Metabolomics to unveil and understand phenotypic diversity between pathogen populations

Visceral leishmaniasis is caused by a parasite called Leishmania donovani, which every year infects about half a million people and claims several thousand lives. Existing treatments are now becoming less effective due to the emergence of drug resistance. Improving our understanding of the mechanisms used by the parasite to adapt to drugs and achieve resistance is crucial for developing future treatment strategies. Unfortunately, the biological mechanism whereby Leishmania acquires drug resistance is poorly understood. Recent years have brought new technologies with the potential to increase greatly our understanding of drug resistance mechanisms. The latest mass spectrometry techniques allow the metabolome of parasites to be studied rapidly and in great detail. We have applied this approach to determine the metabolome of drug-sensitive and drug-resistant parasites isolated from patients with leishmaniasis. The data show that there are wholesale differences between the isolates and that the membrane composition has been drastically modified in drug-resistant parasites compared with drug-sensitive parasites. Our findings demonstrate that untargeted metabolomics has great potential to identify major metabolic differences between closely related parasite strains and thus should find many applications in distinguishing parasite phenotypes of clinical relevance

PTF11eon/SN2011dh: Discovery of a Type IIb Supernova From a Compact Progenitor in the Nearby Galaxy M51

On May 31, 2011 UT a supernova (SN) exploded in the nearby galaxy M51 (the Whirlpool Galaxy). We discovered this event using small telescopes equipped with CCD cameras, as well as by the Palomar Transient Factory (PTF) survey, and rapidly confirmed it to be a Type II supernova. Our early light curve and spectroscopy indicates that PTF11eon resulted from the explosion of a relatively compact progenitor star as evidenced by the rapid shock-breakout cooling seen in the light curve, the relatively low temperature in early-time spectra and the prompt appearance of low-ionization spectral features. The spectra of PTF11eon are dominated by H lines out to day 10 after explosion, but initial signs of He appear to be present. Assuming that He lines continue to develop in the near future, this SN is likely a member of the cIIb (compact IIb; Chevalier and Soderberg 2010) class, with progenitor radius larger than that of SN 2008ax and smaller than the eIIb (extended IIb) SN 1993J progenitor. Our data imply that the object identified in pre-explosion Hubble Space Telescope images at the SN location is possibly a companion to the progenitor or a blended source, and not the progenitor star itself, as its radius (~10^13 cm) would be highly inconsistent with constraints from our post-explosion photometric and spectroscopic data

Drug Discovery for Kinetoplastid Diseases : Future Directions

International audienceKinetoplastid parasites have caused human disease for millennia. Significant achievements have been made toward developing new treatments for leishmaniasis (particularly on the Indian subcontinent) and for human African trypanosomiasis (HAT). Moreover, the sustained decrease in the incidence of HAT has made the prospect of elimination a tantalizing reality. Despite the gains, no new chemical or biological entities to treat kinetoplastid diseases have been registered in more than three decades, and more work is needed to discover safe and effective therapies for patients with Chagas disease and leishmaniasis. Advances in tools for drug discovery and novel insights into the biology of the host-parasite interaction may provide opportunities for accelerated progress. Here, we summarize the output from a gathering of scientists and physicians who met to discuss the current status and future directions in drug discovery for kinetoplastid diseases

Protective Antibody and CD8+ T-Cell Responses to the Plasmodium falciparum Circumsporozoite Protein Induced by a Nanoparticle Vaccine

