Maternal childhood adversity and child temperament: An association moderated by child 5‐HTTLPR genotype

We examined transgenerational effects of maternal childhood adversity on child temperament and a functional promoter polymorphism, 5‐HTTLPR, in the serotonin‐transporter gene (SLC6A4) as potential moderators of such maternal influences in 154 mother–child dyads, recruited into a longitudinal birth cohort study. We examined the interactive effects of maternal childhood experience using an integrated measure derived from Childhood Trauma Questionnaire (CTQ) and Parental Bonding Index (PBI). Triallelic genotyping of 5‐HTTLPR was performed. A measure of ‘negative emotionality/behavioural dysregulation’ was derived from the Early Childhood Behaviour Questionnaire at 18 and 36 months. Negative emotionality/behavioural dysregulation was highly stable between 18 and 36 months and predicted psychosocial problems at 60 months. After controlling multiple demographics as well as both previous and concurrent maternal depression there was a significant interaction effect of maternal childhood adversity and offspring 5‐HTTLPR genotype on child negative emotionality/behavioural dysregulation (β = 1.03, t_11,115 = 2.71, P < .01). The results suggest a transgenerational effect of maternal developmental history on emotional function in the offspring, describing a pathway that likely contributes to the familial transmission of vulnerability for psychopathology.     

N-Substituted carbazolyloxyacetic acids modulate Alzheimer associated gamma-secretase

N-Sulfonylated and N-alkylated carbazolyloxyacetic acids were investigated for the inhibition and modulation of the Alzheimer's disease associated gamma-secretase. The introduction of a lipophilic substituent, which may vary from arylsulfone to alkyl, turned 2-carbazolyloxyacetic acids into potent gamma-secretase modulators. This resulted in the selective reduction of Abeta(42) and an increase of the less aggregatory Abeta(38) fragment by several compounds (e.g., 7d and 8c). Introduction of an electron donating group at position 6 and 8 of N-substituted carbazolyloxyacetic acids either decreased the activity or inversed modulation. The most active compounds displayed activity on amyloid precursor protein (APP) overexpressing cell lines in the low micromolar range and little or no effect on the gamma-secretase cleavage at the epsilon-site.     

Early Cambrian origin of modern food webs: evidence from predator arrow worms

Although palaeontological evidence from exceptional biota demonstrates the existence of diverse marine communities in the Early Cambrian (approx. 540-520 Myr ago), little is known concerning the functioning of the marine ecosystem, especially its trophic structure and the full range of ecological niches colonized by the fauna. The presence of a diverse zooplankton in Early Cambrian oceans is still an open issue. Here we provide compelling evidence that chaetognaths, an important element of modern zooplankton, were present in the Early Cambrian Chengjiang biota with morphologies almost identical to Recent forms. New information obtained from the lowermost Cambrian of China added to previous studies provide convincing evidence that protoconodont-bearing animals also belonged to chaetognaths. Chaetognaths were probably widespread and diverse in the earliest Cambrian. The obvious raptorial function of their circumoral apparatuses (grasping spines) places them among the earliest active predator metazoans. Morphology, body ratios and distribution suggest that the ancestral chaetognaths were planktonic with possible ecological preferences for hyperbenthic niches close to the sea bottom. Our results point to the early introduction of prey-predator relationships into the pelagic realm, and to the increase of trophic complexity (three-level structure) during the Precambrian-Cambrian transition, thus laying the foundations of present-day marine food chains.     

Endoplasmic reticulum retention of the gamma-secretase complex component Pen2 by Rer1

gamma-Secretase is involved in the production of amyloid beta-peptide, which is the principal component of amyloid plaques in the brains of patients with Alzheimer disease. gamma-Secretase is a complex composed of presenilin (PS), nicastrin, anterior pharynx-defective phenotype 1 (Aph1) and PS enhancer 2 (Pen2). We previously proposed a mechanism of complex assembly by which unassembled subunits are retained in the endoplasmic reticulum (ER) and only the fully assembled complex is exported from the ER. We have now identified Retention in endoplasmic reticulum 1 (Rer1) as a protein that is involved in the retention/retrieval of unassembled Pen2 to the ER. Direct binding of unassembled Pen2 to Rer1 is mediated by the first transmembrane domain of Pen2, and a conserved asparagine in this domain is required. Downregulation of Rer1 leads to increased surface localization of Pen2, whereas overexpression of Rer1 stabilizes unassembled Pen2. To our knowledge, Rer1 is the first identified interaction partner of mammalian transmembrane-based retention/retrieval signals.     

The invariant phenylalanine of precursor proteins discloses the importance of Omp85 for protein translocation into cyanelles

Background  

Today it is widely accepted that plastids are of cyanobacterial origin. During their evolutionary integration into the metabolic and regulatory networks of the host cell the engulfed cyanobacteria lost their independency. This process was paralleled by a massive gene transfer from symbiont to the host nucleus challenging the development of a retrograde protein translocation system to ensure plastid functionality. Such a system includes specific targeting signals of the proteins needed for the function of the plastid and membrane-bound machineries performing the transfer of these proteins across the envelope membranes. At present, most information on protein translocation is obtained by the analysis of land plants. However, the analysis of protein import into the primitive plastids of glaucocystophyte algae, revealed distinct features placing this system as a tool to understand the evolutionary development of translocation systems. Here, bacterial outer membrane proteins of the Omp85 family have recently been discussed as evolutionary seeds for the development of translocation systems.     

