Plasmodium falciparum Apicomplexan-Specific Glucosamine-6-Phosphate N-Acetyltransferase Is Key for Amino Sugar Metabolism and Asexual Blood Stage Development

UDP-N-acetylglucosamine (UDP-GlcNAc), the main product of the hexosamine biosynthetic pathway, is an important metabolite in protozoan parasites since its sugar moiety is incorporated into glycosylphosphatidylinositol (GPI) glycolipids and N- and O-linked glycans. Apicomplexan parasites have a hexosamine pathway comparable to other eukaryotic organisms, with the exception of the glucosamine-phosphate N-acetyltransferase (GNA1) enzymatic step that has an independent evolutionary origin and significant differences from nonapicomplexan GNA1s. By using conditional genetic engineering, we demonstrate the requirement of GNA1 for the generation of a pool of UDP-GlcNAc and for the development of intraerythrocytic asexual Plasmodium falciparum parasites. Furthermore, we present the 1.95 A resolution structure of the GNA1 ortholog from Cryptosporidium parvum, an apicomplexan parasite which is a leading cause of diarrhea in developing countries, as a surrogate for P. falciparum GNA1. The indepth analysis of the crystal shows the presence of specific residues relevant for GNA1 enzymatic activity that are further investigated by the creation of site-specific mutants. The experiments reveal distinct features in apicomplexan GNA1 enzymes that could be exploitable for the generation of selective inhibitors against these parasites, by targeting the hexosamine pathway. This work underscores the potential of apicomplexan GNA1 as a drug target against malaria. IMPORTANCE Apicomplexan parasites cause a major burden on global health and economy. The absence of treatments, the emergence of resistances against available therapies, and the parasite''s ability to manipulate host cells and evade immune systems highlight the urgent need to characterize new drug targets to treat infections caused by these parasites. We demonstrate that glucosamine-6-phosphate N-acetyltransferase (GNA1), required for the biosynthesis of UDP-N-acetylglucosamine (UDP-GlcNAc), is essential for P. falciparum asexual blood stage development and that the disruption of the gene encoding this enzyme quickly causes the death of the parasite within a life cycle. The high-resolution crystal structure of the GNA1 ortholog from the apicomplexan parasite C. parvum, used here as a surrogate, highlights significant differences from human GNA1. These divergences can be exploited for the design of specific inhibitors against the malaria parasite

Thermostatistics of deformed bosons and fermions

Based on the q-deformed oscillator algebra, we study the behavior of the mean occupation number and its analogies with intermediate statistics and we obtain an expression in terms of an infinite continued fraction, thus clarifying successive approximations. In this framework, we study the thermostatistics of q-deformed bosons and fermions and show that thermodynamics can be built on the formalism of q-calculus. The entire structure of thermodynamics is preserved if ordinary derivatives are replaced by the use of an appropriate Jackson derivative and q-integral. Moreover, we derive the most important thermodynamic functions and we study the q-boson and q-fermion ideal gas in the thermodynamic limit.Comment: 14 pages, 2 figure

Microvawe pyrolysis of biomass: control of process parameters for high pyrolysis oil yields and enhanced oil quality

The oil yield and quality of pyrolysis oil from microwave heating of biomass was established by studying the behaviour of Larch in microwave processing. This is the first study in biomass pyrolysis to use a microwave processing technique and methodology that is fundamentally scalable, from which the basis of design for a continuous processing system can be derived to maximise oil yield and quality. It is shown systematically that sample size is a vital parameter that has been overlooked by previous work in this field. When sample size is controlled the liquid product yield is comparable to conventional pyrolysis, and can be achieved at an energy input of around 600 kWh/t. The quality of the liquid product is significantly improved compared to conventional pyrolysis processes, which results from the very rapid heating and quenching that can be achieved with microwave processing. The yields of Levoglucosan and phenolic compounds were found to be an order of magnitude higher in microwave pyrolysis when compared with conventional fast pyrolysis. Geometry is a key consideration for the development of a process at scale, and the opportunities and challenges for scale-up are discussed within this paper

Rationale and design of the hip fracture accelerated surgical treatment and care track (hip attack) trial : A protocol for an international randomised controlled trial evaluating early surgery for hip fracture patients

