Advanced schemes for underdense plasma photocathode wakefield accelerators: pathways towards ultrahigh brightness electron beams.

The 'Trojan Horse' underdense plasma photocathode scheme applied to electron beam-driven plasma wakefield acceleration has opened up a path which promises high controllability and tunability and to reach extremely good quality as regards emittance and five-dimensional beam brightness. This combination has the potential to improve the state-of-the-art in accelerator technology significantly. In this paper, we review the basic concepts of the Trojan Horse scheme and present advanced methods for tailoring both the injector laser pulses and the witness electron bunches and combine them with the Trojan Horse scheme. These new approaches will further enhance the beam qualities, such as transverse emittance and longitudinal energy spread, and may allow, for the first time, to produce ultrahigh six-dimensional brightness electron bunches, which is a necessary requirement for driving advanced radiation sources. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.

Single-stage plasma-based correlated energy spread compensation for ultrahigh 6D brightness electron beams.

Plasma photocathode wakefield acceleration combines energy gains of tens of GeV m-1 with generation of ultralow emittance electron bunches, and opens a path towards 5D-brightness orders of magnitude larger than state-of-the-art. This holds great promise for compact accelerator building blocks and advanced light sources. However, an intrinsic by-product of the enormous electric field gradients inherent to plasma accelerators is substantial correlated energy spread-an obstacle for key applications such as free-electron-lasers. Here we show that by releasing an additional tailored escort electron beam at a later phase of the acceleration, when the witness bunch is relativistically stable, the plasma wave can be locally overloaded without compromising the witness bunch normalized emittance. This reverses the effective accelerating gradient, and counter-rotates the accumulated negative longitudinal phase space chirp of the witness bunch. Thereby, the energy spread is reduced by an order of magnitude, thus enabling the production of ultrahigh 6D-brightness beams.

Laser-plasma-based Space Radiation Reproduction in the Laboratory.

Space radiation is a great danger to electronics and astronauts onboard space vessels. The spectral flux of space electrons, protons and ions for example in the radiation belts is inherently broadband, but this is a feature hard to mimic with conventional radiation sources. Using laser-plasma-accelerators, we reproduced relativistic, broadband radiation belt flux in the laboratory, and used this man-made space radiation to test the radiation hardness of space electronics. Such close mimicking of space radiation in the lab builds on the inherent ability of laser-plasma-accelerators to directly produce broadband Maxwellian-type particle flux, akin to conditions in space. In combination with the established sources, utilisation of the growing number of ever more potent laser-plasma-accelerator facilities worldwide as complementary space radiation sources can help alleviate the shortage of available beamtime and may allow for development of advanced test procedures, paving the way towards higher reliability of space missions.

Venous thromboembolism--prophylactic and therapeutic practice guideline.

BACKGROUND: Pharmacological prophylactic anticoagulation in many countries, including South Africa, is under-prescribed, which unfortunately results in unacceptable morbidity and mortality in a substantial number of patients. METHOD: The Southern African Society of Thrombosis and Haemostasis reviewed the available literature as well as guidelines from other societies. Specialties represented on the committees included anaesthetics, cardiology, clinical haematology, critical care, gynaecology, haematopathology, internal medicine, neurology, orthopaedic surgery, pulmonology and vascular surgery. A draft document was produced, which was revised by consensus agreement. To avoid local bias, the guidelines were adjudicated by recognised independent international external experts. RESULTS AND CONCLUSION. A concise, practical guideline for thrombo-prophylaxis and treatment in medical and surgical patients has been produced for South African conditions. These guidelines will hopefully lead to improved anticoagulation practice in this country, which we believe will directly benefit patient outcomes.

Cytokines, matrix metalloproteases, angiogenic and growth factors in tears of normal subjects and vernal keratoconjunctivitis patients.

