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Abstract Background In areas where malaria endemicity is high, many people harbour blood stage parasites without acute febrile illness, complicating the estimation of disease burden from infection data. For Plasmodium falciparum the density of parasitaemia that can be tolerated is low in the youngest children, but reaches a maximum in the age groups at highest risk of infection. There is little data on the age dependence of tolerance in other species of human malaria. Methods Parasite densities measured in 24,386 presumptive malaria cases at two local health centres in the Wosera area of Papua New Guinea were compared with the distributions of parasite densities recorded in community surveys in the same area. We then analyse the proportions of cases attributable to each of Plasmodium falciparum, P. vivax, and P. malariae as functions of parasite density and age using a latent class model. These attributable fractions are then used to compute the incidence of attributable disease. Results Overall 33.3%, 6.1%, and 0.1% of the presumptive cases were attributable to P. falciparum, P. vivax, and P. malariae respectively. The incidence of attributable disease and parasite density broadly follow similar age patterns. The logarithm of the incidence of acute illness is approximately proportion to the logarithm of the parasite density for all three malaria species, with little age variation in the relationship for P. vivax or P. malariae. P. falciparum shows more age variation in disease incidence at given levels of parasitaemia than the other species. Conclusion The similarities between Plasmodium species in the relationships between parasite density and risk of attributable disease are compatible with the hypothesis that pan-specific mechanisms may regulate tolerance to different human Plasmodia. A straightforward mathematical expression might be used to project disease burden from parasite density distributions assessed in community-based parasitological surveys.

diode-pumped Q-switched and injection-seeded single-frequency laser, generating tunable laser radiation at 935 nm, is presented. Using Nd:YGG (YGaO) as the active medium, the laser that was developed to serve as a transmitter for water-vapor lidar measurements. The configuration consists of a stable resonator in rod geometry that is injection seeded by a narrowband diode laser and stabilized by the ramp-and-fire technique. Energy scaling was done in a power amplifier in slab geometry. Both oscillator and amplifier crystal were diode pumped at 806 nm. More than 30 mJ pulse energy at 100 Hz repetition rate with a beam propagation factor of M<1.4 and pulse duration of 52 ns in single-frequency mode were generated. To our knowledge this is the first direct generation of 935 nm Q-switched pulses from Nd:YGG suitable for water-vapor measurements. The reported results show great promise of this laser in applications where high efficiency and reduced complexity is indispensable, such as for spaceborne or airborne water-vapor lidar instruments. [ABSTRACT FROM AUTHOR]

diode-pumped, single-frequency laser system emitting at 935 nm has recently been developed to serve as the transmitter for water vapor differential absorption lidar (DIAL) measurements. This laser uses Nd:YGG (YGaO) as the active medium and emits radiation directly at 935 nm without the need of additional frequency conversion processes. The system was diode-pumped at 806 nm and was built up in a master-oscillator-power-amplifier configuration. It generates more than 30 mJ of pulse energy at 100 Hz repetition rate with a beam quality ( M) of better than 1.4. Since water vapor DIAL demands for stringent requirements of the spectral properties those were carefully investigated in the scope of this paper. Single-frequency operation is achieved by injection seeding and active length control of the oscillator cavity. The range of continuously tunable single-frequency radiation extends to ∼0.4 nm centered around 935.31 nm. Values of the spectral purity of >99.996% were determined using long-pass absorption measurements in the atmosphere exceeding the requirements by a large margin. Finally, for the first time water vapor DIAL measurements were performed using a Nd:YGG laser. The reported results show much promise of these directly pumped lasers at 935 nm for future spaceborne but also airborne water vapor lidar systems. [ABSTRACT FROM AUTHOR]