Background The worldwide burden of malaria remains a major public health problem due, in part, to the lack of an effective vaccine against the Plasmodium falciparum parasite. An effective vaccine will most likely require the induction of antigen specific CD8+ and CD4+ T-cells as well as long-lasting antibody responses all working in concert to eliminate the infection. We report here the effective modification of a self-assembling protein nanoparticle (SAPN) vaccine previously proven effective in control of a P. berghei infection in a rodent model to now present B- and T-cell epitopes of the human malaria parasite P. falciparum in a platform capable of being used in human subjects. Methodology/Principal Findings To establish the basis for a SAPN-based vaccine, B- and CD8+ T-cell epitopes from the P. falciparum circumsporozoite protein (PfCSP) and the universal CD4 T-helper epitope PADRE were engineered into a versatile small protein (∼125 amino acids) that self-assembles into a spherical nanoparticle repetitively displaying the selected epitopes. P. falciparum epitope specific immune responses were evaluated in mice using a transgenic P. berghei malaria parasite of mice expressing the human malaria full-length P. falciparum circumsporozoite protein (Tg-Pb/PfCSP). We show that SAPN constructs, delivered in saline, can induce high-titer, long-lasting (1 year) protective antibody and poly-functional (IFNγ+, IL-2+) long-lived central memory CD8+ T-cells. Furthermore, we demonstrated that these Ab or CD8+ T–cells can independently provide sterile protection against a lethal challenge of the transgenic parasites. Conclusion The SAPN construct induces long-lasting antibody and cellular immune responses to epitope specific sequences of the P. falciparum circumsporozoite protein (PfCSP) and prevents infection in mice by a transgenic P. berghei parasite displaying the full length PfCSP

Adverse Drug Reactions in Hospital In-Patients: A Prospective Analysis of 3695 Patient-Episodes

Adverse drug reactions (ADRs) are a major cause of hospital admissions, but recent data on the incidence and clinical characteristics of ADRs which occur following hospital admission, are lacking. Patients admitted to twelve wards over a six-month period in 2005 were assessed for ADRs throughout their admission. Suspected ADRs were recorded and analysed for causality, severity and avoidability and whether they increased the length of stay. Multivariable analysis was undertaken to identify the risk factors for ADRs. The 5% significance level was used when assessing factors for inclusion in multivariable models. Out of the 3695 patient episodes assessed for ADRs, 545 (14.7%, 95% CI 13.6–15.9%) experienced one or more ADRs. Half of ADRs were definitely or possibly avoidable. The patients experiencing ADRs were more likely to be older, female, taking a larger number of medicines, and had a longer length of stay than those without ADRs. However, the only significant predictor of ADRs, from the multivariable analysis of a representative sample of patients, was the number of medicines taken by the patient with each additional medication multiplying the hazard of an ADR episode by 1.14 (95% CI 1.09, 1.20). ADRs directly increased length of stay in 147 (26.8%) patients. The drugs most frequently associated with ADRs were diuretics, opioid analgesics, and anticoagulants. In conclusion, approximately one in seven hospital in-patients experience an ADR, which is a significant cause of morbidity, increasing the length of stay of patients by an average of 0.25 days/patient admission episode. The overall burden of ADRs on hospitals is high, and effective intervention strategies are urgently needed to reduce this burden

The Case for a Sustained Greenland Ice Sheet-Ocean Observing System (GrIOOS)

Rapid mass loss from the Greenland Ice Sheet (GrIS) is affecting sea level and, through increased freshwater and sediment discharge, ocean circulation, sea-ice, biogeochemistry, and marine ecosystems around Greenland. Key to interpreting ongoing and projecting future ice loss, and its impact on the ocean, is understanding exchanges of heat, freshwater, and nutrients that occur at the GrIS marine margins. Processes governing these exchanges are not well understood because of limited observations from the regions where glaciers terminate into the ocean and the challenge of modeling the spatial and temporal scales involved. Thus, notwithstanding their importance, ice sheet/ocean exchanges are poorly represented or not accounted for in models used for projection studies. Widespread community consensus maintains that concurrent and long-term records of glaciological, oceanic, and atmospheric parameters at the ice sheet/ocean margins are key to addressing this knowledge gap by informing understanding, and constraining and validating models. Through a series of workshops and documents endorsed by the community-at-large, a framework for an international, collaborative, Greenland Ice sheet-Ocean Observing System (GrIOOS), that addresses the needs of society in relation to a changing GrIS, has been proposed. This system would consist of a set of ocean, glacier, and atmosphere essential variables to be collected at a number of diverse sites around Greenland for a minimum of two decades. Internationally agreed upon data protocols and data sharing policies would guarantee uniformity and availability of the information for the broader community. Its development, maintenance, and funding will require close international collaboration. Engagement of end-users, local people, and groups already active in these areas, as well as synergy with ongoing, related, or complementary networks will be key to its success and effectiveness

