Regular mindfulness practice benefits people both mentally and physically, but many populations who could benefit do not practice mindfulness. Virtual Reality (VR) is a new technology that helps ...capture participants' attention and gives users the illusion of "being there" in the 3D computer generated environment, facilitating sense of presence. By limiting distractions from the real world, increasing sense of presence and giving people an interesting place to go to practice mindfulness, Virtual Reality may facilitate mindfulness practice. Traditional Dialectical Behavioral Therapy (DBT®) mindfulness skills training was specifically designed for clinical treatment of people who have trouble focusing attention, however severe patients often show difficulties or lack of motivation to practice mindfulness during the training. The present pilot study explored whether a sample of mindfulness experts would find useful and recommend a new VR Dialectical Behavioral Therapy (DBT®) mindfulness skills training technique and whether they would show any benefit. Forty four participants attending a mindfulness conference put on an Oculus Rift DK2 Virtual Reality helmet and floated down a calm 3D computer generated virtual river while listening to digitized DBT® mindfulness skills training instructions. On subjective questionnaires completed by the participants before and after the VR DBT® mindfulness skills training session, participants reported increases/improvements in state of mindfulness, and reductions in negative emotional states. After VR, participants reported significantly less sadness, anger, and anxiety, and reported being significantly more relaxed. Participants reported a moderate to strong illusion of going inside the 3D computer generated world (i.e., moderate to high "presence" in VR) and showed high acceptance of VR as a technique to practice mindfulness. These results show encouraging preliminary evidence of the feasibility and acceptability of using VR to practice mindfulness based on clinical expert feedback. VR is a technology with potential to increase computerized dissemination of DBT® skills training modules. Future research is warranted.
The bacterial second messenger bis-(3'-5') cyclic dimeric guanosine monophosphate (c-di-GMP) has emerged as a central regulator for biofilm formation. Increased cellular c-di-GMP levels lead to ...stable cell attachment, which in Pseudomonas fluorescens requires the transmembrane receptor LapD. LapD exhibits a conserved and widely used modular architecture containing a HAMP domain and degenerate diguanylate cyclase and phosphodiesterase domains. c-di-GMP binding to the LapD degenerate phosphodiesterase domain is communicated via the HAMP relay to the periplasmic domain, triggering sequestration of the protease LapG, thus preventing cleavage of the surface adhesin LapA. Here, we elucidate the molecular mechanism of autoinhibition and activation of LapD based on structure-function analyses and crystal structures of the entire periplasmic domain and the intracellular signaling unit in two different states. In the absence of c-di-GMP, the intracellular module assumes an inactive conformation. Binding of c-di-GMP to the phosphodiesterase domain disrupts the inactive state, permitting the formation of a trans-subunit dimer interface between adjacent phosphodiesterase domains via interactions conserved in c-di-GMP-degrading enzymes. Efficient mechanical coupling of the conformational changes across the membrane is realized through an extensively domain-swapped, unique periplasmic fold. Our structural and functional analyses identified a conserved system for the regulation of periplasmic proteases in a wide variety of bacteria, including many free-living and pathogenic species.
A taskforce comprised of an expert group of 21 rheumatologists, radiologists and methodologists from 11 countries developed evidence-based recommendations on the use of imaging in the clinical ...management of both axial and peripheral spondyloarthritis (SpA). Twelve key questions on the role of imaging in SpA were generated using a process of discussion and consensus. Imaging modalities included conventional radiography, ultrasound, magnetic resonance imaging, computed tomography (CT), positron emission tomography, single photon emission CT, dual-emission x-ray absorptiometry and scintigraphy. Experts applied research evidence obtained from systematic literature reviews using MEDLINE and EMBASE to develop a set of 10 recommendations. The strength of recommendations (SOR) was assessed by taskforce members using a visual analogue scale. A total of 7550 references were identified in the search process, from which 158 studies were included in the systematic review. Ten recommendations were produced using research-based evidence and expert opinion encompassing the role of imaging in making a diagnosis of axial SpA or peripheral SpA, monitoring inflammation and damage, predicting outcome, response to treatment, and detecting spinal fractures and osteoporosis. The SOR for each recommendation was generally very high (range 8.9-9.5). These are the first recommendations which encompass the entire spectrum of SpA and evaluate the full role of all commonly used imaging modalities. We aimed to produce recommendations that are practical and valuable in daily practice for rheumatologists, radiologists and general practitioners.
