Amygdala functional connectivity as a longitudinal biomarker of symptom changes in generalized anxiety

Generalized anxiety disorder (GAD) is characterized by excessive worry, autonomic dysregulation and functional amygdala dysconnectivity, yet these illness markers have rarely been considered together, nor their interrelationship tested longitudinally. We hypothesized that an individual's capacity for emotion regulation predicts longer-term changes in amygdala functional connectivity, supporting the modification of GAD core symptoms. Sixteen patients with GAD (14 women) and individually matched controls were studied at two time points separated by 1 year. Resting-state fMRI data and concurrent measurement of vagally mediated heart rate variability were obtained before and after the induction of perseverative cognition. A greater rise in levels of worry following the induction predicted a stronger reduction in connectivity between right amygdala and ventromedial prefrontal cortex, and enhanced coupling between left amygdala and ventral tegmental area at follow-up. Similarly, amplified physiological responses to the induction predicted increased connectivity between right amygdala and thalamus. Longitudinal shifts in a distinct set of functional connectivity scores were associated with concomitant changes in GAD symptomatology over the course of the year. Results highlight the prognostic value of indices of emotional dysregulation and emphasize the integral role of the amygdala as a critical hub in functional neural circuitry underlying the progression of GAD symptomatolog

Development of Soft-Hardware Platform for Training System Design of Electrotechnical Complexes and Electric Drives

The article presents the results of the development of software and hardware platform as the equipment for the training of children and youth work skills with robotics, allowing in the future to apply this knowledge in practice, implementing automation system for home use. We consider the problems of existing solutions. The main difference is the integration of the proposed fees and extensions into a single set by connecting the connectors and the ability to connect third-party components from different manufacturers, without limiting users. As well as a simplified method using a visual object-oriented programming allows you to immediately engage in the work. Prepared lessons and tasks in the game style simplifies the information and allows you to understand how you can apply one or another technical solution

Alterations in amygdala-prefrontal functional connectivity account for excessive worry and autonomic dysregulation in generalized anxiety disorder

Background: Generalized anxiety disorder (GAD) is characterized by the core symptom of uncontrollable worry. Functional magnetic resonance imaging studies link this symptom to aberrant functional connectivity between the amygdala and prefrontal cortex. Patients with GAD also display a characteristic pattern of autonomic dysregulation. Although frontolimbic circuitry is implicated in the regulation of autonomic arousal, no previous study to our knowledge combined functional magnetic resonance imaging with peripheral physiologic monitoring in these patients to test the hypothesis that core symptoms of worry and autonomic dysregulation in GAD arise from a shared underlying neural mechanism. Methods: We used resting-state functional magnetic resonance imaging and the measurement of parasympathetic autonomic function (heart rate variability) in 19 patients with GAD and 21 control subjects to define neural correlates of autonomic and cognitive responses before and after induction of perseverative cognition. Seed-based analyses were conducted to quantify brain changes in functional connectivity with the right and left amygdala. Results: Before induction, patients showed relatively lower connectivity between the right amygdala and right superior frontal gyrus, right paracingulate/anterior cingulate cortex, and right supramarginal gyrus than control subjects. After induction, such connectivity patterns increased in patients with GAD and decreased in control subjects, and these changes tracked increases in state perseverative cognition. Moreover, decreases in functional connectivity between the left amygdala and subgenual cingulate cortex and between the right amygdala and caudate nucleus predicted the magnitude of reduction in heart rate variability after induction. Conclusions: Our results link functional brain mechanisms underlying worry and rumination to autonomic dyscontrol, highlighting overlapping neural substrates associated with cognitive and autonomic responses to the induction of perseverative cognitions in patients with GAD

Synthesis and structural characterization of a mimetic membrane-anchored prion protein

