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Research on human posture and balance control has grown in recent years, leading to continued advances in their understanding. The ability to maintain balance is attributed to the interplay of the visual, vestibular, and somatosensory systems, although an important role is also played by the auditory system. The lack or deficit in any of these systems leads to a reduced stability that may be counterbalanced by the integration of all the remaining sensory information. Auditory and vibratory stimulation have been found to be useful to enhance balance alongside daily activities either in healthy or pathological subjects; nevertheless, while widely investigated, the literature relating to these approaches is still fragmented. This review aims at addressing this by collecting, organising, and discussing all the literature to date on the effects of the various acoustic and vibratory stimulation techniques available on static upright posture in healthy subjects. In addition, this review intends to provide a solid and comprehensive starting point for all the researchers interested in these research areas. A systematic search of the literature was performed and a total of 33 articles (24 on vibratory stimulation and 9 on acoustic stimulation) were included in our analysis. For all articles, several elements were highlighted including: the study sample, the characteristics of the stimulations, the recording instruments, the experimental protocols, and outcomes. Overall, both stimulations analysed were found to have a positive effect on balance but more research is needed to align those alternative approaches to the traditional ones.

The point of the text is to contribute to a reflection on the production of knowledge in the modern era, considering a set of spatial configurations that also refer to the world scale.

Inflammatory bowel disease (IBD) is characterized by multiple and complex pathogenic mechanisms that make its etiology unclear. Nevertheless, it is known that the interaction between genetic and adverse environmental factors may reduce the variety of the intestinal microbiota, and this could result in inflammation having effects on the brain functions through the gut-brain axis. In this paper, we assumed possible alterations in the large-scale brain organization in IBD. To test our hypothesis, we analyzed source-reconstructed magnetoencephalography (MEG) signals in resting state condition in 25 patients and 28 healthy controls. Then, we applied the graph theory to evaluate the brain network topology. Finally, to assess whether changes in the whole-brain activity were linked to IBD clinical evolution, we correlated brain network alterations to disease duration. We found that the betweenness centrality (BC) of the left hippocampus was higher in IBD patients as compared to controls, in the gamma frequency band. We observed a negative correlation between topological data and disease duration, with only a trend toward the statistical significance. The hippocampus is a key region in the gut-brain axis, and the chronic intestinal inflammation specifically alters its functioning. In addition, given the large number of glucocorticoid receptors, the hippocampus is highly susceptible to long-term stress, probably explaining the increase of the local BC. Furthermore, the trend toward a negative correlation with disease duration may be interpreted as a brain compensatory mechanism for IBD-related stress. However, although these findings are promising, we need to recruit more patients to clarify their clinical impact.

Functional connectivity has been widely used as a framework to investigate widespread brain interactions underlying cognitive deficits in Mild Cognitive Impairment (MCI). However, one of the main constraints of functional connectivity is that it is averaged over a time interval and therefore may not take into account the aperiodic and scale-free burst of activity (i.e., the neuronal avalanches) characterising the large-scale dynamic activity of the brain. Here, we used the recently proposed Avalanche Transition Matrix framework to source-reconstructed magnetoencephalography signals in a cohort of 32 MCI patients and 32 healthy controls (HC) to deepen the spatio-temporal features of neuronal avalanches and explore their topological properties. Our results showed that MCI patients exhibited a more centralised network (as assessed by higher values of degree divergence and leaf fraction) compared to HC. Furthermore, we found that the degree divergence (in the theta band) was predictive of the episodic memory impairment, assessed by FCSRT immediate total recall. These findings highlight the role of dynamical features in detecting functional and structural changes in clinical conditions. Hopefully, the proposed framework may be helpful in monitoring the development of the disease by adding subtle information that contributes to a more thorough phenotypical assessment of patients.

