Regulation of store-operated and voltage-operated Ca2+ channels in the proliferation and death of oligodendrocyte precursor cells by golli proteins

OPCs (oligodendrocyte precursor cells) express golli proteins which, through regulation of Ca2+ influx, appear to be important in OPC process extension/retraction and migration. The aim of the present study was to examine further the role of golli in regulating OPC development. The effects of golli ablation and overexpression were examined in primary cultures of OPCs prepared from golli-KO (knockout) and JOE (golli J37-overexpressing) mice. In OPCs lacking golli, or overexpressing golli, differentiation induced by growth factor withdrawal was impaired. Proliferation analysis in the presence of PDGF (platelet-derived growth factor), revealed that golli enhanced the mitogen-stimulated proliferation of OPCs through activation of SOCCs (store-operated Ca2+ channels). PDGF treatment induced a biphasic increase in OPC intracellular Ca2+, and golli specifically increased Ca2+ influx during the second SOCC-dependent phase that followed the initial release of Ca2+ from intracellular stores. This store-operated Ca2+ uptake appeared to be essential for cell division, since specific SOCC antagonists completely blocked the effects of PDGF and golli on OPC proliferation. Additionally, in OPCs overexpressing golli, increased cell death was observed after mitogen withdrawal. This phenomenon could be prevented by exposure to VOCC (voltage-operated Ca2+ channel) blockers, indicating that the effect of golli on cell death involved increased Ca2+ influx through VOCCs. The results showed a clear effect of golli on OPC development and support a role for golli in modulating multiple Ca2+-regulatory events through VOCCs and SOCCs. Our results also suggest that PDGF engagement of its receptor resulting in OPC proliferation proceeds through activation of SOCCs

Region-Specific Myelin Pathology in Mice Lacking the Golli Products of the Myelin Basic Protein Gene

The myelin basic protein (MBP) gene encodes two families of proteins, the classic MBP constituents of myelin and the golli-MBPs, the function of which is less well understood. In this study, targeted ablation of the golli-MBPs, but not the classic MBPs, resulted in a distinct phenotype unlike that of knock-outs (KOs) of the classic MBPs or other myelin proteins. Although the golli KO animals did not display an overt dysmyelinating phenotype, they did exhibit delayed and/or hypomyelination in selected areas of the brain, such as the visual cortex and the optic nerve, as determined by Northern and Western blots and immunohistochemical analysis with myelin protein markers. Hypomyelination in some areas, such as the visual cortex, persisted into adulthood. Ultrastructural analysis of the KOs confirmed both the delay and hypomyelination and revealed abnormalities in myelin structure and in some oligodendrocytes. Abnormal visual-evoked potentials indicated that the hypomyelination in the visual cortex had functional consequences in the golli KO brain. Evidence that the abnormal myelination in these animals was a consequence of intrinsic problems with the oligodendrocyte was indicated by an impaired ability of oligodendrocytes to form myelin sheets in culture and by the presence of abnormal Ca^(2+) transients in purified cortical oligodendrocytes studied in vitro. The Ca^(2+) results reported in this study complement previous results implicating golli proteins in modulating intracellular signaling in T-cells. Together, all these findings suggest a role for golli proteins in oligodendrocyte differentiation, migration, and/or myelin elaboration in the brain

Targeted overexpression of a golli–myelin basic protein isoform to oligodendrocytes results in aberrant oligodendrocyte maturation and myelination

