Lysosome positioning and mTOR activity in Lowe syndrome.

Lowe syndrome is a rare, developmental disorder caused by mutations in the phosphatase, OCRL. A study in this issue of EMBO Reports shows that OCRL is required for microtubule nucleation and that mutations in this protein lead to an inability to activate mTORC1 signaling and consequent cell proliferation in the presence of nutrients. These defects are the result of impaired microtubule-dependent lysosomal trafficking to the cell periphery and are independent of OCRL phosphatase activity

Thrombospondin-1 protects against Aβ-induced mitochondrial fragmentation and dysfunction in hippocampal cells.

Alzheimer's disease (AD) is often characterized by the impairment of mitochondrial function caused by excessive mitochondrial fragmentation. Thrombospondin-1 (TSP-1), which is primarily secreted from astrocytes in the central nervous system (CNS), has been suggested to play a role in synaptogenesis, spine morphology, and synaptic density of neurons. In this study, we investigate the protective role of TSP-1 in the recovery of mitochondrial morphology and function in amyloid β (Aβ)-treated mouse hippocampal neuroblastoma cells (HT22). We observe that TSP-1 inhibits Aβ-induced mitochondrial fission by maintaining phosphorylated-Drp1 (p-Drp1) levels, which results in reduced Drp1 translocation to the mitochondria. By using gabapentin, a drug that antagonizes the interaction between TSP-1 and its neuronal receptor α2δ1, we observe that α2δ1 acts as one of the target receptors for TSP-1, and blocks the reduction of the p-Drp1 to Drp1 ratio, in the presence of Aβ. Taken together, TSP-1 appears to contribute to maintaining the balance in mitochondrial dynamics and mitochondrial functions, which is crucial for neuronal cell viability. These data suggest that TSP-1 may be a potential therapeutic target for AD

Characteristics of the aberrant pyramidal tract in comparison with the pyramidal tract in the human brain

<p>Abstract</p> <p>Background</p> <p>The aberrant pyramidal tract (APT) refers to the collateral pathway of the pyramidal tract (PT) through the medial lemniscus in the midbrain and pons. Using diffusion tensor tractography (DTT), we investigated the characteristics of the APT in comparison with the PT in the normal human brain.</p> <p>Results</p> <p>In thirty-four (18.3%, right hemisphere: 20, left hemisphere: 14) of the 186 hemispheres, the APTs separated from the PT at the upper midbrain level, descended through the medial lemniscus from the midbrain to the pons, and then rejoined with the PT at the upper medulla. Nine (26.5%) of the 34 APTs were found to originate from the primary somatosensory cortex without a primary motor cortex origin. Values of fractional anisotropy (FA) and tract volume of the APT were lower than those of the PT (<it>P </it>< 0.05); however, no difference in mean diffusivity (MD) value was observed (<it>P ></it>0.05).</p> <p>Conclusion</p> <p>We found that the APT has different characteristics, including less directionality, fewer neural fibers, and less origin from the primary motor cortex than the PT.</p

2,4-Bis(2-methoxy­phenyl)-3-aza­bicyclo­[3.3.1]nonan-9-one

In the title compound, C22H25NO3, the mol­ecule has a pseudo-mirror plane. The structure is a positional isomer of 2,4-bis(4-methoxy­phenyl)-3-aza­bicyclo­[3.3.1]nonan-9-one [Cox, McCabe, Milne & Sim (1985 ▶). J. Chem. Soc. Chem. Commun. pp. 626–628]. The 3-aza­bicyclo­[3.3.1]nonan-9-one moiety adopts a double chair conformation with equatorial orientations of both 2-methoxy­phenyl substituents on either side of the secondary amino group. The benzene rings are oriented at an angle of 33.86 (4)° with respect to each other and the meth­oxy groups point towards the carbonyl group. The crystal structure is stabilized by intermolecular N—H⋯π inter­actions

The Biological Safety of Stainless Steel Needles Used in Warm-needling

Warm-needling (also called thermo-acupuncture) is a combination of acupuncture and moxibustion. Due to the intense heat involved, there have been concerns over the biological safety of the acuneedles used in the treatment. This paper reports two phases of a safety test. For a preliminary test, we compared the temperature change patterns of stainless steel (SS304) needles and traditional gold alloy needles, which have been increasingly replaced by the former. To verify the effects of the presence of coating materials, the main test involved three different kinds of SS304: silicone-coated, salicylic acid-coated and non-coated needles. Each group of needles was tested for pH level, heavy metals and UV absorbance spectrum along with biological tests on the cytotoxicity and hemolysis of the needle. All the tests on the extractants from the needles were negative. In the biological tests, each test result showed a significant difference from the positive control samples, while no significant difference was observed compared with the negative control samples. In the hemolysis tests, all samples satisfied the Korean Government Standards. All the results suggest that SS304 needles are biologically safe to be used in warm-needling, though they can be improved to perform as well as the gold alloy needles in terms of temperature fluctuations

