Long-term cerebral plasticity-related gene expression : a study of the respective role of CBP and CRTC1 in CREB transcriptional activation

1.1 AbstractThe treatment of memory disorders and cognitive deficits in various forms of mental retardation may greatly benefit from a better understanding of the molecular and cellular mechanisms of memory formation. Different forms of memory have distinct molecular requirements.Short-term memory (STM) is thought to be mediated by covalent modifications of existing synaptic molecules, such as phosphorylation or dephosphorylation of enzymes, receptors or ion channels. In contrast, long-term memoiy (LTM) is thought to be mediated by growth of new synapses and restructuring of existing synapses. There is extensive evidence that changes in gene expression and de novo protein synthesis are key processes for LTM formation. In this context, the transcription factor CREB (cAMP-response element-binding protein) was shown to be crucial. Activation of CREB requires phosphorylation of a serine residue (Ser-133), and the subsequent recruitment of a coactivator called CREB-binding protein (CBP). Moreover, we have recently shown that another coactivator called CREB Regulated Transcription Coactivator 1 (CRTC1) functions as a calcium- and cAMP-sensitive coincidence detector in neurons, and is involved in hippocampal long-term synaptic plasticity. Given the importance of cAMP and calcium signaling for plasticity-related gene expression in neurons and in astrocytes, we sought to determine the respective involvement of the CREB coactivators CBP and CRTC1 in CREB-mediated transcription.We developed various strategies to selectively interfere with these CREB coactivators in mouse primary neurons and in astrocytes in vitro. However, despite several pieces of evidence implicating CBP and/or CRTC1 in the regulation of neuronal plasticity genes, we could not clearly determine the respective requirement of these coactivators for the activation of these genes. Nevertheless, we showed that calcineurin activity, which is important for CRTC1 nuclear translocation, is necessary for the expression of some CREB-regulated plasticity genes. We associated this phenomena to physiopathological conditions observed in Down's syndrome. In addition, we demonstrated that in astrocytes, noradrenaline stimulates CREB-target gene expression through β-adrenergic receptor activation, intracellular cAMP pathway activation, and CRTC-induced CREB transactivation.Defining the respective role of CREB and its coactivators CBP and CRTC1 in neuronal and astrocytic cultures in vitro sets the stage for future in vivo studies and for the possible development of new therapeutic strategies to improve the treatment of memoiy and cognitive disorders.1.2 RésuméUne meilleure connaissance des mécanismes moléculaires et cellulaires responsables de la formation de la mémoire pourrait grandement améliorer le traitement des troubles de la mémoire ainsi que des déficits cognitifs observés dans différentes formes de pathologies psychiatriques telles que le retard mental. Les différentes formes de mémoire dépendent de processus moléculaires différents.La mémoire à court terme (STM) semble prendre forme suite à des modifications covalentes de molécules synaptiques préexistantes, telles que la phosphorylation ou la déphosphorylation d'enzymes, de récepteurs ou de canaux ioniques. En revanche, la mémoire à long terme (LTM) semble être due à la génération de nouvelles synapses et à la restructuration des synapses existantes. De nombreuses études ont permis de démontrer que les changements dans l'expression des gènes et la synthèse de protéine de novo sont des processus clés pour la formation de la LTM. Dans ce contexte, le facteur de transcription CREB (cAMP-response element-binding protein) s'est avéré être un élément crucial. L'activation de CREB nécessite la phosphorylation d'un résidu sérine (Ser-133), et le recrutement d'un coactivateur nommé CBP (CREB binding protein). En outre, nous avons récemment démontré qu'un autre coactivateur de CREB nommé CRTC1 (CREB Regulated Transcription Coactivator 1) agit comme un détecteur de coïncidence de l'AMP cyclique (AMPc) et du calcium dans les neurones et qu'il est impliqué dans la formation de la plasticité synaptique à long terme dans l'hippocampe. Etant donné l'importance des voies de l'AMPc et du calcium dans l'expression des gènes impliqués dans la plasticité cérébrale, nous voulions déterminer le rôle respectif des coactivateurs de CREB, CBP et CRTC1.Nous avons développé diverses stratégies pour interférer de façon sélective avec les coactivateurs de CREB dans les neurones et dans les astrocytes chez la souris in vitro. Nos résultats indiquent que CBP et CRTC1 sont tous deux impliqués dans la transcription dépendante de CREB induite par l'AMPc et le calcium dans les neurones. Cependant, malgré plusieurs évidences impliquant CBP et/ou CRTC1 dans l'expression de gènes de plasticité neuronale, nous n'avons pas pu déterminer clairement leur nécessité respective pour l'activation de ces gènes. Toutefois, nous avons montré que l'activité de la calcineurine, dont dépend la translocation nucléaire de CRTC1, est nécessaire à l'expression de certains de ces gènes. Nous avons pu associer ce phénomène à une condition physiopathologique observée dans le syndrome de Down. Nous avons également montré que dans les astrocytes, la noradrénaline stimule l'expression de gènes cibles de CREB par une activation des récepteurs β- adrénergiques, l'activation de la voie de l'AMPc et la transactivation de CREB par les CRTCs.Définir le rôle respectif de CREB et de ses coactivateurs CBP et CRTC1 dans les neurones et dans les astrocytes in vitro permettra d'acquérir les connaissances nécessaires à de futures études in vivo et, à plus long terme d'éventuellement développer des stratégies thérapeutiques pour améliorer les traitements des troubles cognitifs.