Programmed cell death-4 tumor suppressor protein contributes to retinoic acid-induced terminal granulocytic differentiation of human myeloid leukemia cells

Programmed cell death-4 (PDCD4) is a recently discovered tumor suppressor protein that inhibits protein synthesis by suppression of translation initiation. We investigated the role and the regulation of PDCD4 in the terminal differentiation of acute myeloid leukemia (AML) cells. Expression of PDCD4 was markedly up-regulated during all-trans retinoic acid (ATRA)-induced granulocytic differentiation in NB4 and HL60 AML cell lines and in primary human promyelocytic leukemia (AML-M3) and CD34(+) hematopoietic progenitor cells but not in differentiation-resistant NB4.R1 and HL60R cells. Induction of PDCD4 expression was associated with nuclear translocation of PDCD4 in NB4 cells undergoing granulocytic differentiation but not in NB4.R1 cells. Other granulocytic differentiation inducers such as DMSO and arsenic trioxide also induced PDCD4 expression in NB4 cells. In contrast, PDCD4 was not up-regulated during monocytic/macrophagic differentiation induced by 1,25-dihydroxyvitamin D3 or 12-O-tetradecanoyl-phorbol-13-acetate in NB4 cells or by ATRA in THP1 myelomonoblastic cells. Knockdown of PDCD4 by RNA interference (siRNA) inhibited ATRA-induced granulocytic differentiation and reduced expression of key proteins known to be regulated by ATRA, including p27(Kip1) and DAP5/p97, and induced c-myc and Wilms' tumor 1, but did not alter expression of c-jun, p21(Waf1/Cip1), and tissue transglutaminase (TG2). Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway was found to regulate PDCD4 expression because inhibition of PI3K by LY294002 and wortmannin or of mTOR by rapamycin induced PDCD4 protein and mRNA expression. In conclusion, our data suggest that PDCD4 expression contributes to ATRA-induced granulocytic but not monocytic/macrophagic differentiation. The PI3K/Akt/mTOR pathway constitutively represses PDCD4 expression in AML, and ATRA induces PDCD4 through inhibition of this pathway.     

Agonist-induced changes of platelet tubulin phosphorylation

Changes in the phosphorylation of platelet tubulin were analyzed as a function of platelet activation. Non-activated platelets incubated with [32P]-phosphate showed multiple peaks of radioactivity when solubilized platelet proteins were analyzed by SDS-polyacrylamide gradient gel electrophoresis. Both tubulin monomers were found to be phosphorylated. Agonistic stimulation (thrombin or 1,2-diacylglycerol) resulted in a lowering of the phosphate incorporation into alpha- and beta-tubulin. Such changes we believe are important in the modulation of the reversible polymerization-depolymerization of platelet tubulin that occurs in the course of the agonistic stimulation of platelets.     

Anfangsorientierung und Heimkehrverhalten von Brieftauben unter dem Einflu? von Kurzwellen

Zusammenfassung Um den potentiellen Einfluß von Kurzwellen auf die Orientierung und das Heimkehrverhalten von Brieftauben zu testen, wurden zwei Schläge in der Nähe eines Kurzwellensenders eingerichtet, der eine der Strahlung voll ausgesetzt, der anderer in einem tagsüber nicht für Sendungen benutzten Sektor und zudem topographisch gegen den Sender geschützt. In beiden Schlägen wurden Jungtauben aufgezogen und im Alter von drei Monaten für Testflüge genutzt. Die mit bzw. ohne Kurzwellen am neuen Standort angewöhnten Alttauben sowie die mit bzw. ohne Kurzwellen an diesem Standort aufgewachsenen Jungtauben wurden von einem etwa 11 km entfernten Auflaßort für Heimflüge gegen den Sender mit und ohne Kurzwellen-Einfluß im relevanten Sektor eingesetzt.Es ergaben sich keine Unterschiede in der Anfangsorientierung zwischen den Versuchsgruppen. Dagegen flogen alle ohne Kurzwellen-Einfluß aufgewachsenen Gruppen tendenziell rascher heim, wenn kein aktueller Kurzwellen-Einfluß vorhanden war. Faßte man alle drei Gruppen zusammen, so wurde dieser Unterschied signifikant. Demgegenüber zeigten die beiden mit Strahlung aufgewachsenen Gruppen unter den beiden Strahlungsbedingungen keine unterschiedlichen Heimkehrgeschwindigkeiten. Die fünf Testgruppen zusammengefaßt zeigten geringere Flughöhen unter Kurzwellen-Einfluß. Diese Ergebnisse lassen darauf schließen, daß die Brieftauben die Kurzwellen fühlen können, daß aber ihre Anfangsorientierung dadurch nicht beeinträchtigt wird. Reduzierte Heimkehrgeschwindigkeiten und geringe Flughöhen unter Kurzwellen-Einfluß, deuten auf einen störenden Effekt der elektromagnetischen Felder hin. Das Verhalten der unter Kurzwellen aufgewachsenen juvenilen Gruppen erlaubt den Schluß, daß sich Tauben an gewisse Kurzwellenbedingungen gewöhnen können.