BACKGROUND: To detect the presence of multiple mediators and growth factors in tears of vernal keratoconjunctivitis (VKC) patients with active disease using stationary phase antibody arrays. METHODS: Tears were collected from 12 normal subjects (CT) and 24 active VKC patients. Tears were centrifuged and successively probed using three microwell plate arrays specific for: (i) cytokines: interleukin (IL)-2, IL-4, IL-5, IL-8, IL-10, IL-12, IL-13, interferon-gamma and tumour necrosis factor-alpha; (ii) growth factors: basic fibroblast growth factor (bFGF), platelet-derived growth factor, thrombopoietin, angiopoietin-2, vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), keratocyte growth factor, tissue inhibitor of metalloprotease (TIMP)-1 and heparin-binding epithelial growth factor (HB-EGF) and (iii) matrix metalloprotease (MMP)-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, MMP-13, TIMP-1 and TIMP-2. RESULTS: Interleukin-8 signals were detected in all CT and highly detected in all VKC samples. The Th2-type cytokines, IL-4, IL-5 and IL-10 were detected only in tears of VKC patients. Signals for bFGF, HB-EGF, VEGF and HGF were detected in 41-87% of VKC samples and in few CT samples. Only TIMP-1 and TIMP-2 were found in all normal and patient tear samples, whereas MMP-1, MMP-2, MMP-3, MMP-9 and MMP-10 were highly present in all VKC samples. CONCLUSIONS: Stationary phase antibody array methodology was useful for the screening of various cytokines, growth factors and MMPs in tears. These analyses identified in tears of VKC patients previously unreported factors including MMP-3 and MMP-10 and multiple proteases, growth factors and cytokines, which may all play an important role in the pathogenesis of conjunctival inflammation.

Thought suppression, intelligence, and working memory capacity.

The importance of individual differences in intelligence and working memory capacity in predicting the ability to intentionally suppress thoughts was investigated. Sixty participants completed a thought suppression task, and measures of working memory capacity (OSPAN), fluid intelligence (Raven's Matrices), and crystallised intelligence (the National Adult Reading Test). As predicted, the results indicated that more effective thought suppression was independently related to higher working memory capacity and greater fluid intelligence, but was unrelated to crystallised intelligence. The findings have theoretical implications for understanding the mechanisms underlying a failure to inhibit unwanted intrusions and clinical implications for disorders involving high levels of intrusive thoughts and memories.

Effect of external ocular surgery and mode of post-operative care on plasminogen, plasmin, angiostatins and alpha(2)-macroglobulin in tears.

PURPOSE: To determine whether corneal surgery and the mode of post-surgical treatment influence the distribution of plasminogen, plasmin, angiostatins and alpha(2)-macrogobulin in tear fluid. METHODS: Subjects underwent either photorefractive keratectomy (PRK), insertion of intra-stromal corneal rings (ICR), or cataract ablation followed by insertion of an intra-ocular lens (IOL). Post-surgical treatment consisted of prophylactic use of antibiotic and anti-inflammatory agents followed either by patching for 24 hours, or covering the wounded cornea with a bandage soft contact lens. Open eye tear fluid (OTF) was obtained prior to surgery and 10 minutes after patch removal or 24 hours after surgery and thereafter with the bandage lens still in place. After centrifugation, supernatants and controls were western blot analyzed using a protocol designed to allow the simultaneous semi- quantitative detection of alpha2-macroglobulin, plasminogen, plasmin, angiostatins and interleukin-8 (IL-8). RESULTS: No obvious differences were apparent in OTF recovered from contralateral control eyes compared to the surgical eyes in individuals who underwent PRK surgery and whose eyes were covered with a bandage contact lens. In contrast, OTF samples recovered 10 minutes after patch removal from all individuals contained elevated levels of alpha2-macroglobulin and a diverse mixture of elevated levels of plasminogen/plasmin, angiostatins and possibly a plasmin-a1-antiplasmin complex. All of these changes were seen, albeit to a lesser extent, in the patched control OTF samples. IL-8 could not be detected in any sample. The composition of the tear film returned to near normal on subsequent sampling 24 hours after patch removal. CONCLUSIONS: Patching results in a marked increase in the concentration of various proteins which could modulate inflammation and wound healing.

Host-defense mechanism of the ocular surfaces.