During pathogenesis of transmissible spongiform encephalopathies (TSEs) an abnormal form (PrPSc) of the host encoded prion protein (PrPC) accumulates in insoluble fibrils and plaques. The two forms of PrP appear to have identical covalent structures, but differ in secondary and tertiary structure. Both PrPC and PrPSc have glycosylphospatidylinositol (GPI) anchors through which the protein is tethered to cell membranes. Membrane attachment has been suggested to play a role in the conversion of PrPC to PrPSc, but the majority of in vitro studies of the function, structure, folding and stability of PrP use recombinant protein lacking the GPI anchor. In order to study the effects of membranes on the structure of PrP, we synthesized a GPI anchor mimetic (GPIm), which we have covalently coupled to a genetically engineered cysteine residue at the C-terminus of recombinant PrP. The lipid anchor places the protein at the same distance from the membrane as does the naturally occurring GPI anchor. We demonstrate that PrP coupled to GPIm (PrP-GPIm) inserts into model lipid membranes and that structural information can be obtained from this membrane-anchored PrP. We show that the structure of PrP-GPIm reconstituted in phosphatidylcholine and raft membranes resembles that of PrP, without a GPI anchor, in solution. The results provide experimental evidence in support of previous suggestions that NMR structures of soluble, anchor-free forms of PrP represent the structure of cellular, membrane-anchored PrP. The availability of a lipid-anchored construct of PrP provides a unique model to investigate the effects of different lipid environments on the structure and conversion mechanisms of PrP

Bose-Einstein condensation for interacting scalar fields in curved spacetime

We consider the model of self-interacting complex scalar fields with a rigid gauge invariance under an arbitrary gauge group $G$. In order to analyze the phenomenon of Bose-Einstein condensation finite temperature and the possibility of a finite background charge is included. Different approaches to derive the relevant high-temperature behaviour of the theory are presented.Comment: 28 pages, LaTe

Talin1 and Rap1 are critical for osteoclast function

To determine talin1's role in osteoclasts, we mated TLN1(fl/fl) mice with those expressing cathepsin K-Cre (CtsK-TLN1) to delete the gene in mature osteoclasts or with lysozyme M-Cre (LysM-TLN1) mice to delete TLN1 in all osteoclast lineage cells. Absence of TLN1 impairs macrophage colony-stimulating factor (M-CSF)-stimulated inside-out integrin activation and cytoskeleton organization in mature osteoclasts. Talin1-deficient precursors normally express osteoclast differentiation markers when exposed to M-CSF and receptor activator of nuclear factor κB (RANK) ligand but attach to substrate and migrate poorly, arresting their development into mature resorptive cells. In keeping with inhibited resorption, CtsK-TLN1 mice exhibit an ∼5-fold increase in bone mass. Osteoclast-specific deletion of Rap1 (CtsK-Rap1), which promotes talin/β integrin recognition, yields similar osteopetrotic mice. The fact that the osteopetrosis of CtsK-TLN1 and CtsK-Rap1 mice is substantially more severe than that of those lacking αvβ3 is likely due to added failed activation of β1 integrins. In keeping with osteoclast dysfunction, mice in whom talin is deleted late in the course of osteoclastogenesis are substantially protected from ovariectomy-induced osteoporosis and the periarticular osteolysis attending inflammatory arthritis. Thus, talin1 and Rap1 are critical for resorptive function, and their selective inhibition in mature osteoclasts retards pathological bone loss

Goal directed worry rules are associated with distinct patterns of amygdala functional connectivity and vagal modulation during perseverative cognition