Microorganisms can switch from a planktonic, free-swimming life-style to a sessile, colonial state, called a biofilm, which confers resistance to environmental stress. Conversion between the motile ...and biofilm life-styles has been attributed to increased levels of the prokaryotic second messenger cyclic di-guanosine monophosphate (c-di-GMP), yet the signaling mechanisms mediating such a global switch are poorly understood. Here we show that the transcriptional regulator VpsT from Vibrio cholerae directly senses c-di-GMP to inversely control extracellular matrix production and motility, which identifies VpsT as a master regulator for biofilm formation. Rather than being regulated by phosphorylation, VpsT undergoes a change in oligomerization on c-di-GMP binding.
Generalized Anxiety Disorder (GAD) is a very prevalent disorder in primary care (PC). Most patients with GAD never seek treatment, and those who do seek treatment often drop out before completing ...treatment. Although it is an understudied treatment, Mindfulness-Based Interventions (MBIs) indicate preliminary efficacy for the treatment of GAD symptoms, but many patients with GAD present other associated symptoms (e.g., attention deficits) that complicate the treatment. Virtual Reality DBT
Mindfulness Skills learning has recently been developed to make learning mindfulness easier for patients with emotion dysregulation who have trouble concentrating. Virtual Reality (VR) might serve as a visual guide for practicing mindfulness as it gives patients the illusion of "being there" in the 3D computer generated world. The main goal of this study was to evaluate the effect of two MBIs (a MBI in a group setting alone and the same MBI plus 10 min VR DBT
Mindfulness skills training) to reduce GAD symptoms. A secondary aim was to explore the effect in depression, emotion regulation, mindfulness, and interoceptive awareness. Other exploratory aims regarding the use of VR DBT
Mindfulness skills were also carried out. The sample was composed of 42 patients (roughly half in each group) with GAD attending PC visits. After treatment, both groups of patients showed significant improvements in General Anxiety Disorder measured by the GAD-7 using mixed regression models MBI alone (
= -5.70;
< 0.001;
= -1.36), MBI+VR DBT
Mindfulness skills (
= -4.38;
< 0.001;
= -1.33). Both groups also showed significant improvements in anxiety, depression, difficulties of emotion regulation and several aspects of mindfulness and interoceptive awareness. Patients in the group that received additional 10 min VR DBT Mindfulness Skills training were significantly more adherent to the treatment than those receiving only standard MBI (100% completion rate in MBI + VR vs. 70% completion rate in MBI alone;
= 0.020). Although randomized controlled studies with larger samples are needed, this pilot study shows preliminary effectiveness of MBI to treat GAD, and preliminary evidence that adjunctive VR DBT
Mindfulness Skills may reduce dropouts.
We analyze the connectivity structure of weighted brain networks extracted from spontaneous magnetoencephalographic signals of healthy subjects and epileptic patients (suffering from absence ...seizures) recorded at rest. We find that, for the activities in the 5-14 Hz range, healthy brains exhibit a sparse connectivity, whereas the brain networks of patients display a rich connectivity with a clear modular structure. Our results suggest that modularity plays a key role in the functional organization of brain areas during normal and pathological neural activities at rest.
Hand stencils are a remarkable graphic expression in Prehistoric rock art, dating back to 42 ka BP. Although these stencils provide direct impressions of the artists' hands, the characterization of ...their biological profile (i.e., biological sex and age) is very challenging. Previous studies have attempted this analysis with traditional morphometrics (TM), whereas little research has been undertaken using Geometric Morphometrics (GM), a method widely used in other disciplines but only tentatively employed in rock art studies. However, the large variation in relative finger position in archaeological hands poses the question of whether these representations can be examined through GM, or, in contrast, if this creates an unmanageable error in the results. To address this issue, a 2D hand scans sample of 70 living individuals (F = 35; M = 35) has been collected in three standardized positions (n = 210) and digitized with 32 2D conventional landmarks. Results show that the intra-individual distance (mean Procrustes distance between Pos. 1-2 = 0.132; 2-3 = 0.191; 1-3 = 0.292) is larger than the inter-individual distance (mean in 1 = 0.122; 2 = 0.142; 3 = 0.165). Finally, it has been demonstrated that the relative finger positions, as well as the inclusion of all hand parts in the analysis, have an overshadowing effect on other variables potentially involved in the morphometric variability of the hand, such as biological sex.