Background and Objectives:Amyotrophic lateral sclerosis (ALS) is a multisystem disorder, as supported by clinical, molecular and neuroimaging evidence. As a consequence, predicting clinical features requires a description of large-scale neuronal dynamics. Normally, brain activity dynamically reconfigures over time, recruiting different brain areas. Brain pathologies induce stereotyped dynamics which, in turn, are linked to clinical impairment. Hence, based on recent evidence showing that brain functional networks become hyper-connected as ALS progresses, we hypothesized that the loss of flexible dynamics in ALS would predict the symptoms severity.Methods:To test this hypothesis, we quantified flexibility utilizing the “functional repertoire” (i.e. the number of configurations of active brain areas) as measured from source-reconstructed magnetoencephalography (MEG) in ALS patients and healthy controls. The activity of brain areas was reconstructed in the classical frequency bands, and the functional repertoire was estimated to quantify spatio-temporal fluctuations of brain activity. Finally, we built a k-fold cross validated multilinear model to predict the individual clinical impairment from the size of the functional repertoire.Results:Comparing 42 ALS patients and 42 healthy controls, we found a more stereotyped brain dynamics in ALS patients (P < 0.05), as conveyed by the smaller functional repertoire. The relationship between the size of the functional repertoire and the clinical scores in the ALS group showed significant correlations in both the delta and the theta frequency bands. Furthermore, through a k-fold cross validated multilinear regression model, we found that the functional repertoire predicted both clinical staging (P < 0.001 and P < 0.01, in delta and theta bands, respectively) and symptoms severity (P < 0.001, in both delta and theta bands).Discussion:Our work shows that: 1) ALS pathology reduces the flexibility of large-scale brain dynamics; 2) sub-cortical regions play a key role in determining brain dynamics; 3) reduced brain flexibility predicts disease stage as well as symptoms severity. Our approach provides a non-invasive tool to quantify alterations in brain dynamics in ALS (and, possibly, other neurodegenerative diseases), thus opening new opportunities in disease management as well as a framework to test, in the near future, the effects of disease-modifying interventions at the whole-brain level.

The possibility to identify subjects from their brain activity was met enthusiastically, as it bears the possibility to individualize brain analyses. However, the nature of the processes generating subject-specific features remains unknown, as the literature does not point to specific mechanisms. In particular, most of the current literature uses techniques that are based on the assumption of stationarity (e.g. Pearson’s correlation), which do not hypothesize any mechanisms, and crashes against a large body of literature showing the complex, highly non-linear nature of brain activity. In this paper, we hypothesize that intermittent moments when large, non-linear perturbations spread across the brain (defined as neuronal avalanches in the context of critical dynamics) are the ones that carry subject-specific information, and that contribute the most to identifiability. To test this hypothesis, we apply the recently-developed avalanche transition matrix (ATM) to source reconstructed magnetoencephalographic data, as to characterize subject-speficic fast dynamics. Then, we perform identifiability analysis based on the ATMs, and compared the performance to more classical ways of estimating large-scale connections (which assume stationareity). We demonstrate that selecting the moments and places where neuronal avalanches spread improves identifiability (p

Amyotrophic lateral sclerosis (ALS) is a multisystem disorder. This view is widely supported by clinical, molecular and neuroimaging evidence. As a consequence, predicting clinical features requires a comprehensive description of large-scale brain activity. Flexible dynamics is key to support complex adaptive responses. In health, brain activity reconfigures over time, involving different brain areas. Brain pathologies can induce more stereotyped dynamics, which, in turn, are linked to clinical impairment. Hence, based on recent evidence that brain functional networks become more connected as ALS progresses, we hypothesized that loss of flexible dynamics in ALS would predict their clinical condition.To test this hypothesis, we quantified flexibility utilizing the “functional repertoire” (i.e. the number of unique patterns) expressed during the magnetoencephalography (MEG) recording, based on source-reconstructed signals. Specifically, 42 ALS patients and 42 healthy controls underwent MEG and MRI recordings. The activity of the brain areas was reconstructed in the classical frequency bands, and the functional repertoire was estimated to quantify spatio-temporal fluctuations of brain activity. In order to verify if the functional repertoire predicted disease severity, we built a multilinear model and validated it using a k-fold cross validation scheme.The comparison between the two groups revealed that ALS patients showed more stereotyped brain dynamics (P < 0.05), with reduced size of the functional repertoire. The relationship between the size of the functional repertoire and the clinical scores in the ALS group was investigated using Spearman’s coefficient, showing significant correlations in both the delta and the theta frequency bands. In order to prove the robustness of our results, the k-fold cross validation model was used. We found that the functional repertoire significantly predicted both clinical staging (P < 0.001 and P < 0.01, in delta and theta bands, respectively) and impairment (P < 0.001, in both delta and theta bands).In conclusion, our work shows that: 1) ALS pathology reduces the flexibility of brain dynamics; 2) sub-cortical regions play a key role in determining brain dynamics; 3) reduced brain flexibility predicts the stage of the disease as well as the severity of the symptoms. Based on these findings, our approach provides a non-invasive tool to quantify alterations in brain dynamics in ALS (and, possibly, other neurodegenerative diseases), thus opening new diagnostic opportunities as well as a framework to test disease-modifying interventions.

