Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3

Genetic linkage studies have indicated that chromosome 14q24.3harbours a major locus for early-onset (onset age <65 years)Alzheimer's disease (AD3). Positional cloning efforts have identifieda novel gene S182 or presenilin 1 as the AD3 gene. We have mappedS182 in the AD3 candidate region between D14S277 and D14S284defined by genetic linkage studies in the two chromosome 14linked, early-onset AD families AD/A and AD/B. We have shownthat S182 is expressed in lymphoblasts and have determined thecomplete cDNA in both brain and lymphoblasts by RT-PCR sequencing.S182 is alternatively spliced in both brain and lymphoblastswithin a putative phosphorylation site located 5' in the codingregion. We identified two novel mutations, Ile143Thr and Gly384Alalocated in, respectively, the second transmembrane domain andin the sixth hydrophilic loop of the putative transmembranestructure of S182. As families AD/A and AD/B have a very similarAD phenotype our observation of two mutations in functionallydifferent domains suggest that onset age and severity of ADmay not be very helpful predictors of the location of putativeS182 mutations.     

Do dysfunctional cognitions mediate the relationship between risk factors and postnatal depression symptomatology?

BACKGROUND: This study investigated the mediating role of general and maternal-specific dysfunctional cognitions, in the relationship between non-cognitive risk factors and postnatal depressive symptomatology. METHODS: An Australian community sample comprising 406 postnatal women responded to the Dysfunctional Attitude Scale (DAS), the Maternal Attitudes Questionnaire (MAQ), the Vulnerable Personality Style Questionnaire (VPSQ) and the Edinburgh Postnatal Depression Scale (EPDS). They also responded to several questions related to perinatal and postnatal experiences. RESULTS: Path analysis demonstrated that different mediational pathways operated for different risk factors. The relationship between having a difficult baby and postnatal depression was fully mediated by maternal-specific dysfunctional cognitions (MAQ scores), whereas the relationship between past history of depression and postnatal depression was partially mediated by general dysfunctional cognitions (DAS scores). Finally, the relationship between a vulnerable personality and depressive symptomatology was mediated by both DAS and MAQ scores. LIMITATIONS: The study employed a correlational design. Thus, all inferences regarding possible causal pathways are tentative. In addition, the generalisability of these findings to other populations needs to be demonstrated in future research. CONCLUSIONS: The results of the study are consistent with the view that risk factors may influence postnatal depression indirectly through at least two distinct cognitive mediators (dysfunctional maternal and general cognitions). It may be possible to target therapies more effectively by identifying the relevant mediating mechanism(s) for individuals with different risk profiles.     

Mammalian transforming growth factor beta1 activated after ingestion by Anopheles stephensi modulates mosquito immunity

During the process of bloodfeeding by Anopheles stephensi, mammalian latent transforming growth factor beta1 (TGF-beta1) is ingested and activated rapidly in the mosquito midgut. Activation may involve heme and nitric oxide (NO), agents released in the midgut during blood digestion and catalysis of L-arginine oxidation by A. stephensi NO synthase (AsNOS). Active TGF-beta1 persists in the mosquito midgut to extended times postingestion and is recognized by mosquito cells as a cytokine. In a manner analogous to the regulation of vertebrate inducible NO synthase and malaria parasite (Plasmodium) infection in mammals by TGF-beta1, TGF-beta1 regulates AsNOS expression and Plasmodium development in A. stephensi. Together, these observations indicate that, through conserved immunological cross talk, mammalian and mosquito immune systems interface with each other to influence the cycle of Plasmodium development.     

Activation of the CD3/T cell receptor (TcR) complex or of protein kinase C potentiate adenylyl cyclase stimulation in a tumoral T cell line: involvement of two distinct intracellular pathways.

A monoclonal antibody (OKT3) directed against the T cell receptor (TcR)/CD3 molecular complex, as well as a protein kinase C (PKC) activator (phorbol 12-myristate 13-acetate, PMA) were added to a culture of tumoral Jurkat T cells, in order to precise the sequence of intracellular signals leading to T cell activation. The experiments were performed in the presence or in absence of various stimulators of adenylate cyclase (AC) such as forskolin (FK), cholera toxin (CT) or prostaglandin E2 (PGE2). OKT3 increased inositol phosphate (IP) production; in parallel, it induced a slight accumulation of cAMP. The effect was markedly potentiated in presence of FK or CT, and to a lesser extent in the presence of PGE2. FK stimulated adenylate cyclase of Jurkat cell membranes, but the effect was not potentiated by OKT3, suggesting that potentiation of cAMP accumulation requires intact cells and is not mediated by direct receptor coupling. On the other hand, elevated cAMP accumulation induced a negative feedback on IP production. The effect of OKT3 on cAMP was mimicked by A23187, a Ca2+ ionophore, and abolished in the absence of extracellular Ca2+. PMA had the same effect as OKT3 on basal or FK- and CT-induced accumulation of cAMP. In contrast, it inhibited the PGE2 effect on the cyclic nucleotide. After desensitization of PKC by pretreatment with a high concentration of PMA, the phorbol ester was no longer effective. Under those conditions, facilitation by OKT3 of FK-induced accumulation of cAMP was preserved, whereas potentiation by the monoclonal antibody of the PGE2 stimulation of AC was even enhanced. The data indicate that cAMP accumulation indirectly elicited by phospholipase C activation is, at least partly, mediated by IP-dependent Ca2+ mobilization, while PKC is preferentially effective as an inhibitor of PGE2 stimulation.     

Volatile substances from larval habitats mediate species-specific oviposition in Anopheles mosquitoes

Oviposition site selection has been recognized as critical both for the survival and population dynamics of mosquitoes. Volatile substances released from larval habitats have been implicated as potential olfactory cues mediating oviposition. In our continuing studies of cues involved in oviposition site selection, we collected material from the larval habitats of Anopheles albimanus Wiedemann and Anopheles vestitipennis Dyar & Knab, i.e., cyanobacterial mats and Typha domingensis Pers. litter, respectively. The volatile compounds were extracted by freeze-drying the material and trapping the volatilized material on a -55 degrees C titanium condenser. For oviposition trials conducted with wild-caught females, the tested volatile materials were pipetted onto filters floating on the surface of distilled water in Teflon beakers that were placed within oviposition cages. For both species, volatile materials in low concentrations increased oviposition, assessed as egg density, whereas there was a shift to reduced oviposition at higher concentrations. Volatile effect was strongly habitat/species-specific as shown by reciprocal treatment tests.     

CD14lowCD16high: A cytokine-producing monocyte subset which expands during human immunodeficiency virus infection

Infection with the human immunodeficiency virus HIV-1 is associated with the expansion of a CD14^lowCD16^high monocyte subset in peripheral blood. This subset, which represents a minor subpopulation of monocytes in healthy individuals, increases during HIV infection and, in patients with AIDS, may represent up to 40% of the total circulating monocyte cell population. The CD14^lowCD16^high circulating monocytes co-express MAX.1, p150,95 and HLADR which are typical of tissue macrophage markers. These cells also express higher levels of intracellular interleukin (IL)-1α and tumor necrosis factor (TNF)-α than the CD14^highCD16^low monocyte population from the same patients. The CD14^lowCD16^high cells also express low levels of CD35, CD11a and CD4 in common with normal monocytes. When cultured in vitro, monocytes from HIV-seropositive individuals differentiated within a few hours into an elongated fibroblastoid shape characteristic of migratory cells. Our results suggest that the expansion of the CD14^lowCD16^high monocyte subset, which produce high amounts of TNF-α and IL-1α, may participate in the immune dysfunction observed during HIV infection.