Can Taichi Reshape the Brain? A Brain Morphometry Study

Although research has provided abundant evidence for Taichi-induced improvements in psychological and physiological well-being, little is known about possible links to brain structure of Taichi practice. Using high-resolution MRI of 22 Tai Chi Chuan (TCC) practitioners and 18 controls matched for age, sex and education, we set out to examine the underlying anatomical correlates of long-term Taichi practice at two different levels of regional specificity. For this purpose, parcel-wise and vertex-wise analyses were employed to quantify the difference between TCC practitioners and the controls based on cortical surface reconstruction. We also adopted the Attention Network Test (ANT) to explore the effect of TCC on executive control. TCC practitioners, compared with controls, showed significantly thicker cortex in precentral gyrus, insula sulcus and middle frontal sulcus in the right hemisphere and superior temporal gyrus and medial occipito-temporal sulcus and lingual sulcus in the left hemisphere. Moreover, we found that thicker cortex in left medial occipito-temporal sulcus and lingual sulcus was associated with greater intensity of TCC practice. These findings indicate that long-term TCC practice could induce regional structural change and also suggest TCC might share similar patterns of neural correlates with meditation and aerobic exercise.     

Class IA Phosphatidylinositol 3-Kinase p110α Regulates Phagosome Maturation

Of the various phosphatidylinositol 3- kinases (PI3Ks), only the class III enzyme Vps34 has been shown to regulate phagosome maturation. During studies of phagosome maturation in THP-1 cells deficient in class IA PI3K p110α, we discovered that this PI3K isoform is required for vacuole maturation to progress beyond acquisition of Rab7 leading to delivery of lysosomal markers. Bead phagosomes from THP-1 cells acquired p110α and contained PI3P and PI(3,4,5)P3; however, p110α and PI(3,4,5)P3 levels in phagosomes from p110α knockdown cells were decreased. Phagosomes from p110α knock down cells showed normal acquisition of both Rab5 and EEA-1, but were markedly deficient in the lysosomal markers LAMP-1 and LAMP-2, and the lysosomal hydrolase, β-galactosidase. Phagosomes from p110α deficient cells also displayed impaired fusion with Texas Red dextran-loaded lysosomes. Despite lacking lysosomal components, phagosomes from p110α deficient cells recruited normal levels of Rab7, Rab-interacting lysosomal protein (RILP) and homotypic vacuole fusion and protein sorting (HOPs) components Vps41 and Vps16. The latter observations demonstrated that phagosomal Rab7 was active and capable of recruiting effectors involved in membrane fusion. Nevertheless, active Rab7 was not sufficient to bring about the delivery of lysosomal proteins to the maturing vacuole, which is shown for the first time to be dependent on a class I PI3K.     

Ultrastructure of Junín Virus in Mouse Whole Brain and Mouse Brain Tissue Cultures

Comparative ultrastructural studies were performed on the development of Junín virus in mouse brain and in cerebellum explants and brain monolayers of the same animal. In mouse brain, neurons and astrocytes released virus particles by a budding mechanism identical to that previously described for this virus. In the neurons, the viral multiplication took place in the perikarion as well as in the cytoplasmic processes, including areas near synapses. Viral particles were observed emerging from pericapillary neurons and astrocytes. In the explants, the budding also occurred in neurons and astrocytes. In the monolayers, however, the virus originated in astrocytes and cells of fibroblastic appearance, which were the two cell types that developed in this substrate. These results indicate that the characteristics of the development of Junín virus in mouse brain are faithfully reproduced in cerebellum explants from the same animal, thus allowing some extrapolation of data from one system to the other. The explant proved to be a better model than the monolayer, not only because it reproduced the structural complexity of nervous tissue better, but also because it contains neurons and astrocytes, i.e., the two cell types that release the virus in the in vivo system.     

Phosphatidylinositol 3′-kinase signalling supports cell height in established epithelial monolayers

Cell–cell interactions influence epithelial morphogenesis through an interplay between cell adhesion, trafficking and the cytoskeleton. These cellular processes are coordinated, often by cell signals found at cell–cell contacts. One such contact-based signal is the phosphatidylinositol 3′-kinase (PI3-kinase; PI3K) pathway. PI3-kinase is best understood for its role in mitogenic signalling, where it regulates cell survival, proliferation and differentiation. Its precise morphogenetic impacts in epithelia are, in contrast, less well-understood. Using phosphoinositide-specific biosensors we confirmed that E-cadherin-based cell–cell contacts are enriched in PIP₃, the principal product of PI3-kinase. We then used pharmacologic inhibitors to assess the morphogenetic impact of PI3-kinase in MDCK and MCF7 monolayers. We found that inhibiting PI3-kinase caused a reduction in epithelial cell height that was reversible upon removal of the drugs. This was not attributable to changes in E-cadherin expression or homophilic adhesion. Nor were there detectable changes in cell polarity. While Myosin II has been implicated in regulating keratinocyte height, we found no effect of PI3-kinase inhibition on apparent Myosin II activity; nor did direct inhibition of Myosin II alter epithelial height. Instead, in pursuing signalling pathways downstream of PI3-kinase we found that blocking Rac signalling, but not mTOR, reduced epithelial cell height, as did PI3-kinase inhibition. Overall, our findings suggest that PI3-kinase exerts a major morphogenetic impact in simple cultured epithelia through preservation of cell height. This is independent of potential effects on adhesion or polarity, but may occur through PI3-kinase-stimulated Rac signaling.     

