Publications

The mycobacterial cell wall component lipoarabinomannan (LAM) has been described as one of the key virulence factors of Mycobacterium tuberculosis. Modification of the terminal arabinan residues of this lipoglycan with mannose caps in M. tuberculosis or with phosphoinositol caps in Mycobacterium smegmatis results in distinct host immune responses. Given that M. tuberculosis typically persists in the phagosomal vacuole after being phagocytosed by macrophages, we performed a proteomic analysis of that organelle after treatment of macrophages with LAMs purified from the two mycobacterial species. The quantitative changes in phagosomal proteins suggested a distinct role for mannose-capped LAM in modulating protein trafficking pathways that contribute to the arrest of phagosome maturation. Enlightened by our proteomic data, we performed further experiments to show that only the LAM from M. tuberculosis inhibits accumulation of autophagic vacuoles in the macrophage, suggesting a new function for this virulence-associated lipid.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Current approved medical treatments for osteoporosis reduce fracture risk to a greater degree than predicted from change in BMD in women with postmenopausal osteoporosis. We hypothesize that bone active agents improve bone strength in osteoporotic bone by altering different material properties of the bone. Eighteen-month-old female Fischer rats were ovariectomized (OVX) or sham-operated and left untreated for 60 days to induce osteopenia before they were treated with single doses of either risedronate (500 μg/kg, IV), zoledronic acid (100 μg/kg, IV), raloxifene (2 mg/kg, PO, three times per week), hPTH(1–34) (25 μg/kg, SC, three times per week), or vehicle (NS; 1 ml/kg, three times per week). Groups of animals were killed after days 60 and 180 of treatment, and either the proximal tibial metaphysis or lumbar vertebral body were studied. Bone volume and architecture were assessed by μCT and histomorphometry. Measurements of bone quality included the degree of bone mineralization (DBM), localized elastic modulus, bone turnover by histomorphometry, compression testing of the LVB, and three-point bending testing of the femur. The trabecular bone volume, DBM, elastic modulus, and compressive bone strength were all significantly lower at day 60 post-OVX (pretreatment, day 0 study) than at baseline. After 60 days of all of the bone active treatments, bone mass and material measurements agent were restored. However, after 180 days of treatment, the OVX + PTH group further increased BV/TV (+30% from day 60, p < 0.05 within group and between groups). In addition, after 180 days of treatment, there was more highly mineralized cortical and trabecular bone and increased cortical bone size and whole bone strength in OVX + PTH compared with other OVX + antiresorptives. Treatment of estrogen-deficient aged rats with either antiresorptive agents or PTH rapidly improved many aspects of bone quality including microarchitecture, bone mineralization, turnover, and bone strength. However, prolonged treatment for 180 days with PTH resulted in additional gains in bone quality and bone strength, suggesting that the maximal gains in bone strength in cortical and trabecular bone sites may require a longer treatment period with PTH.

We present spectroscopic and photometric observations of the Type IIn supernova (SN) 2008iy. SN 2008iy showed an unprecedentedly long rise time of ∼400 d, making it the first known SN to take significantly longer than 100 d to reach peak optical luminosity. The peak absolute magnitude of SN 2008iy was <it>M<inf>r</inf></it>≈−19.1 mag, and the total radiated energy over the first ∼700 d was ∼2 × 1050 erg. Spectroscopically, SN 2008iy is very similar to the Type IIn SN 1988Z at late times and, like SN 1988Z, it is a luminous X-ray source (both SNe had an X-ray luminosity <it>L</it><inf>X</inf> > 1041 erg s−1). SN 2008iy has a growing near-infrared excess at late times similar to several other SNe IIn. The Hα emission-line profile of SN 2008iy shows a narrow P Cygni absorption component, implying a pre-SN wind speed of ∼100 km s−1. We argue that the luminosity of SN 2008iy is powered via the interaction of the SN ejecta with a dense, clumpy circumstellar medium. The ∼400-d rise time can be understood if the number density of clumps increases with distance over a radius ∼1.7 × 1016 cm from the progenitor. This scenario is possible if the progenitor experienced an episodic phase of enhanced mass loss <1 century prior to explosion or if the progenitor wind speed increased during the decades before core collapse. We favour the former scenario, which is reminiscent of the eruptive mass-loss episodes observed for luminous blue variable (LBV) stars. The progenitor wind speed and increased mass-loss rates serve as further evidence that at least some, and perhaps all, Type IIn SNe experience LBV-like eruptions shortly before core collapse. We also discuss the host galaxy of SN 2008iy, a subluminous dwarf galaxy, and offer a few reasons why the recent suggestion that unusual, luminous SNe preferentially occur in dwarf galaxies may be the result of observational biases.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Targeted covalent inhibitors are powerful entities in drug discovery, but their application has so far mainly been limited to addressing cysteine residues. The development of cysteine-directed covalent inhibitors has largely profited from determining their proteome-wide selectivity using competitive residue-specific proteomics. Several probes have recently been described to monitor other amino acids using this technology and many more electrophiles exist to modify proteins. Nevertheless, a direct, proteome‑wide comparison of the selectivity of diverse probes is still entirely missing. Here, we developed a completely unbiased workflow to analyse electrophile selectivity proteome‑wide and applied it to directly compare 54 alkyne probes containing diverse reactive groups. In this way, we verified and newly identified probes to monitor a total of nine different amino acids as well as the N ‑terminus proteome‑wide. This selection includes the first probes to globally monitor tryptophans, histidines and arginines as well as novel tailored probes for methionines, aspartates and glutamates.