Recently, several in vitro studies have shown that the golli–myelin basic proteins regulate Ca2+ homoeostasis in OPCs (oligodendrocyte precursor cells) and immature OLs (oligodendrocytes), and that a number of the functions of these cells are affected by cellular levels of the golli proteins. To determine the influence of golli in vivo on OL development and myelination, a transgenic mouse was generated in which the golli isoform J37 was overexpressed specifically within OLs and OPCs. The mouse, called JOE (J37-overexpressing), is severely hypomyelinated between birth and postnatal day 50. During this time, it exhibits severe intention tremors that gradually abate at later ages. After postnatal day 50, ultrastructural studies and Northern and Western blot analyses indicate that myelin accumulates in the brain, but never reaches normal levels. Several factors appear to underlie the extensive hypomyelination. In vitro and in vivo experiments indicate that golli overexpression causes a significant delay in OL maturation, with accumulation of significantly greater numbers of pre-myelinating OLs that fail to myelinate axons during the normal myelinating period. Immunohistochemical studies with cell death and myelin markers indicate that JOE OLs undergo a heightened and extended period of cell death and are unable to effectively myelinate until 2 months after birth. The results indicate that increased levels of golli in OPC/OLs delays myelination, causing significant cell death of OLs particularly in white matter tracts. The results provide in vivo evidence for a significant role of the golli proteins in the regulation of maturation of OLs and normal myelination

Automated telephone communication systems for preventive healthcare and management of long-term conditions

Background Automated telephone communication systems (ATCS) can deliver voice messages and collect health-related information from patients using either their telephone’s touch-tone keypad or voice recognition software. ATCS can supplement or replace telephone contact between health professionals and patients. There are four different types of ATCS: unidirectional (one-way, non-interactive voice communication), interactive voice response (IVR) systems, ATCS with additional functions such as access to an expert to request advice (ATCS Plus) and multimodal ATCS, where the calls are delivered as part of a multicomponent intervention. Objectives To assess the effects of ATCS for preventing disease and managing long-term conditions on behavioural change, clinical, process, cognitive, patient-centred and adverse outcomes. Search methods We searched 10 electronic databases (the Cochrane Central Register of Controlled Trials; MEDLINE; Embase; PsycINFO; CINAHL; Global Health; WHOLIS; LILACS; Web of Science; and ASSIA); three grey literature sources (Dissertation Abstracts, Index to Theses, Australasian Digital Theses); and two trial registries (www.controlled-trials.com; www.clinicaltrials.gov) for papers published between 1980 and June 2015. Selection criteria Randomised, cluster- and quasi-randomised trials, interrupted time series and controlled before-and-after studies comparing ATCS interventions, with any control or another ATCS type were eligible for inclusion. Studies in all settings, for all consumers/carers, in any preventive healthcare or long term condition management role were eligible. Data collection and analysis We used standard Cochrane methods to select and extract data and to appraise eligible studies. Main results We included 132 trials (N = 4,669,689). Studies spanned across several clinical areas, assessing many comparisons based on evaluation of different ATCS types and variable comparison groups. Forty-one studies evaluated ATCS for delivering preventive healthcare, 84 for managing long-term conditions, and seven studies for appointment reminders. We downgraded our certainty in the evidence primarily because of the risk of bias for many outcomes. We judged the risk of bias arising from allocation processes to be low for just over half the studies and unclear for the remainder. We considered most studies to be at unclear risk of performance or detection bias due to blinding, while only 16% of studies were at low risk. We generally judged the risk of bias due to missing data and selective outcome reporting to be unclear. For preventive healthcare, ATCS (ATCS Plus, IVR, unidirectional) probably increase immunisation uptake in children (risk ratio (RR) 1.25, 95% confidence interval (CI) 1.18 to 1.32; 5 studies, N = 10,454; moderate certainty) and to a lesser extent in adolescents (RR 1.06, 95% CI 1.02 to 1.11; 2 studies, N = 5725; moderate certainty). The effects of ATCS in adults are unclear (RR 2.18, 95% CI 0.53 to 9.02; 2 studies, N = 1743; very low certainty). For screening, multimodal ATCS increase uptake of screening for breast cancer (RR 2.17, 95% CI 1.55 to 3.04; 2 studies, N = 462; high certainty) and colorectal cancer (CRC) (RR 2.19, 95% CI 1.88 to 2.55; 3 studies, N = 1013; high certainty) versus usual care. It may also increase osteoporosis screening. ATCS Plus interventions probably slightly increase cervical cancer screening (moderate certainty), but effects on osteoporosis screening are uncertain. IVR systems probably increase CRC screening at 6 months (RR 1.36, 95% CI 1.25 to 1.48; 2 studies, N = 16,915; moderate certainty) but not at 9 to 12 months, with probably little or no effect of IVR (RR 1.05, 95% CI 0.99, 1.11; 2 studies, 2599 participants; moderate certainty) or unidirectional ATCS on breast cancer screening. Appointment reminders delivered through IVR or unidirectional ATCS may improve attendance rates compared with no calls (low certainty). For long-term management, medication or laboratory test adherence provided the most general evidence across conditions (25 studies, data not combined). Multimodal ATCS versus usual care showed conflicting effects (positive and uncertain) on medication adherence. ATCS Plus probably slightly (versus control; moderate certainty) or probably (versus usual care; moderate certainty) improves medication adherence but may have little effect on adherence to tests (versus control). IVR probably slightly improves medication adherence versus control (moderate certainty). Compared with usual care, IVR probably improves test adherence and slightly increases medication adherence up to six months but has little or no effect at longer time points (moderate certainty). Unidirectional ATCS, compared with control, may have little effect or slightly improve medication adherence (low certainty). The evidence suggested little or no consistent effect of any ATCS type on clinical outcomes (blood pressure control, blood lipids, asthma control, therapeutic coverage) related to adherence, but only a small number of studies contributed clinical outcome data. The above results focus on areas with the most general findings across conditions. In condition-specific areas, the effects of ATCS varied, including by the type of ATCS intervention in use. Multimodal ATCS probably decrease both cancer pain and chronic pain as well as depression (moderate certainty), but other ATCS types were less effective. Depending on the type of intervention, ATCS may have small effects on outcomes for physical activity, weight management, alcohol consumption, and diabetes mellitus. ATCS have little or no effect on outcomes related to heart failure, hypertension, mental health or smoking cessation, and there is insufficient evidence to determine their effects for preventing alcohol/ substance misuse or managing illicit drug addiction, asthma, chronic obstructive pulmonary disease, HIV/AIDS, hypercholesterolaemia, obstructive sleep apnoea, spinal cord dysfunction or psychological stress in carers. Only four trials (3%) reported adverse events, and it was unclear whether these were related to the intervention

