Translocation through the nuclear pore: Kaps pave the way

Transport through the nuclear pore complex (NPC), a keystone of the eukaryotic building plan, is known to involve a large channel and an abundance of phenylalanine–glycine (FG) protein domains serving as binding sites for soluble nuclear transport receptors and their cargo complexes. However, the conformation of the FG domains in vivo, their arrangement in relation to the transport channel and their function(s) in transport are still vividly debated. Here, we revisit a number of representative transport models—specifically Brownian affinity gating, selective phase gating, reversible FG domain collapse, and reduction of dimensionality (ROD)—in the light of new data obtained by optical single transporter recording, optical superresolution microscopy, artificial nanopores, and many other techniques. The analysis suggests that a properly adapted, simplified version of the ROD model accounts well for the available data. This has implications for nucleocytoplasmic transport in general.     

Follow the leader: LIM kinases pave the way for collective tumor cell invasion

Comment on: Scott RW, et al. J Cell Biol 2010; 191:169-85.     

A biological treasure metagenome: pave a way for big science

The trend of recent researches, in which synthetic biology and white technology through system approaches based on “Omics technology” are recognized as the ground of biotechnology, indicates the coming of the ‘metagenome era’ that accesses the genomes of all microbes aiming at the understanding and industrial application of the whole microbial resources. The remarkable advance of technologies for digging out and analyzing metagenome is enabling not only practical applications of metagenome but also system approaches on a mixed-genome level based on accumulated information. In this situation, the present review is purposed to introduce the trends and methods of research on metagenome and to examine big science led by related resources in the future.     

Protein folding in the cell: molecular chaperones pave the way

In vitro, many unfolded polypeptides are able to fold to the native state spontaneously, indicating that the amino acid sequence of a protein contains all the information necessary to specify its three-dimensional conformation. It had been assumed that protein folding in vivo also generally occurs in a spontaneous process. This view has changed only recently due to the discovery of a number of proteins, now commonly called 'molecular chaperones', which are essential for cellular protein folding and occur ubiquitously in eubacteria, archaebacteria and in eukaryotic cells.     

Mechanisms of asymmetric cell division: flies and worms pave the way

Asymmetric cell division is fundamental for generating diversity in multicellular organisms. The mechanisms that govern asymmetric cell division are increasingly well understood, owing notably to studies that were conducted in Drosophila melanogaster and Caenorhabditis elegans. Lessons learned from these two model organisms also apply to cells that divide asymmetrically in other metazoans, such as self-renewing stem cells in mammals.     

Therapeutic application of ultrasound: contrast-enhanced thrombolysis in acute ST-elevation myocardial infarction; the Sonolysis study

Contrast enhancement by microbubble infusion has proven its applicability in the field of diagnostic ultrasound. Recent studies also indicate a therapeutic effect of the combined use of ultrasound and microbubbles. Results from animal studies demonstrate that diagnostic ultrasound in combination with intravenous microbubbles can dissolve thrombi. So far, this effect has never been tested in patients with an acute ST-elevation myocardial infarction (STEMI). We recently launched a pilot study in acute STEMI patients to assess safety, feasibility and efficacy of the treatment in this patient group with transthoracic three-dimensional diagnostic ultrasound and intravenous microbubbles immediately after prehospital thrombolysis, but prior to primary percutaneous coronary intervention.     

Prospective observational cohort study of time saved by prehospital thrombolysis for ST elevation myocardial infarction delivered by paramedics

Objectives To evaluate a system of prehospital thrombolysis, delivered by paramedics, in meeting the national service framework''s targets for the management of acute myocardial infarction.Design Prospective observational cohort study comparing patients with suspected acute myocardial infarction considered for thrombolysis in the prehospital environment with patients treated in hospital.Setting The catchment area of a large teaching hospital, including urban and rural areas.Participants 201 patients presenting concurrently over a 12 month period who had changes to the electrocardiogram that were diagnostic of acute myocardial infarction or who received thrombolysis for suspected acute myocardial infarction.Main outcome measures Time from first medical contact to initiation of thrombolysis (call to needle time), number of patients given thrombolysis appropriately, and all cause mortality in hospital.Results The median call to needle time for patients treated before arriving in hospital (n=28) was 52 (95% confidence interval 41 to 62) minutes. Patients from similar rural areas who were treated in hospital (n=43) had a median time of 125 (104 to 140) minutes. This represents a median time saved of 73 minutes (P < 0.001). Sixty minutes after medical contact 64% of patients (18/28) treated before arrival in hospital had received thrombolysis; this compares with 4% of patients (2/43) in a cohort from similar areas. Median call to needle time for patients from urban areas (n=107) was 80 (78 to 93) minutes. Myocardial infarction was confirmed in 89% of patients (25/28) who had received prehospital thrombolysis; this compares with 92% (138/150) in the two groups of patients receiving thrombolysis in hospital.Conclusions Thrombolysis delivered by paramedics with support from the base hospital can meet the national targets for early thrombolysis. The system has been shown to work well and can be introduced without delay.     

