Regulation of the neuronal proteasome by Zif268 (Egr1)

Most forms of neuronal plasticity are associated with induction of the transcription factor Zif268 (Egr1/Krox24/NGF-IA). In a genomewide scan, we obtained evidence for potential modulation of proteasome subunit and regulatory genes by Zif268 in neurons, a finding of significance considering emerging evidence that the proteasome modulates synaptic function. Bioinformatic analysis indicated that the candidate proteasome Zif268 target genes had a rich concentration of putative Zif268 binding sites immediately upstream of the transcriptional start sites. Regulation of the mRNAs encoding the psmb9 (Lmp2) and psme2 (PA28�) proteasome subunits, along with the proteasome-regulatory kinase serum/glucocorticoid-regulated kinase (SGK) and the proteasome-associated antigen peptide transporter subunit 1 (Tap1), was confirmed after transfection of a neuronal cell line with Zif268. Conversely, these mRNAs were upregulated in cerebral cortex tissue from Zif268 knock-out mice relative to controls, confirming that Zif268 suppresses their expression in the CNS. Transfected Zif268 reduced the activity of psmb9, SGK, and Tap1 promoter–reporter constructs. Altered psmb9, SGK, and Tap1 mRNA levels were also observed in an in vivo model of neuronal plasticity involving Zif268 induction: the effect of haloperidol administration on striatal gene expression. Consistent with these effects on proteasome gene expression, increased Zif268 expression suppressed proteasome activity, whereas Zif268 knock-out mice exhibited elevated cortical proteasome activity. Our findings reveal that Zif268 regulates the expression of proteasome and related genes in neuronal cells and provide new evidence that altered expression of proteasome activity after Zif268 induction may be a key component of long-lasting CNS plasticity

Molecular clocks: Defusing the Cambrian ‘explosion’?

AbstractA recent molecular phylogenetic study argues against the orthodox view that metazoan phyla emerged abruptly during the Cambrian ‘explosion’, pointing instead to a protracted history for metazoans that arguably stretches back a billion years or more; the fossils, however, seem to tell a different story

Predicting what extraterrestrials will be like: and preparing for the worst

It is difficult to imagine evolution in alien biospheres operating in any manner other than Darwinian. Yet, it is also widely assumed that alien life-forms will be just that: strange, un-nerving and probably repulsive. There are two reasons for this view. First, it is assumed that the range of habitable environments available to extra-terrestrial life is far wider than on Earth. I suggest, however, that terrestrial life is close to the physical and chemical limits of life anywhere. Second, it is a neo-Darwinian orthodoxy that evolution lacks predictability; imagining what extra-terrestrial life would look like in any detail is a futile exercise. To the contrary, I suggest that the outcomes of evolution are remarkably predictable. This, however, leads us to consider two opposites, both of which should make our blood run cold. The first, and actually extremely unlikely, is that alien biospheres will be strikingly similar to our terrestrial equivalent and that in such biospheres intelligence will inevitably emerge. The reasons for this revolve around the ubiquity of evolutionary convergence, the determinate structure of the Tree of Life and molecular inherency. But if something like a human is an inevitability, why do I also claim that the first possibility is ‘extremely unlikely’? Simply because the other possibility is actually the correct answer. Paradoxically, we and our biosphere are completely alone. So which is worse? Meeting ourselves or meeting nobody

Management of pneumonia in intensive care

Pneumonia, an inflammatory infiltrate of the alveolar airspace, is commonly triggered by bacterial infection of the lungs, or less commonly by viral or fungal infection. It remains the commonest infective reason for admission to Intensive Care as well as being the most common secondary infection acquired whilst in the Intensive Care Unit. It presents a significant global burden of disease and is especially prevalent in low- and middle-income countries. The major categories of pneumonia encountered by the Intensive Care clinician are community-acquired, ventilator-acquired, non-ventilator hospital-acquired and pneumonia in the immunocompromised patient. An appreciation of the type of pneumonia a patient has developed is critical to its effective treatment. Pneumonia is the commonest precipitant of acute respiratory distress syndrome (ARDS) and clinicians should be mindful that the evidence-base surrounding ARDS will, in large part, apply to severe pneumonia. The causative organisms which lead to pneumonia vary depending on the site of acquisition (community or hospital-acquired), the immune status of the patient and the presence of intercurrent medications including antibiotics. Current standard microbiological testing is seldom able to give a rapid answer as to which microorganisms are present and causing infection. Therefore, empirical therapy guided by a knowledge of local microbial flora and resistance patterns is the recommended course of action. This approach risks the over-treatment of pneumonia with unnecessarily broad-spectrum agents which bring with them the problems of antibiotic-associated harm. Novel rapid diagnostic tests aimed at both the pathogen and the host response hold promise in the rationalisation and appropriate targeting of antimicrobial therapy. At present neither scoring systems nor diagnostic tests are able to accurately risk stratify a patient’s need for intensive care admission. Beyond antibiotic therapy, a number of adjuvant therapies have been trialled in pneumonia although none have yet made it into widespread clinical use. Corticosteroids are recommended in some cases of community-acquired pneumonia, but their role in the patient with severe community-acquired pneumonia in ICU remains uncertain whilst they are a risk factor for the development of hospital and ventilator-acquired pneumonia. Immuno-stimulation has not yet translated from small scale clinical trials into clinical use. Supportive management includes lung protective ventilation, and those interventions proven to improve outcomes in ARDS. This review will give an overview of the epidemiology of severe pneumonia, the microbiological causes and diagnostic strategies. It will then turn to management, including antimicrobial therapy, role of adjuvant therapies, respiratory support and prevention of complications

