Population genetics of trypanosoma brucei rhodesiense: clonality and diversity within and between foci

African trypanosomes are unusual among pathogenic protozoa in that they can undergo their complete morphological life cycle in the tsetse fly vector with mating as a non-obligatory part of this development. Trypanosoma brucei rhodesiense, which infects humans and livestock in East and Southern Africa, has classically been described as a host-range variant of the non-human infective Trypanosoma brucei that occurs as stable clonal lineages. We have examined T. b. rhodesiense populations from East (Uganda) and Southern (Malawi) Africa using a panel of microsatellite markers, incorporating both spatial and temporal analyses. Our data demonstrate that Ugandan T. b. rhodesiense existed as clonal populations, with a small number of highly related genotypes and substantial linkage disequilibrium between pairs of loci. However, these populations were not stable as the dominant genotypes changed and the genetic diversity also reduced over time. Thus these populations do not conform to one of the criteria for strict clonality, namely stability of predominant genotypes over time, and our results show that, in a period in the mid 1990s, the previously predominant genotypes were not detected but were replaced by a novel clonal population with limited genetic relationship to the original population present between 1970 and 1990. In contrast, the Malawi T. b. rhodesiense population demonstrated significantly greater diversity and evidence for frequent genetic exchange. Therefore, the population genetics of T. b. rhodesiense is more complex than previously described. This has important implications for the spread of the single copy T. b. rhodesiense gene that allows human infectivity, and therefore the epidemiology of the human disease, as well as suggesting that these parasites represent an important organism to study the influence of optional recombination upon population genetic dynamics

A Fokker-Planck formalism for diffusion with finite increments and absorbing boundaries

Gaussian white noise is frequently used to model fluctuations in physical systems. In Fokker-Planck theory, this leads to a vanishing probability density near the absorbing boundary of threshold models. Here we derive the boundary condition for the stationary density of a first-order stochastic differential equation for additive finite-grained Poisson noise and show that the response properties of threshold units are qualitatively altered. Applied to the integrate-and-fire neuron model, the response turns out to be instantaneous rather than exhibiting low-pass characteristics, highly non-linear, and asymmetric for excitation and inhibition. The novel mechanism is exhibited on the network level and is a generic property of pulse-coupled systems of threshold units.Comment: Consists of two parts: main article (3 figures) plus supplementary text (3 extra figures

Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response

Background: Human African trypanosomiasis progresses from an early (hemolymphatic) stage, through CNS invasion to the late (meningoencephalitic) stage. In experimental infections disease progression is associated with neuroinflammatory responses and neurological symptoms, but this concept requires evaluation in African trypanosomiasis patients, where correct diagnosis of the disease stage is of critical therapeutic importance. Methodology/Principal Findings: This was a retrospective study on a cohort of 115 T.b.rhodesiense HAT patients recruited in Eastern Uganda. Paired plasma and CSF samples allowed the measurement of peripheral and CNS immunoglobulin and of CSF cytokine synthesis. Cytokine and immunoglobulin expression were evaluated in relation to disease duration, stage progression and neurological symptoms. Neurological symptoms were not related to stage progression (with the exception of moderate coma). Increases in CNS immunoglobulin, IL-10 and TNF-α synthesis were associated with stage progression and were mirrored by a reduction in TGF-β levels in the CSF. There were no significant associations between CNS immunoglobulin and cytokine production and neurological signs of disease with the exception of moderate coma cases. Within the study group we identified diagnostically early stage cases with no CSF pleocytosis but intrathecal immunoglobulin synthesis and diagnostically late stage cases with marginal CSF pleocytosis and no detectable trypanosomes in the CSF. Conclusions: Our results demonstrate that there is not a direct linkage between stage progression, neurological signs of infection and neuroinflammatory responses in rhodesiense HAT. Neurological signs are observed in both early and late stages, and while intrathecal immunoglobulin synthesis is associated with neurological signs, these are also observed in cases lacking a CNS inflammatory response. While there is an increase in inflammatory cytokine production with stage progression, this is paralleled by increases in CSF IL-10. As stage diagnostics, the CSF immunoglobulins and cytokines studied do not have sufficient sensitivity to be of clinical value

Misdiagnosis of narcolepsy

BACKGROUND: Narcolepsy is a chronic primary sleep disorder, characterized by excessive daytime sleepiness and sleep dysfunction with or without cataplexy. Narcolepsy is uncommon, with a low prevalence rate which makes it difficult to diagnose definitively without a complex series of tests and a detailed history. The aim of this study was to review patients referred to a tertiary sleep centre who had been labelled with a diagnosis of narcolepsy prior to referral in order to assess if the diagnosis was accurate, and if not, to determine the cause of diagnostic misattribution. METHODS: All patients seen at a sleep centre from 2007–2013 (n = 551) who underwent detailed objective testing including an MSLT PSG, as well as wearing an actigraphy watch and completing a sleep diary for 2 weeks, were assessed for a pre-referral and final diagnosis of narcolepsy. RESULTS: Of the 41 directly referred patients with a diagnostic label of narcolepsy, 19 (46 %) were subsequently confirmed to have narcolepsy on objective testing and assessment by a sleep physician using ICSD-2 criteria. CONCLUSIONS: The diagnosis of narcolepsy was incorrectly attributed to almost 50 % of patients labelled with a diagnosis of narcolepsy who were referred for further opinion by a variety of specialists and generalists. Accurate diagnosis of narcolepsy is critical for many reasons, such as the impact it has on quality of life, driving, employment, insurance and pregnancy in women as well as medication management

