Leishmania-Specific Surface Antigens Show Sub-Genus Sequence Variation and Immune Recognition

Single-celled Leishmania parasites, transmitted by sand flies, infect humans and other mammals in many tropical and sub-tropical regions, giving rise to a spectrum of diseases called the leishmaniases. Species of parasite within the Leishmania genus can be divided into two groups (referred to as sub-genera) that are separated by up to 100 million years of evolution yet are highly related at the genome level. Our research is focused on identifying gene differences between these sub-genera that may identify proteins that impact on the transmission and pathogenicity of different Leishmania species. Here we report the presence of a highly-variant genomic locus (OHL) that was previously described as absent in parasites of the L. (Viannia) subgenus (on the basis of lack of key genes) but is present and well-characterised (as the LmcDNA16 locus) in all members of the alternative subgenus, L. (Leishmania). We demonstrate that the proteins encoded within the LmcDNA16 and OHL loci are similar in their structure and surface localisation in mammalian-infective amastigotes, despite significant differences in their DNA sequences. Most importantly, we demonstrate that the OHL locus proteins, like the HASP proteins from the LmcDNA16 locus, contain highly variable amino acid repeats that are antigenic in man and may therefore contribute to future vaccine development

Development of a measurement tool to assess public awareness of cancer

<p>Objective: We aimed to develop and validate a measurement tool to assess cancer awareness in the general population: the cancer awareness measure (CAM).</p> <p>Methods: Items assessing awareness of cancer warning signs, risk factors, incidence, screening programmes and attitudes towards help seeking were extracted from the literature or generated by expert groups. To determine reliability, the CAM was administered to a university participant panel (n=148), with a sub-sample (n=94) completing it again 2 weeks later. To establish construct validity, CAM scores of cancer experts (n=12) were compared with those of non-medical academics (n=21). Finally, university students (n=49) were randomly assigned to read either a cancer information leaflet or a leaflet with control information before completing the measure, to ensure the CAM was sensitive to change.</p> <p>Results: Cognitive interviewing indicated that the CAM was being interpreted as intended. Internal reliability (Cronbach's α=0.77) and test–retest reliability (r=0.81) were high. Scores for cancer experts were significantly higher than those for non-medical academics (t(31)=6.8, P<0.001). CAM scores were higher among students who received an intervention leaflet than the control leaflet (t(47)=4.8, P<0.001).</p> <p>Conclusions: These studies show the psychometric properties of the CAM and support its validity as a measure of cancer awareness in the general population.</p&gt

Innate Killing of Leishmania donovani by Macrophages of the Splenic Marginal Zone Requires IRF-7

Highly phagocytic macrophages line the marginal zone (MZ) of the spleen and the lymph node subcapsular sinus. Although these macrophages have been attributed with a variety of functions, including the uptake and clearance of blood and lymph-borne pathogens, little is known about the effector mechanisms they employ after pathogen uptake. Here, we have combined gene expression profiling and RNAi using a stromal macrophage cell line with in situ analysis of the leishmanicidal activity of marginal zone macrophages (MZM) and marginal metallophilic macrophages (MMM) in wild type and gene targeted mice. Our data demonstrate a critical role for interferon regulatory factor-7 (IRF-7) in regulating the killing of intracellular Leishmania donovani by these specialised splenic macrophage sub-populations. This study, therefore, identifies a new role for IRF-7 as a regulator of innate microbicidal activity against this, and perhaps other, non-viral intracellular pathogens. This study also highlights the importance of selecting appropriate macrophage populations when studying pathogen interactions with this functionally diverse lineage of cells

Hydroclimatic Contrasts Over Asian Monsoon Areas and Linkages to Tropical Pacific SSTs

Knowledge of spatial and temporal hydroclimatic differences is critical in understanding climatic mechanisms. Here we show striking hydroclimatic contrasts between northern and southern parts of the eastern margin of the Tibetan Plateau (ETP), and those between East Asian summer monsoon (EASM) and Indian summer monsoon (ISM) areas during the past ~2,000 years. During the Medieval Period, and the last 100 to 200 years, the southern ETP (S-ETP) area was generally dry (on average), while the northern ETP (N-ETP) area was wet. During the Little Ice Age (LIA), hydroclimate over S-ETP areas was wet, while that over N-ETP area was dry (on average). Such hydroclimatic contrasts can be broadly extended to ISM and EASM areas. We contend that changes in sea surface temperatures (SSTs) of the tropical Pacific Ocean could have played important roles in producing these hydroclimatic contrasts, by forcing the north-south movement of the Intertropical Convergence Zone (ITCZ) and intensification/slowdown of Walker circulation. The results of sensitivity experiments also support such a proposition