Modulation of canonical transient receptor potential channel 1 in the proliferation of oligodendrocyte precursor cells by the golli products of the myelin basic protein gene

Golli proteins, products of the myelin basic protein gene, function as a new type of modulator of intracellular Ca(++) levels in oligodendrocyte progenitor cells (OPCs). Because of this, they affect a number of Ca(++) dependent functions such as OPC migration and process extension. To examine further the Ca(++) channels regulated by golli, we studied the store operated Ca(++) channels (SOCCs) in OPCs and acute brain slice preparations from golli-KO and golli-overexpressing mice. Our results showed that pharmacologically-induced Ca(++) release from intracellular stores evoked a significant extracellular Ca(++) entry after store depletion in OPCs. They also indicated that under these pharmacological conditions golli promoted activation of Ca(++) influx by SOCCs in cultured OPCs as well as in tissue slices. The Canonical TRP (Transient Receptor Potential) family of Ca(++) channels (TRPCs) has been postulated to be SOCC subunits in oligodendrocytes. Using a siRNA knock down approach, we provided direct evidence that TRPC1 is involved in store-operated Ca(++) influx in OPCs, and that it is modulated by golli. Furthermore, our data indicated that golli is probably associated with TRPC1 at OPC processes. Additionally, we found that TRPC1 expression is essential for the effects of golli on OPC proliferation. In summary, our data indicate a key role for golli proteins in the regulation of TRPC mediated Ca(++) influx, a finding that has profound consequences for the regulation of multiple biological processes in OPCs. More important, we have shown that extracellular Ca(++) uptake through TRPC1 is an essential component in the mechanism of OPC proliferation