The defense of the ocular surfaces presents an unique challenge in that not only must integrity be maintained against microbial, inflammatory and physical assault, but it must be done while minimizing the risk of loss of corneal transparency. This puts severe limitations on the degree to which scarring or neovascularization can occur in the cornea secondary to any infectious, inflammatory, immunological or wound healing process. Moreover, this defense system must be equally effective under two extremes of conditions: those found in the open eye and the closed eye environments. It is our contention that these constraints have resulted in the evolution of a highly complex fail-safe defense system that utilizes distinctly different strategies in open and closed eye conditions. The extraordinary effectiveness of this system is evidenced by the fact that despite continued exposure to a microbe rich environment, the external ocular surfaces maintain a very low microbial titer and are highly resistant to breaching by all but a few pathogens. It is the intent of this review to provide a working model of this defense system as it operates under both open and closed eye conditions, to provide evidence in support of this model as well as highlight some of the many areas of uncertainty.

Towards a closed eye model of the pre-ocular tear layer.

Although the tear film has been extensively studied as it exists in the open eye state, until recently very little was known as to what happens to the tear film on eye closure. Recent studies have shown that eye closure results in a profound change in the composition, origins, turnover and physiological functions of the tear film. These changes include a shift from an inducible, neurologically controlled, lacrimal secretion containing among other proteins primarily lysozyme, lactoferrin and tear specific lipocalin, to a much slower, constitutive-type of secretion, composed almost exclusively of sIgA. This change is accompanied by the build-up of sialoglycoproteins of epithelial and goblet cell origin, the build-up and activation of complement and the build-up of serum proteins. In addition, various cytokines and proinflammatory mediators accumulate, including some which are potent inducers of angiogenesis and leukochemotaxis. The closed eye also exhibits the recruitment and activation of massive numbers of PMN cells. This results in a stagnant, closed eye layer, which is extremely rich in reactive complement products, PMN cell proteases including protease-3, elastase, capthepsin G, MMP-9 and urokinase. We have postulated that this shift represents a fundamental change in host-defense strategies from a passive-barrier defense to an active immune, inflammatory, phagocyte-mediated process and that this shift is necessitated in order to protect the cornea from entrapped microorganisms. Studies have shown that autologous cell damage is avoided in closed eye tear fluid, by the accumulation of several modulators of complement activation, which shift activation towards opsonization of entrapped microorganisms and the build-up of a wide array of antiproteases. Some of the latter are likely to arise from the ocular surface tissues. Corneal neovascularization may be avoided in part by the build-up of alpha2-macroglobulin and the conversion of plasminogen to angiostatin. It is highly probable that other bioactive protein fragments are produced in the closed eye, which contribute to homeostasis. Areas of future study are indicated.

The Berkeley Drosophila Genome Project gene disruption project: Single P-element insertions mutating 25% of vital Drosophila genes.

A fundamental goal of genetics and functional genomics is to identify and mutate every gene in model organisms such as Drosophila melanogaster. The Berkeley Drosophila Genome Project (BDGP) gene disruption project generates single P-element insertion strains that each mutate unique genomic open reading frames. Such strains strongly facilitate further genetic and molecular studies of the disrupted loci, but it has remained unclear if P elements can be used to mutate all Drosophila genes. We now report that the primary collection has grown to contain 1045 strains that disrupt more than 25% of the estimated 3600 Drosophila genes that are essential for adult viability. Of these P insertions, 67% have been verified by genetic tests to cause the associated recessive mutant phenotypes, and the validity of most of the remaining lines is predicted on statistical grounds. Sequences flanking >920 insertions have been determined to exactly position them in the genome and to identify 376 potentially affected transcripts from collections of EST sequences. Strains in the BDGP collection are available from the Bloomington Stock Center and have already assisted the research community in characterizing >250 Drosophila genes. The likely identity of 131 additional genes in the collection is reported here. Our results show that Drosophila genes have a wide range of sensitivity to inactivation by P elements, and provide a rationale for greatly expanding the BDGP primary collection based entirely on insertion site sequencing. We predict that this approach can bring >85% of all Drosophila open reading frames under experimental control.