Phosphatidylinositol 3′-kinase-mediated calcium mobilization regulates chemotaxis in phosphatidic acid-stimulated human neutrophils

Phosphatidylinositol 3′-kinase (PI 3′-kinase) plays an important role in the migration of hepatocytes, endothelial cells and neoplastic cells to agonists which activate cellular tyrosine kinases. We examined the PI 3′-kinase-dependent chemotactic responses of neutrophilic leukocytes induced by phosphatidic acid (PA) in order to clarify mechanisms by which the enzyme potentially influences cellular migration. Western analysis of immunoprecipitates indicated that PA induced the tyrosine phosphorylation of three distinct proteins involved in functional activation which co-immunoprecipitated in PA-stimulated cells. These proteins were identified as lyn, syk and the 85 kDa regulatory subunit of PI 3′-kinase. Chemotactic responses to PA but not to several other neutrophil agonists were inhibited by the PI 3′-kinase inhibitors wortmannin and LY294002. Chemotactic inhibition resulted from upstream inhibition of calcium mobilization. Chelation of extracellular calcium by ethylene glycol-bis(β-aminoethyl ether) N,N,N′,N′-tetraacetic acid (EGTA) did not affect the PA-induced chemotaxis, whereas chelation of intracellular calcium by 1,2-bis(2-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid (BAPTA) attenuated this response. Thus, changes in intracellular Ca²⁺ levels that can be effected by Ca²⁺ mobilized from intracellular stores in the absence of Ca²⁺ influx regulate PA-induced chemotaxis. Furthermore, PI 3′-kinase inhibition blunted the agonist-dependent generation of inositol 1,4,5-trisphosphate (IP₃), suggesting that PI 3′-kinase exerted its effects on calcium mobilization from intracellular sources by mediating activation of phospholipase C (PLC) in PA-stimulated cells. Moreover, the PI 3′-kinase inhibitor LY294002 also inhibited phosphorylation of syk in PA-stimulated cells. We, therefore, propose that products of PI 3′-kinase confined to the inner leaflet of the plasma membrane play a role in activation of syk, calcium mobilization and induction of chemotactic migration.     

Phosphatidylinositol 3-Kinase γ Is Required for the Development of Experimental Cerebral Malaria

Experimental cerebral malaria (ECM) is characterized by a strong immune response, with leukocyte recruitment, blood-brain barrier breakdown and hemorrhage in the central nervous system. Phosphatidylinositol 3-kinase γ (PI3Kγ) is central in signaling diverse cellular functions. Using PI3Kγ-deficient mice (PI3Kγ^-/-) and a specific PI3Kγ inhibitor, we investigated the relevance of PI3Kγ for the outcome and the neuroinflammatory process triggered by Plasmodium berghei ANKA (PbA) infection. Infected PI3Kγ^-/- mice had greater survival despite similar parasitemia levels in comparison with infected wild type mice. Histopathological analysis demonstrated reduced hemorrhage, leukocyte accumulation and vascular obstruction in the brain of infected PI3Kγ^-/- mice. PI3Kγ deficiency also presented lower microglial activation (Iba-1+ reactive microglia) and T cell cytotoxicity (Granzyme B expression) in the brain. Additionally, on day 6 post-infection, CD3⁺CD8⁺ T cells were significantly reduced in the brain of infected PI3Kγ^-/- mice when compared to infected wild type mice. Furthermore, expression of CD44 in CD8+ T cell population in the brain tissue and levels of phospho-IkB-α in the whole brain were also markedly lower in infected PI3Kγ^-/- mice when compared with infected wild type mice. Finally, AS605240, a specific PI3Kγ inhibitor, significantly delayed lethality in infected wild type mice. In brief, our results indicate a pivotal role for PI3Kγ in the pathogenesis of ECM.     

