Variation in the incidence of congenital malformations in spontaneous abortions,stillbirths and artificially interrupted pregnancies

Summary The study describes the nation wide rate of stillbirths and the incidence of mal-development in a series of spontaneous and induced abortions in Great Britain. Special reference is made to CNS malformations. Comparative study of these various types of births revealed that the incidence of maldevelopment is higher in induced abortion and in spontaneous abortion than in total or in stillbirths respectively. CNS malformations showed a higher frequency in stillbirths than in that of spontaneous abortions.

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Zusammenfassung Dies Arbeit betrifft die Rate von Totgeburten in ganz England und die Mißbildungshäufigkeit in einer englischen Serie von spontanen und induzierten Aborten. Auf die Mißbildungen des Zentralnervensystems wird besonders Bezug genommen. Ein Vergleich der verschiedenen Arten von Geburten hat ergeben, daß die Häufigkeit von Mißbildungen bei induzierten Aborten und bei Spontanaborten höher ist als insgesamt bzw. bei Totgeburten. Mißbildungen des Zentralnervensystems waren bei Totgeburten häufiger als bei Spontanaborten.

     

Protein Tyrosine Phosphatase Epsilon Regulates Integrin-mediated Podosome Stability in Osteoclasts by Activating Src

The nonreceptor isoform of tyrosine phosphatase epsilon (cyt-PTPe) supports osteoclast adhesion and activity in vivo, leading to increased bone mass in female mice lacking PTPe (EKO mice). The structure and organization of the podosomal adhesion structures of EKO osteoclasts are abnormal; the molecular mechanism behind this is unknown. We show here that EKO podosomes are disorganized, unusually stable, and reorganize poorly in response to physical contact. Phosphorylation and activities of Src, Pyk2, and Rac are decreased and Rho activity is increased in EKO osteoclasts, suggesting that integrin signaling is defective in these cells. Integrin activation regulates cyt-PTPe by inducing Src-dependent phosphorylation of cyt-PTPe at Y638. This phosphorylation event is crucial because wild-type—but not Y638F—cyt-PTPe binds and further activates Src and restores normal stability to podosomes in EKO osteoclasts. Increasing Src activity or inhibiting Rho or its downstream effector Rho kinase in EKO osteoclasts rescues their podosomal stability phenotype, indicating that cyt-PTPe affects podosome stability by functioning upstream of these molecules. We conclude that cyt-PTPe participates in a feedback loop that ensures proper Src activation downstream of integrins, thus linking integrin signaling with Src activation and accurate organization and stability of podosomes in osteoclasts.     

Zooplankton contribution to the particulate N and P in Lake Kinneret,Israel, under changing water levels

The association of water level changes and the relative (%) contributions of crustacean zooplankton to particulate N (PNz) and particulate P (PPz) in Lake Kinneret, Israel were studied. The PNz and PPz were assessed for a period of 10 years (1999–2008) in relation to water level (WL) changes which occurred during that period. We estimated PNz and PPz, based on crustacean N and P content measured seasonally over 2 years, and a 10-year record of zooplankton densities. Mean cladoceran N and P contents were 8.7 and 1.2% of dry weight, respectively, while for copepods they were 9.5 and 1.5% of dry weight, respectively. Zooplankton density, and hence PNz and PPz, changed dramatically during the 10 years, concurrent with extreme variations in the lake’s WL. The lowest mean values of PNz and PPz occurred during high WL years and the highest PNz and PPz were during low WL years. PNz and PPz were negatively correlated with the total PN and PP concentrations, respectively, in the lake. The reduction in zooplankton contribution to the particulate N and P during high WL is probably due to higher loading of particulate matter in wet years, causing an increase of PN and PP concentration in the lake, as well as lower densities of zooplankton, caused by higher fish predation pressure, both are a by-product of the large water influx during extreme wet winters.     

In vitro reductive metabolism of N-nitrosodibenzylamine: Evidence for new reactive intermediates

N-Nitrosodibenzylamine was incubated with rabbit-whole-liver homogenates. Gas-chromatographic and mass spectrometric analysis of the incubation extracts showed the formation of bibenzyl. This biotransformation is the result of a 2-electron reduction of the substrate to 1-hydroxy-2,2-dibenzylhydrazine, an unstable compound which breaks down to bibenzyl and nitrogen. It is suggested that such reductive metabolism may be involved in the generation of toxic metabolites of nitrosamines.     

