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Group-3 medulloblastoma (MBL) is highly resistant to radiation (IR) and chemotherapy and has the worst prognosis. Hence, there is an urgent need to elucidate targets that sensitize these tumors to chemotherapy and IR. Employing standard assays for viability and sensitization to IR, we identified PRDX1 as a therapeutic target in Group-3 MBL. Specifically, targeting PRDX1 by RNAi or inhibition by Adenanthin led to specific killing and sensitization to IR of Group-3 MBL cells. We rescued sensitization of Daoy and UW228 cells by hypermorphic expression of PRDX1. PRDX1 knockdown caused oxidative DNA damage and induced apoptosis. We correlated PRDX1 expression to patient outcomes in a validated MBL tumor-microarray. Whole genome sequencing identified pathways/genes that were dysregulated with PRDX1 inhibition or silencing. Our in vivo studies in mice employing flank/orthotopic tumors from patient derived xenografts/Group-3 MBL cells confirmed in vitro observations. Animals with tumors in which PRDX1 was targeted by RNAi or Adenanthin (using mini osmotic pumps) showed decreased tumor burden and increased survival when compared to controls. Since, Adenanthin does not cross the blood brain barrier (BBB) we used HAV6 peptide to transiently disrupt the BBB and deliver Adenanthin to the tumor. Immunohistochemistry confirmed that targeting PRDX1 resulted in increased oxidative DNA damage, apoptosis and decreased proliferation. In summary, we have validated PRDX1 as a therapeutic target in group-3 MBL, identified Adenanthin as a potent chemical inhibitor of PRDX1 and confirmed the role of HAV peptide (in the transient modulation of BBB permeability) in an orthotopic model of group-3 MBL.
Perovskite compositions are used to investigate the relationship between the minor components (i.e. LREE, Fe3+ and Nb) and the oxygen fugacity (fo2) of perovskite in four different kimberlite lithofacies from the Dutoitspan pipe, Kimberley, South Africa, which range from diamondiferous to barren. The perovskite textures and chemical variations provide insight into magmatic and eruptive processes. Some crystals display cores with rims separated by a sharp boundary. The cores contain larger Na and LREE contents relative to the rims, which show a large increase in Fe3+ and Al. The mid-grade and barren kimberlites have bi-modal cores, reflected in the mineral chemistry, signifying multiple batches of magma and magma mixing. The fo2 of the magma is determined by an Fe-Nb oxygen barometer. The most diamondiferous kimberlite has the greatest Fe3+ content and highest fo2 (NNO –3.6 to –1.1). The kimberlite containing large diamonds has the smallest Fe3+ content and lowest fo2 (NNO –5.2 to –3.0). The barren and mid-grade kimberlites display a wide range of fo2,(NNO –5.3 to –1.5) as a result of perovskites forming in different melts and subsequently mixing together. Chemical and petrological evidence suggests that the volatile content, degassing, decompression and rate of crystallization can influence the rate at which the magma is erupted. One possibility is that the most oxidized magma, containing the highest volatile content, is therefore erupted much more rapidly, preserving diamond as a consequence.
Common genetic variants, such as the brain-derived neurotrophic factor
(BDNF) Val/66/Met polymorphism (rs6265), are known to interact with
environmental factors such as early adversity to increase the risk of
subsequent major depression. Much less is known about how they interact
with individual differences in cortisol, although these also represent a
risk for major depression.
To determine whether this BDNF variant moderated the risk represented by
higher levels of morning salivary cortisol in adult women.
We recruited 279 premenopausal women who were at high risk of major
depressive disorder because of either negative self-evaluation,
unsupportive core relationship or chronic subclinical symptoms of
depression or anxiety. Morning salivary cortisol was measured daily for
up to 10 days at entry. Participants were followed up for about 12 months
by telephone calls at 3–4 monthly intervals. Major depression and severe
life events were assessed through interviews at baseline and follow-up;
DNA was obtained from the saliva.
There were 53 onsets (19%) of depressive episodes during follow-up. There
was a significant U-shaped relationship between adjusted morning cortisol
levels at baseline and the probability of depression onset during
follow-up. In total, 51% experienced at least one severe life
event/difficulty, and this strongly predicted subsequent onsets of
depressive episodes. The BDNF Val/66/Met genotype was
not directly associated with onsets of depression or with cortisol
levels, but there was significant interaction between Val/66/Met and
cortisol: the association between baseline cortisol and depression was
limited to those with the Val/66/Val variant. There was no interaction
between life events and either this BDNF polymorphism or cortisol
Morning salivary cortisol interacts with the BDNF Val/66/Met polymorphism
in predicting new depressive episodes. This paper adds to the evidence
that single gene polymorphisms interact with endogenous factors to
It has been suggested that individuals might be more readily colonized with bacteria that cause meningitis through enhanced binding of the bacteria to virusinfected epithelial cells. As respiratory syncytial virus (RSV) affects infants and children in the age group also susceptible to bacterial meningitis, we tested the hypothesis that infection of HEp-2 cells by RSV might enhance binding of Neisseria meningitidis or Haemophilus influenzae type b (Hib). Attachment of fluorescein-labelled bacteria to HEp-2 cells was measured by flow cytometry, and RSV-infected cells bound significantly more meningococci (P < 0·001) and Hib (P < 0·01) than uninfected cells. Although the isolates expressed different antigenic characteristics (3 meningococci and 5 Hib), all showed a similar pattern of binding. The results are discussed with reference to the methods used for detection of bacterial binding and to interactions that might explain the increased binding to RSV-infected cells.