Evolution: like any other science it is predictable

Evolutionary biology rejoices in the diversity of life, but this comes at a cost: other than working in the common framework of neo-Darwinian evolution, specialists in, for example, diatoms and mammals have little to say to each other. Accordingly, their research tends to track the particularities and peculiarities of a given group and seldom enquires whether there are any wider or deeper sets of explanations. Here, I present evidence in support of the heterodox idea that evolution might look to a general theory that does more than serve as a tautology (‘evolution explains evolution’). Specifically, I argue that far from its myriad of products being fortuitous and accidental, evolution is remarkably predictable. Thus, I urge a move away from the continuing obsession with Darwinian mechanisms, which are entirely uncontroversial. Rather, I emphasize why we should seek explanations for ubiquitous evolutionary convergence, as well as the emergence of complex integrated systems. At present, evolutionary theory seems to be akin to nineteenth-century physics, blissfully unaware of the imminent arrival of quantum mechanics and general relativity. Physics had its Newton, biology its Darwin: evolutionary biology now awaits its Einstein

A primitive fish from the Cambrian of North America

Knowledge of the early evolution of fish largely depends on soft-bodied material from the Lower (Series 2) Cambrian period of South China. Owing to the rarity of some of these forms and a general lack of comparative material from other deposits, interpretations of various features remain controversial, as do their wider relationships amongst post-Cambrian early un-skeletonized jawless vertebrates. Here we redescribe Metaspriggina on the basis of new material from the Burgess Shale and exceptionally preserved material collected near Marble Canyon, British Columbia, and three other Cambrian Burgess Shale-type deposits from Laurentia. This primitive fish displays unambiguous vertebrate features: a notochord, a pair of prominent camera-type eyes, paired nasal sacs, possible cranium and arcualia, W-shaped myomeres, and a post-anal tail. A striking feature is the branchial area with an array of bipartite bars. Apart from the anterior-most bar, which appears to be slightly thicker, each is associated with externally located gills, possibly housed in pouches. Phylogenetic analysis places Metaspriggina as a basal vertebrate, apparently close to the Chengjiang taxa Haikouichthys and Myllokunmingia, demonstrating also that this primitive group of fish was cosmopolitan during Lower–Middle Cambrian times (Series 2–3). However, the arrangement of the branchial region in Metaspriggina has wider implications for reconstructing the morphology of the primitive vertebrate. Each bipartite bar is identified as being respectively equivalent to an epibranchial and ceratobranchial. This configuration suggests that a bipartite arrangement is primitive and reinforces the view that the branchial basket of lampreys is probably derived. Other features of Metaspriggina, including the external position of the gills and possible absence of a gill opposite the more robust anterior-most bar, are characteristic of gnathostomes and so may be primitive within vertebrates

The earliest annelids: Lower Cambrian polychaetes from the Sirius Passet Lagerstätte, Peary Land, North Greenland

Apart from the Phyllopod Bed of the Burgess Shale (Middle Cambrian) polychaete annelids are practically unknown from any of the Cambrian Lagerstätten. This is surprising both because their diversity in the Burgess Shale is considerable, while to date the Chengjiang Lagerstätte which is equally impressive in terms of faunal diversity has no reliable records of any annelids. Here we describe, on the basis of about 40 specimens, Phragmochaeta canicularis gen. et sp. nov. from the Lower Cambrian Sirius Passet Lagerstätte of Peary Land, North Greenland. This makes it by far the oldest known polychaete, with a likely age of lower to middle Atdabanian, The body consists of approximately 20 segments, each bearing notochaetae and neurochaetae. The former appeared to have formed a felt-like covering on the dorsum, whilst the neurochaetae projected obliquely to the longitudinal axis. Apart from minor differences in chaetal size at either end there is no other tagmosis. Details of the head are obscure, and presence of palps, tentacles and eyes are conjectural. Jaws appear to have been absent. The gut was straight, and flanked by massive longitudinal musculature. P. canicularis was evidently benthic, propelling itself on the neurochaetae, with the dorsal neurochaetae conferring protection. Its stratigraphic position and generalized appearance are consistent with P. canicularis being primitive, but the phylogenetic relationships within the polychaetes remain problematic, principally because of paucity of relevant morphological information

Middle Cambrian priapulids and other soft-bodied fossils from Utah and Spain

22 p., 11 fig.http://paleo.ku.edu/contributions.htm

More soft-bodied animals and algae from the Middle Cambrian of Utah and British Columbia

48 p., 32 fig.http://paleo.ku.edu/contributions.htm