Introduction Annually, millions of adults suffer hip fractures. The mortality rate post a hip fracture is 7%-10% at 30 days and 10%-20% at 90 days. Observational data suggest that early surgery can improve these outcomes in hip fracture patients. We designed a clinical trial - HIP fracture Accelerated surgical TreaTment And Care tracK (HIP ATTACK) to determine the effect of accelerated surgery compared with standard care on the 90-day risk of all-cause mortality and major perioperative complications. Methods and analysis HIP ATTACK is a multicentre, international, parallel group randomised controlled trial (RCT) that will include patients ≥45 years of age and diagnosed with a hip fracture from a low-energy mechanism requiring surgery. Patients are randomised to accelerated medical assessment and surgical repair (goal within 6 h) or standard care. The co-primary outcomes are (1) all-cause mortality and (2) a composite of major perioperative complications (ie, mortality and non-fatal myocardial infarction, pulmonary embolism, pneumonia, sepsis, stroke, and life-threatening and major bleeding) at 90 days after randomisation. All patients will be followed up for a period of 1 year. We will enrol 3000 patients. Ethics and dissemination All centres had ethics approval before randomising patients. Written informed consent is required for all patients before randomisation. HIP ATTACK is the first large international trial designed to examine whether accelerated surgery can improve outcomes in patients with a hip fracture. The dissemination plan includes publishing the results in a policy-influencing journal, conference presentations, engagement of influential medical organisations, and providing public awareness through multimedia resources. Trial registration number NCT02027896; Pre-results

Proficiency testing of virus diagnostics based on bioinformatics analysis of simulated in silico high-throughput sequencing data sets

Quality management and independent assessment of high-throughput sequencing-based virus diagnostics have not yet been established as a mandatory approach for ensuring comparable results. The sensitivity and specificity of viral high-throughput sequence data analysis are highly affected by bioinformatics processing using publicly available and custom tools and databases and thus differ widely between individuals and institutions. Here we present the results of the COMPARE [Collaborative Management Platform for Detection and Analyses of (Re-) emerging and Foodborne Outbreaks in Europe] in silico virus proficiency test. An artificial, simulated in silico data set of Illumina HiSeq sequences was provided to 13 different European institutes for bioinformatics analysis to identify viral pathogens in high-throughput sequence data. Comparison of the participants’ analyses shows that the use of different tools, programs, and databases for bioinformatics analyses can impact the correct identification of viral sequences from a simple data set. The identification of slightly mutated and highly divergent virus genomes has been shown to be most challenging. Furthermore, the interpretation of the results, together with a fictitious case report, by the participants showed that in addition to the bioinformatics analysis, the virological evaluation of the results can be important in clinical settings. External quality assessment and proficiency testing should become an important part of validating high-throughput sequencing-based virus diagnostics and could improve the harmonization, comparability, and reproducibility of results. There is a need for the establishment of international proficiency testing, like that established for conventional laboratory tests such as PCR, for bioinformatics pipelines and the interpretation of such results

Scarabaeoidea (Insecta : Coleoptera) in the Brazilian Cerrado : current state of knowledge

Besouros pertencentes à superfamília Scarabaeoidea ocupam habitats variados, possuem hábitos alimentares diversifi cados, desempenham importante papel ecológico e diversas espécies apresentam importância agrícola. No entanto, estudos com esse grupo na região do Cerrado são escassos. Nesta revisão realizou-se um levantamento dos artigos publicados nos últimos 30 anos a respeito dos Scarabaeoidea no Cerrado. Foram recuperados 64 artigos, realizados em nove unidades da federação, que focavam quatro temas principais espécies praga, aspectos bioecológicos, biodiversidade e importância ecológica, e técnicas e metodologias de coleta de Scarabaeoidea. Os resultados desta revisão indicam que poucos estudos foram realizados com os Scarabaeoidea no Cerrado brasileiro nas últimas décadas frente à importância e diversidade desse grupo de insetos.Beetles belonging to the superfamily Scarabaeoidea occupy different habitats, present feeding habits diversifi ed, play an important ecological role and several species have agricultural importance. However, studies with this group in the Brazilian Cerrado are scarce. In this review we carried out a survey of scientifi c articles published in the past 30 years concerning Scarabaeoidea in the Cerrado. Were found 64 studies in nine Brazilian states. The studies focused on four main topics: pest species, bioecology, biodiversity and ecological importance, techniques and methodologies for collecting Scarabaeoidea. The results of this review indicate that few studies have been conducted with Scarabaeoidea in the Cerrado in recent decades compared to the importance and diversity of this group of insects