Surface antigens of three stages of three species of the filarial nematode genus Brugia have been analysed by radio-iodination and immunoprecipitation. These surface antigens have been shown to be characteristic for each stage by polyacrylamide gel electrophoresis. For example, infective larvae and adult worms have relatively complex patterns while microfilariae have few bands which are not found when other stages are radio-isotope labelled by the same technique. The surface antigens of Brugia malayi, B. timori and B. pahangi adult worms are all closely homologous, as are the surface antigens of infective larvae of the same three species, and of microfilariae of B. malayi and B. pahangi. Immunoprecipitation revealed that antibody raised in mice against one stage or species reacted with surface antigens from other stages and species. For example, sera raised against B. pahangi male adults reacted strongly with surface antigens from all three species. This cross-reactivity was dominant despite the apparent stage-specificity of the surface pattern seen on SDS-PAGE analysis. Moreover, in cross-immunization experiments, infective larvae were able to stimulate a secondary antibody response in mice previously primed with microfilarial surface antigens. The major microfilarial surface antigens (of mol. wt 65−70000 Daltons) were recognized by serum antibody from microfilariae-, infective larvae- or adult-infected animals. Thus, although the dominant antigens from each stage are of different molecular weight, cross-reactions with stage-specific antisera suggest that there must be shared epitopes on Brugia surface antigens from each stage. Such shared antigenic determinants dominate the immune response, although other evidence, including the differences in molecular weight, indicates the existence of stage-and species-specific components.
In rats treated with compound 48/80 or histamine, worm expulsion was inhibited. Treatment with a histidine decarboxylase inhibitor accelerated worm expulsion. Treatment with compound 48/80 elevates histamine and histidine decarboxylase levels and reduces circulating reagin titres. These results show that histamine is not responsible for worm expulsion.
Compounds such as isoprenaline and theophylline which increase cellular levels of cyclic 3′,5-AMP, prevented worm expulsion.
It is concluded that the evidence that amines are involved in worm expulsion needs reassessing and that cellular release mechanisms in general may be affected by drugs thought to act solely on amine release. In particular, the release of effector substances from sensitized lymphocytes on contact with antigen may be affected by these treatments.
The skilful technical assistance of Miss R. Keist and Miss I. Beeger is gratefully acknowledged. We thank Mr H. Berchtold, Biostatistisches Zentrum der Universität Zürich, for the statistical evaluation of the data.
When adult Nippostrongylus brasiliensis were maintained in vitro they became damaged. Using the criteria of ultrastructural morphology, acetylcholinesterase isoenzyme pattern and the behaviour of the worms after transfer to a normal rat, this damage appeared to be similar to that produced by the in vivo action of antibodies.
Antibodies were shown to be responsible for the anterior migration of adult worms which occurs during primary infections in mature rats and in the prolonged infections seen in lactating and immature rats.
Antibody damaged worms and worms unaffected by antibodies were equally able to stimulate the immune response required for worm expulsion. Apparently antibody damage is not required for the initiation of the second immune component necessary for expulsion of this parasite.
Adult Onchocerca volvulus worms obtained by enzyme digestion from nodules of infected Mexicans were radio-isotope labelled by the chloramine-T or Bolton–Hunter methods. No antigenic determinants were detected in extracts of worms labelled by the chloramine-T method but 3 antigens were detected in extracts of the Bolton–Hunter labelled worms. Two were present in such small amounts that it was impractical to investigate them further, but a major component of mol. wt 20 kDa was purified by gel filtration and used in a serological survey of inhabitants of villages in Southern Mexico. Using the 20 kDa antigen, which is superficially located on both sexes of O. volvulus, sera from both non-endemic and endemic regions were analysed by radio-immunoprecipitation of this antigen. In Southern Mexico, the average sensitivity of the test was 92%, and the specificity 98%. Whilst the 20 kDa antigen did not detect antibodies in the sera of Trinidadians infected with Wuncheria bancrofti or Mansonella ozzardi, this antigen detected high levels of antibodies in Indians exposed to W. bancrofti.
This volume of the second edition of the Cambridge Ancient History traces the history of Rome from its origins to the eve of the Second Punic War. Although the period covered is essentially the same as in the undivided Volume VII of the first edition, the treatment of the material is completely fresh and is much more extensive. Account is taken of new scholarly insights and of the considerable amount of new evidence, much of it archaeological, which has become available since the first edition was published. After a survey of the sources of our information the origins of Rome are discussed, beginning with the first discernible traces of the bronze Age settlement and going on to an assessment of the regal period. The complex and often controversial history of the early Republic is examined with reference to its internal development, the evolution of its relationships with the Latins, and the remorseless, if occasionally erratic, advance of Roman power in parts of Italy less immediately adjacent to the city. These developments are traced further in relation to the intervention of Pyrrhus and its aftermath, leading to consideration of Rome's relationships with Carthage, the First Punic War, and the beginnings of overseas empire. Rome is considered from a different perspective in a chapter on society and religion.
This chapter first deals with the main literary and archaeological sources for early Roman history. Then, it considers the type of material which was at the disposal of the historians of Rome for the regal period and the fifth century and how they used it. Roman historiography began at the end of the third century BC, but the earliest historical work was almost certainly the epic poem on the First Punic War written in the later third century by one of the combatants, Cn. Naevius. Iunius Gracchanus and Sempronius Tuditanus, Cincius, Q. Cornificius, Nigidius Figulus, Cornelius Nepos and Atticus, who made the first serious attempts to utilize the principles set by Eratosthenes to establish Roman chronology. At all events the surviving inscriptions earlier than the tombs of the Scipios in the third century are meagre and highly controversial, adding knowledge of early Roman history. Roman historical information comes mainly from the annalists particularly Livy and Timaeus.