Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus.

Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin-NFAT activation is phagocytosis dependent and collaborates with NF-κB for TNF-α production. For yeast zymosan particles, activation of macrophage calcineurin-NFAT occurs via the phagocytic Dectin-1-spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9-dependent and Bruton's tyrosine kinase-dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF-κB for TNF-α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9-BTK-calcineurin-NFAT signalling pathway as a key immune defect that leads to organ transplant-related invasive aspergillosis

Cohesin Protects Genes against γH2AX Induced by DNA Double-Strand Breaks

Chromatin undergoes major remodeling around DNA double-strand breaks (DSB) to promote repair and DNA damage response (DDR) activation. We recently reported a high-resolution map of γH2AX around multiple breaks on the human genome, using a new cell-based DSB inducible system. In an attempt to further characterize the chromatin landscape induced around DSBs, we now report the profile of SMC3, a subunit of the cohesin complex, previously characterized as required for repair by homologous recombination. We found that recruitment of cohesin is moderate and restricted to the immediate vicinity of DSBs in human cells. In addition, we show that cohesin controls γH2AX distribution within domains. Indeed, as we reported previously for transcription, cohesin binding antagonizes γH2AX spreading. Remarkably, depletion of cohesin leads to an increase of γH2AX at cohesin-bound genes, associated with a decrease in their expression level after DSB induction. We propose that, in agreement with their function in chromosome architecture, cohesin could also help to isolate active genes from some chromatin remodelling and modifications such as the ones that occur when a DSB is detected on the genome

A framework for assessing the feasibility of malaria elimination

The recent scale-up of malaria interventions, the ensuing reductions in the malaria burden, and reinvigorated discussions about global eradication have led many countries to consider malaria elimination as an alternative to maintaining control measures indefinitely. Evidence-based guidance to help countries weigh their options is thus urgently needed. A quantitative feasibility assessment that balances the epidemiological situation in a region, the strength of the public health system, the resource constraints, and the status of malaria control in neighboring areas can serve as the basis for robust, long-term strategic planning. Such a malaria elimination feasibility assessment was recently prepared for the Minister of Health in Zanzibar. Based on the Zanzibar experience, a framework is proposed along three axes that assess the technical requirements to achieve and maintain elimination, the operational capacity of the malaria programme and the public health system to meet those requirements, and the feasibility of funding the necessary programmes over time. Key quantitative and qualitative metrics related to each component of the assessment are described here along with the process of collecting data and interpreting the results. Although further field testing, validation, and methodological improvements will be required to ensure applicability in different epidemiological settings, the result is a flexible, rational methodology for weighing different strategic options that can be applied in a variety of contexts to establish data-driven strategic plans

Estimating the Global Clinical Burden of Plasmodium falciparum Malaria in 2007

Simon Hay and colleagues derive contemporary estimates of the global clinical burden of Plasmodium falciparum malaria (the deadliest form of malaria) using cartography-based techniques

Intravitreal triamcinolone acetonide for rebound phenomenon after high-dose intravenous steroid treatment in Vogt-Koyanagi-Harada disease

Ik Soo Byon1, Ji Hun Kim1, Ji Eun Lee1,2, Boo Sup Oum1,2 1Department of Ophthalmology, Pusan National University Hospital; 2Medical Institute, School of Medicine, Pusan National University, Busan, Republic of Korea Abstract: The authors report two cases of rebound phenomenon treated with intravitreal triamcinolone acetonide in Vogt-Koyanagi-Harada (VKH) disease. Patients in the acute phase of VKH disease were treated with high-dose intravenous (IV) methylprednisolone (1 g/day) for 3 days. Serous retinal detachment decreased and visual acuity improved during IV steroid treatment. After switching to oral steroid treatment, choroiditis and visual acuity worsened. An injection of triamcinolone acetonide (4 mg) into the vitreous resulted in gradual resolution of subretinal fluid and improvement of visual acuity. Systemic steroids were tapered to discontinuation without a relapse of inflammation. Adjuvant intravitreal triamcinolone is useful in the management of the rebound phenomenon in VKH disease. Keywords: adjuvant intravitreal steroid, serous retinal detachment, visual acuity, choroiditi

A study on doping density in InAs/GaAs quantum dot infrared photodetector

We study the influence of doping density and the resulting optimum operation voltage on the performance of quantum dot infrared photodetectors (QDIPs). The optimum operation voltage, where detectivity becomes maximum, becomes smaller as the doping density increases. This is because the optimum dark current levels are similar regardless of the doping density. We confirmed experimentally that the optimum dark current level is similar to5 mA (current density: similar toA/cm(2)) for our samples. It is found that the higher doping density improves the performance in the range used in this experiment (5 x 10(16)-5 x 10(17)/cm(3)). The response to a normal incident light is confirmed and the possibility of high-temperature operation of QDIP is shown.X111013sciescopu