Long-term effects of ACTH combined with angiotensin II on steroidogenesis and adrenal zona glomerulosa morphology in the rat.

To test the hypothesis that the trophic action of angiotensin II on the adrenal zona glomerulosa may allow a sustained stimulation of aldosterone by ACTH by preventing the morphological changes of the zona glomerulosa cells into zona fasciculata-like elements we investigated the effects in rats of a 6-day treatment with ACTH (100 micrograms/kg/day) alone or combined with angiotensin II (300 ng/kg/day) on corticosterone and aldosterone production and adrenal morphology. The responsiveness of both steroids to an acute ACTH dose was also studied on the last day of long-term treatment. Morphologic data showed that prolonged ACTH treatment stimulated the growth of zona glomerulosa cells, though it transformed the tubulo-lamellar cristae of mitochondria into a homogeneous population of vesicles. Angiotensin II furthered the trophic effects of ACTH but prevented the mitochondrial transformation. Despite its ability to conserve the well differentiated aspect of the zona glomerulosa cells, the administration of angiotensin II was unable to prevent the fall in the secretion of aldosterone caused by chronic ACTH treatment and its subsequent unresponsiveness to ACTH stimulation.

Secondary Accident Data Fusion for Assessing Long-Term Performance of Transportation Systems, 2007

Secondary accident statistics can be useful for studying the impact of traffic incident management strategies. An easy-to-implement methodology is presented for classifying secondary accidents using data fusion of a police accident database with intranet incident reports. A current method for classifying secondary accidents uses a static threshold that represents the spatial and temporal region of influence of the primary accident, such as two miles and one hour. An accident is considered secondary if it occurs upstream from the primary accident and is within the duration and queue of the primary accident. However, using the static threshold may result in both false positives and negatives because accident queues are constantly varying. The methodology presented in this report seeks to improve upon this existing method by making the threshold dynamic. An incident progression curve is used to mark the end of the queue throughout the entire incident. Four steps in the development of incident progression curves are described. Step one is the processing of intranet incident reports. Step two is the filling in of incomplete incident reports. Step three is the nonlinear regression of incident progression curves. Step four is the merging of individual incident progression curves into one master curve. To illustrate this methodology, 5,514 accidents from Missouri freeways were analyzed. The results show that secondary accidents identified by dynamic versus static thresholds can differ by more than 30%.

Severe postoperative complications adversely affect long-term survival after r1 resection for pancreatic head adenocarcinoma.

