental rotation. Neurotypical participants (N = 128) underwent an assessment of autistic-like traits, a flanker task with hierarchical stimuli, and a mental rotation task. Path analysis showed that Reaction Times on the incongruent/local condition of the flanker task mediated the relationship between attention-to-detail and mental rotation accuracy. These findings indicate that a better capacity of ignoring incongruent global information to identify local information (reduced global interference) in persons with high non-social autistic-like traits, as attention-to-detail, facilitates mental rotation performance.

Research and characterization of fibrous microplastics and natural microfibers in pelagic and benthic fish species of commercial interest.

The ingestion of synthetic microfibers, the most prevalent type of microplastics in marine environments, and natural fibers was assessed in Engraulis engrasicolus and Mullus barbatus, two commercially important fish species in the Mediterranean Sea. Microfibers were isolated from the fish gastrointestinal tract using a 10% potassium hydroxide solution. For the microfiber characterization, the evaluation of specific morphological features using a light microscope, coupled with the Fourier-transform infrared (FTIR) analysis of a subsample of isolated particles, was applied. The preliminary results showed the occurrence of microfibers in 53 and 60% of European anchovy and Red mullet, respectively. A mean of 6.9 microfibers/individual was detected in anchovies, while on average Red mullet samples contained 9.2 microfibers/individual. The most common colors of fibers in both species were black, blue, and transparent. Visual characterization of fibers allowed the classification of 40% of the items as synthetic microfibers. FTIR spectroscopy confirmed the visual classification by fiber morphology. Microfibers were made of different typologies of polymers, represented by cellulose, cotton, and polyester. These findings confirm as the wide distribution of fibrous microplastics, and natural microfibers may impact both pelagic and deep-sea trophic webs. Despite the presence of microfibers in fish species poses a potential risk to human health, the literature is scarce regarding studies on the uptake by commercial marine fish mostly due to methodological issues. The visual characterization, corroborated by spectroscopic techniques, may be useful to differentiate synthetic and natural fibers, representing a fast and easy method to assess fibrous microplastic pollution in commercially important fish species.

Properties of the endogenous components of the thioredoxin system in the psychrophilic eubacterium Pseudoalteromonas haloplanktis TAC 125.

The endogenous components of the thioredoxin system in the Antarctic eubacterium Pseudoalteromonas haloplanktis have been purified and characterised. The temperature dependence of the activities sustained by thioredoxin (PhTrx) and thioredoxin reductase (PhTrxR) pointed to their adaptation in the cold growth environment. PhTrxR was purified as a flavoenzyme and its activity was significantly enhanced in the presence of molar concentration of monovalent cations. The energetics of the partial reactions leading to the whole electron transfer from NADPH to the target protein substrate in the reconstituted thioredoxin system was also investigated. While the initial electron transfer from NADPH to PhTrxR was energetically favoured, the final passage to the heterologous protein substrate enhanced the energetic barrier of the whole process. The energy of activation of the heat inactivation process essentially reflected the psychrophilic origin of PhTrxR. Vice versa, PhTrx possessed an exceptional heat resistance (half-life, 4.4 h at 95 °C), ranking this protein among the most thermostable enzymes reported so far in psychrophiles. PhTrxR was covalently modified by glutathione, mainly by its oxidised or nitrosylated forms. A mutagenic analysis realised on three non catalytic cysteines of the flavoenzyme allowed the identification of C(303) as the target for the S-glutathionylation reaction.

Empathy through the Pandemic: Changes of Different Emphatic Dimensions during the COVID-19 Outbreak.

Growing evidence suggests that empathy is a relevant psychological trait to face the challenges imposed by the COVID-19 pandemic, but at the present very little is known on whether this multi-dimensional construct has been affected by the pandemic outbreak differently in its separate components. Here, we aimed at filling this gap by capitalizing on the opportunity of having collected data from different self-report measures and cognitive tasks assessing the main dimensions of empathy immediately before the beginning of the global pandemic and about one year later. The results showed a detrimental impact of the pandemic outbreak on empathic social skills but not on both cognitive (perspective-taking) and emotional empathy that instead significantly improved. Thus, reduced empathic social skills could be a weakness to be targeted in psychological interventions to help people cope with the mental health challenges related to COVID-19 pandemic, whereas the ability of understanding another's mental states and emotions could represent a strength in dealing with the current long-lasting crisis.

Anxiety Sensitivity Domains are Differently Affected by Social and Non-social Autistic Traits.

Anxiety sensitivity (AS) is implicated in the development and maintenance of several psychopathological conditions. Non-clinical individuals with high autistic traits may develop anxiety disorders and depressive symptoms. Here, we investigated the relationships of autistic traits with AS dimensions and depression, considering sex. We referred to the two-factor model of the autism spectrum quotient to distinguish social and non-social autistic traits and assessed 345 university students on AS and depression scales. Results showed that only social autistic traits predicted general AS and anxiety-related concerns regarding social and cognitive domains. The present results emphasize the need of assessing multiple domains of anxiety in individuals on the autistic spectrum, differentiating social and non-social traits.