Antigenic polymorphism and HLA restriction may limit the immunogenicity of a subunit vaccine against liver-stage Plasmodium falciparum. We examined 59 clinical isolates and five laboratory clones of P. falciparum for polymorphism in the N- and C-terminal regions of LSA-1, evaluated binding of the corresponding peptides to selected HLA class I alleles, and measured IFN-γ responses in residents of a malaria-endemic area of Papua New Guinea where HLA-A*1101, -24, -B13, and -B40 are the most common class I alleles. LSA-1 polymorphism was limited to a single non-synonymous mutation encoding serine (S), proline (P), or threonine (T) at amino acid 85. Nine-mer 84–92 peptides with S, T, or P at the primary anchor position bound differentially to HLA-A11, -A2, and -B7. IFN-γ ELISPOT responses increased with age in malaria-exposed subjects: 14–16% and 30–36% of 2–5- and 6–54-year-olds, respectively, had ≥ 10 IFN-γ-secreting cells/106 peripheral blood mononuclear cells when stimulated with at least one peptide variant (P < 0·05). IFN-γ responses to all three peptides were also greater for older than younger individuals. No children < 3 years old had lymphocytes that responded to all three 84–92 peptides, whereas 45% of adults (mean age 48 years) had aggregated IFN-γ responses. These data support the notion that age-related cumulative exposure to P. falciparum increases the frequency of IFN-γ responses to polymorphic epitopes of liver-stage antigens such as LSA-1. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) have emerged as integral components of E2F1-regulated gene regulatory networks (GRNs), but their implication in advanced or treatment-refractory malignancy is unknown. Methods: We combined high-throughput transcriptomic approaches with bioinformatics and structure modeling to search for lncRNAs that participate in E2F1-activated prometastatic GRNs and their phenotypic targets in the highly-relevant case of E2F1-driven aggressive bladder cancer (BC). RNA immunoprecipitation was performed to verify RNA-protein interactions. Functional analyses including qRT-PCR, immunoblotting, luciferase assays and measurement of extracellular fluxes were conducted to validate expression and target gene regulation. Results: We identified E2F1-responsive lncRNA-SLC16A1-AS1 and its associated neighboring protein-coding gene, SLC16A1/MCT1, which both promote cancer invasiveness. Mechanistically, upon E2F1-mediated co-transactivation of the gene pair, SLC16A1-AS1 associates with E2F1 in a structure-dependent manner and forms an RNA-protein complex that enhances SLC16A1/MCT1 expression through binding to a composite SLC16A1-AS1:E2F1-responsive promoter element. Moreover, SLC16A1-AS1 increases aerobic glycolysis and mitochondrial respiration and fuels ATP production by fatty acid β-oxidation. These metabolic changes are accompanied by alterations in the expression of the SLC16A1-AS1:E2F1-responsive gene PPARA, a key mediator of fatty acid β-oxidation. Conclusions: Our results unveil a new gene regulatory program by which E2F1-induced lncRNA-SLC16A1-AS1 forms a complex with its transcription factor that promotes cancer metabolic reprogramming towards the acquisition of a hybrid oxidative phosphorylation/glycolysis cell phenotype favoring BC invasiveness., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Kuru is a prion disease which became epidemic among the Fore and surrounding linguistic groups in Papua New Guinea, peaking in the late 1950s. It was transmitted during the transumption (endocannibalism) of dead family members at mortuary feasts. In this study, we aimed to explain the historical spread and the changing epidemiological patterns of kuru by analysing factors that affected its transmission. We also examined what cultural group principally determined a family's behaviour during mortuary rituals. Our investigations showed that differences in mortuary practices were responsible for the initial pattern of the spread of kuru and the ultimate shape of the epidemic, and for subsequent spatio-temporal differences in the epidemiology of kuru. Before transumption stopped altogether, the South Fore continued to eat the bodies of those who had died of kuru, whereas other linguistic groups, sooner or later, stopped doing so. The linguistic group was the primary cultural group that determined behaviour but at linguistic boundaries the neighbouring group's cultural practices were often adopted. The epidemiological changes were not explained by genetic differences, but genetic studies led to an understanding of genetic susceptibility to kuru and the selection pressure imposed by kuru, and provided new insights into human history and evolution.

Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.

While the neuropathology of kuru is well defined, there are few data concerning the distribution of disease-related prion protein in peripheral tissues. Here we report the investigation of brain and peripheral tissues from a kuru patient who died in 2003. Neuropathological findings were compared with those seen in classical (sporadic and iatrogenic) Creutzfeldt-Jakob disease (CJD) and variant CJD (vCJD). The neuropathological findings of the kuru patient showed all the stereotypical changes that define kuru, with the occurrence of prominent PrP plaques throughout the brain. Lymphoreticular tissue showed no evidence of prion colonization, suggesting that the peripheral pathogenesis of kuru is similar to that seen in classical CJD rather than vCJD. These findings now strongly suggest that the characteristic peripheral pathogenesis of vCJD is determined by prion strain type alone rather than route of infection.

The aims of this descriptive study were to confirm the high incidence of subacute sclerosing panencephalitis (SSPE) previously reported from Papua New Guinea (PNG) and to relate SSPE to previous measles vaccination and measles illness. From February 1997 to April 1999 we diagnosed a total of 55 patients with SSPE at Goroka Base General Hospital in Eastern Highlands Province (EHP) of PNG. The diagnosis was based on high cerebrospinal fluid and serum measles virus antibody titres with progressive neurological disorder and myoclonic jerks. Of these 55 patients 42 were from EHP, including 32 whose onset was in the 2-year period 1997-1998. The annual incidence of SSPE in EHP in these 2 years was 98 per million population under 20 years of age, the highest ever reported. This incidence was more than ten times higher than the highest incidence in the prevaccine era reported from elsewhere. The mean age of onset of SSPE was 7.7 years (range 2.8-14.8 years) and the interval between measles and the onset of SSPE, where known, had a mean of 5.9 years and a range of 2.5-11.1 years. Among the SSPE patients 19 had a documented history of measles vaccination. Eight of these 19 also had documentation of previous measles illness; of these, seven were vaccinated after the development of measles and one was vaccinated 20 days before measles illness. Two non-SSPE children received vaccination twice which was documented and subsequently developed measles which was also substantiated by documentation. Two patients with SSPE yielded amplified nucleotide sequences of measles virus that were different from any of the vaccine strains. We found no evidence to implicate measles vaccination in the development of SSPE.

Papua New Guinea (PNG) is a patchwork of different ecological zones, inhabited by human populations of exceptional cultural and linguistic diversity. This results in complex variations in vector ecology and malaria epidemiology. Malaria is the main cause of morbidity in many health facilities in lowland areas, but it is absent in much of the highlands. All four human malaria species occur, but endemicity varies widely, with Plasmodium falciparum locally reaching holo-endemic levels that are rarely found outside sub-Saharan Africa. The high frequency of Plasmodium vivax is an important difference to most African situations. PNG is therefore a prime location for studies of interactions between different parasite species, and of the biology of local human genetic adaptation and its implications for malaria morbidity and mortality.

Kuru is an acquired prion disease largely restricted to the Fore linguistic group of the Papua New Guinea Highlands, which was transmitted during endocannibalistic feasts. Heterozygosity for a common polymorphism in the human prion protein gene (PRNP) confers relative resistance to prion diseases. Elderly survivors of the kuru epidemic, who had multiple exposures at mortuary feasts, are, in marked contrast to younger unexposed Fore, predominantly PRNP 129 heterozygotes. Kuru imposed strong balancing selection on the Fore, essentially eliminating PRNP 129 homozygotes. Worldwide PRNP haplotype diversity and coding allele frequencies suggest that strong balancing selection at this locus occurred during the evolution of modern humans.

For daytime operation a new receiver for potassium resonance temperature lidars was developed that includes a twin Faraday anomalous dispersion optical filter and a high-performance photon-counting avalanche photodiode instead of a photomultiplier. The design of a flat spectral filter shape over the lidar scan range avoids instrumental error on the temperature results. Initial temperature measurements under daylight conditions were realized.