A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect siz

DHODH modulates transcriptional elongation in the neural crest and melanoma

Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma1. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation

Assessing recent trends in high-latitude Southern Hemisphere surface climate

Understanding the causes of recent climatic trends and variability in the high-latitude Southern Hemisphere is hampered by a short instrumental record. Here, we analyse recent atmosphere, surface ocean and sea-ice observations in this region and assess their trends in the context of palaeoclimate records and climate model simulations. Over the 36-year satellite era, significant linear trends in annual mean sea-ice extent, surface temperature and sea-level pressure are superimposed on large interannual to decadal variability. Most observed trends, however, are not unusual when compared with Antarctic palaeoclimate records of the past two centuries. With the exception of the positive trend in the Southern Annular Mode, climate model simulations that include anthropogenic forcing are not compatible with the observed trends. This suggests that natural variability overwhelms the forced response in the observations, but the models may not fully represent this natural variability or may overestimate the magnitude of the forced response.Support was provided by the following organizations: N.J.A: QEII fellowship and Discovery Project awarded by the Australian Research Council (ARC DP110101161 and DP140102059); M.H.E., ARC Laureate Fellowship (FL100100214); V.M.D., Agence Nationale de la Recherche, project ANR-14-CE01-0001 (ASUMA), and logistical support to French Antarctic studies from the Institut Polaire Paul-Emile Victor (IPEV); B.S., PAGES Antarctica 2k and the ESF-PolarClimate HOLOCLIP project; H.G., the Fonds National de la Recherche Scientifique (F.R.S.-FNRS-Belgium), where he is Research Director; P.O.C., research grant ANPCyT PICT2012 2927; R.L.F., NSF grant 1341621; E.J.S., the Leverhulme Trust; S.T.G., NSF grants OCE-1234473 and PLR-1425989; D.P.S., NSF grant 1235231; NCAR is sponsored by the National Science Foundation (NSF); G.R.S., NSF grants AGS-1206120 and AGS-1407360; D.S., the French ANR CEPS project Green Greenland (ANR-10-CEPL-0008); G.J.M., UK Natural Environment Research Council (NERC) through the British Antarctic Survey research programme Polar Science for Planet Earth; A.K.M., US Department of Energy under contract DE-SC0012457; K.R.C., VUW doctoral scholarship; L.M.F., Australian Research Council (FL100100214); D.J.C., NERC grant NE/H014896/1; C.d.L., UPMC doctoral scholarship; A.J.O., EU grant FP7-PEOPLE-2012-IIF 331615; X.C., the French ANR CLIMICE (ANR-08-CEXC-012-01) and the FP7 PAST4FUTURE (243908) projects; J.A.R., Marsden grant VUW1408; I.E., NSF grant OCE-1357078; T.R.V., the Australian Government's Cooperative Research Centres programme, through the ACE CRC

Multiple populations in globular clusters. Lessons learned from the Milky Way globular clusters

Recent progress in studies of globular clusters has shown that they are not simple stellar populations, being rather made of multiple generations. Evidence stems both from photometry and spectroscopy. A new paradigm is then arising for the formation of massive star clusters, which includes several episodes of star formation. While this provides an explanation for several features of globular clusters, including the second parameter problem, it also opens new perspectives about the relation between globular clusters and the halo of our Galaxy, and by extension of all populations with a high specific frequency of globular clusters, such as, e.g., giant elliptical galaxies. We review progress in this area, focusing on the most recent studies. Several points remain to be properly understood, in particular those concerning the nature of the polluters producing the abundance pattern in the clusters and the typical timescale, the range of cluster masses where this phenomenon is active, and the relation between globular clusters and other satellites of our Galaxy.Comment: In press (The Astronomy and Astrophysics Review

Cross validation of bi-modal health-related stress assessment

This study explores the feasibility of objective and ubiquitous stress assessment. 25 post-traumatic stress disorder patients participated in a controlled storytelling (ST) study and an ecologically valid reliving (RL) study. The two studies were meant to represent an early and a late therapy session, and each consisted of a "happy" and a "stress triggering" part. Two instruments were chosen to assess the stress level of the patients at various point in time during therapy: (i) speech, used as an objective and ubiquitous stress indicator and (ii) the subjective unit of distress (SUD), a clinically validated Likert scale. In total, 13 statistical parameters were derived from each of five speech features: amplitude, zero-crossings, power, high-frequency power, and pitch. To model the emotional state of the patients, 28 parameters were selected from this set by means of a linear regression model and, subsequently, compressed into 11 principal components. The SUD and speech model were cross-validated, using 3 machine learning algorithms. Between 90% (2 SUD levels) and 39% (10 SUD levels) correct classification was achieved. The two sessions could be discriminated in 89% (for ST) and 77% (for RL) of the cases. This report fills a gap between laboratory and clinical studies, and its results emphasize the usefulness of Computer Aided Diagnostics (CAD) for mental health care

The Spin Structure of the Nucleon

We present an overview of recent experimental and theoretical advances in our understanding of the spin structure of protons and neutrons.Comment: 84 pages, 29 figure