Phosphatidylinositol 4-kinase IIα is palmitoylated by Golgi-localized palmitoyltransferases in cholesterol-dependent manner

Phosphatidylinositol 4-kinase IIα (PI4KIIα) is predominantly Golgi-localized, and it generates >50% of the phosphatidylinositol 4-phosphate in the Golgi. The lipid kinase activity, Golgi localization, and "integral" membrane binding of PI4KIIα and its association with low buoyant density "raft" domains are critically dependent on palmitoylation of its cysteine-rich (173)CCPCC(177) motif and are also highly cholesterol-dependent. Here, we identified the palmitoyl acyltransferases (Asp-His-His-Cys (DHHC) PATs) that palmitoylate PI4KIIα and show for the first time that palmitoylation is cholesterol-dependent. DHHC3 and DHHC7 PATs, which robustly palmitoylated PI4KIIα and were colocalized with PI4KIIα in the trans-Golgi network (TGN), were characterized in detail. Overexpression of DHHC3 or DHHC7 increased PI4KIIα palmitoylation by >3-fold, whereas overexpression of the dominant-negative PATs or PAT silencing by RNA interference decreased PI4KIIα palmitoylation, "integral" membrane association, and Golgi localization. Wild-type and dominant-negative DHHC3 and DHHC7 co-immunoprecipitated with PI4KIIα, whereas non-candidate DHHC18 and DHHC23 did not. The PI4KIIα (173)CCPCC(177) palmitoylation motif is required for interaction because the palmitoylation-defective SSPSS mutant did not co-immunoprecipitate with DHHC3. Cholesterol depletion and repletion with methyl-β-cyclodextrin reversibly altered PI4KIIα association with these DHHCs as well as PI4KIIα localization at the TGN and "integral" membrane association. Significantly, the Golgi phosphatidylinositol 4-phosphate level was altered in parallel with changes in PI4KIIα behavior. Our study uncovered a novel mechanism for the preferential recruitment and activation of PI4KIIα to the TGN by interaction with Golgi- and raft-localized DHHCs in a cholesterol-dependent manner.     

Brain death: a durable consensus?

Is it even conceivable that this global consensus [on the whole-brain definition of death] could, in time, be regarded as a very temporary and makeshift expedient, a momentary substitute for a resolution of some profoundly difficult issues which for a time, perhaps a brief time, fit with both the technical capacities and the legal needs of those who endorsed it? And that in the long run it could linger as a footnote, or perhaps a chapter heading, in the long history of man's conceptions of life and death? This suggestion is so far from conventional wisdom today that one who espouses it risks being regarded as a crank. Nevertheless, I believe that the argument in its favor, while not conclusive, is much stronger than the argument against it (and in favor of the prevailing consensus). I will state the argument briefly, with particular reference to the landmark report in 1982 in Washington of the President's Commission for the Study of Ethical Problems in Medicine, and will situate the argument in the context of trends in contemporary bioethics. I do not expect to win over, in this one pass, those who have been convinced of the validity of the conventional view. I do hope, however, to re-open the issue; in particular, to provide reasons to regard the issue as far from settled.     

Brain donation: who and why?

Understanding what influences people to donate, or not donate, body organs and tissues is very important for the future of transplant surgery and medical research (Garrick in J Clin Neurosci 13:524–528, 2006). A previous web-based motivation survey coordinated by the New South Wales Tissue Resource Centre found that most people who participated in brain donation were young, female, educated Australians, not affiliated with any particular religion, and with a higher prevalence of medical illness than the general Australian population. It discussed the main motivating factors for brain donation to be “the benefits of the research to medicine and science”. This study has been replicated in a paper-based version to capture a broader cross-section of the general population, to find out who they are and what motivates them to donate. All consented and registered brain donors (n = 1,323) were sent a questionnaire via the post and recipients were given 3 months to complete the questionnaire and return it in a reply paid envelope. Results were entered into the original web-based survey and analyzed using SPSS version 10. Six hundred and fifty-eight questionnaires were returned completed, a response rate of 53%. The results show that people from all age groups are interested in brain donation. The over 65’s are the largest of the groups (30.7%). The majority of the participants were female (60.6%), married (49.2%) with children (65.8%), employed (52.9%) and have a tertiary education (73.3%). They were either non-religious (48.2%) or Christian (41.6%) and were mostly Australian (65.4%). Most (81%) had pledged to donate other organs and tissues for transplantation. The most commonly cited reasons for the donation were to benefit science (27.6%), to benefit medicine (23.9%), a family illness (17.5%) and to benefit the community (16.6%). This study demonstrates that people across all age groups are interested in brain donation. Recruitment of new brain donors could target the over 65 female Australians, who are not religious or Christian and who have also donated other organs and tissues for transplant purposes. It also indicates the need to make donation for research part of the national transplant donation program.     