A versatile approach to evaluate the occurrence of microfibers in mussels Mytilus galloprovincialis.

Microplastics of fibrous shape are esteemed to be the most abundant micro-debris form present in the environment. Despite the occurrence of microfibers in fish may pose a risk to human health, the literature is scarce regarding studies on the contamination in commercial marine fish mostly due to methodological issues. In this study, a versatile approach, able to discriminate among natural and synthetic microfibers according to the evaluation of specific morphological features, is proposed in farmed mussels (Mytilus galloprovincialis). The approach was useful to determine that microfibers were present in 74% of mussel samples, with a mean number of 14.57 microfibers/individual, corresponding to 3.13 microfibers/g w.w. A negative correlation between the size of analysed mussels and the amount of microfibers/g w.w. was detected, showing that smaller specimens contained more microfibers than the larger ones. This work paves the way to further studies aimed to adequately assess the risk that microfibers may pose to marine biota, also considering the commercial value as seafood items of many species of the Mytilus genus and the potential implication for human exposure.

Kv7.4 channels regulate potassium permeability in neuronal mitochondria.

Mitochondrial K+ permeability regulates neuronal apoptosis, energy metabolism, autophagy, and protection against ischemia-reperfusion injury. Kv7.4 channels have been recently shown to regulate K+ permeability in cardiac mitochondria and exert cardioprotective effects. Here, the possible expression and functional role of Kv7.4 channels in regulating membrane potential, radical oxygen species (ROS) production, and Ca2+ uptake in neuronal mitochondria was investigated in both clonal (F11 cells) and native brain neurons. In coupled mitochondria isolated from F11 cells, K+-dependent changes of mitochondrial membrane potential (ΔΨ) were unaffected by the selective mitoBKCa channel blocker iberiotoxin and only partially inhibited by the mitoKATP blockers glyburide or ATP. Interestingly, K+-dependent ΔΨ decrease was significantly reduced by the Kv7 blocker XE991 and enhanced by the Kv7 activator retigabine. Among Kv7s, western blot experiments showed the expression of only Kv7.4 subunits in F11 mitochondrial fractions; immunocytochemistry experiments showed a strong overlap between the Kv7.4 fluorescent signal and that of the mitochondrial marker Mitotracker. Silencing of Kv7.4 expression significantly suppressed retigabine-dependent decrease in ΔΨ in intact F11 cells. Expression of Kv7.4 subunits was also detected by western blot in isolated mitochondria from total mouse brain and by immunofluorescence in mouse primary cortical neurons. Pharmacological experiments revealed a relevant functional role for Kv7.4 channels in regulating membrane potential and Ca2+ uptake in isolated neuronal mitochondria, as well as ΔΨ and ROS production in intact cortical neurons. In conclusion, these findings provide the first experimental evidence for the expression of Kv7.4 channels and their contribution in regulating K+ permeability of neuronal mitochondria.

Extraction and identification of microplastics from mussels: Method development and preliminary results.

Microplastics (MPs) are an emerging threat to marine ecosystems. One of the primary environmental risks is their bioavailability for aquatic organisms. Some fish and bivalves are of particular interest because their feeding strategies expose them to particles present in the water column. The aim of the study was to assess an extraction method in order to isolate and quantify MPs from fish gastrointestinal tract (n.8) and muscle (n.4), and bivalves (n.8) samples. The accuracy of the method was assessed through the calculation of the recovery percentage in samples spiked with a known number of MPs using microscopic observation. Successively, the extraction was preliminarily applied on n.20 mussels collected from mariculture plants of the Tyrrhenian and the Adriatic Sea. The results of the digestion protocol showed an average extraction yield of 80% in fish gastrointestinal tracts, 90% in fish muscle samples, and 95% in mussels. Preliminary analysis carried out on farmed mussels showed an average abundance of 3.8 items/individual, and 0.5 items/g of tissue, among those black, was the most represented color.

Switching between the Forest and the Trees: The Contribution of Global to Local Switching to Spatial Constructional Abilities in Typically Developing Children.