Diurnal variations in angiostatin in human tear fluid: a possible role in prevention of corneal neovascularization.

PURPOSE: Although overnight eye closure is known to result in hypoxia and release of potent angiogenic factors, even prolonged eye closure does not result in corneal neovascularization. This suggests that the closed eye tear film may contain factors that can impede neovascularization. Closed eye tear fluid is known to contain proteases capable of converting plasminogen/plasmin to angiostatin and other angiostatin-like A-chain fragments which are potent inhibitors of angiogenesis. This study was designed to characterize open and closed eye tear fluid for the presence of these entities. METHODS: Open and closed eye tears were collected by microcapillaries from normal individuals. Tears were centrifuged and the supernatants analyzed by SDS-PAGE and western blotting. Membranes were probed with antibodies specific for the A-chain of plasmin and plasminogen and with antibodies specific for conformational domains on the smaller N terminal kringles 1-->4 and kringles 1-->3 fragments which are known angiogenesis inhibitors. Supernatants were also analyzed after fractionation by HPLC and binding to lysine sepharose 4B. The isolated fragments were identified based on size, lysine-binding capabilities, antigenic properties and by comparison with standards. RESULTS: Open eye tear fluid from all normal individuals contained low levels of plasminogen, but no detectable antigens consistent with free A-chain or angiostatins. Tears collected after overnight eye closure contained significant amounts of plasminogen, A-chain antigen and various A-chain fragments including kringles 1-->4 and kringles 1-->3 and most likely free kringle 5, all known to have anti-angiogenesis properties. These were often present in concentrations likely to be physiologically significant. In samples collected from an atopic subject, the concentration of angiostatins in CTF increased markedly during active phases of the disease reaching levels of several ng/microl. In these instances and in similar samples obtained from other atopic individuals experiencing active reactions, angiostatin was often detectable in basal-type tear fluid. CONCLUSION: A-chain fragments, which can inhibit angiogenesis, are often present at physiologically significant levels in human tear fluid collected after overnight eye closure. These fragments may play a role in preventing neovascularization in the hypoxic closed eye environment and may well be up regulated during inflammatory reactions.

Identification, origins and the diurnal role of the principal serine protease inhibitors in human tear fluid.

PURPOSE: Previous work identified polymorphonuclear leukocyte (PMN) elastase as the major caseinolytic entity in tears collected after overnight eye closure. This study was designed to identify the principal serine protease inhibitors (serpins) in tears and to determine their function in the regulation of PMN cell proteases on eye closure. METHODS: Reflex and closed eye tear samples were collected by microcapillary tube and centrifuged. After reflex and closed eye supernatants (R and C) were fractionated by HPLC, samples were subjected to casein zymography and reverse zymography. Western blots were utilized to screen tears and HPLC fractions for elastase, cathepsin G and proteinase-3 and to obtain semi-quantitative data on alpha 1-protease inhibitor (alp1), alpha 1-antichymotrypsin (alpha 1-Achy), secretory leukocyte protease inhibitor (SLPI), elafin and alpha 2-macroglobulin (alpha 2-M) as well as associated complexes and products. To confirm specificity of reactivity, samples were immunoprecipitated for a given protease or serpin and screened for the coprecipitation of interacting species. RESULTS: Although R fluid contains no caseinolytic activity, it contains low levels of serpin-like activity principally in the form of SLPI (5-10 ng/microliter). Lesser amounts of alpha 2-M, alpha 1-Achy and alp1 (approximately < 1-3 ng/microliter) are also evident. C fluid is associated with very high levels of PMN cell proteases along with a approximately 5-20-fold increase in the concentrations of all of the above inhibitors. Trace levels of elafin were also detected. The concentrations of rapid reacting inhibitors exceeded that of proteases, with SLPI, alpha 1-Achy and alp1 being the principal functional entities. In atypical samples, complexes of elastase and alpha 2-M were also encountered. CONCLUSIONS: SLPI, a known antimicrobial agent and an elastase and cathepsin G inhibitor, is the principal serpin in R fluid. C fluid is associated with a marked increase in the concentrations of an array of rapid reacting serpins capable of inhibiting all known PMN cell serine proteases. In the normal closed eye, the concentration of rapid reacting inhibitors always exceeds that of proteases with C fluid also containing a functional reserve of the slow reacting inhibitor alpha 2-M.