Multiple kinase pathways regulate voltage-dependent Ca2+ influx and migration in oligodendrocyte precursor cells

It is becoming increasingly clear that voltage-operated Ca(++) channels (VOCCs) play a fundamental role in the development of oligodendrocyte progenitor cells (OPCs). Since direct phosphorylation by different kinases is one of the most important mechanisms involved in VOCC modulation, the aim of this study was to evaluate the participation of serine-threonine (Ser/Thr) kinases and tyrosine kinases (TK) on Ca(++) influx mediated by VOCCs in OPCs. Calcium imaging revealed that OPCs exhibited Ca(++) influx following plasma membrane depolarization via L-type VOCCs. Furthermore, VOCC-mediated Ca(++) influx declined with OPC differentiation, indicating that VOCCs are developmentally regulated in OPCs. PKC activation significantly increased VOCC activity in OPCs, while PKA activation produced the opposite effect. The results also indicated that OPC morphological changes induced by PKC activation were partially mediated by VOCCs. Our data clearly suggest that TKs exert an activating influence on VOCC function in OPCs. Furthermore, using the PDGF response as a model to probe the role of TK receptors (TKr) on OPCs Ca(++) uptake, we found that TKr activation potentiated Ca(++) influx after membrane depolarization. Interestingly, this TKr modulation of VOCCs appeared to be essential for the PDGF enhancement of OPC migration rate, since cell motility was completely blocked by TKr antagonists, as well as VOCC inhibitors, in migration assays. The present study strongly demonstrates that PKC and TKrs enhance Ca(++) influx induced by depolarization in OPCs, while PKA has an inhibitory effect. These kinases modulate voltage-operated Ca(++) uptake in OPCs and participate in the modulation of process extension and migration

Golli myelin basic proteins regulate oligodendroglial progenitor cell migration through voltage-gated Ca2+ influx

Migration of OL progenitor cells (OPCs) from proliferative zones to their final location in the brain is an essential step in nervous system development. Golli proteins, products of the myelin basic protein gene, can modulate voltage-gated Ca(++) uptake in OPCs during process extension and retraction. Given the importance of process extension/retraction on movement, the consequences of golli expression on OPC migration were examined in vivo and in vitro using time-lapse imaging of isolated OPCs and acute brain slice preparations from golli KO and golli overexpressing mice (JOE). The results indicated that golli stimulated migration, and this enhanced motility was associated with increases in the activity of voltage operated Ca(++) channels (VOCCs). Activation of VOCCs by high K(+) resulted in a significant increase in the migration speed of JOE OPCs vs control cells and golli-mediated modulation of OPC migration disappeared in the presence of VOCC antagonists. During migration, OPCs generated Ca(++) oscillations that were dependent on voltage-calcium influx and both the amplitude and frequency of these Ca(++) transients correlated positively with the rate of cell movement under a variety of pharmacological treatments. The Ca(++) transient amplitude and the rate of cell movement were significantly lower in KO cells and significantly higher in JOE cells suggesting that the presence of golli promotes OPC migration by increasing the size of voltage-mediated Ca(++) oscillations. These data define a new molecule that regulates Ca(++) homeostasis in OPCs, and are the first to demonstrate that voltage-gated Ca(++) channels can regulate an OPC function, such as migration

The utility of olfactory function in distinguishing early-stage Alzheimer's disease from HIV-associated neurocognitive disorders