Cardiac and vascular structure and function parameters do not improve with alternate nightly home hemodialysis: An interventional cohort study

Background: Nightly extended hours hemodialysis may improve left ventricular hypertrophy and function and endothelial function but presents problems of sustainability and increased cost. The effect of alternate nightly home hemodialysis (NHD) on cardiovascular structure and function is not known

The JCMT BISTRO Survey: The Magnetic Field Strength in the Orion A Filament

We determine the magnetic field strength in the OMC 1 region of the Orion A filament via a new implementation of the Chandrasekhar-Fermi method using observations performed as part of the James Clerk Maxwell Telescope (JCMT) B-Fields In Star-Forming Region Observations (BISTRO) survey with the POL-2 instrument. We combine BISTRO data with archival SCUBA-2 and HARP observations to find a plane-of-sky magnetic field strength in OMC 1 of B_pos=6.6±4.7 mG, where δB_pos=4.7 mG represents a predominantly systematic uncertainty. We develop a new method for measuring angular dispersion, analogous to unsharp masking. We find a magnetic energy density of ~1.7×10^-7 Jm^-3 in OMC 1, comparable both to the gravitational potential energy density of OMC 1 (~10^-7 Jm^-3), and to the energy density in the Orion BN/KL outflow (~10^-7 Jm^-3). We find that neither the Alfvén velocity in OMC 1 nor the velocity of the super-Alfvénic outflow ejecta is sufficiently large for the BN/KL outflow to have caused large-scale distortion of the local magnetic field in the ~500-year lifetime of the outflow. Hence, we propose that the hour-glass field morphology in OMC 1 is caused by the distortion of a primordial cylindrically-symmetric magnetic field by the gravitational fragmentation of the filament and/or the gravitational interaction of the BN/KL and S clumps. We find that OMC 1 is currently in or near magnetically-supported equilibrium, and that the current large-scale morphology of the BN/KL outflow is regulated by the geometry of the magnetic field in OMC 1, and not vice versa

Characteristics of surface “melt potential” over Antarctic ice shelves based on regional atmospheric model simulations of summer air temperature extremes from 1979/80 to 2018/19

We calculate a regional surface “melt potential” index (MPI) over Antarctic ice shelves that describes the frequency (MPI-freq, %) and intensity (MPI-int, K) of daily maximum summer temperatures exceeding a melt threshold of 273.15 K. This is used to determine which ice shelves are vulnerable to melt-induced hydrofracture and is calculated using near-surface temperature output for each summer from 1979/80 to 2018/19 from two high-resolution regional atmospheric model hindcasts (using the MetUM and HIRHAM5). MPI is highest for Antarctic Peninsula ice shelves (MPI-freq 23-35%, MPI-int 1.2-2.1 K), lowest (2-3%, < 0 K) for Ronne-Filchner and Ross ice shelves, and around 10-24% and 0.6-1.7 K for the other West and East Antarctic ice shelves. Hotspots of MPI are apparent over many ice shelves, and they also show a decreasing trend in MPI-freq. The regional circulation patterns associated with high MPI values over West and East Antarctic ice shelves are remarkably consistent for their respective region but tied to different large-scale climate forcings. The West Antarctic circulation resembles the central Pacific El Niño pattern with a stationary Rossby wave and a strong anticyclone over the high-latitude South Pacific. By contrast, the East Antarctic circulation comprises a zonally symmetric negative Southern Annular Mode pattern with a strong regional anticyclone on the plateau and enhanced coastal easterlies/weakened Southern Ocean westerlies. Values of MPI are 3-4 times larger for a lower temperature/melt threshold of 271.15 K used in a sensitivity test, as melting can occur at temperatures lower than 273.15 K depending on snowpack properties