The clinical connectome fingerprint (CCF) was recently introduced as a way to assess brain dynamics. It is an approach able to recognize individuals, based on the brain network. It showed its applicability providing network features used to predict the cognitive decline in preclinical Alzheimer's disease. In this article, we explore the performance of CCF in 47 Parkinson's disease (PD) patients and 47 healthy controls, under the hypothesis that patients would show reduced identifiability as compared to controls, and that such reduction could be used to predict motor impairment. We used source-reconstructed magnetoencephalography signals to build two functional connectomes for 47 patients with PD and 47 healthy controls. Then, exploiting the two connectomes per individual, we investigated the identifiability characteristics of each subject in each group. We observed reduced identifiability in patients compared to healthy individuals in the beta band. Furthermore, we found that the reduction in identifiability was proportional to the motor impairment, assessed through the Unified Parkinson's Disease Rating Scale, and, interestingly, able to predict it (at the subject level), through a cross-validated regression model. Along with previous evidence, this article shows that CCF captures disrupted dynamics in neurodegenerative diseases and is particularly effective in predicting motor clinical impairment in PD.

Human voluntary movement stems from the coordinated activations in space and time of many musculoskeletal segments. However, the current methodological approaches to study human movement are still limited to the evaluation of the synergies among a few body elements. Network science can be a useful approach to describe movement as a whole and to extract features that are relevant to understanding both its complex physiology and the pathophysiology of movement disorders. Here, we propose to represent human movement as a network (that we named the kinectome), where nodes represent body points, and edges are defined as the correlations of the accelerations between each pair of them. We applied this framework to healthy individuals and patients with Parkinson's disease, observing that the patients' kinectomes display less symmetrical patterns as compared to healthy controls. Furthermore, we used the kinectomes to successfully identify both healthy and diseased subjects using short gait recordings. Finally, we highlighted topological features that predict the individual clinical impairment in patients. Our results define a novel approach to study human movement. While deceptively simple, this approach is well-grounded, and represents a powerful tool that may be applied to a wide spectrum of frameworks.

Background: Dried blood spot (DBS) testing is a well-known method of bio-sampling by which blood samples are blotted and dried on filter paper. The dried samples can then be analyzed by several techniques such as DNA amplification and HPLC. We have developed a homemade DBS method followed by an alternative protocol for genomic DNA extraction from a drop of blood adsorbed on paper support. This protocol consists of two separate steps: (1) organic DNA extraction from the DBS, followed by (2) DNA amplification by polymerase chain reaction (PCR). The PCR-restriction fragment length polymorphism (PCR-RFLP) is an advantageous and simple approach to detect single nucleotide polymorphisms (SNPs). Results: We have evaluated the efficiency of our method for the extraction of genomic DNA from DBS by testing its performance in genotyping mouse models of obesity and herein discuss the sensitivity, specificity and feasibility of this novel procedure. Conclusions: Our protocol is easy to perform, fast and inexpensive and allows the isolation of pure DNA from a miniscule amount of sample.

