Combined chemotherapy in 76 children with non-Hodgkin's lymphoma excluding Burkitt's lymphoma.

From January 1983 to December 1986 seventy-six previously untreated children with non-Hodgkin's lymphoma (NHL) were treated by combination chemotherapy. Burkitt's lymphoma patients were ineligible. The treatment regimens include intermittent chemotherapy and for non-localized patients, prophylactic central nervous system chemotherapy. Intrathoracic non-Hodgkin's lymphoma patients also had cranial prophylactic radiotherapy. Sixty-six patients (86.8%) achieved complete remission. Two year failure-free survival rate was 82.1% for localized (stage I and II) NHL and 53.3% for non-localized (stage III and IV) NHL patients. Failure-free survival did not differ significantly for the two major histologic diagnoses, but two year survival rate was lower in diffuse poorly differentiated lymphoblastic than undifferentiated non-Burkitt's lymphoma (50% versus 66.8% respectively). Failure-free survival rate was 53.7% in mediastinal disease and, 73.2% in abdominal disease at 24 months. Relapse rate was higher in mediastinal cases (46.1%) than primary abdominal cases (24.3%) at 24 months. Eleven (13.5%) died of treatment related sepsis. Although the overall survival rate was 72.4% at 2 years we need novel or more intensive programmes for mediastinal and non-localized disease

From von Neumann architecture and Atanasoff’s ABC to Neuromorphic Computation and Kasabov’s NeuCube. Part II: Applications

Spatio/Spector-Temporal Data (SSTD) analyzing is a challenging task, as temporal features may manifest complex interactions that may also change over time. Making use of suitable models that can capture the “hidden” interactions and interrelationship among multivariate data, is vital in SSTD investigation. This chapter describes a number of prominent applications built using the Kasabov’s NeuCube-based Spiking Neural Network (SNN) architecture for mapping, learning, visualization, classification/regression and better understanding and interpretation of SSTD

Cd81 Interacts with the T Cell Receptor to Suppress Signaling

CD81 (TAPA-1) is a ubiquitously expressed tetraspanin protein identified as a component of the B lymphocyte receptor (BCR) and as a receptor for the Hepatitis C Virus. In an effort to identify trans-membrane proteins that interact with the T-cell antigen receptor (TCR), we performed a membrane yeast two hybrid screen and identified CD81 as an interactor of the CD3delta subunit of the TCR. We found that in the absence of CD81, in thymocytes from knockout mice, TCR engagement resulted in stronger signals. These results were recapitulated in T cell lines that express low levels of CD81 through shRNA mediated silencing. Increased signaling did not result from alterations in the levels of TCR on the surface of T lymphocytes. Although CD81 is not essential for normal T lymphocyte development, it plays an important role in regulating TCR and possibly pre-TCR signal transduction by controlling the strength of signaling. CD81 dependent alterations in thymocyte signaling are evident in increased CD5 expression on CD81 deficient double positive (DP) thymocytes. We conclude that CD81 interacts with the T cell receptor to suppress signaling. © 2012 Cevik et al

Source apportionment of fine particulate matter in Houston, Texas: insights to secondary organic aerosols

Online and offline measurements of ambient particulate matter (PM) near the urban and industrial Houston Ship Channel in Houston, Texas, USA, during May 2015 were utilized to characterize its chemical composition and to evaluate the relative contributions of primary, secondary, biogenic, and anthropogenic sources. Aerosol mass spectrometry (AMS) on nonrefractory PM1 (PM  ≤  1&thinsp;µm) indicated major contributions from sulfate (averaging 50&thinsp;% by mass), organic aerosol (OA, 40&thinsp;%), and ammonium (14&thinsp;%). Positive matrix factorization (PMF) of AMS data categorized OA on average as 22&thinsp;% hydrocarbon-like organic aerosol (HOA), 29&thinsp;% cooking-influenced less-oxidized oxygenated organic aerosol (CI-LO-OOA), and 48&thinsp;% more-oxidized oxygenated organic aerosol (MO-OOA), with the latter two sources indicative of secondary organic aerosol (SOA). Chemical analysis of PM2.5 (PM  ≤  2.5&thinsp;µm) filter samples agreed that organic matter (35&thinsp;%) and sulfate (21&thinsp;%) were the most abundant components. Organic speciation of PM2.5 organic carbon (OC) focused on molecular markers of primary sources and SOA tracers derived from biogenic and anthropogenic volatile organic compounds (VOCs). The sources of PM2.5 OC were estimated using molecular marker-based positive matric factorization (MM-PMF) and chemical mass balance (CMB) models. MM-PMF resolved nine factors that were identified as diesel engines (11.5&thinsp;%), gasoline engines (24.3&thinsp;%), nontailpipe vehicle emissions (11.1&thinsp;%), ship emissions (2.2&thinsp;%), cooking (1.0&thinsp;%), biomass burning (BB, 10.6&thinsp;%), isoprene SOA (11.0&thinsp;%), high-NOx anthropogenic SOA (6.6&thinsp;%), and low-NOx anthropogenic SOA (21.7&thinsp;%). Using available source profiles, CMB apportioned 41&thinsp;% of OC to primary fossil sources (gasoline engines, diesel engines, and ship emissions), 5&thinsp;% to BB, 15&thinsp;% to SOA (including 7.4&thinsp;% biogenic and 7.6&thinsp;% anthropogenic), and 39&thinsp;% to other sources that were not included in the model and are expected to be secondary.This study presents the first application of in situ AMS-PMF, MM-PMF, and CMB for OC source apportionment and the integration of these methods to evaluate the relative roles of biogenic, anthropogenic, and BB-SOA. The three source apportionment models agreed that  ∼ &thinsp;50&thinsp;% of OC is associated with primary emissions from fossil fuel use, particularly motor vehicles. Differences among the models reflect their ability to resolve sources based upon the input chemical measurements, with molecular marker-based methods providing greater source specificity and resolution for minor sources. By combining results from MM-PMF and CMB, BB was estimated to contribute 11&thinsp;% of OC, with 5&thinsp;% primary emissions and 6&thinsp;% BB-SOA. SOA was dominantly anthropogenic (28&thinsp;%) rather than biogenic (11&thinsp;%) or BB-derived. The three-model approach demonstrates significant contributions of anthropogenic SOA to fine PM. More broadly, the findings and methodologies presented herein can be used to advance local and regional understanding of anthropogenic contributions to SOA.</p

