Three-dimensional structure determination from a single view

The ability to determine the structure of matter in three dimensions has profoundly advanced our understanding of nature. Traditionally, the most widely used schemes for 3D structure determination of an object are implemented by acquiring multiple measurements over various sample orientations, as in the case of crystallography and tomography (1,2), or by scanning a series of thin sections through the sample, as in confocal microscopy (3). Here we present a 3D imaging modality, termed ankylography (derived from the Greek words ankylos meaning 'curved' and graphein meaning 'writing'), which enables complete 3D structure determination from a single exposure using a monochromatic incident beam. We demonstrate that when the diffraction pattern of a finite object is sampled at a sufficiently fine scale on the Ewald sphere, the 3D structure of the object is determined by the 2D spherical pattern. We confirm the theoretical analysis by performing 3D numerical reconstructions of a sodium silicate glass structure at 2 Angstrom resolution and a single poliovirus at 2 - 3 nm resolution from 2D spherical diffraction patterns alone. Using diffraction data from a soft X-ray laser, we demonstrate that ankylography is experimentally feasible by obtaining a 3D image of a test object from a single 2D diffraction pattern. This approach of obtaining complete 3D structure information from a single view is anticipated to find broad applications in the physical and life sciences. As X-ray free electron lasers (X-FEL) and other coherent X-ray sources are under rapid development worldwide, ankylography potentially opens a door to determining the 3D structure of a biological specimen in a single pulse and allowing for time-resolved 3D structure determination of disordered materials.Comment: 30 page

The Role of Bile in the Regulation of Exocrine Pancreatic Secretion

As early as 1926 Mellanby (1) was able to show that introduction of bile into the duodenum of anesthetized cats produces a copious flow of pancreatic juice. In conscious dogs, Ivy & Lueth (2) reported, bile is only a weak stimulant of pancreatic secretion. Diversion of bile from the duodenum, however, did not influence pancreatic volume secretion stimulated by a meal (3,4). Moreover, Thomas & Crider (5) observed that bile not only failed to stimulate the secretion of pancreatic juice but also abolished the pancreatic response to intraduodenally administered peptone or soap

Pitfalls in TCR gene clonality testing: teaching cases

Clonality testing in T-lymphoproliferations has technically become relatively easy to perform in routine laboratories using standardized multiplex polymerase chain reaction protocols for T-cell receptor (TCR) gene analysis as developed by the BIOMED-2 Concerted Action BMH4-CT98-3936. Expertise with clonality diagnostics and knowledge about the biology of TCR gene recombination are essential for correct interpretation of TCR clonality data. Several immunobiological and technical pitfalls that should be taken into account to avoid misinterpretation of data are addressed in this report. Furthermore, we discuss the need to integrate the molecular data with those from immunohistology, and preferably also flow cytometric immunophenotyping, for appropriate interpretation. Such an interactive, multidisciplinary diagnostic model guarantees integration of available data to reach the most reliable diagnosis

Can Simply Answering Research Questions Change Behaviour? Systematic Review and Meta Analyses of Brief Alcohol Intervention Trials

BACKGROUND: Participant reports of their own behaviour are critical for the provision and evaluation of behavioural interventions. Recent developments in brief alcohol intervention trials provide an opportunity to evaluate longstanding concerns that answering questions on behaviour as part of research assessments may inadvertently influence it and produce bias. The study objective was to evaluate the size and nature of effects observed in randomized manipulations of the effects of answering questions on drinking behaviour in brief intervention trials. METHODOLOGY/PRINCIPAL FINDINGS: Multiple methods were used to identify primary studies. Between-group differences in total weekly alcohol consumption, quantity per drinking day and AUDIT scores were evaluated in random effects meta-analyses. Ten trials were included in this review, of which two did not provide findings for quantitative study, in which three outcomes were evaluated. Between-group differences were of the magnitude of 13.7 (-0.17 to 27.6) grams of alcohol per week (approximately 1.5 U.K. units or 1 standard U.S. drink) and 1 point (0.1 to 1.9) in AUDIT score. There was no difference in quantity per drinking day. CONCLUSIONS/SIGNIFICANCE: Answering questions on drinking in brief intervention trials appears to alter subsequent self-reported behaviour. This potentially generates bias by exposing non-intervention control groups to an integral component of the intervention. The effects of brief alcohol interventions may thus have been consistently under-estimated. These findings are relevant to evaluations of any interventions to alter behaviours which involve participant self-report

