If good things come from above,do bad things come from below?

Factors in the synovial fluid that maintain healthy articular cartilage, such as hyaluronic acid and lubricin, come from above. Is it possible that factors which lead to the destruction of cartilage come from below in the subchondral bone? The recent acquisition of tools to probe early events in osteoarthritis is shedding new light on possible contributions from this compartment on the initiation and progression of the disease. Tanamas and co-workers now provide evidence that bone marrow lesions in the subchondral bone are predictive, both of loss of cartilage and of formation of subchondral cysts. These data provoke questions about the nature and role of bone marrow lesions.Finding the factors that initiate, or the mechanisms that lead to progression of, osteoarthritis (OA) has proven frustrating and largely unproductive. Identification of risk factors for the condition - such as prior trauma to the joint, elevated body weight and female sex - may have helped with management of OA but has done little to progress understanding of the underlying factors that drive it. OA research has been more difficult than research for some other diseases of the skeleton, for several important reasons. Early OA, at the level of symptoms, can be episodic, making it difficult to identify the disease and to follow it longitudinally. Since the main early symptom is pain, clinical trials of new therapies have been problematic. Animal experiments have been bedevilled by a lack of models that accurately replicate the human disease. And perhaps, as argued by a minority of workers in the field, disease initiators have been sought in the wrong place; that is, cartilage versus bone.The recent study of Tanamas and colleagues highlights the way in which new-generation imaging holds the promise of shedding new light on this old problem [1]. In particular, high-resolution magnetic resonance imaging (MRI) can now deliver objective, measurable information about all structures of the joint, including the amount and quality of articular cartilage, and is also a powerful tool to investigate the subchondral bone. The holy grail of clinical investigation, namely longitudinal study with quantitative endpoints, is now accessible for OA. What Tanamas and colleagues'' study shows is important because it adds to emerging evidence that processes in the subchondral bone relate strongly to changes in the volumetric amount of articular cartilage. Specifically, bone marrow lesions (BMLs), the mysterious MRI-bright regions in the subchondral bone that occur more commonly in OA, were shown to be predictive of loss of cartilage and of formation of subchondral cysts. In turn, cysts were more likely than BMLs to occur in association with loss of cartilage.These data pose the intriguing question of whether BMLs encode key clues to the aetiology of OA. Longitudinal studies have shown that the presence of BMLs constitutes a potent risk factor for structural deterioration in knee OA [2]. BML enlargement has been strongly associated with increased cartilage loss, and Tanamas and colleagues'' data further suggest that their conversion into cysts is even more predictive of cartilage loss. Significantly, a reduction in the extent of BMLs on MRI has been shown to associate with a decrease in cartilage degradation [3]. Since the origin of BMLs is not known, its investigation needs to be prioritised as an important research topic. Current informed guesses are that BMLs comprise regions of oedema, perhaps secondary to episodes of local ischaemia. Although it is not possible to biopsy BMLs in patients with early OA, several studies have sought to correlate the MRI findings with histology in more severe disease. Regions of BMLs in end-stage OA patients at knee replacement were more likely to exhibit oedema, bone necrosis and trabecular abnormalities than were control sites [4].If BMLs are secondary to local ischaemia in the subchondral bone, there are several possible consequences. Firstly, the supply of nutrients and oxygen from regions of ischaemic subchondral bone, to the overlying articular cartilage, might be reduced. Cartilage nutrition has been considered to derive from the synovial fluid. The work of Imhof and colleagues, however, suggested that more than 50% of the glucose, oxygen and water requirements of cartilage are provided by perfusion from the subchondral vessels [5]. They described the dense subchondral vasculature in close proximity to the cartilage, and the micro-channels that penetrate the subchondral mineralisation zone and permit communication between the bone and the cartilage. More recent work indicates that small molecules can diffuse, in healthy joints, bidirectionally from the synovial compartment into the cartilage and underlying bone and from the subchondral bone into the overlying cartilage [6]. Inspection of the osteochondral junction of long bones reveals that osteocytes and osteocyte canaliculi, which are also probable conduits of nutrients, are intimately associated with the articular cartilage. Experimental interruption of contact between articular cartilage and subchondral bone results in degeneration of the cartilage, and osteoblasts from OA subchondral bone conferred catabolic changes in articular chondrocytes [7].Secondly, osteocyte death in bone is becoming recognised as a signalling event for osteoclastic removal of the nonviable bone and its replacement in a remodelling episode [8]. Although subchondral bone is constantly being remodelled, concentration of this activity in a particular region of the bone could alter its mechanical integrity and its ability to properly support the overlying cartilage.Tanamas and colleagues conclude that cysts (and BMLs) may provide therapeutic targets for the treatment of knee OA [1]. Certainly, the recent acquisition of tools to probe early events in subchondral bone in OA should deliver rapid advances in our understanding of the natural history of this condition.     