BACKGROUND: Spatial analysis encompasses the ability to perceive the visual world by arranging the local elements ("the trees") into a coherent global configuration ("the forest"). During childhood, this ability gradually switches from a local to a global precedence, which contributes to changes in children's spatial construction abilities, such as drawing or building blocks. At present, it is not clear whether enhanced global or local processing or, alternatively, whether switching between these two levels best accounts for children's spatial constructional abilities. METHODS: We assessed typically developing children 7 to 8 years old on a global/local switching task and on two widely used spatial construction tasks (the Rey-Osterrieth Complex Figure and the Block Design test). RESULTS: The ability to switch from global to local level, rather than a global or a local advantage, best accounted for children's performance on both spatial construction tasks. CONCLUSIONS: The present findings contribute to elucidate the relationship between visual perception and spatial construction in children showing that the ease with which children switch perception from global to local processing is an important factor in their performance on tasks requiring complex drawing and block assembling.

Sex differences in implicit motor imagery: Evidence from the hand laterality task.

Behavioural evidence suggest that males outperform females in mentally transforming objects, whereas whether sex differences exist in mentally transforming body part images (implicit motor imagery) is an open issue. The aim of the present study was to fill this gap testing performance of 360 healthy participants on a classical behavioural measure of implicit motor imagery: the hand laterality task. Participants had to judge handedness of hand images portrayed from back and palm and presented in different spatial orientations. Two main findings emerged. First, males were significantly faster than females in judging hands portrayed from palm, in particular left palms at 0°, 90° and 180° orientation, whereas females were faster than males in judging backs, in particular left and right backs at 0° and the left back at 90°. Second, both males and females showed a significant biomechanical effect (faster responses for hands portrayed in medial vs. lateral positions) while judging palms, albeit the effect was stronger in males, whereas only females showed a significant biomechanical effect when judging backs. Thus, males and females seem to differently exploit motor simulation processes during mental transformation of hand images depending on a specific familiarity with body parts portrayed from different views. This result might be taken into account when tailoring motor imagery tasks in applied contexts, as motor rehabilitation.

Stability against temperature of Sulfolobus solfataricus elongation factor 1 alpha, a multi-domain protein.

The elongation factors (EF-Tu/EF-1 alpha) are universal proteins, involved in protein biosynthesis. A detailed characterization of the stability against temperature of SsEF-1 alpha, a three-domain protein isolated from the hyperthermophilic archaeon Sulfolobus solfataricus is presented. Thermal denaturation of both the GDP-bound (SsEF-1 alpha*.GDP) and the ligand-free (nfSsEF-1 alpha) forms was investigated by means of circular dichroism and fluorescence measurements, over the 4.0-7.5 pH interval. Data indicate that the unfolding process is cooperative with no intermediate species and that the few inter-domain contacts identified in the crystal structure of SsEF-1 alpha play a role also at high temperatures. Finally, it is shown that the enzyme exhibits two different interchangeable thermally denatured states, depending on pH.

Proteases Upregulation in Sporadic Alzheimer's Disease Brain.

Certain proteases are involved in Alzheimer's disease (AD) and their erroneous control may contribute to the pathology onset and progression. In this study we evaluated the cerebral expression of eight proteases, involved in both AßPP processing and extracellular matrix remodeling. Among these proteases, ADAM10, ADAMTS1, Cathepsin D, and Meprin ß show a significantly higher mRNAs expression in sporadic AD subjects versus controls, while ADAMTS1, Cathepsin D, and Meprin ß show an increment also at the protein level. These data indicate that transcriptional events affecting brain proteases are activated in AD patients, suggesting a link between proteolysis and AD.

Complexity and Selectivity of γ-Secretase Cleavage on Multiple Substrates: Consequences in Alzheimer's Disease and Cancer.

The processing of the amyloid-ß protein precursor (AßPP) by ß- and γ-secretases is a pivotal event in the genesis of Alzheimer's disease (AD). Besides familial mutations on the AßPP gene, or upon its overexpression, familial forms of AD are often caused by mutations or deletions in presenilin 1 (PSEN1) and 2 (PSEN2) genes: the catalytic components of the proteolytic enzyme γ-secretase (GS). The "amyloid hypothesis", modified over time, states that the aberrant processing of AßPP by GS induces the formation of specific neurotoxic soluble amyloid-ß (Aß) peptides which, in turn, cause neurodegeneration. This theory, however, has recently evidenced significant limitations and, in particular, the following issues are debated: 1) the concept and significance of presenilin's "gain of function" versus "loss of function"; and 2) the presence of several and various GS substrates, which interact with AßPP and may influence Aß formation. The latter consideration is suggestive: despite the increasing number of GS substrates so far identified, their reciprocal interaction with AßPP itself, even in the AD field, is significantly unexplored. On the other hand, GS is also an important pharmacological target in the cancer field; inhibitors or GS activity are investigated in clinical trials for treating different tumors. Furthermore, the function of AßPP and PSENs in brain development and in neuronal migration is well known. In this review, we focused on a specific subset of GS substrates that directly interact with AßPP and are involved in its proteolysis and signaling, by evaluating their role in neurodegeneration and in cell motility or proliferation, as a possible connection between AD and cancer.