Landscape Movements of Migratory Birds and Bats Reveal an Expanded Scale of Stopover

Many species of birds and bats undertake seasonal migrations between breeding and over-wintering sites. En-route, migrants alternate periods of flight with time spent at stopover – the time and space where individuals rest and refuel for subsequent flights. We assessed the spatial scale of movements made by migrants during stopover by using an array of automated telemetry receivers with multiple antennae to track the daily location of individuals over a geographic area ∼20×40 km. We tracked the movements of 322 individuals of seven migratory vertebrate species (5 passerines, 1 owl and 1 bat) during spring and fall migratory stopover on and adjacent to a large lake peninsula. Our results show that many individuals leaving their capture site relocate within the same landscape at some point during stopover, moving as much as 30 km distant from their site of initial capture. We show that many apparent nocturnal departures from stopover sites are not a resumption of migration in the strictest sense, but are instead relocations that represent continued stopover at a broader spatial scale

Childhood rhabdomyosarcoma metastatic to bone marrow presenting with disseminated intravascular coagulation and acute tumour lysis syndrome: review of the literature apropos of two cases

The paper presents diagnostic and therapeutic difficulties in two adolescents with widespread rhabdomyosarcoma (RMS) presenting with severe haemorrhages resulting from disseminated intravascular coagulation (DIC) and with laboratory features of acute tumour lysis syndrome (ATLS). Other published cases of childhood RMS with DIC at admission have been listed and reviewed. It has been concluded that the clinical picture of a widespread RMS in children may resemble acute hematologic malignancy and pose a big diagnostic problem. That is why the presence of small blue round cells morphologically similar to lymphoblasts and/or myeloblasts in bone marrow (BM), lacking hematopoietic makers, should prompt the pathologist to consider possible diagnosis of RMS. Inclusion of desmin, MyoD1 and myogenin Myf4 to the immunohistochemical panel is obligatory in such cases. When the representative histopathological tumour specimens are difficult to obtain, the flow cytometric immunophenotyping of BM metastases could help the standard morphological/immunohistological diagnostic procedures and advance the diagnosis. Recently, the flow cytometric CD45− CD56+ immunophenotype together with Myf4 transcript has been assigned to RMS cells infiltrating BM. In children with disseminated RMS complicated with DIC rapid polychemotherapy aimed at diminishing the malignancy-triggered procoagulant activity should be initiated. However, in cases with concomitant ATLS the initial doses of chemotherapy should be reduced and the metabolic disorders and renal function monitored. The prognosis in children with RMS metastatic to BM with signs of DIC or ATLS at admission depends on the response to chemotherapy, however generally it is highly disappointing

CYP2C8 and CYP2C9 polymorphisms in relation to tumour characteristics and early breast cancer related events among 652 breast cancer patients

BACKGROUND: CYP2C8/9 polymorphisms may influence breast cancer-free survival after diagnosis due to their role in the metabolism of tamoxifen, paclitaxel, and other chemotherapy. cytochrome P450 (CYP)2C8/9 metabolise arachidonic acid to epoxyeicosatrienoic acids, which enhance migration and invasion in vitro and promote angiogenesis in vivo. We aimed to investigate the frequency of CYP2C8/9 polymorphisms in relation to breast tumour characteristics and disease-free survival. METHODS: A prospective series of 652 breast cancer patients from southern Sweden was genotyped for CYP2C8*3, CYP2C8*4, CYP2C9*2, and CYP2C9*3. Blood samples and questionnaires were obtained pre- and postoperatively. Clinical information and tumour characteristics were obtained from patients' charts and pathology reports. RESULTS: Frequencies of CYP2C8/9 polymorphisms were similar to healthy European populations. Significantly less node involvement (P=0.002) and fewer PR+ tumours (P=0.012) were associated with CYP2C8*4. Median follow-up was 25 months and 52 breast cancer-related events were reported. In a multivariate model, CYP2C8/9*3/*1*/*2/*1 was the only factor associated with increased risk for early events in 297 tamoxifen-treated, ER-positive patients, adjusted HR 2.54 (95%CI 1.11-5.79). The effect appeared to be driven by CYP2C8*3, adjusted HR 8.56 (95%CI 1.53-51.1). CONCLUSION: Polymorphic variants of CYP2C8/9 may influence breast tumour characteristics and disease-free survival in tamoxifen-treated patients