BACKGROUND: Survival after pancreatic head adenocarcinoma surgery is determined by tumor characteristics, resection margins, and adjuvant chemotherapy. Few studies have analyzed the long-term impact of postoperative morbidity. The aim of the present study was to assess the impact of postoperative complications on long-term survival after pancreaticoduodenectomy for cancer. METHODS: Of 294 consecutive pancreatectomies performed between January 2000 and July 2011, a total of 101 pancreatic head resections for pancreatic ductal adenocarcinoma were retrospectively analyzed. Postoperative complications were classified on a five-grade validated scale and were correlated with long-term survival. Grade IIIb to IVb complications were defined as severe. RESULTS: Postoperative mortality and morbidity were 5 and 57 %, respectively. Severe postoperative complications occurred in 16 patients (16 %). Median overall survival was 1.4 years. Significant prognostic factors of survival were the N-stage of the tumor (median survival 3.4 years for N0 vs. 1.3 years for N1, p = 0.018) and R status of the resection (median survival 1.6 years for R0 vs. 1.2 years for R1, p = 0.038). Median survival after severe postoperative complications was decreased from 1.9 to 1.2 years (p = 0.06). Median survival for N0 or N1 tumor or after R0 resection was not influenced by the occurrence and severity of complications, but patients with a R1 resection and severe complications showed a worsened median survival of 0.6 vs. 2.0 years without severe complications (p = 0.0005). CONCLUSIONS: Postoperative severe morbidity per se had no impact on long-term survival except in patients with R1 tumor resection. These results suggest that severe complications after R1 resection predict poor outcome.

The effects of poor financial information systems on the long term sustainability of local public services. Empirical evidence from the Catalan Municipalities

In this paper we describe the existence of financial illusion in public accountingand we comment on its effects for the future sustainability of local publicservices. We relate these features to the lack of incentives amongst publicmanagers for improving the financial reporting and thus management of publicassets. Financial illusion pays off for politicians and managers since it allowsfor larger public expenditure increases and managerial slack, these beingarguments in their utility functions. This preference is strengthen by the shorttime perspective of politically appointed public managers. Both factors runagainst public accountability. This hypothesis is tested for Spain by using anunique sample. We take data from around forty Catalan local authorities withpopulation above 20,000 for the financial years 1993-98. We build this databasis from the Catalan Auditing Office Reports in a way that it can be linkedto some other local social and economic variables in order to test ourassumptions. The results confirm that there is a statistical relationship between the financialillusion index (FI as constructed in the paper) and higher current expenditure.This reflects on important overruns and increases of the delay in payingsuppliers, as well as on a higher difficulties to face capital finance. Mechanismsfor FI creation have to do among other factors, with delays in paying suppliers(and thereafter higher future financial costs per unit of service), no adequateprovision for bad debts and lack of appropriate capital funding either forreposition or for new equipments. For this, it is crucial to monitor the way inwhich capital transfers are accounted in local public sheet balances. As a result,for most of the Municipalities we analyse, the funds for guaranteeing continuityand sustainability of public services provision are today at risk.Given managerial incentives at present in public institutions, we conclude thatpublic regulation recently enforced for assuring better information systems inlocal public management may not be enough to change the current state of affairs.

Civil conflict and human capital accumulation: The long-term effects of political violence in Perú

This paper provides empirical evidence of the persistent effect of exposure to political violence on humancapital accumulation. I exploit the variation in conflict location and birth cohorts to identify the longandshort-term effects of the civil war on educational attainment. Conditional on being exposed toviolence, the average person accumulates 0.31 less years of education as an adult. In the short-term,the effects are stronger than in the long-run; these results hold when comparing children within thesame household. Further, exposure to violence during early childhood leads to permanent losses. I alsoexplore the potential causal mechanisms.

Long-term swimming exercise does not modulate the Akt-dependent endothelial nitric oxide synthase phosphorylation in healthy mice.

Molecular mechanisms by which exercise exerts cardiovascular benefits are poorly understood. Exercise-induced increase of endothelial NO synthase (eNOS) phosphorylation through the protein kinase Akt has been shown to be a key mechanism underlying the beneficial effect of exercise in coronary artery disease patients. We examined whether this protective pathway might also be activated in long-term-exercised healthy mice. C57BL/6 wild-type mice swam for 24 weeks. A group of sedentary animals were used as controls. Aortic levels of total protein kinase Akt (protein kinase B), phosphorylated Akt at ser473 (p-Akt), total eNOS, phosphorylated eNOS at Ser1177 (p-eNOS), and PECAM-1 (platelet endothelial cell adhesion molecule-1) were assessed by Western blotting. Protein expressions of Akt, p-Akt, eNOS, p-eNOS, and PECAM-1 were not modulated by 24 weeks of exercise. The Akt-dependent eNOS phosphorylation did not seem to be a primary molecular adaptation in response to long-term exercise in healthy mice.

