A Non-Stationary Relationship between Global Climate Phenomena and Human Plague Incidence in Madagascar

Background

Plague, a zoonosis caused by Yersinia pestis, is found in Asia and the Americas, but predominantly in Africa, with the island of Madagascar reporting almost one third of human cases worldwide. Plague''s occurrence is affected by local climate factors which in turn are influenced by large-scale climate phenomena such as the El Niño Southern Oscillation (ENSO). The effects of ENSO on regional climate are often enhanced or reduced by a second large-scale climate phenomenon, the Indian Ocean Dipole (IOD). It is known that ENSO and the IOD interact as drivers of disease. Yet the impacts of these phenomena in driving plague dynamics via their effect on regional climate, and specifically contributing to the foci of transmission on Madagascar, are unknown. Here we present the first analysis of the effects of ENSO and IOD on plague in Madagascar.

Methodology/principal findings

We use a forty-eight year monthly time-series of reported human plague cases from 1960 to 2008. Using wavelet analysis, we show that over the last fifty years there have been complex non-stationary associations between ENSO/IOD and the dynamics of plague in Madagascar. We demonstrate that ENSO and IOD influence temperature in Madagascar and that temperature and plague cycles are associated. The effects on plague appear to be mediated more by temperature, but precipitation also undoubtedly influences plague in Madagascar. Our results confirm a relationship between plague anomalies and an increase in the intensity of ENSO events and precipitation.

Conclusions/significance

This work widens the understanding of how climate factors acting over different temporal scales can combine to drive local disease dynamics. Given the association of increasing ENSO strength and plague anomalies in Madagascar it may in future be possible to forecast plague outbreaks in Madagascar. The study gives insight into the complex and changing relationship between climate factors and plague in Madagascar.     

Flame Experiments at the Advanced Light Source: New Insights into Soot Formation Processes

The following experimental protocols and the accompanying video are concerned with the flame experiments that are performed at the Chemical Dynamics Beamline of the Advanced Light Source (ALS) of the Lawrence Berkeley National Laboratory^1-4. This video demonstrates how the complex chemical structures of laboratory-based model flames are analyzed using flame-sampling mass spectrometry with tunable synchrotron-generated vacuum-ultraviolet (VUV) radiation. This experimental approach combines isomer-resolving capabilities with high sensitivity and a large dynamic range^5,6. The first part of the video describes experiments involving burner-stabilized, reduced-pressure (20-80 mbar) laminar premixed flames. A small hydrocarbon fuel was used for the selected flame to demonstrate the general experimental approach. It is shown how species’ profiles are acquired as a function of distance from the burner surface and how the tunability of the VUV photon energy is used advantageously to identify many combustion intermediates based on their ionization energies. For example, this technique has been used to study gas-phase aspects of the soot-formation processes, and the video shows how the resonance-stabilized radicals, such as C₃H₃, C₃H₅, and i-C₄H₅, are identified as important intermediates⁷. The work has been focused on soot formation processes, and, from the chemical point of view, this process is very intriguing because chemical structures containing millions of carbon atoms are assembled from a fuel molecule possessing only a few carbon atoms in just milliseconds. The second part of the video highlights a new experiment, in which an opposed-flow diffusion flame and synchrotron-based aerosol mass spectrometry are used to study the chemical composition of the combustion-generated soot particles⁴. The experimental results indicate that the widely accepted H-abstraction-C₂H₂-addition (HACA) mechanism is not the sole molecular growth process responsible for the formation of the observed large polycyclic aromatic hydrocarbons (PAHs).     

Structure of a helically extended SH3 domain of the T cell adapter protein ADAP

The adapter protein ADAP (FYB/SLAP-130) provides a critical link between T cell receptor (TCR) signaling and cell adhesion via the activation of integrins. The C-terminal 70 residues of ADAP show homology to SH3 domains; however, conserved residues of the fold are absent. An alignment and annotation of this domain has therefore been elusive. We have solved the three-dimensional structure of the ADAP C-terminal domain by NMR spectroscopy and show that it represents an altered SH3 domain fold. An N-terminal, amphipathic helix makes extensive contacts to residues of the regular SH3 domain fold, and thereby a composite surface with unusual surface properties is created. We propose this SH3 domain variant to be classified as a helically extended SH3 domain (hSH3 domain) and show that the ADAP-hSH3 domain can no longer bind conventional proline-rich peptides.     

Amniotic fluid stem cells to study mTOR signaling in differentiation

The protein kinase mTOR is the central player within a pathway, which is known to be involved in the regulation of e.g., cell size, cell cycle, apoptosis, autophagy, aging and differentiation. mTOR activity responds to many signals, including cellular stress, oxygen, nutrient availability, energy status and growth factors. Deregulation of this enzyme is causatively involved in the molecular development of monogenic human diseases, cancer, obesity, type 2 diabetes or neurodegeneration. Recently, mTOR has also been demonstrated to control stem cell homeostasis. A more detailed investigation of this new mTOR function will be of highest relevance to provide more explicit insights into stem cell regulation in the near future. Different cellular tools, including adult stem cells, embryonic stem cells or induced pluripotent stem cells could be used to investigate the role of mTOR in mammalian stem cell biology. Here we discuss the potential of amniotic fluid stem cells to become a promising cellular model to study the role of signaling cascades in stem cell homeostasis.     