Have biopesticides come of age?

Biopesticides based on living microbes and their bioactive compounds have been researched and promoted as replacements for synthetic pesticides for many years. However, lack of efficacy, inconsistent field performance and high cost have generally relegated them to niche products. Recently, technological advances and major changes in the external environment have positively altered the outlook for biopesticides. Significant increases in market penetration have been made, but biopesticides still only make up a small percentage of pest control products. Progress in the areas of activity spectra, delivery options, persistence of effect and implementation have contributed to the increasing use of biopesticides, but technologies that are truly transformational and result in significant uptake are still lacking.     

Where will new antibiotics come from?

There is a constant need for new antibacterial drugs owing to the inevitable development of resistance that follows the introduction of antibiotics to the clinic. When a new class of antibiotic is introduced, it is effective at first, but will eventually select for survival of the small fraction of bacterial populations that have an intrinsic or acquired resistance mechanism. Pathogens that are resistant to multiple drugs emerge around the globe, so how robust are antibiotic discovery processes?     

Where does our behaviour come from?

Conclusion Looking for single causes, whether genetic or environmental, may yield answers of a kind, but little sense of what happens as each individual grows up. The language of nature versus nurture, or genes versus environment, gives only a feeble insight into the processes that I have called developmental cooking. The best that can be said of the nature/nurture split is that it provides a framework for uncovering a few of the genetic and environmental ingredients that generate differences between people. At worst, it satisfies a demand for simplicity in ways that are fundamentally misleading.     

SL trans-splicing: easy come or easy go?

Is spliced-leader (SL) trans-splicing an ancestral eukaryotic characteristic that has been lost in multiple lineages, or did it arise independently in the various phyla in which it occurs? Recent studies have discovered SL trans-splicing in new metazoan phyla, including the chordates. Its discovery in chordates identifies, for the first time, a phylum that clearly contains both trans-splicing and non-trans-splicing major groups, and defines a limited and well-understood field in which to study the evolutionary dynamics of SL trans-splicing. In this article, I summarize the evolutionarily relevant aspects of SL trans-splicing and consider the interplay among SL trans-splicing, pre-mRNA splice-signal syntax and evolutionary genomics.     

Asymmetric segregation: the shape of things to come?

Yeast mother cells pay a sacrifice during budding: they keep the extrachromosomal rDNA circles (ERCs) so that their buds have a full lifespan ahead. Two new studies indicate that retention of ERCs in mother cells occurs not by tethering to the nuclear periphery but rather by the simple rules of diffusion in a time-limited and complex landscape.     

Where does heteroclisis come from? Evidence from Romanian dialects

This study examines some cases of heteroclisis in the history of Romanian dialects, and concludes that the data call for a reconsideration of Stump’s distinction (Language 82:279–322, 2006) between ‘cloven’ heteroclisis, where the intraparadigmatic ‘split’ is aligned with some morphosyntactic feature distinction, and ‘fractured’ heteroclisis, where this is not the case and the pattern of heteroclisis is purely morphological. Stump’s account creates the impression that the ‘cloven’ variety is universally predominant, and that the ‘fractured’ variety tends to follow very closely the available ‘cloven’ patterns of the language. I shall suggest, instead, that the ‘fractured-only’ situation may in fact underlie heteroclisis cross-linguistically, the phenomenon being in general sensitive not directly to morphosyntactic content, but rather to characteristic, and often purely ‘morphomic’, patterns of stem-allomorphy. Research for this paper was undertaken as part of the Arts and Humantities Research Council-funded project Autonomous Morphology in Diachrony: comparative evidence from the Romance Languages, currently being conducted at Oxford University.     

Ecological engineering - An idea whose time has come?