Critical Role of IRF-5 in the Development of T helper 1 responses to Leishmania donovani infection

The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leishmaniasis to investigate the role of IRF-5 in the generation of Th1 responses and in the formation of Th1-type liver granulomas in Leishmania donovani infected mice. We show that TLR7-mediated activation of IRF-5 is essential for the development of Th1 responses to L. donovani in the spleen during chronic infection. We also demonstrate that IRF-5 deficiency leads to the incapacity to control L. donovani infection in the liver and to the formation of smaller granulomas. Granulomas in Irf5-/- mice are characterized by an increased IL-4 and IL-10 response and concomitant low iNOS expression. Collectively, these results identify IRF-5 as a critical molecular switch for the development of Th1 immune responses following L. donovani infections and reveal an indirect role of IRF-5 in the regulation of iNOS expression

Critical Role of IRF-5 in the Development of T helper 1 responses to Leishmania donovani infection

The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leishmaniasis to investigate the role of IRF-5 in the generation of Th1 responses and in the formation of Th1-type liver granulomas in Leishmania donovani infected mice. We show that TLR7-mediated activation of IRF-5 is essential for the development of Th1 responses to L. donovani in the spleen during chronic infection. We also demonstrate that IRF-5 deficiency leads to the incapacity to control L. donovani infection in the liver and to the formation of smaller granulomas. Granulomas in Irf5-/- mice are characterized by an increased IL-4 and IL-10 response and concomitant low iNOS expression. Collectively, these results identify IRF-5 as a critical molecular switch for the development of Th1 immune responses following L. donovani infections and reveal an indirect role of IRF-5 in the regulation of iNOS expression

Late Holocene linkages between decade–century scale climate variability and productivity at Lake Tanganyika, Africa

Microlaminated sediment cores from the Kalya slope region of Lake Tanganyika provide a near-annually resolved paleoclimate record between ~~2,840 and 1,420 cal. yr B.P. demonstrating strong linkages between climate variability and lacustrine productivity. Laminae couplets comprise dark, terrigenous-dominated half couplets, interpreted as low density underflows deposited from riverine sources during the rainy season, alternating with light, planktonic diatomaceous ooze, with little terrigenous component, interpreted as windy/dry season deposits. Laminated portions of the studied cores consist of conspicuous dark and light colored bundles of laminae couplets. Light and dark bundles alternate at decadal time scales. Within dark bundles, both light and dark half couplets are significantly thinner than within light bundles, implying slower sediment accumulation rates during both seasons over those intervals. Time series analyses of laminae thickness patterns demonstrate significant periodicities at interannual¿centennial time scales. Longer time scale periodicities (multidecadal to centennial scale) of light and dark half couplet thicknesses are coherent and in some cases are similar to solar cycle periods on these time scales. Although laminae thickness cycles do not strongly covary with the actual ¿14C record for this same time period, two large ¿14C anomalies are associated with substantial decreases in both light and dark laminae thickness. In contrast to the multidecadal¿ centennial time scale, significant annual to decadal periodicities, which are broadly consistent with ENSO/PDO forcing and their impact on East African climate, are not coherent between light and dark half couplets. The coherency of light¿dark couplets at decadal¿centennial time scales, but not at shorter time scales, is consistent with a model of a long-term relationship between precipitation (recorded in wet season dark laminae thickness) and productivity (light laminae thickness), which is not manifest at shorter time scales. We hypothesize that this coupling results from long-term recharging of internal nutrient loading during wet periods (higher erosion of soil P) and reduced loading during drought intervals. The relationship is not expressed on short time scales during which the dominant control on productivity is wind-driven, dry season upwelling, which is uncorrelated with wet-season precipitation. Our record greatly extends the temporal record of this quasi-periodic behavior throughout the late Holocene and provides the first evidence linking decade- to century-scale episodes of enhanced productivity to enhanced precipitation levels and nutrient recharge in a productive tropical lake

Randomized Controlled Trial of Fish Oil and Montelukast and Their Combination on Airway Inflammation and Hyperpnea-Induced Bronchoconstriction

