Principles of assembly reveal a periodic table of protein complexes

Structural insights into protein complexes have had a broad impact on our understanding of biological function and evolution. Here we seek a comprehensive understanding of the general principles underlying quaternary structure organisation in protein complexes. To do this, we first examine the fundamental steps by which protein complexes can assemble using experimental and structure-based characterisation of assembly pathways. Most assembly transitions can be classified into three basic types, which can then be used to exhaustively enumerate a large set of possible quaternary structure topologies. These topologies, which include the vast majority of observed protein complex structures, give rise to a natural organisation into a periodic table. Based upon this, we are then able to accurately predict the expected frequencies of quaternary structure topologies, including those not yet observed. Overall, these results have important implications for quaternary structure prediction, modelling and engineering.This work was supported by the Royal Society (S.E.A. and C.V.R.), the Human Frontier Science Program (J.A.M.), the Medical Research Council grant G1000819 (H.H. and C.V.R.) and the Lister Institute for Preventative Medicine (S.A.T.).This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aaa224

Principles of assembly reveal a periodic table of protein complexes.

Structural insights into protein complexes have had a broad impact on our understanding of biological function and evolution. In this work, we sought a comprehensive understanding of the general principles underlying quaternary structure organization in protein complexes. We first examined the fundamental steps by which protein complexes can assemble, using experimental and structure-based characterization of assembly pathways. Most assembly transitions can be classified into three basic types, which can then be used to exhaustively enumerate a large set of possible quaternary structure topologies. These topologies, which include the vast majority of observed protein complex structures, enable a natural organization of protein complexes into a periodic table. On the basis of this table, we can accurately predict the expected frequencies of quaternary structure topologies, including those not yet observed. These results have important implications for quaternary structure prediction, modeling, and engineering.This work was supported by the Royal Society (S.E.A. and C.V.R.), the Human Frontier Science Program (J.A.M.), the Medical Research Council grant G1000819 (H.H. and C.V.R.) and the Lister Institute for Preventative Medicine (S.A.T.).This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aaa224

Survey of physicochemical characteristics and microbial contamination in selected food locally vended in Morogoro Municipality, Tanzania

Biomed central Research notel 2015Background: Raw milk, raw fruit juice and raw fish are enriched with essential nutrients for human diet but are prone to microbial contamination along the value chain. This cross sectional study was conducted to assess physicochemical characteristics and microbial quality of raw milk, fruit juice and fish from food vendors in Morogoro Municipality, Tanzania. The physicochemical assessment of food samples was done by smell, colour, presence of debris, turbidity, consistence, pH and clot on alcohol test. Hygiene of food containers, personnel and the vending environment was also assessed. Qualitative and quantitative microbial assessment of food was done using standard laboratory protocols as described by Tanzania Bureau of Standards and International Systems of Standards. Results: Raw milk sold in Morogoro was of poor quality since was adulterated with water, contained sediments and clotted on alcohol test. Up to 63 % of the milk samples were contaminated with Escherichia coli and 60 % had higher total viable count (TVC) than the recommended values. Raw fruit juice was stored in dirty containers and sold under unhygienic environment. Seventy-three percent of juice samples had TVC beyond the recommendations while E. coli contamination rate was 63.3 %. The raw fish samples had started spoiling as depicted through sensory evaluation. E. coli contamination rate was 55 % and that of Campylobacter jejuni was 0.5 %. The mean TVC of raw fish was 8.1 (Log cfu/g) and 96.2 % of the fish samples had TVC beyond the recommended limits of 5.0 Log cfu/g. Conclusions: The physicochemical characteristics of food vended in Morogoro Municipality were of poor quality. The food had high bacterial contaminations. This situation poses health risks to the public and losses to food vendors due to spoilage. Stakeholders in food value chain should be educated on safe production and good hygienic practices. Routine quality and safety assessment of locally vended food, inspection of selling premises and regular health checkup of the personnel involved in food vending industry should be instituted

Knowledge Utopias: An epistemological perspective on the convergence of museums, libraries and archives

Since 2005, convergence of museums, libraries and archives has emerged as a prominent trend in both the international and Australia collection sectors, made manifest through the development of digital platforms that allow integrated access to diverse collection databases, as well as collaborations and mergers of bricks-and-mortar cultural institutions to incorporate various types of collections and professional disciplines. The convergence phenomenon has led to significant investments in technology and infrastructure, provoking considerable scholarly and professional discourse across collecting domains. Yet, the existence of only a handful of empirical studies reflects a nascent field of study where the majority of research is characterised by inventory-style attempts to quantify and classify types of collaborative projects. This thesis extends current research by examining convergence through a dual commitment to both theory and fieldwork. Focussing on the interpretation of museum collections within converged institutions, I combine conceptual analysis of the epistemological implications of convergence with five detailed case studies of converged organisations in Australia and New Zealand. In a museological context, the research explores ways in which the integration of collecting institutions influences understandings of objects through its impact on museum practices. The findings suggest that convergence not only produces a new institutional framework for museum practice, but also that the integration of collecting institutions has the potential to reshape fundamental understandings of identity, place, heritage and culture

