DNA replication licensing and cell cycle kinetics of oligodendroglial tumours

The convergence point of growth-signalling pathways that control cell proliferation is the initiation of genome replication, the core of which is the assembly of pre-replicative complexes (pre-RCs), resulting in chromatin being ‘licensed’ for DNA replication in the subsequent S phase. The Mcm2–7 complex is a core constituent of the pre-RC, whose recruitment to replication origins is dependent on the Cdt1 loading factor. Geminin is a potent inhibitor of the initiation of DNA replication by preventing Mcm2–7 assembly at origins via its interaction with Cdt1, ensuring genomic integrity through suppression of re-initiation events in S phase. Here we investigate the regulation of Ki67, Mcm2, p21, caspase 3 and Geminin in a series of 55 oligodendrogliomas to provide an integrated picture of how cellular proliferation and programmed cell death are dysregulated in these tumours. Geminin does not behave as an inhibitor of cell proliferation, its labelling index rising with increasing growth fraction as defined by Ki67 or Mcm2 expression. Geminin is expressed in a higher proportion of cells in higher grade tumours (P<0.001) and shows a strong correlation to proliferation and replication licensing (P<0.01), but not apoptosis. Increasing tumour anaplasia is not associated with loss of Geminin. Importantly, the G1 phase of the proliferative cell cycle, as assessed by the Geminin/Ki67 ratio, shortens with increasing anaplasia, providing new potential algorithms for prognostic assessment. Origin licensing proteins thus provide powerful novel tools for assessment of tumour cell cycle kinetics in routinely processed surgical biopsy material

Mechanisms of progression of chronic kidney disease

Chronic kidney disease (CKD) occurs in all age groups, including children. Regardless of the underlying cause, CKD is characterized by progressive scarring that ultimately affects all structures of the kidney. The relentless progression of CKD is postulated to result from a self-perpetuating vicious cycle of fibrosis activated after initial injury. We will review possible mechanisms of progressive renal damage, including systemic and glomerular hypertension, various cytokines and growth factors, with special emphasis on the renin–angiotensin–aldosterone system (RAAS), podocyte loss, dyslipidemia and proteinuria. We will also discuss possible specific mechanisms of tubulointerstitial fibrosis that are not dependent on glomerulosclerosis, and possible underlying predispositions for CKD, such as genetic factors and low nephron number

Hypothesis for the evolution of three-helix Chl a/b and Chl a/c light-harvesting antenna proteins from two-helix and four-helix ancestors

The nuclear-encoded Chl a/b and Chl a/c antenna proteins of photosynthetic eukaryotes are part of an extended family of proteins that also includes the early light-induced proteins (ELIPs) and the 22 kDa intrinsic protein of PS II (encoded by psb S gene). All members of this family have three transmembrane helices except for the psb S protein, which has four. The amino acid sequences of these proteins are compared and related to the three-dimensional structure of pea LHC II Type I (Kühlbrandt and Wang, Nature 350: 130–134, 1991). The similarity of psb S to the three-helix members of the family suggests that the latter arose from a four-helix ancestor that lost its C-terminal helix by deletion. Strong internal similarity between the two halves of the psb S protein suggests that it in turn arose as the result of the duplication of a gene encoding a two-helix protein. Since psb S is reported to be present in at least one cyanobacterium, the ancestral four-helix protein may have been present prior to the endosymbiotic event or events that gave rise to the photosynthetic eukaryotes. The Chl a/b and Chl a/c antenna proteins, and the immunologically-related proteins in the rhodophytes may have had a common ancestor which was present in the early photosynthetic eukaryotes, and predated their division into rhodophyte, chromophyte and chlorophyte lineages. The LHC I-LHC II divergence probably occurred before the separation of higher plants from chlorophyte algae and euglenophytes, and the different Types of LHC I and LHC II proteins arose prior to the separation of angiosperms and gymnosperms.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43538/1/11120_2004_Article_BF00029382.pd

Influence of handaxe size and shape on cutting efficiency: a large-scale experiment and morphometric analysis

Handaxes represent one of the most temporally enduring and geographically widespread of Palaeolithic artifacts and thus comprised a key technological strategy of many hominin populations. Archaeologically observable variation in the size (i.e., mass) and shape properties of handaxes has been frequently noted. It is logical to ask whether some of this variability may have had functional implications. Here, we report the results of a large-scale (n = 500 handaxes) experiment designed to examine the influence of variation in handaxe size and shape on cutting efficiency rates during a laboratory task. We used a comprehensive dataset of morphometric (size-adjusted) shape variables and statistical methods (including multivariate methods) to address this issue. Our first set of analyses focused on handaxe mass/size variability. This analysis demonstrated that, at a broad-scale level of variation, handaxe mass may have been free to vary independently of functional (cutting) efficiency. Our analysis also, however, identified that there will be a task-specific threshold in terms of functional effectiveness at the lower end of handaxe mass variation. This implies that hominins may have targeted design forms to meet minimal (task-specific) thresholds, and may also have managed handaxe reduction and discard in respect to such factors. Our second set of analyses focused on handaxe shape variability. This analysis also indicated that considerable variation in handaxe shape may occur independently of any strong effect on cutting efficiency. We discuss how these results have several implications for considerations of handaxe variation in the archaeological record. At a general level, our results demonstrate that variability within and between handaxe assemblages in terms of their size and shape properties will not necessarily have had immediate or strong impact on their effectiveness when used for cutting, and that such variability may have been related to factors other than functional issues