Excessive and uncontrollable worry is a defining feature of Generalized Anxiety Disorder (GAD). An important endeavor in the treatment of pathological worry is to understand why some people are unable to stop worrying once they have started. Worry perseveration is associated with a tendency to deploy goal-directed worry rules (known as “as many as can” worry rules; AMA). These require attention to the goal of the worry task and continuation of worry until the aims of the “worry bout” are achieved. This study examined the association between the tendency to use AMA worry rules and neural and autonomic responses to a perseverative cognition induction. To differentiate processes underlying the AMA worry rule use from trait worry, we also examined the relationship between scores on the Penn State Worry Questionnaire (PSWQ) and neural and autonomic responses following the same induction. We used resting-state functional magnetic resonance brain imaging (fMRI) while measuring emotional bodily arousal from heart rate variability (where decreased HRV indicates stress-related parasympathetic withdrawal) in 19 patients with GAD and 21 control participants. Seed-based analyses were conducted to quantify brain changes in functional connectivity (FC) with the amygdala. The tendency to adopt an AMA worry rule was associated with validated measures of worry, anxiety, depression and rumination. AMA worry rule endorsement predicted a stronger decrease in HRV and was positively associated with increased connectivity between right amygdala and locus coeruleus (LC), a brainstem noradrenergic projection nucleus. Higher AMA scores were also associated with increased connectivity between amygdala and rostral superior frontal gyrus. Higher PSWQ scores amplified decreases in FC between right amygdala and subcallosal cortex, bilateral inferior frontal gyrus, middle frontal gyrus, and areas of parietal cortex. Our results identify neural mechanisms underlying the deployment of AMA worry rules. We propose that the relationship between AMA worry rules and increased connectivity between the amygdala and prefrontal cortex (PFC) represents attempts by high worriers to maintain arousal and distress levels in order to feel prepared for future threats. Furthermore, we suggest that neural mechanisms associated with the PSWQ represent effortful inhibitory control during worry. These findings provide unique information about the neurobiological processes that underpin worry perseveration.</p

A conserved lipid-binding loop in the kindlin FERM F1 domain is required for kindlin-mediated aIIbB3 integrin coactivation

The activation of heterodimeric integrin adhesion receptors from low to high affinity states occurs in response to intracellular signals that act on the short cytoplasmic tails of integrin beta subunits. Binding of the talin FERM (four-point-one, ezrin, radixin, moesin) domain to the integrin beta-tail provides one key activation signal, but recent data indicate that the kindlin family of FERM domain proteins also play a central role. Kindlins directly bind integrin beta subunit cytoplasmic domains at a site distinct from the talin-binding site, and target to focal adhesions in adherent cells. However, the mechanisms by which kindlins impact integrin activation remain largely unknown. A notable feature of kindlins is their similarity to the integrin-binding and activating talin FERM domain. Drawing on this similarity, here we report the identification of an unstructured insert in the kindlin F1 FERM domain, and provide evidence that a highly conserved polylysine motif in this loop supports binding to negatively charged phospholipid head groups. We further show that the F1 loop and its membrane-binding motif are required for kindlin-1 targeting to focal adhesions, and for the cooperation between kindlin-1 and -2 and the talin head in aIIbB3 integrin activation, but not for kindlin binding to integrin beta tails. These studies highlight the structural and functional similarities between kindlins and the talin head and indicate that as for talin, FERM domain interactions with acidic membrane phospholipids as well beta-integrin tails contribute to the ability of kindlins to activate integrins

Preserved emotional awareness of pain in a patient with extensive bilateral damage to the insula, anterior cingulate, and amygdala

Functional neuroimaging investigations of pain have discovered a reliable pattern of activation within limbic regions of a putative "pain matrix" that has been theorized to reflect the affective dimension of pain. To test this theory, we evaluated the experience of pain in a rare neurological patient with extensive bilateral lesions encompassing core limbic structures of the pain matrix, including the insula, anterior cingulate, and amygdala. Despite widespread damage to these regions, the patient's expression and experience of pain was intact, and at times excessive in nature. This finding was consistent across multiple pain measures including self-report, facial expression, vocalization, withdrawal reaction, and autonomic response. These results challenge the notion of a "pain matrix" and provide direct evidence that the insula, anterior cingulate, and amygdala are not necessary for feeling the suffering inherent to pain. The patient's heightened degree of pain affect further suggests that these regions may be more important for the regulation of pain rather than providing the decisive substrate for pain's conscious experience