---

Initial orientation and homing behaviour of pigeons under the influence of short wave transmissions

Summary In order to test the potential influence of short wave radiation on the homing behaviour of pigeons we positioned two lofts with adult homing pigeons in the vicinity of a short wave transmitter. One loft was next to the transmitter and fully exposed to the radiation, the second protected against the radiation (a) by topographical features and (b) by its position in a sector that was not used for transmission during daytime. In both lofts young pigeons were raised and used for experimental flights at the age of three months. Adults accustomed to the new sites as well as young birds from the exposed and non-exposed lofts, respectively, were released some 11 km from the loft for homeward flights towards the transmitter, with and without transmission towards the relevant sector.Vanishing direction and vanishing time were not affected by the short wave radiation in any of the groups, thus corroborating earlier experiments with pigeons flying homewards from the transmitter towards distant lofts. However, all three groups raised in the absence of short wave radiation (A–, A+, J–) homed tendentially faster in situations where radiation was absent compared to situations with radiation. Pooled in one data set the three groups were significantly faster without radiation. On the other hand, the two juvenile groups raised under radiation (J1+ and J2+) homed at the same speed under both short wave situations. Furthermore, all five groups tended to choose lower flight altitudes when released under the influence of short wave radiation (significantly when groups were pooled). Besides the experiments, observations near the loft gave the impression that the pigeons kept in the exposed loft were reluctant to fly in the neighbourhood of the loft, particularly the adults.We conclude that short wave radiation can be felt by the pigeons, but does not interfere with their initial orientation. Reduced homing speeds of birds grown up without experiencing radiation, low flight levels in flights under radiation in all groups, and a general reluctance to fly of the pigeons next to the exposed loft, suggest that the radiation has an undefined negative effect on the birds. Unimpaired homing speeds in juveniles having grown up under varying field strengths suggest that homing pigeons can become accustomed to short wave radiation to a certain extent.

     

A loss of function mutation of presenilin-2 interferes with amyloid beta-peptide production and notch signaling.

Presenilin-1 (PS1) facilitates gamma-secretase cleavage of the beta-amyloid precursor protein and the intramembraneous cleavage of Notch1. Although Alzheimer's disease-associated mutations in the homologous presenilin (PS2) gene elevate amyloid beta-peptide (Abeta42) production like PS1 mutations, here we demonstrate that a gene ablation of PS2 (unlike that of PS1) in mice does not result in a severe phenotype resembling that of Notch-ablated animals. To investigate the amyloidogenic function of PS2 more directly, we mutagenized a conserved aspartate at position 366 to alanine, because the corresponding residue of PS1 is known to be required for its amyloidogenic function. Cells expressing the PS2 D366A mutation exhibit significant deficits in proteolytic processing of beta-amyloid precursor protein indicating a defect in gamma-secretase activity. The reduced gamma-secretase activity results in the almost complete inhibition of Abeta and p3 production in cells stably expressing PS2 D366A, whereas cells overexpressing the wild-type PS2 cDNA produce robust levels of Abeta and p3. Using highly sensitive in vivo assays, we demonstrate that the PS2 D366A mutation not only blocks gamma-secretase activity but also inactivates PS2 activity in Notch signaling by inhibiting the proteolytic release of the cytoplasmic Notch1 domain. These data suggest that PS2 is functionally involved in Abeta production and Notch signaling by facilitating similar proteolytic cleavages.     

Anterior patterning by synergistic activity of the early gastrula organizer and the anterior germ layer tissues of the mouse embryo.

Fragments of the germ layer tissues isolated from the early-primitive-streak (early-streak) stage mouse embryos were tested for axis induction activity by transplantation to late-gastrula (late-streak to early-bud) stage host embryos. The posterior epiblast fragment that contains the early gastrula organizer was able to recruit the host tissues to form an ectopic axis. However, the most anterior neural gene that was expressed in the ectopic axis was Krox20 that marks parts of the hindbrain, but markers of the mid- and forebrain (Otx2 and En1) were not expressed. Anterior visceral endoderm or the anterior epiblast alone did not induce any ectopic neural tissue. However, when these two anterior germ layer tissues were transplanted together, they can induce the formation of ectopic host-derived neural tissues but these tissues rarely expressed anterior neural genes and did not show any organization of an ectopic axis. Therefore, although the anterior endoderm and epiblast together may display some inductive activity, they do not act like a classical organizer. Induction of the anterior neural genes in the ectopic axis was achieved only when a combination of the posterior epiblast fragment, anterior visceral endoderm and the anterior epiblast was transplanted to the host embryo. The formation of anterior neural structures therefore requires the synergistic interaction of the early gastrula organizer and anterior germ layer tissues.