Lactation-associated and prolactin-responsive changes in protein synthesis in mouse mammary cells.

Lactational function in the mammary epithelial cell is subject to complex regulation, most probably involving multiple extracellular and intracellular proteins that act at any of a number of levels. Although some of these proteins have been identified it is likely that additional controllers of lactation exist, but have yet to be discovered. In an effort to identify such proteins, a search was made for non-milk lactation-associated or prolactin-responsive proteins in primary mouse mammary epithelial cells and the mouse mammary epithelial cell line, COMMA-D using two-dimensional electrophoresis on large-format gels. These analyses revealed 12 proteins whose rate of synthesis was dependent on lactation state or on response to prolactin. Two of these (p77 and p63) were lactation-associated in primary cells and prolactin-responsive in COMMA-D cells. These two proteins were identified by amino acid sequencing as glucose-regulated protein 78 (GRP78) and protein disulphide isomerase (PDI). The localization of these proteins in the endoplasmic reticulum and their presence in other secretory cell types and tissues suggests that they have a function in the processing or secretion of milk proteins.

The relation of planum temporale asymmetry and morphology of the corpus callosum to handedness, gender, and dyslexia: a review of the evidence.

Asymmetry of the planum temporale in relation to handedness, gender, and dyslexia is reviewed. The frequency of rightward asymmetry is rather higher than are estimates of the proportion of right hemisphere speech representation in the general population. Conversely, the frequency of leftward asymmetry is lower than the proportion of the population with left hemisphere speech. Neuro-anatomic asymmetry may relate more to handedness than to language lateralization. There are suggestions that neuroanatomic asymmetry is reduced in females compared to males but the data are inconclusive. Reports concerning handedness and gender differences in callosal structure are conflicting but, as with planum asymmetry, any effect of handedness is as likely to relate to degree as to direction of handedness. It has been reported that the plana are more often symmetrical in size or larger on the right side among dyslexics than controls but this has not always been found. However, greater frequency of atypical (a)symmetry of the planum in dyslexia would be consistent with the absence of a factor which, when present, biases the distribution of planum asymmetry toward the left (and handedness towards the right) as hypothesized by Annett (1985). Studies of the size of the corpus callosum in dyslexia have produced conflicting findings.

Polymorphonuclear leukocyte cells and elastase in tears.

PURPOSE: To characterize the effects that mode of sampling and overnight eye closure have on the nature of caseinolytic activity recovered in tear fluid. METHODS: Reflex, open and closed (R, O and C) eye tear fluids were collected by microcapillary tubes or from the inferior formix by Schirmer strip. Microcapillary collected samples were centrifuged and recovered cells cytochemically characterized and probed by immunofluorescence microscopy, or alternatively extracted in acidic PBS. Tear supernatants, pellets and Schirmer strip extracts were subjected to casein zymography or SDS-PAGE and immunoprobed for plasmin/plasminogen. To identify caseinolytic activity, samples were immunoprecipitated with antibodies to plasmin/plasminogen or to elastase, and the immunoprecipitated materials were subjected to zymographic analysis. RESULTS: Immunoblot assays revealed R and O samples contained low levels of plasminogen (approximately 1.1 micrograms/ml) and only trace levels of plasmin (< 0.1 ng/ml). Insufficient levels of caseinolytic activity were present to allow zymographic detection. Cytochemical analysis revealed that R and O pellets consisted almost exclusively of desquamated epithelium. Immunoblot analysis revealed that C fluid was associated with an increase in plasminogen and its partial conversion to plasmin (approximately 3.2 ng/ microliter), high molecular weight covalent complexes and degradative products. Zymographic analysis disclosed much greater caseinolytic activity than could be attributed to plasmin or its cleavage products. This consisted primarily of three bands (30-26 kDa) which were identified as polymorphonuclear leukocyte (PMN) cell elastase based on size and antigenicity. This is derived from PMNs recovered from the C pellet. Elastase could also be recovered from Schirmer strips from 90% of donors, provided that the strips were extracted in sample loading buffer. The activity was restricted to the portion of the strip that had been in contact with the ocular tissue. CONCLUSIONS: The main source of caseinolytic activity in C fluid is elastase. This arises from PMNs that undergo recruitment, activation and degranulation in the C environment. In contrast, the elastase recovered in Schirmer strip extracts is derived from intact PMNs that adhere to the strip during sample collection. This would suggest that PMN cells undergo a low level of recruitment into the open eye environment.