IKAP/hELP1 downregulation in neuroblastoma cells causes enhanced cell adhesion mediated by contactin overexpression

A splicing mutation in the IKBKAP gene encoding the IKAP/hELP1 (IKAP) protein was found to be the major cause of Familial Dysautonomia (FD). This mutation affects both the normal development and survival of sensory and sympathetic neurons of the peripheral nervous system (PNS). To understand the FD phenotype it is important to study the specific role played by IKAP in developing and mature PNS neurons. We used the neuroblastoma SHSY5Y cell line, originated from neural crest adrenal tumor and simulated the FD phenotype by reducing IKAP expression with retroviral constructs. We observed that IKAP-downregulated cells formed cell clusters compared to control cells under regular culture conditions. We examined the ability of these cells to differentiate into mature neurons in the presence of laminin, an essential extracellular matrix for developing PNS neurons. We found that the cells showed reduced attachment to laminin, morphological changes and increased cell-to-cell adhesion resulting in cell aggregates. We identified Contactin as the adhesion molecule responsible for this phenotype. We show that Contactin expression is related to IKAP expression, suggesting that IKAP regulates Contactin levels for appropriate cell-cell adhesion that could modulate neuronal growth of PNS neurons during development.Key words: Familial Dysautonomia, IKAP/hELP1, neuronal differentiation, laminin, contactin, peripheral nervous system     

Selection of Aptamers for Amyloid β-Protein,the Causative Agent of Alzheimer's Disease

Alzheimer''s disease (AD) is a progressive, age-dependent, neurodegenerative disorder with an insidious course that renders its presymptomatic diagnosis difficult¹. Definite AD diagnosis is achieved only postmortem, thus establishing presymptomatic, early diagnosis of AD is crucial for developing and administering effective therapies^2,3.Amyloid β-protein (Aβ) is central to AD pathogenesis. Soluble, oligomeric Aβ assemblies are believed to affect neurotoxicity underlying synaptic dysfunction and neuron loss in AD^4,5. Various forms of soluble Aβ assemblies have been described, however, their interrelationships and relevance to AD etiology and pathogenesis are complex and not well understood⁶. Specific molecular recognition tools may unravel the relationships amongst Aβ assemblies and facilitate detection and characterization of these assemblies early in the disease course before symptoms emerge. Molecular recognition commonly relies on antibodies. However, an alternative class of molecular recognition tools, aptamers, offers important advantages relative to antibodies^7,8. Aptamers are oligonucleotides generated by in-vitro selection: systematic evolution of ligands by exponential enrichment (SELEX)^9,10. SELEX is an iterative process that, similar to Darwinian evolution, allows selection, amplification, enrichment, and perpetuation of a property, e.g., avid, specific, ligand binding (aptamers) or catalytic activity (ribozymes and DNAzymes).Despite emergence of aptamers as tools in modern biotechnology and medicine¹¹, they have been underutilized in the amyloid field. Few RNA or ssDNA aptamers have been selected against various forms of prion proteins (PrP)^12-16. An RNA aptamer generated against recombinant bovine PrP was shown to recognize bovine PrP-β¹⁷, a soluble, oligomeric, β-sheet-rich conformational variant of full-length PrP that forms amyloid fibrils¹⁸. Aptamers generated using monomeric and several forms of fibrillar β₂-microglobulin (β₂m) were found to bind fibrils of certain other amyloidogenic proteins besides β₂m fibrils¹⁹. Ylera et al. described RNA aptamers selected against immobilized monomeric Aβ40²⁰. Unexpectedly, these aptamers bound fibrillar Aβ40. Altogether, these data raise several important questions. Why did aptamers selected against monomeric proteins recognize their polymeric forms? Could aptamers against monomeric and/or oligomeric forms of amyloidogenic proteins be obtained? To address these questions, we attempted to select aptamers for covalently-stabilized oligomeric Aβ40²¹ generated using photo-induced cross-linking of unmodified proteins (PICUP)^22,23. Similar to previous findings^17,19,20, these aptamers reacted with fibrils of Aβ and several other amyloidogenic proteins likely recognizing a potentially common amyloid structural aptatope²¹. Here, we present the SELEX methodology used in production of these aptamers²¹.Download video file.^{(175M, mp4)}