Search for Gravitational Waves from Primordial Black Hole Binary Coalescences in the Galactic Halo

We use data from the second science run of the LIGO gravitational-wave detectors to search for the gravitational waves from primordial black hole (PBH) binary coalescence with component masses in the range 0.2--$1.0 M_\odot$. The analysis requires a signal to be found in the data from both LIGO observatories, according to a set of coincidence criteria. No inspiral signals were found. Assuming a spherical halo with core radius 5 kpc extending to 50 kpc containing non-spinning black holes with masses in the range 0.2--$1.0 M_\odot$, we place an observational upper limit on the rate of PBH coalescence of 63 per year per Milky Way halo (MWH) with 90% confidence.Comment: 7 pages, 4 figures, to be submitted to Phys. Rev.

MF59®-Adjuvanted H5N1 Vaccine Induces Immunologic Memory and Heterotypic Antibody Responses in Non-Elderly and Elderly Adults

Pathogenic avian influenza virus (H5N1) has the potential to cause a major global pandemic in humans. Safe and effective vaccines that induce immunologic memory and broad heterotypic response are needed.Healthy adults aged 18-60 and > 60 years (n = 313 and n = 173, respectively) were randomized (1:1) to receive two primary and one booster injection of 7.5 microg or 15 microg doses of a subunit MF59-adjuvanted H5N1 (A/Vietnam/1194/2004) (clade 1) vaccine. Safety was monitored until 6 months after booster. Immunogenicity was assessed by hemagglutination inhibition (HI), single radial hemolysis (SRH) and microneutralization assays (MN). Mild injection-site pain was the most common adverse reaction. No serious adverse events relating to the vaccine were reported. The humoral immune responses to 7.5 microg and 15 microg doses were comparable. The rates for seroprotection (HI>40; SRH>25 mm(2); MN > or = 40) after the primary vaccination ranged 72-87%. Six months after primary vaccination with the 7.5 microg dose, 18% and 21% of non-elderly and elderly adults were seroprotected; rates increased to 90% and 84%, respectively, after the booster vaccination. In the 15 microg group, seroprotection rates among non-elderly and elderly adults increased from 25% and 62% after primary vaccination to 92% and 88% after booster vaccination, respectively. A heterologous immune response to the H5N1/turkey/Turkey/05 strain was elicited after second and booster vaccinations.Both formulations of MF59-adjuvanted influenza H5N1 vaccine were well tolerated. The European Union requirement for licensure for pre-pandemic vaccines was met by the lower dose tested. The presence of cross-reactive antibodies to a clade 2 heterologous strain demonstrates that this vaccine may be appropriate for pre-pandemic programs.(ClinicalTrials.gov) NCT00311480

Genomic copy number and expression patterns in testicular germ cell tumours

Testicular germ cell tumours of adults and adolescents (TGCT) include seminomas (SE) and nonseminomas (NS), with spermatocytic seminomas (SSE) representing a distinct entity in older men. SE and NS have gain of 12p material in all cases, whereas SSE are associated with overrepresentation of chromosome 9. Here, we compare at the chromosomal level, copy number imbalances with global expression changes, identified by comparative expressed sequence hybridisation analyses, in seven SE, one combined tumour, seven NS and seven cell lines. Positive correlations were found consistent with copy number as a main driver of expression change, despite reported differences in methylation status in SE and NS. Analysis of chromosomal copy number and expression data could not distinguish between SE and NS, in-keeping with a similar genetic pathogenesis. However, increased expression from 4q22, 5q23.2 and 9p21 distinguished SSE from SE and NS and decreased copy number and expression from 2q36–q37 and 6q24 was a specific feature of NS-derived cell lines. Our analysis also highlights 19 regions with both copy number and expression imbalances in greater than 40% of cases. Mining available expression array data identified genes from these regions as candidates for involvement in TGCT development. Supplementary data is available at http://www.crukdmf.icr.ac.uk/array/array.html