Ipr1 gene mediates innate immunity to tuberculosis

An estimated eight million people are infected each year with the pathogen Mycobacterium tuberculosis, and more than two million die annually. Yet only about 10% of those infected develop tuberculosis. Genetic variation within host populations is known to be significant in humans and animals, but the nature of genetic control of host resistance to tuberculosis remains poorly understood. Previously we mapped a new genetic locus on mouse chromosome 1, designated sst1 (for supersusceptibility to tuberculosis 1). Here we show that this locus mediates innate immunity in sst1 congenic mouse strains and identify a candidate gene, Intracellular pathogen resistance 1 (Ipr1), within the sst1 locus. The Ipr1 gene is upregulated in the sst1 resistant macrophages after activation and infection, but it is not expressed in the sst1 susceptible macrophages. Expression of the Ipr1 transgene in the sst1 susceptible macrophages limits the multiplication not only of M. tuberculosis but also of Listeria monocytogenes and switches a cell death pathway of the infected macrophages from necrosis to apoptosis. Our data indicate that the Ipr1 gene product might have a previously undocumented function in integrating signals generated by intracellular pathogens with mechanisms controlling innate immunity, cell death and pathogenesis.     

Computational redesign of endonuclease DNA binding and cleavage specificity

The reprogramming of DNA-binding specificity is an important challenge for computational protein design that tests current understanding of protein-DNA recognition, and has considerable practical relevance for biotechnology and medicine. Here we describe the computational redesign of the cleavage specificity of the intron-encoded homing endonuclease I-MsoI using a physically realistic atomic-level forcefield. Using an in silico screen, we identified single base-pair substitutions predicted to disrupt binding by the wild-type enzyme, and then optimized the identities and conformations of clusters of amino acids around each of these unfavourable substitutions using Monte Carlo sampling. A redesigned enzyme that was predicted to display altered target site specificity, while maintaining wild-type binding affinity, was experimentally characterized. The redesigned enzyme binds and cleaves the redesigned recognition site approximately 10,000 times more effectively than does the wild-type enzyme, with a level of target discrimination comparable to the original endonuclease. Determination of the structure of the redesigned nuclease-recognition site complex by X-ray crystallography confirms the accuracy of the computationally predicted interface. These results suggest that computational protein design methods can have an important role in the creation of novel highly specific endonucleases for gene therapy and other applications.     

Spinoza on the resistance of bodies

Commentators often claim that the bodies of Spinoza’s physics resist the changes they undergo. But it’s not always clear what they mean when they say this, or whether they are entitled to say it. This article clarifies what it might mean to for Spinoza’s bodies to resist change, and examines the evidence for such a view. In the first half, the author argues that there is some limited evidence for such a view, but not nearly as much as people think. In the second half, the author proposes looking for a mental analogue to collision in the realm of ideas and argues that adequacy amounts to a meaningful concept of resistance in Spinoza, albeit one that is incomplete.     

Control of the carrier-envelope phases of a synchronously pumped femtosecond optical parametric oscillator and its applications

The intrinsic synchronization, multi-color outputs and related carrier-envelope phases （CEP） among pulses bring advantages to synchronously pumped femtosecond optical parametric oscillators and the pumping sources for broadband frequency comb generation and ultrashort waveform coherent syn-thesis. In this paper, we discuss our latest research results in this field, which cover the following as-pects： the phase relationship and energy conservation law in an OPO and related experimental verifi-cation; control of the pumping Ti-sapphire femtosecond laser＇s CEP by self-referencing technology, and its repetition-rate locking by piezoelectric transducer （PZT）; CEP locking of the pulses from the OPO by beating the non-phase-matched visible outputs against pump supercontinuum to obtain a driving signal for a fast PZT on the OPO end mirror; the generation of a broadband frequency comb spanning from 400 nm to 2.4 μm with 1.2 kHz bandwidth; and the realization of coherent interference between phase controlled pump pulses and signal second harmonic pulses.