The Protective Mechanism for the Blood–Brain Barrier Induced by Aminoguanidine in Surgical Brain Injury in Rats

This study was performed to investigate the mechanism of blood–brain barrier (BBB) permeability change, which was induced by aminoguanidine (AG) after surgical brain injury (SBI) in rats. Compared to control group, AG (150 mg/kg, i.p.) significantly reduced Evans blue extravasation into brain tissue at 24 h after surgical resection, it also induced a 32% decrease of malondialdehyde (MDA) values and a 1.1-fold increase of the glutathione (GSH) levels at 12 h after injury. The expression of inducible nitric oxide synthase (iNOS) reached the peak value at 24 h after SBI, which was significantly attenuated after AG treatment. In addition, ZO-1 protein was up-regulated by AG (150 mg/kg) treatment at 24 h after SBI. Our results indicated that AG could protect the BBB after SBI, which could be correlated with antioxidative property, the down-regulation of iNOS and up-regulation of tight junction protein expression.     

The Effects of Zinc Treatment on the Blood–Brain Barrier Permeability and Brain Element Levels During Convulsions

We evaluated the effect of zinc treatment on the blood–brain barrier (BBB) permeability and the levels of zinc (Zn), natrium (Na), magnesium (Mg), and copper (Cu) in the brain tissue during epileptic seizures. The Wistar albino rats were divided into four groups, each as follows: (1) control group, (2) pentylenetetrazole (PTZ) group: rats treated with PTZ to induce seizures, (3) Zn group: rats treated with ZnCl₂ added to drinking water for 2 months, and (4) Zn?+?PTZ group. The brains were divided into left, right hemispheres, and cerebellum?+?brain stem regions. Evans blue was used as BBB tracer. Element concentrations were analyzed by inductively coupled plasma optical emission spectroscopy. The BBB permeability has been found to be increased in all experimental groups (p?<?0.05). Zn concentrations in all brain regions in Zn-supplemented groups (p?<?0.05) showed an increase. BBB permeability and Zn level in cerebellum?+?brain stem region were significantly high compared to cerebral hemispheres (p?<?0.05). In all experimental groups, Cu concentration decreased, whereas Na concentrations showed an increase (p?<?0.05). Mg content in all the brain regions decreased in the Zn group and Zn?+?PTZ groups compared to other groups (p?<?0.001). We also found that all elements’ levels showed hemispheric differences in all groups. During convulsions, Zn treatment did not show any protective effect on BBB permeability. Chronic Zn treatment decreased Mg and Cu concentration and increased Na levels in the brain tissue. Our results indicated that Zn treatment showed proconvulsant activity and increased BBB permeability, possibly changing prooxidant/antioxidant balance and neuronal excitability during seizures.     

Poloxamer-188 Attenuates TBI-Induced Blood–Brain Barrier Damage Leading to Decreased Brain Edema and Reduced Cellular Death

Neurochemical Research - Plasmalemma permeability plays an important role in the secondary neuronal death induced by traumatic brain injury (TBI). Previous works showed that Poloxamer 188 (P188)...     

Phosphatidylinositol 4,5-bisphosphate and calcium at ER-PM junctions — Complex interplay of simple messengers

Endoplasmic reticulum-plasma membrane contact sites (ER-PM MCS) are a specialised domain involved in the control of Ca²⁺ dynamics and various Ca²⁺-dependent cellular processes. Intracellular Ca²⁺ signals are broadly supported by Ca²⁺ release from intracellular Ca²⁺ channels such as inositol 1,4,5-trisphosphate receptors (IP₃Rs) and subsequent store-operated Ca²⁺ entry (SOCE) across the PM to replenish store content. IP₃Rs sit in close proximity to the PM where they can easily access newly synthesised IP₃, interact with binding partners such as actin, and localise adjacent to ER-PM MCS populated by the SOCE machinery, STIM1–2 and Orai1–3, to possibly form a locally regulated unit of Ca²⁺ influx. PtdIns(4,5)P₂ is a multiplex regulator of Ca²⁺ signalling at the ER-PM MCS interacting with multiple proteins at these junctions such as actin and STIM1, whilst also being consumed as a substrate for phospholipase C to produce IP₃ in response to extracellular stimuli. In this review, we consider the mechanisms regulating the synthesis and turnover of PtdIns(4,5)P₂ via the phosphoinositide cycle and its significance for sustained signalling at the ER-PM MCS. Furthermore, we highlight recent insights into the role of PtdIns(4,5)P₂ in the spatiotemporal organization of signalling at ER-PM junctions and raise outstanding questions on how this multi-faceted regulation occurs.     

Brain Connectivity: The Feel of Blindsight

A visual subcortical pathway to the amygdala that undergoes structural plastic strengthening in blindsight has been identified in humans?-?neuroanatomical evidence for a pathway that might mediate rapid non-conscious processing of salient information.