Osteopontin (OPN) is a phosphoglycoprotein secreted into the extracellular matrix upon liver injury, acting as a cytokine stimulates the deposition of fibrillary collagen in liver fibrogenesis. In livers of mice subjected to bile duct ligation (BDL) and in cultured activated hepatic stellate cells (HSCs), we show that OPN, besides being overexpressed, is substantially phosphorylated by family with sequence similarity 20, member C (Fam20C), formerly known as Golgi casein kinase (G-CK), which is exclusively resident in the Golgi apparatus. In both experimental models, Fam20C becomes overactive when associated with a 500-kDa multiprotein complex, as compared with the negligible activity in livers of sham-operated rats and in quiescent HSCs. Fam20C knockdown not only confirmed the role of Fam20C itself in OPN phosphorylation, but also revealed that phosphorylation was essential for OPN secretion. However, OPN acts as a fibrogenic factor independently of its phosphorylation state, as demonstrated by the increased expression of Collagen-I by HSCs incubated with either a phosphorylated or nonphosphorylated form of recombinant OPN. Collectively, our results confirm that OPN promotes liver fibrosis and highlight Fam20C as a novel factor driving this process by favoring OPN secretion from HSCs, opening new avenues for deciphering yet unidentified mechanisms underlying liver fibrogenesis.

During the century of colonial expansion by the Iberian monarchies, the presence of the Church alongside the colonizers was not just a logical continuation of the medieval idea of the good prince who was advised and accompanied by men of faith. It also underlined the political dimension of the ‘spiritual conquest’ and the equally political dimension of the cultural practices accompanying it. There are numerous works that have emphasized this with regard to the American continents in particular, where the connection between the forces present, which quickly led to the destruction and subjugation of the local populations, brought about Spanish colonial domination over large swathes of the ‘West Indies’. Those scholars who have concentrated on the ‘East Indies’, and China in particular, have emphasized acculturation or accommodation, highlighting the cultural rather than the political dimension of contact. This article explores the significant asymmetries in the understanding of humankind developed by the missionaries in their analyses of the Americas and the East Indies. These asymmetries stemmed largely from their distinct roles and functions in the process of colonial or imperial contact. I argue that these asymmetries obscure our understanding of what missionaries contributed to the global circulation of knowledge of lands and peoples new to Europeans in the 16th and 17th centuries, in part by defining ‘savagery’ and locating it mostly in the ‘West Indies’.

Significance Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by limitation of expiratory airflow. Cellular and molecular pathways involved in disease pathogenesis are not completely defined. Our study reveals that metabolism and immune response cooperate in COPD pathogenesis and progression. COPD subjects with different disease stages showed progressive increase of systemic leptin, an adipose tissue-derived proinflammatory molecule, that, at high concentrations, impaired the capacity of T cells to engage in glycolysis and to generate regulatory T cells. Thus, the loss of these immunoregulatory circuits during COPD determined the hyperactivation of effector T cells that amplified inflammation, leading to progressive decline of lung function. Understanding these immunometabolic mechanisms can have important implications for monitoring COPD progression and for disease treatment., Chronic obstructive pulmonary disease (COPD) is an inflammatory condition associated with abnormal immune responses, leading to airflow obstruction. Lungs of COPD subjects show accumulation of proinflammatory T helper (Th) 1 and Th17 cells resembling that of autoreactive immune responses. As regulatory T (Treg) cells play a central role in the control of autoimmune responses and their generation and function are controlled by the adipocytokine leptin, we herein investigated the association among systemic leptin overproduction, reduced engagement of glycolysis in T cells, and reduced peripheral frequency of Treg cells in different COPD stages. These phenomena were also associated with an impaired capacity to generate inducible Treg (iTreg) cells from conventional T (Tconv) cells. At the molecular level, we found that leptin inhibited the expression of forkhead-boxP3 (FoxP3) and its splicing variants containing the exon 2 (FoxP3-E2) that correlated inversely with inflammation and weakened lung function during COPD progression. Our data reveal that the immunometabolic pathomechanism leading to COPD progression is characterized by leptin overproduction, a decline in the expression of FoxP3 splicing forms, and an impairment in Treg cell generation and function. These results have potential implications for better understanding the autoimmune-like nature of COPD and the pathogenic events leading to lung damage.