Both fish oil and montelukast have been shown to reduce the severity of exercise-induced bronchoconstriction (EIB). The purpose of this study was to compare the effects of fish oil and montelukast, alone and in combination, on airway inflammation and bronchoconstriction induced by eucapnic voluntary hyperpnea (EVH) in asthmatics. In this model of EIB, twenty asthmatic subjects with documented hyperpnea-induced bronchoconstriction (HIB) entered a randomized double-blind trial. All subjects entered on their usual diet (pre-treatment, n = 20) and then were randomly assigned to receive either one active 10 mg montelukast tablet and 10 placebo fish oil capsules (n = 10) or one placebo montelukast tablet and 10 active fish oil capsules totaling 3.2 g EPA and 2.0 g DHA (n = 10) taken daily for 3-wk. Thereafter, all subjects (combination treatment; n = 20) underwent another 3-wk treatment period consisting of a 10 mg active montelukast tablet or 10 active fish oil capsules taken daily. While HIB was significantly inhibited (p0.017) between treatment groups; percent fall in forced expiratory volume in 1-sec was −18.4±2.1%, −9.3±2.8%, −11.6±2.8% and −10.8±1.7% on usual diet (pre-treatment), fish oil, montelukast and combination treatment respectively. All three treatments were associated with a significant reduction (p0.017) in these biomarkers between treatments. While fish oil and montelukast are both effective in attenuating airway inflammation and HIB, combining fish oil with montelukast did not confer a greater protective effect than either intervention alone. Fish oil supplementation should be considered as an alternative treatment for EIB

The role of historical and contemporary processes on phylogeographic structure and genetic diversity in the Northern Cardinal, Cardinalis cardinalis

Background Earth history events such as climate change are believed to have played a major role in shaping patterns of genetic structure and diversity in species. However, there is a lag between the time of historical events and the collection of present-day samples that are used to infer contemporary population structure. During this lag phase contemporary processes such as dispersal or non-random mating can erase or reinforce population differences generated by historical events. In this study we evaluate the role of both historical and contemporary processes on the phylogeography of a widespread North American songbird, the Northern Cardinal, Cardinalis cardinalis. Results Phylogenetic analysis revealed deep mtDNA structure with six lineages across the species\u27 range. Ecological niche models supported the same geographic breaks revealed by the mtDNA. A paleoecological niche model for the Last Glacial Maximum indicated that cardinals underwent a dramatic range reduction in eastern North America, whereas their ranges were more stable in México. In eastern North America cardinals expanded out of glacial refugia, but we found no signature of decreased genetic diversity in areas colonized after the Last Glacial Maximum. Present-day demographic data suggested that population growth across the expansion cline is positively correlated with latitude. We propose that there was no loss of genetic diversity in areas colonized after the Last Glacial Maximum because recent high-levels of gene flow across the region have homogenized genetic diversity in eastern North America. Conclusion We show that both deep historical events as well as demographic processes that occurred following these events are critical in shaping genetic pattern and diversity in C. cardinalis. The general implication of our results is that patterns of genetic diversity are best understood when information on species history, ecology, and demography are considered simultaneously

The role of historical and contemporary processes on phylogeographic structure and genetic diversity in the Northern Cardinal, Cardinalis cardinalis

<p>Abstract</p> <p>Background</p> <p>Earth history events such as climate change are believed to have played a major role in shaping patterns of genetic structure and diversity in species. However, there is a lag between the time of historical events and the collection of present-day samples that are used to infer contemporary population structure. During this lag phase contemporary processes such as dispersal or non-random mating can erase or reinforce population differences generated by historical events. In this study we evaluate the role of both historical and contemporary processes on the phylogeography of a widespread North American songbird, the Northern Cardinal, <it>Cardinalis cardinalis</it>.</p> <p>Results</p> <p>Phylogenetic analysis revealed deep mtDNA structure with six lineages across the species' range. Ecological niche models supported the same geographic breaks revealed by the mtDNA. A paleoecological niche model for the Last Glacial Maximum indicated that cardinals underwent a dramatic range reduction in eastern North America, whereas their ranges were more stable in México. In eastern North America cardinals expanded out of glacial refugia, but we found no signature of decreased genetic diversity in areas colonized after the Last Glacial Maximum. Present-day demographic data suggested that population growth across the expansion cline is positively correlated with latitude. We propose that there was no loss of genetic diversity in areas colonized after the Last Glacial Maximum because recent high-levels of gene flow across the region have homogenized genetic diversity in eastern North America.</p> <p>Conclusion</p> <p>We show that both deep historical events as well as demographic processes that occurred following these events are critical in shaping genetic pattern and diversity in <it>C. cardinalis</it>. The general implication of our results is that patterns of genetic diversity are best understood when information on species history, ecology, and demography are considered simultaneously.</p