Bacterial biofilm formation during chronic infections confers increased fitness, antibiotic tolerance, and cytotoxicity. In many pathogens, the transition from a planktonic lifestyle to ...collaborative, sessile biofilms represents a regulated process orchestrated by the intracellular second-messenger c-di-GMP. A main effector for c-di-GMP signaling in the opportunistic pathogen Pseudomonas aeruginosa is the transcription regulator FleQ. FleQ is a bacterial enhancer-binding protein (bEBP) with a central AAA+ ATPase σ54-interaction domain, flanked by a C-terminal helix-turn-helix DNA-binding motif and a divergent N-terminal receiver domain. Together with a second ATPase, FleN, FleQ regulates the expression of flagellar and exopolysaccharide biosynthesis genes in response to cellular c-di-GMP. Here we report structural and functional data that reveal an unexpected mode of c-di-GMP recognition that is associated with major conformational rearrangements in FleQ. Crystal structures of FleQ’s AAA+ ATPase domain in its apo-state or bound to ADP or ATP-γ-S show conformations reminiscent of the activated ring-shaped assemblies of other bEBPs. As revealed by the structure of c-di-GMP–complexed FleQ, the second messenger interacts with the AAA+ ATPase domain at a site distinct from the ATP binding pocket. c-di-GMP interaction leads to active site obstruction, hexameric ring destabilization, and discrete quaternary structure transitions. Solution and cell-based studies confirm coupling of the ATPase active site and c-di-GMP binding, as well as the functional significance of crystallographic interprotomer interfaces. Taken together, our data offer unprecedented insight into conserved regulatory mechanisms of gene expression under direct c-di-GMP control via FleQ and FleQ-like bEBPs.
Aliment Pharmacol Ther 2011; 34: 11–20
Summary
Background Drug‐induced liver injury (DILI) is a significant cause of morbidity and mortality accounting for at least 13% of acute liver failure cases ...in the US. It is the leading cause of acute liver failure among patients referred for liver transplantation and the most common reason that drugs in development do not obtain FDA approval. The incidence of DILI has been reported to be one in 10 000 to one in 100 000 patients; however, the actual incidence is probably higher due in part to the difficulty of diagnosis.
Aim To present a review of the current literature on DILI with a focus on its pathophysiology and evolving diagnostic modalities.
Methods A PubMed literature search was conducted using the terms ‘drug induced liver injury’, ‘pathophysiology’, ‘causality’, ‘diagnosis’, ‘toxicogenomics’ and ‘pharmacogenetics’.
Results Drug‐induced liver injury is an area of ongoing research. From the time it was first recognised, our understanding of the pathophysiology, its classification, diagnosis and reporting by established national networks continues to challenge and evolve. Metabonomics, pharmacogenetics, proteomics and transcriptomics are more recent areas of study that have been applied to further the understanding of DILI.
Conclusions Despite recent advances in our understanding of drug‐induced liver injury, many aspects of its pathophysiology and clinical impact remain unclear. In addition, genomic‐based studies are evolving concepts, which undoubtedly continue to contribute to our understanding of the underlying mechanisms of drug‐induced liver injury.
Activation of the gonadotropic axis critically depends on sufficient body energy stores, and conditions of negative energy balance result in lack of puberty onset and reproductive failure. Recently, ...KiSS-1 gene-derived kisspeptin, signaling through the G protein-coupled receptor 54 (GPR54), has been proven as a pivotal regulator in the control of gonadotropin secretion and puberty. However, the impact of body energy status upon hypothalamic expression and function of this system remains unexplored. In this work, we evaluated the expression of KiSS-1 and GPR54 genes at the hypothalamus as well as the ability of kisspeptin-10 to elicit GnRH and LH secretion in prepubertal rats under short-term fasting. In addition, we monitored the actions of kisspeptin on food intake and the effects of its chronic administration upon puberty onset in undernutrition. Food deprivation induced a concomitant decrease in hypothalamic KiSS-1 and increase in GPR54 mRNA levels in prepubertal rats. In addition, LH responses to kisspeptin in vivo were enhanced, and its GnRH secretagogue action in vitro was sensitized, under fasting conditions. Central kisspeptin administration failed to change food intake patterns in animals fed ad libitum or after a 12-h fast. However, chronic treatment with kisspeptin was able to restore vaginal opening (in ∼60%) and to elicit gonadotropin and estrogen responses in a model of undernutrition. In summary, our data are the first to show an interaction between energy status and the hypothalamic KiSS-1 system, which may constitute a target for disruption (and eventual therapeutic intervention) of pubertal development in conditions of negative energy balance.
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