A bacterial-fungal metaproteomic analysis enlightens an intriguing multicomponent interaction in the rhizosphere of Lactuca sativa

Fusarium oxysporum MSA 35 [wild-type (WT) strain] is an antagonistic isolate that protects plants against pathogenic Fusaria. This strain lives in association with ectosymbiotic bacteria. When cured of the prokaryotic symbionts [cured (CU) form], the fungus is pathogenic, causing wilt symptoms similar to those of F. oxysporum f.sp. lactucae. The aim of this study was to understand if and how the host plant Lactuca sativa contributes to the expression of the antagonistic/pathogenic behaviors of MSA 35 strains. A time-course comparative analysis of the proteomic profiles of WT and CU strains was performed. Fungal proteins expressed during the early stages of plant-fungus interaction were involved in stress defense, energy metabolism, and virulence and were equally induced in both strains. In the late phase of the interkingdom interaction, only CU strain continued the production of virulence- and energy-related proteins. The expression analysis of lettuce genes coding for proteins involved in resistance-related processes corroborated proteomic data by showing that, at the beginning of the interaction, both fungi are perceived by the plant as pathogen. On the contrary, after 8 days, only the CU strain is able to induce plant gene expression. For the first time, it was demonstrated that an antagonistic F. oxysporum behaves initially as pathogen, showing an interesting similarity with other beneficial organisms such as mychorrizae.     

Detection of IGF2BP3, HOXB7, and NEK2 mRNA Expression in Brush Cytology Specimens as a New Diagnostic Tool in Patients with Biliary Strictures

Introduction

It is a challenging task to distinguish between benign and malignant lesions in patients with biliary strictures. Here we analyze whether determination of target gene mRNA levels in intraductal brush cytology specimens may be used to improve the diagnosis of bile duct carcinoma.

Materials and Methods

Brush cytology specimens from 119 patients with biliary strictures (malignant: n = 72; benign: n = 47) were analyzed in a retrospective cohort study. mRNA of IGF-II mRNA-binding protein 3 (IGF2BP3), homeobox B7 (HOXB7), Forkhead box M1 (FOXM1), kinesin family member 2C (KIF2C) and serine/threonine kinase NEK2 was determined by semi-quantitative RT-PCR using the ΔCt method.

Results

IGF2BP3 (p<0.0001), HOXB7 (p<0.0001), and NEK2 (p<0.0001) mRNA expression levels were significantly increased in patients with cholangiocarcinoma or pancreatic cancer. Median ΔCt values differed by 3.5 cycles (IGF2BP3), 2.8 cycles (HOXB7) and 1.3 cycles (NEK2) corresponding to 11-fold, 7-fold and 2.5-fold increased mRNA levels in malignant versus benign samples. Sensitivity to detect biliary cancer was 76.4% for IGF2BP3 (80.9% specificity); 72.2% for HOXB7 (78.7% specificity) and 65.3% for NEK2 (72.3% specificity), whereas routine cytology reached only 43.1% sensitivity (85.4% specificity). Diagnostic precision was further improved, when all three molecular markers were assessed in combination (77.8% sensitivity, 87.2% specificity) and achieved 87.5% sensitivity and 87.2% specificity when molecular markers were combined with routine cytology.

Conclusions

Our data suggest that measuring IGF2BP3, HOXB7 and NEK2 mRNA levels by RT-PCR in addition to cytology has the potential to improve detection of malignant biliary disorders from brush cytology specimens.     

Retinal Nerve Fibre Layer Thinning in Patients with Clinically Isolated Optic Neuritis and Early Treatment with Interferon-Beta

Background

Optic neuritis is associated with neurodegeneration leading to chronic impairment of visual functions.

Objective

This study investigated whether early treatment with interferon beta (IFN-β) slows retinal nerve fibre layer (RNFL) thinning in clinically isolated optic neuritis.

Methods

Twenty patients with optic neuritis and visual acuity decreased to ≤0.5 (decimal system) were included into this prospective, open-label, parallel group 4-month observation. After methylprednisolone pulse therapy, 10 patients received IFN-β from week 2 onwards. This group was compared to 10 patients free of any disease modifying treatment (DMT). The parameter of interest was change in RNFL thickness assessed at baseline and at weeks 4, 8, and 16. Changes in visual acuity, visual field, and visual evoked potentials (VEPs) served as additional outcome parameters.

Results

RNFL thinning did not differ between the groups with a mean reduction of 9.80±2.80 µm in IFN-β-treated patients (±SD) vs. 12.44±5.79 µm in patients who did not receive DMT (baseline non-affected eye minus affected eye at week 16; p = 0.67, t-test, 95% confidence interval: −15.77 to 10.48). Parameters of visual function did not show any differences between the groups either.

Conclusions

In isolated optic neuritis, early IFN-β treatment did not influence RNFL thinning nor had it any effect on recovery of visual functions.