Distinct modes of derepression of an Arabidopsis immune receptor complex by two different bacterial effectors

Plant intracellular nucleotide-binding leucine-rich repeat (NLR) immune receptors often function in pairs to detect pathogen effectors and activate defense. The Arabidopsis RRS1-R–RPS4 NLR pair recognizes the bacterial effectors AvrRps4 and PopP2 via an integrated WRKY transcription factor domain in RRS1-R that mimics the effector’s authentic targets. How the complex activates defense upon effector recognition is unknown. Deletion of the WRKY domain results in an RRS1 allele that triggers constitutive RPS4-dependent defense activation, suggesting that in the absence of effector, the WRKY domain contributes to maintaining the complex in an inactive state. We show the WRKY domain interacts with the adjacent domain 4, and that the inactive state of RRS1 is maintained by WRKY–domain 4 interactions before ligand detection. AvrRps4 interaction with the WRKY domain disrupts WRKY–domain 4 association, thus derepressing the complex. PopP2-triggered activation is less easily explained by such disruption and involves the longer C-terminal extension of RRS1-R. Furthermore, some mutations in RPS4 and RRS1 compromise PopP2 but not AvrRps4 recognition, suggesting that AvrRps4 and PopP2 derepress the complex differently. Consistent with this, a “reversibly closed” conformation of RRS1-R, engineered in a method exploiting the high affinity of colicin E9 and Im9 domains, reversibly loses AvrRps4, but not PopP2 responsiveness. Following RRS1 derepression, interactions between domain 4 and the RPS4 C-terminal domain likely contribute to activation. Simultaneous relief of autoinhibition and activation may contribute to defense activation in many immune receptors

Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol.

Background: This study sought to establish the long-term effects of Covid-19 following hospitalisation. Methods: 327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L). Findings: 55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age. Interpretation: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females. Funding: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Department for International Development and the Bill and Melinda Gates Foundation

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

The crystal structure of the Hazara virus nucleocapsid protein

Background: Hazara virus (HAZV) is a member of the Bunyaviridae family of segmented negative stranded RNA viruses, and shares the same serogroup as Crimean-Congo haemorrhagic fever virus (CCHFV). CCHFV is responsible for fatal human disease with a mortality rate approaching 30 %, which has an increased recent incidence within southern Europe. There are no preventative or therapeutic treatments for CCHFV-mediated disease, and thus CCHFV is classified as a hazard group 4 pathogen. In contrast HAZV is not associated with serious human disease, although infection of interferon receptor knockout mice with either CCHFV or HAZV results in similar disease progression. To characterise further similarities between HAZV and CCHFV, and support the use of HAZV as a model for CCHFV infection, we investigated the structure of the HAZV nucleocapsid protein (N) and compared it to CCHFV N. N performs an essential role in the viral life cycle by encapsidating the viral RNA genome, and thus, N represents a potential therapeutic target. Results: We present the purification, crystallisation and crystal structure of HAZV N at 2.7 Å resolution. HAZV N was expressed as an N-terminal glutathione S-transferase (GST) fusion protein then purified using glutathione affinity chromatography followed by ion-exchange chromatography. HAZV N crystallised in the P212121 space group with unit cell parameters a = 64.99, b = 76.10, and c = 449.28 Å. HAZV N consists of a globular domain formed mostly of alpha helices derived from both the N- and C-termini, and an arm domain comprising two long alpha helices. HAZV N has a similar overall structure to CCHFV N, with their globular domains superposing with an RMSD = 0.70 Å, over 368 alpha carbons that share 59 % sequence identity. Four HAZV N monomers crystallised in the asymmetric unit, and their head-to-tail assembly reveals a potential interaction site between monomers. Conclusions: The crystal structure of HAZV N reveals a close similarity to CCHFV N, supporting the use of HAZV as a model for CCHFV. Structural similarity between the N proteins should facilitate study of the CCHFV and HAZV replication cycles without the necessity of working under containment level 4 (CL-4) conditions