Diurnal variations in tear glycoproteins: evidence for an epithelial origin for the major non-reducible > or = 450 kDa sialoglycoprotein(s).

PURPOSE: To characterize the nature and origin of changes in tear glycoproteins accompanying eye closure. METHODS: Reflex (R) and overnight closed (C) eye tears collected by capillary tubes were centrifuged with the resulting R pellets (primarily desquamated epithelial cells) and C pellets (primarily PMN and some epithelial cells) extracted in acidic PBS. Extracts and supernatants were separated by size-exclusion HPLC and/or SDS-PAGE. Gels were stained or blotted and immune- or lectin-probed. An HPLC glycoprotein fraction of > or = 450 kDa isolated from all four sources was characterized before and after partial deglycosylation, using antibodies specific to known mucin and carbohydrate epitopes. Immunofluorescence microscopy was carried out on human conjunctiva, using as probe a MAb to salivary mucin specific for a sialyl Lea epitope, which was found to cross-react specifically with the major non-reducible high molecular weight sialoglycoproteins (SGs) in tears. These SGs were immunoprecipitated and blot-probed along with tissue extracts. RESULTS: R fluid contained minor amounts of numerous glycoproteins, including probably several of inducible lacrimal secretory origin. Results confirmed sIgA as the principal source of the intense reducible glycoprotein bands common to C fluid. Smaller amounts of free secretory component and serum glycoproteins were also visualized. The HPLC fraction (> or = 450 kDa) consisted of four major non-reducible glycoproteins. In R fluid, this fraction (< 1% total protein) consisted primarily of two entities: a 450-500 kDa SG and a larger asialoglycoprotein. The SG accounts for as much as 85% of the total protein in the R pellet extract. C fluid was associated with a selective increase in SGs and a shift in distribution to two SGs > 500 kDa. All SGs exhibited a common antigenicity reacting specifically with the MAb for the sialyl Lea epitope. SGs indistinguishable in size and antigenicity were recovered in epithelial extracts. Immunofluorescence microscopy revealed that reactivity was localized to the epithelial plasma membrane, increasing in intensity from basal to apical cells. Although these SGs exhibited some properties in common with MUC1, immunological and other data suggest a unique SG. CONCLUSIONS: Tear glycoproteins are derived from four principal sources. In R fluid, an inducible lacrimal secretion predominates. In C fluid, a constitutive sIgA secretion predominates, augmented by a serum exudate and SGs derived at least in part from the epithelium. In R fluid and pellet extracts, the SGs consist primarily of a 450-500 kDa species that is most probably derived from the plasma membrane. Larger antigenically related SGs are prevalent in C fluid.

Howzat?! Why is there an over-representation of left-handed bowlers in professional cricket in the UK?

An analysis of the bowling action of professional cricketers in the UK for four seasons between 1981 and 1991 shows there to be a significant association between handedness and bowling style (seam or spin bowling). Furthermore, there is a significantly higher number of left-handed spin bowlers than would be predicted from the general population, but not left-handed seam bowlers. As the technical differences between left- and right-handed orthodox spin bowlers are much greater than those between left- and right-handed seam bowlers, these data are consistent with the view that the over-representation of left-handed bowlers reported by Wood and Aggleton (1989) is due to strategic rather than neuropsychological factors.