Resistin enhances the expansion of regulatory T cells through modulation of dendritic cells

<p>Abstract</p> <p>Background</p> <p>Resistin, a member of adipokine family, is known to be involved in the modulation of immune responses including inflammatory activity. Interestingly, resistin is secreted by adipocytes in mice and rats whereas it is secreted by leukocytes in humans. However, the mechanism behind the effect of resistin on the expansion of regulatory T cells (Tregs) remains poorly understood. Therefore, we examined regulatory effect of resistin on the induction and cellular modification of Tregs.</p> <p>Results</p> <p>Both protein and mRNA expression of <it>FoxP3</it>, a representative marker of Tregs, increased in a dose-dependent manner when peripheral blood mononuclear cells were treated with resistin. At the same time, resistin had no direct effect on the induction of <it>FoxP3 </it>in CD4⁺T cells, suggesting an indirect role through other cells type(s). Since DCs are an important player in the differentiation of T cells, we focused on the role of DCs in the modulation of Tregs by resistin. Resistin suppressed the expression of interferon regulatory factor (IRF)-1 and its target cytokines, IL-6, IL-23p19 and IL-12p40, in DCs. Furthermore, <it>FoxP3 </it>expression is increased in CD4⁺T cells when co-cultured with DCs and concomitantly treated with resistin.</p> <p>Conclusion</p> <p>Our results suggest that resistin induces expansion of functional Tregs only when co-cultured with DCs.</p

Relationship of Vertigo and Postural Instability in Patients With Vestibular Schwannoma

Objectives Growth of vestibular schwannomas (VS) causes progressive vestibular symptoms and postural instability. Since the tumor grows slowly, compensation of decaying vestibular input may decrease subjective symptoms of dizziness. This study aims to estimate the relationship of subjective vestibular symptoms and objective postural instability in patients with VS. Methods A retrospective review of 18 patients newly diagnosed with VS and with subjective vertigo symptoms was performed. The results of vestibular function tests including the sensory organization test (SOT) using computerized dynamic posturography, caloric test, and self-report measures of subjective dizziness handicap (Dizziness Handicap Inventory) and visual analogue scale were compared according to the onset of vertigo symptoms. Results In VS patients, SOT showed decreased equilibrium score for all vestibular function related conditions, condition (C) 5 and 6, and composite (COMP) score. COMP scores were not correlated with visual analogue scale or Dizziness Handicap Inventory scores. Acute onset group included six patients and insidious onset group, 12 patients. Equilibrium scores for C5 and C6, and COMP scores were lower for insidious onset group, but the difference was not statistically significant. Conclusion Our findings confirmed postural instability is prevalent in VS patients. SOT parameters did not differ significantly between acute onset and insidious onset groups, but increased tumor size and canal weakness were noted in the insidious onset group. Clinicians should consider that postural instability is likely present even in patients who do not complain of acute vertigo, and appropriate counseling should be discussed with the patients

Autophagy regulation by acetylation—implications for neurodegenerative diseases

Funder: UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society) Cambridge Centre for Parkinson-Plus National Institute for Health Research Cambridge Biomedical Research CentreAbstract: Posttranslational modifications of proteins, such as acetylation, are essential for the regulation of diverse physiological processes, including metabolism, development and aging. Autophagy is an evolutionarily conserved catabolic process that involves the highly regulated sequestration of intracytoplasmic contents in double-membrane vesicles called autophagosomes, which are subsequently degraded after fusing with lysosomes. The roles and mechanisms of acetylation in autophagy control have emerged only in the last few years. In this review, we describe key molecular mechanisms by which previously identified acetyltransferases and deacetylases regulate autophagy. We highlight how p300 acetyltransferase controls mTORC1 activity to regulate autophagy under starvation and refeeding conditions in many cell types. Finally, we discuss how altered acetylation may impact various neurodegenerative diseases in which many of the causative proteins are autophagy substrates. These studies highlight some of the complexities that may need to be considered by anyone aiming to perturb acetylation under these conditions

2,4-Bis(2-bromo­phen­yl)-3-aza­bicyclo­[3.3.1]nonan-9-one

In the mol­ecular structure of the title compound, C20H19Br2NO, the fused six-membered heterocyclic and cyclo­hexane rings adopt a twin-chair conformation with equatorial orientations of all the substituents. Both the ortho-bromo substituents of the benzene rings are oriented towards the carbonyl group; the dihedral angle between the ring planes is 29.13 (3)°. In the crystal structure, the N—H group does not participate in any hydrogen bonds