Arachidonic acid and DHA status in pregnant women is not associated with cognitive performance of their children at 4 or 6–7 years

Arachidonic acid (ARA) and DHA, supplied primarily from the mother, are required for early development of the central nervous system. Thus, variations in maternal ARA or DHA status may modify neurocognitive development. We investigated the relationship between maternal ARA and DHA status in early (11·7 weeks) or late (34·5 weeks) pregnancy on neurocognitive function at the age of 4 years or 6–7 years in 724 mother–child pairs from the Southampton Women’s Survey cohort. Plasma phosphatidylcholine fatty acid composition was measured in early and late pregnancy. ARA concentration in early pregnancy predicted 13 % of the variation in ARA concentration in late pregnancy (β=0·36, P&lt;0·001). DHA concentration in early pregnancy predicted 21 % of the variation in DHA concentration in late pregnancy (β=0·46, P&lt;0·001). Children’s cognitive function at the age of 4 years was assessed by the Wechsler Preschool and Primary Scale of Intelligence and at the age of 6–7 years by the Wechsler Abbreviated Scale of Intelligence. Executive function at the age of 6–7 years was assessed using elements of the Cambridge Neuropsychological Test Automated Battery. Neither DHA nor ARA concentrations in early or late pregnancy were associated significantly with neurocognitive function in children at the age of 4 years or the age of 6–7 years. These findings suggest that ARA and DHA status during pregnancy in the range found in this cohort are unlikely to have major influences on neurocognitive function in healthy children.</p

Uniparental disomy 7 in Silver—Russell syndrome and primordial growth retardation

Maternal uniparental disomy for the entire chromosome 7 has so far been reported in three patients with intrauterine and postnatal growth retardation. Two were detected because they were homozygous for a cystic fibrosis mutation for which only the mother was heterozygous, and one because he was homozygous for a rare COL1A2 mutation. We investigated 35 patients with either the Silver-Russell syndrome or primordial growth retardation and their parents with PCR markers to search for uniparental disomy 7. Four of 35 patients were found to have maternal disomy, including three with isodisomy and one with heterodisomy. The data confirm the hypothetical localization of a maternally imprinted gene (or more than one such gene) on chromosome 7. It is suggested to search for UPD 7 in families with an offspring with sporadic Silver-Russell syndrome or primordial growth retardatio

Adult and paediatric mortality patterns in a referral hospital in Liberia 1 year after the end of the war

The aim of this study was to describe and analyse hospital mortality patterns after the Liberian war. Data were collected retrospectively from January to July 2005 in a referral hospital in Monrovia, Liberia. The overall fatality rate was 17.2% (438/2543) of medical admissions. One-third of deaths occurred in the first 24h. The adult fatality rate was 23.3% (241/1034). Non-infectious diseases accounted for 56% of the adult deaths. The main causes of death were meningitis (16%), stroke (14%) and heart failure (10%). Associated fatality rates were 48%, 54% and 31% respectively. The paediatric fatality rate was 13.1% (197/1509). Infectious diseases caused 66% of paediatric deaths. In infants <1 month old, the fatality rate was 18% and main causes of death were neonatal sepsis (47%), respiratory distress (24%) and prematurity (18%). The main causes of death in infants > or =1 month old were respiratory infections (27%), malaria (23%) and severe malnutrition (16%). Associated fatality rates were 12%, 10% and 19%. Fatality rates were similar to those found in other sub-Saharan countries without a previous conflict. Early deaths could decrease through recognition and early referral of severe cases from health centres to the hospital and through assessment and priority treatment of these patients at arrival

Effect of a strategy of a supraglottic airway device vs tracheal intubation during out-of-hospital cardiac arrest on functional outcome