Long-Term Care Insurance Companies, September 2007

The companies on this list have been approved to sell long-term-care insurance in the State of Iowa. Customer service numbers are listed for each company. Please open pdf for the numbers.

The impact of interest-rate subsidies on long-term household debt: Evidence from a large program

The responsiveness of long-term household debt to the interest rate is acrucial parameter for assessing the effectiveness of public policies aimedat promoting specific types of saving. This paper estimates the effect ofa reform of Credito Bonificado, a large program in Portugal that subsidizedmortgage interest rates, on long-term household debt. The reform establisheda ceiling in the price of the house that could be financed through theprogram, and provides plausibly exogenous variation in incentives. Usinga unique dataset of matched household survey data and administrative recordsof debt, we document a large decrease in the probability of signing a newloan after the removal of the subsidy.

The long term effects of legalizing divorce on children

We estimate the effect of divorce legalization on the long-term well-being ofchildren. Our identification strategy relies on exploiting the different timing of divorcelegalization across European countries. Using European Community Household Paneldata, we compare the adult outcomes of cohorts who were raised in an environmentwhere divorce was banned with cohorts raised after divorce was legalized in the samecountry. We also have control countries where all cohorts were exposed (or notexposed) to divorce as children, thus leading to a difference-in-differences approach. Wefind that women who grew up under legal divorce have lower earnings and income aswell as worse health as adults compared with women who grew up under illegal divorce.These effects are not found for men. We find no effects of divorce legalization onchildren s family formation or dissolution patterns.

Office of the State Long-Term Care Ombudsman Annual Report 2004, January 2005.

The State Long-Term Care Ombudsman program operates as a unit within the Office of Elder Rights at Iowa Department of Elder Affairs. Duties of all long-term care ombudsmen are mandated by the Older Americans Act. This office serves people living in nursing facilities, residential care facilities, elder group homes and assisted living programs. Iowa’s State Long-Term Care Ombudsman’s Office has gone through many changes this past year ranging from staff changes to increase in jurisdiction area. Jeanne Yordi is now the State Long-Term Care Ombudsman, joining this promotion, will be three additional Long-Term Care Ombudsmen to the unit. With additional staff this office hopes to create more public awareness; however, cases and complaints are top priority as this office may begin to fulfill the mandates of the Older Americans Act.

Office of the State Long-Term Care Ombudsman Annual Report 2007, January 2008.

The State Long-Term Care Ombudsman program operates as a unit within the Office of Elder Rights at Iowa Department of Elder Affairs. Duties of all long-term care ombudsmen are mandated by the Older Americans Act. This office serves people living in nursing facilities, residential care facilities, elder group homes and assisted living programs. With the addition of 2 ombudsmen, regional offices were closed and 7 local programs were established in 2007. Local long-term care ombudsmen are becoming more aware of issues that need to be addressed, yet as evidenced by the tables included in this report, the increase in work load has been phenomenal, and is reaching the point of being unmanageable with the current staff.

Office of the State Long-Term Care Ombudsman Annual Report 2006, January 2007

The State Long-Term Care Ombudsman program operates as a unit within the Office of Elder Rights at Iowa Department of Elder Affairs. Duties of all long-term care ombudsmen are mandated by the Older Americans Act. This office serves people living in nursing facilities, residential care facilities, elder group homes and assisted living programs. With an increasing number of complaints for federal fiscal year 2006 this office continues to struggle with fulfilling all of the mandates of the Older Americans Act. Complaint investigations and working with residents and families remain the priority.

Office of the State Long-Term Care Ombudsman Annual Report 2005, January 2006.

The State Long-Term Care Ombudsman program operates as a unit within the Office of Elder Rights at Iowa Department of Elder Affairs. Duties of all long-term care ombudsmen are mandated by the Older Americans Act. This office serves people living in nursing facilities, residential care facilities, elder group homes and assisted living programs. Cases and complaints remain to be this office’s top priority. Facility closures take a tremendous amount of time, and with 1 Long-Term Care Ombudsman per 10,500 beds this office struggles to meet all of the mandates of the Older Americans Act.