ObjectivesGiven the rising number of older people with HIV (PWH) and the overlap in cognitive dysfunction profiles in HIV-associated neurocognitive disorders (HAND) and Alzheimer's disease and its precursor, amnestic mild cognitive impairment (aMCI), methods are needed to distinguish aMCI/Alzheimer's disease from HAND. As an early indicator of Alzheimer's disease, we examined whether olfactory dysfunction could help to distinguish between aMCI/Alzheimer's disease and HAND among PWH.DesignAn observational cohort study.MethodsEighty-one older (≥50 years) PWH (83% men, 65% white) from the California NeuroAIDS Tissue Consortium completed the University of Pennsylvania Smell Identification Test (UPSIT; higher scores = better smell identification) and a comprehensive seven-domain neuropsychological test battery and neuromedical evaluation. HAND was classified via Frascati criteria. High aMCI risk was defined as impairment (>1.0 SD below normative mean) on two of four delayed recall or recognition outcomes (at least one recognition impairment required) from the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised. We examined UPSIT scores in relation to aMCI risk and HAND status, and continuous memory scores considering adjustments for demographics and relevant clinical or HIV disease characteristics.ResultsFifty-seven participants were classified with HAND (70%) and 35 participants were classified as high aMCI risk (43%). UPSIT scores were lower (worse) in the high versus low aMCI risk group [F (1,76) = 10.04, P = 0.002], but did not differ by HAND status [F (1,76) = 0.62, P = 0.43]. UPSIT scores positively correlated with all memory outcomes (Ps < 0.05).ConclusionOlfactory assessments may help in detecting early aMCI/Alzheimer's disease among PWH and allow for appropriate and early disease intervention

Spondylus crassisquama Lamarck, 1819 as a microecosystem and the effects of associated macrofauna on its shell integrity: isles of biodiversity or sleeping with the enemy?

In May 2009, we studied the bivalve Spondylus crassisquama and its relevance for macrobenthic biodiversity off the north Ecuadorian coast. We found that the large and heavy shells offer an exclusive substrate for numerous epibiont species and highly specialized carbonate-drilling endobiont species (71 species in total), which is a distinctly different and much more diverse habitat than the surrounding sandy bottoms (13 species, 4 of them found in both habitats). This is reflected by a Bray–Curtis dissimilarity index of 0.88. We discuss in detail the live habits of all 9 species of drilling endobionts that we found, and conclude that these can be seen as true mutualists, with the exception of boring sipunculids and bivalves. To further illustrate this complex co-existence, we visualize and quantify for the first time the tremendous effects of boring organisms on the shell structure of S. crassisquama by means of magnetic resonance imaging and a video appendix is provided

Ice core and climate reanalysis analogs to predict Antarctic and Southern Hemisphere climate changes

A primary goal of the SCAR (Scientific Committee for Antarctic Research) initiated AntClim21 (Antarctic Climate in the 21st Century) Scientific Research Programme is to develop analogs for understanding past, present and future climates for the Antarctic and Southern Hemisphere. In this contribution to AntClim21 we provide a framework for achieving this goal that includes: a description of basic climate parameters; comparison of existing climate reanalyses; and ice core sodium records as proxies for the frequencies of marine air mass intrusion spanning the past ∼2000 years. The resulting analog examples include: natural variability, a continuation of the current trend in Antarctic and Southern Ocean climate characterized by some regions of warming and some cooling at the surface of the Southern Ocean, Antarctic ozone healing, a generally warming climate and separate increases in the meridional and zonal winds. We emphasize changes in atmospheric circulation because the atmosphere rapidly transports heat, moisture, momentum, and pollutants, throughout the middle to high latitudes. In addition, atmospheric circulation interacts with temporal variations (synoptic to monthly scales, inter-annual, decadal, etc.) of sea ice extent and concentration. We also investigate associations between Antarctic atmospheric circulation features, notably the Amundsen Sea Low (ASL), and primary climate teleconnections including the SAM (Southern Annular Mode), ENSO (El Nîno Southern Oscillation), the Pacific Decadal Oscillation (PDO), the AMO (Atlantic Multidecadal Oscillation), and solar irradiance variations