The era of cheap fossil fuels is nearing its end. industrial, agricultural and human pollutants have reached alarming levels in water, soil, air and stratosphere. Consumers no longer tolerate poisons in their food and water, are now concerned with global warming and ozone depletion, and value fields and forests for their scenery and wildlife as well as food and fibre. We are at the crossroads, searching for answers to these and many other pressing ecological problems. On one side sit 'deep ecologists' who patiently await the reactions of global Gaia. On the other sit 'biotechnologists' who would design and build new organisms and new ecosystems. The first approach is defeatist, for it awaits the decimation of the human population. The otheris activist, but will it work? Here we examine the idea of 'ecological engineering', which offers some promise of solutions to our problems if it can integrate the practical sides of ecosystem, landscape, community and population ecology with relevant formal concepts from the engineering sciences.     

Where do animal alpha-amylases come from? An interkingdom trip

Alpha-amylases are widely found in eukaryotes and prokaryotes. Few amino acids are conserved among these organisms, but at an intra-kingdom level, conserved protein domains exist. In animals, numerous conserved stretches are considered as typical of animal alpha-amylases. Searching databases, we found no animal-type alpha-amylases outside the Bilateria. Instead, we found in the sponge Reniera sp. and in the sea anemone Nematostella vectensis, alpha-amylases whose most similar cognate was that of the amoeba Dictyostelium discoideum. We found that this "Dictyo-type" alpha-amylase was shared not only by these non-Bilaterian animals, but also by other Amoebozoa, Choanoflagellates, and Fungi. This suggested that the Dictyo-type alpha-amylase was present in the last common ancestor of Unikonts. The additional presence of the Dictyo-type in some Ciliates and Excavates, suggests that horizontal gene transfers may have occurred among Eukaryotes. We have also detected putative interkingdom transfers of amylase genes, which obscured the historical reconstitution. Several alternative scenarii are discussed.     

Where do human schistosomes come from? An evolutionary approach

Schistosomiases affect between 200 and 400 million people, mainly in the tropical and poorly developed zones of the globe. They are often considered as the 'second' disease of mankind, just after malaria. One important question regarding human parasites is: are they the descendants of parasites that used to infect our primate ancestors and have had an evolution parallel to that of the human lineage, or are they the result of lateral transfers of parasites that evolved in different hosts? Recently, knowledge of the biology of schistosomes has dramatically increased, and answers to this and other questions are beginning to emerge.     

Zebra mussels in Italy: where do they come from?

The zebra mussel Dreissena polymorpha is widely present in Italy, but Italian populations of this bivalve have never been genetically characterized. The mitochondrial Cytochrome Oxidase subunit I gene fragments have been used to determine the genetic structures of 3 populations from Lake Garda (n = 30), the first Italian basin colonized by this species, as well as 2 populations from Lake Constance, Germany (n = 14). A Neighbor-Joining tree and a Maximum Likelihood analysis were performed with 4 new Italian (LG1-LG4) and 3 German (LC1-LC3) haplotypes, also considering all the available Dreissena sequences from GenBank in order to estimate phylogeographic relationships. Almost all Italian haplotypes clustered with German and mid-European samples providing evidences of a mixed origin for Italian mussels. We speculate about Lake Garda colonization, for which the hypothesized "German origin" has been partially confirmed as well as the necessity of more efficient control strategies at least to minimize new colonizations.     

Where did the BLOSUM62 alignment score matrix come from?

Many sequence alignment programs use the BLOSUM62 score matrix to score pairs of aligned residues. Where did BLOSUM62 come from?     

Daddy, where did (PS)I come from?

The reacton centre I (RCI)-type photosystems from plants, cyano-, helio- and green sulphur bacteria are compared and the essential properties of an archetypal RCI are deduced. Species containing RCI-type photosystems most probably cluster together on a common branch of the phylogenetic tree. The predicted branching order is green sulphur, helio- and cyanobacteria. Striking similarities between RCI- and RCII-type photosystems recently became apparent in the three-dimensional structures of photosystem I (PSI), PSII and RCII. The phylogenetic relationship between all presently known photosystems is analysed suggesting (a) RCI as the ancestral photosystem and (b) the descendence of PSII from RCI via gene duplication and gene splitting. An evolutionary model trying to rationalise available data is presented.