Food web structure and interaction strength pave the way for vulnerability to extinction

This paper focuses on how food web structure and interactions among species affects the vulnerability, due to environmental variability, to extinction of species at different positions in model food webs. Vulnerability is here not measured by a traditional extinction threshold but is instead inspired by the IUCN criteria for endangered species: an observed rapid decline in population abundance. Using model webs influenced by stochasticity with zero autocorrelation, we investigate the ecological determinants of species vulnerability, i.e. the trophic interactions between species and food web structure and how these interact with the risk of sudden drops in abundance of species. We find that (i) producers fulfil the criterion of vulnerable species more frequently than other species, (ii) food web structure is related to vulnerability, and (iii) the vulnerability of species is greater when involved in a strong trophic interaction than when not. We note that our result on the relationship between extinction risk and trophic position of species contradict previous suggestions and argue that the main reason for the discrepancy probably is due to the fact that we study the vulnerability to environmental stochasticity and not extinction risk due to overexploitation, habitat destruction or interactions with introduced species. Thus, we suggest that the vulnerability of species to environmental stochasticity may be differently related to trophic position than the vulnerability of species to other factors. Earlier research on species extinctions has looked for intrinsic traits of species that correlate with increased vulnerability to extinction. However, to fully understand the extinction process we must also consider that species interactions may affect vulnerability and that not all extinctions are the result of long, gradual reductions in species abundances. Under environmental stochasticity (which importance frequently is assumed to increase as a result of climate change) and direct and indirect interactions with other species some extinctions may occur rapidly and apparently unexpectedly. To identify the first declines of population abundances that may escalate and lead to extinctions as early as possible, we need to recognize which species are at greatest risk of entering such dangerous routes and under what circumstances. This new perspective may contribute to our understanding of the processes leading to extinction of populations and eventually species. This is especially urgent in the light of the current biodiversity crisis where a large fraction of the world's biodiversity is threatened.     

Catastrophic floods may pave the way for increased genetic diversity in endemic artesian spring snail populations

The role of disturbance in the promotion of biological heterogeneity is widely recognised and occurs at a variety of ecological and evolutionary scales. However, within species, the impact of disturbances that decimate populations are neither predicted nor known to result in conditions that promote genetic diversity. Directly examining the population genetic consequences of catastrophic disturbances however, is rarely possible, as it requires both longitudinal genetic data sets and serendipitous timing. Our long-term study of the endemic aquatic invertebrates of the artesian spring ecosystem of arid central Australia has presented such an opportunity. Here we show a catastrophic flood event, which caused a near total population crash in an aquatic snail species (Fonscochlea accepta) endemic to this ecosystem, may have led to enhanced levels of within species genetic diversity. Analyses of individuals sampled and genotyped from the same springs sampled both pre (1988-1990) and post (1995, 2002-2006) a devastating flood event in 1992, revealed significantly higher allelic richness, reduced temporal population structuring and greater effective population sizes in nearly all post flood populations. Our results suggest that the response of individual species to disturbance and severe population bottlenecks is likely to be highly idiosyncratic and may depend on both their ecology (whether they are resilient or resistant to disturbance) and the stability of the environmental conditions (i.e. frequency and intensity of disturbances) in which they have evolved.     

Effect of "fast track" admission for acute myocardial infarction on delay to thrombolysis.

OBJECTIVE--To evaluate the impact of a fast track triage system for patients with acute myocardial infarction. DESIGN--Comparison of delays in admission to hospital and in receiving thrombolytic treatment before and after introducing fast track system with delays recorded in 1987-8. Patients fulfilling clinical and electrocardiographic criteria for myocardial infarction were selected for rapid access to the cardiac care team, bypassing evaluation by the medical registrar. SETTING--Major accident and emergency, cardiac and trauma centre. SUBJECTS--359 patients admitted to the cardiac care unit during 1 February to 31 July 1990 with suspected acute infarction. MAIN OUTCOME MEASURES--Accuracy of diagnosis and delay from arrival at hospital to thrombolytic treatment. RESULTS--248 of the 359 patients had myocardial infarction confirmed, of whom 127 received thrombolytic treatment. The fast track system correctly identified 79 out of 127 (62%) patients who subsequently required thrombolytic treatment. 95% (79/83) of patients treated with thrombolysis after fast track admission had the diagnosis confirmed by electrocardiography and enzyme analysis. The median delay from hospital admission to thrombolytic treatment fell from 93 minutes in 1987-8 to 49 minutes in fast track patients (p less than 0.001). Delay in admission to the cardiac care unit was reduced by 47% for fast tract patients (median 60 minutes in 1987-8 v 32 minutes in 1990, p less than 0.001) and by 25% for all patients (60 minutes v 45 minutes, p less than 0.001). CONCLUSION--This fast track system requires no additional staff or equipment, and it halves inhospital delay to thrombolytic treatment without affecting the accuracy of diagnosis among patients requiring thrombolysis.     