The estrogen receptor (ER) signaling regulates numerous physiological processes mainly through activation of gene transcription (genomic pathways). Caveolin1 (CAV1) is a membrane-resident protein that behaves as platform to enable different signaling molecules and receptors for membrane-initiated pathways. CAV1 directly interacts with ERs and allows their localization on membrane with consequent activation of ER-non-genomic pathways. Loss of CAV1 function is a common feature of different types of cancers, including breast cancer. Two protein isoforms, CAV1&alpha, and CAV1&beta, derived from two alternative translation initiation sites, are commonly described for this gene. However, the exact transcriptional regulation underlying CAV1 expression pattern is poorly elucidated. In this study, we dissect the molecular mechanism involved in selective expression of CAV1&beta, isoform, induced by estrogens and downregulated in breast cancer. Luciferase assays and Chromatin immunoprecipitation demonstrate that transcriptional activation is triggered by estrogen-responsive elements embedded in CAV1 intragenic regions and DNA-binding of estrogen-ER complexes. This regulatory control is dynamically established by local chromatin changes, as proved by the occurrence of histone H3 methylation/demethylation events and association of modifier proteins as well as modification of H3 acetylation status. Thus, we demonstrate for the first time, an estrogen-ERs-dependent regulatory circuit sustaining selective CAV1&beta, expression.

The aim of this study was to evaluate the treatment of bovine semen with the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK), before or after freezing on semen quality. After the initial assessment, sperm from 4 bulls were pooled (Experiment 1) and cryopreserved in BioXcell containing 0, 20 and 100 μM Z-VAD-FMK. After thawing semen viability, motility, membrane integrity, as well as DNA fragmentation and ΔΨm were evaluated. In Experiment 2, bovine frozen/thawed sperm were incubated for 1 hr with 0, 20 and 100 µM Z-VAD-FMK before assessing the semen quality. The treatment with Z -VAD-FMK before cryopreservation improved post-thawing sperm motility compared to the control group (p < .05), while no differences were recorded in sperm viability and membrane integrity among groups (on average 86.8 ± 1.5 and 69.1 ± 1.4, respectively). Interestingly, at the highest concentration, DNA fragmentation decreased (p < .05), while the percentage of spermatozoa with high ΔΨm increased (p < .05). The results of Experiment 2 showed that 1-hr treatment with Z-VAD-FMK did not affect sperm motility and viability (on average 63.4 ± 5.8 and 83.7.1 ± 1.2, respectively). However, Z-VAD-FMK improved sperm membrane integrity (p < .05) and at the highest concentration tested decreased the proportion of sperm showing DNA fragmentation (p < .05). No differences were recorded in the percentage of spermatozoa with high ΔΨm (on average 57.0 ± 11.4). In conclusion, the treatment with 100 µM of the caspase inhibitor Z-VAD-FMK before freezing increased bovine sperm mass motility and ΔΨm, while decreasing sperm DNA fragmentation. Treatment of semen after thawing with 100 µM Z-VAD-FMK improved sperm membrane integrity and reduced DNA fragmentation.

AIMS: Excessive glucose serum concentration, endothelial dysfunction and microangiopathy are key features of diabetes mellitus, being both diagnostic parameters and pathogenetic mechanisms. Vascular endothelial growth factor (VEGF) is importantly implicated in the physiology and pathology of blood vessels, including diabetic vascular damage. METHODS: These factors certainly affect endothelial cells, and to evaluate mechanisms involved, we took advantage of telomerase-immortalized human microvascular endothelial (TIME) cells. TIME cells were exposed to different glucose concentrations and to VEGF treatments. Culture conditions also included the use of basement membrane extract, as an in vitro differentiation model. Cell morphology was then evaluated in the different conditions, and cellular proteins were extracted to analyze specific protein products by Western blot. RESULTS: High glucose concentrations and VEGF did substantially affect neither morphology nor growth of cultured TIME cells, while both considerably increased differentiation into "capillary-like" structures when cells were cultured on basement membrane extract. CONCLUSIONS: Under these conditions, high glucose concentration and VEGF also produced a short-term increase in pERK1/2 and p85 proteins, while total and phosphorylated AKT were not affected. These data suggest a direct angiogenetic effect of glucose, affecting intracellular transduction mechanisms with an action similar to that of VEGF. This effect on endothelial cell proliferation and differentiation could be part of pathogenetic mechanisms producing diabetic microvascular alterations.

Guido Ruggiero The Renaissance in Italy: A Social and Cultural History of the Rinascimento New York, Cambridge University Press, 2015, 648 p.