Importance The optimal approach to airway management during out-of-hospital cardiac arrest is unknown. Objective To determine whether a supraglottic airway device (SGA) is superior to tracheal intubation (TI) as the initial advanced airway management strategy in adults with nontraumatic out-of-hospital cardiac arrest. Design, Setting, and Participants Multicenter, cluster randomized clinical trial of paramedics from 4 ambulance services in England responding to emergencies for approximately 21 million people. Patients aged 18 years or older who had a nontraumatic out-of-hospital cardiac arrest and were treated by a participating paramedic were enrolled automatically under a waiver of consent between June 2015 and August 2017; follow-up ended in February 2018. Interventions Paramedics were randomized 1:1 to use TI (764 paramedics) or SGA (759 paramedics) as their initial advanced airway management strategy. Main Outcomes and Measures The primary outcome was modified Rankin Scale score at hospital discharge or 30 days after out-of-hospital cardiac arrest, whichever occurred sooner. Modified Rankin Scale score was divided into 2 ranges: 0-3 (good outcome) or 4-6 (poor outcome; 6 = death). Secondary outcomes included ventilation success, regurgitation, and aspiration. Results A total of 9296 patients (4886 in the SGA group and 4410 in the TI group) were enrolled (median age, 73 years; 3373 were women [36.3%]), and the modified Rankin Scale score was known for 9289 patients. In the SGA group, 311 of 4882 patients (6.4%) had a good outcome (modified Rankin Scale score range, 0-3) vs 300 of 4407 patients (6.8%) in the TI group (adjusted risk difference [RD], −0.6% [95% CI, −1.6% to 0.4%]). Initial ventilation was successful in 4255 of 4868 patients (87.4%) in the SGA group compared with 3473 of 4397 patients (79.0%) in the TI group (adjusted RD, 8.3% [95% CI, 6.3% to 10.2%]). However, patients randomized to receive TI were less likely to receive advanced airway management (3419 of 4404 patients [77.6%] vs 4161 of 4883 patients [85.2%] in the SGA group). Two of the secondary outcomes (regurgitation and aspiration) were not significantly different between groups (regurgitation: 1268 of 4865 patients [26.1%] in the SGA group vs 1072 of 4372 patients [24.5%] in the TI group; adjusted RD, 1.4% [95% CI, −0.6% to 3.4%]; aspiration: 729 of 4824 patients [15.1%] vs 647 of 4337 patients [14.9%], respectively; adjusted RD, 0.1% [95% CI, −1.5% to 1.8%]). Conclusions and Relevance Among patients with out-of-hospital cardiac arrest, randomization to a strategy of advanced airway management with a supraglottic airway device compared with tracheal intubation did not result in a favorable functional outcome at 30 days

Integrating the complexity of healthcare improvement with implementation science:a longitudinal qualitative case study

Background: Implementation science seeks to enable change, underpinned by theories and frameworks such as the Consolidated Framework for Implementation Research (CFIR). Yet academia and frontline healthcare improvement remain largely siloed, with limited integration of implementation science methods into frontline improvement where the drivers include pragmatic, rapid change. Using the CIFR lens, we aimed to explore how pragmatic and complex healthcare improvement and implementation science can be integrated. Methods: Our research involved the investigation of a case study that was undertaking the implementation of an improvement intervention at a large public health service. Our research involved qualitative data collection methods of semi-structured interviews and non-participant observations of the implementation team delivering the intervention. Thematic analysis identified key themes from the qualitative data. We examined our themes through the lens of CFIR to gain in-depth understanding of how the CFIR components operated in a ‘real-world’ context. Results: The key themes emerging from our research outlined that leadership, context and process are the key components that dominate and affect the implementation process. Leadership which cultivates connections with front line clinicians, fosters engagement and trust. Navigating context was facilitated by ‘bottom-up’ governance. Multi-disciplinary and cross-sector capability were key processes that supported pragmatic and agile responses in a changing complex environment. Process reflected the theoretically-informed, and iterative implementation approach. Mapping CFIR domains and constructs, with these themes demonstrated close alignment with the CFIR. The findings bring further depth to CFIR. Our research demonstrates that leadership which has a focus on patient need as a key motivator to engage clinicians, which applies and ensures iterative processes which leverage contextual factors can achieve successful, sustained implementation and healthcare improvement outcomes. Conclusions: Our longitudinal study highlights insights that strengthen alignment between implementation science and pragmatic frontline healthcare improvement. We identify opportunities to enhance the relevance of CFIR in the ‘real-world’ setting through the interconnected nature of our themes. Our study demonstrates actionable knowledge to enhance the integration of implementation science in healthcare improvement.</p

Mutations causing medullary cystic kidney disease type 1 (MCKD1) lie in a large VNTR in MUC1 missed by massively parallel sequencing

While genetic lesions responsible for some Mendelian disorders can be rapidly discovered through massively parallel sequencing (MPS) of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple Mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing, and de novo assembly, we found that each of six MCKD1 families harbors an equivalent, but apparently independently arising, mutation in sequence dramatically underrepresented in MPS data: the insertion of a single C in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (~1.5-5 kb), GC-rich (>80%), coding VNTR in the mucin 1 gene. The results provide a cautionary tale about the challenges in identifying genes responsible for Mendelian, let alone more complex, disorders through MPS