Short and long term prognosis of acute myocardial infarction since introduction of thrombolysis.

OBJECTIVE--To record prognosis and determinants of outcome in patients with acute myocardial infarction since thrombolysis was introduced. DESIGN--Observational study. SETTING--London district general hospital. PATIENTS--608 consecutive patients admitted to the coronary care unit with acute myocardial infarction between 1 January 1988 and 31 December 1991. MAIN OUTCOME MEASURE--All cause mortality, non-fatal ischaemic events (myocardial infarction, unstable angina), and revascularisation. RESULTS--Of the 608 patients, 89 (14.6%) died in hospital. 507 [corrected] patients were followed up after discharge from hospital. Mortality (95% confidence interval) at 30 days, one year, and three years was 16.0% (13.4% to 19.2%), 21.7% (18.6% to 25.2%), and 29.4% (25.3% to 33.9%) respectively. Event free survival (survival without a non-fatal ischaemic event) was 80.4% (77.0% to 83.4%) at 30 days, 66.8% (62.8% to 70.5%) at one year, and 56.1% (51.3% to 60.6%) at three years. Survival in patients treated with thrombolysis was considerably higher than in those not given thrombolysis (three year survival: 76.7% v 54.3%), although the incidence of non-fatal ischaemic events was the same in the two groups. Multivariate determinants of six month survival were left ventricular failure, treatment with thrombolysis and aspirin, smoking history, bundle branch block, and age. For patients who survived six months, age was the only factor related to long term survival. CONCLUSIONS--Although patients treated by thrombolysis had a relatively good prognosis, long term mortality and the incidence of non-fatal recurrent ischaemic events remained high. Effective strategies for the identification and treatment of high risk patients need to be reassessed.     

Quality improvement report: Safety and efficacy of nurse initiated thrombolysis in patients with acute myocardial infarction

ProblemDelay in starting thrombolytic treatment in patients arriving at hospital with chest pain who are diagnosed as having acute myocardial infarction.DesignAudit of “door to needle times” for patients presenting with chest pain and an electrocardiogram on admission that confirmed acute myocardial infarction. A one year period in each of three phases of development was studied.

Background and setting

The goal of the national service framework for coronary heart disease is that by April 2002, 75% of eligible patients should receive thrombolysis within 30 minutes of arriving at hospital. A district general hospital introduced a strategy to improve door to needle times. In phase 1 (1989-95), patients with suspected acute myocardial infarction, referred by general practitioners, were assessed in the coronary care unit; all other patients were seen first in the accident and emergency department. In phase 2 (1995-7), all patients with suspected acute myocardial infarction were transferred directly to a fast track area within the coronary care unit, where nurses assess patients and doctors started treatment.

Key measures for improvement

Median door to needle time in phase 1 of 45 minutes (range 5-300 minutes), with 38% of patients treated within 30 minutes. Median door to needle time in phase 2 of 40 minutes (range 5-180 minutes), with 47% treated within 30 minutes

Strategies for change

In phase 3 (1997-2001), all patients with suspected acute myocardial infarction were transferred directly to the fast track area and assessed by a “coronary care thrombolysis nurse.” If electrocardiography confirmed the diagnosis of acute myocardial infarction, the nurse could initiate thrombolytic therapy (subject to guidelines and exclusions determined by the consultant cardiologists).

Effects of change

Median door to needle time in phase 3 of 15 minutes (range 5-70 minutes), with 80% of patients treated within 30 minutes. Systematic clinical review showed no cases in which a nurse initiated inappropriate thrombolysis.

Lessons learnt

Thrombolysis started by nurses is safe and effective in patients with acute myocardial infarction. It may provide a way by which the national service framework''s targets for door to needle times can be achieved.     

Evidence-based management of acute myocardial infarction in the elderly--current perspectives

Cardiovascular disease accounts for significant morbidity and mortality in the elderly. Despite several, large cardiovascular clinical trials, data to guide therapy in this growing population subset are relatively limited. This review focuses on treatment approaches and recommendations for the management of elderly patients with acute myocardial infarction (MI) obtained from subgroup analyses from major clinical trials.Treatment options for acute MI in the elderly have changed dramatically since the 1990s. Reperfusion therapy by primary percutaneous coronary intervention has superseded the use of thrombolytic therapy for the treatment of acute ST-elevation myocardial infarction (STEMI). Clinical trial data have demonstrated that even transferring patients to facilities that have primary angioplasty capabilities is better than thrombolytic therapy, if the anticipated transfer time is of acceptable duration. Additionally, adjunctive use of the intravenous glycoprotein (GP) receptor antagonist, abciximab, during primary angioplasty affords a reduction in the composite primary end point of death, reinfarction, and target vessel revascularization, with much of the benefit derived from the latter. Thrombolytic therapy, barring any contraindication, must be used when mechanical revascularization is not available; however, the risk for complications in the elderly is higher, especially for those 75 years and older. Studies investigating the use of thrombolytics plus GP receptor antagonists with and without percutaneous coronary intervention show questionable benefit in the elderly.