Mass spectrometry captures off-target drug binding and provides mechanistic insights into the human metalloprotease ZMPSTE24.

Off-target binding of hydrophobic drugs can lead to unwanted side effects, either through specific or non-specific binding to unintended membrane protein targets. However, distinguishing the binding of drugs to membrane proteins from that of detergents, lipids and cofactors is challenging. Here, we use high-resolution mass spectrometry to study the effects of HIV protease inhibitors on the human zinc metalloprotease ZMPSTE24. This intramembrane protease plays a major role in converting prelamin A to mature lamin A. We monitored the proteolysis of farnesylated prelamin A peptide by ZMPSTE24 and unexpectedly found retention of the C-terminal peptide product with the enzyme. We also resolved binding of zinc, lipids and HIV protease inhibitors and showed that drug binding blocked prelamin A peptide cleavage and conferred stability to ZMPSTE24. Our results not only have relevance for the progeria-like side effects of certain HIV protease inhibitor drugs, but also highlight new approaches for documenting off-target drug binding

False-positive iodine-131 whole-body scan findings in patients with differentiated thyroid carcinoma: report of 11 cases and review of the literature

BACKGROUND: Iodine-131 (I-131) whole-body scan (WBS) plays an important role in the management of patients with differentiated thyroid carcinoma (DTC), to detect normal thyroid remnants and recurrent or metastatic disease. A focus of I-131 accumulation outside the thyroid bed and the areas of physiological uptake is strongly suggestive of a distant functioning metastasis. However, many false-positive I-131 WBS findings have been reported in the literature. PATIENT FINDINGS: We describe a series of 11 personal cases of patients with DTC, collected from 1992 to 2011, in whom diagnostic or post-treatment WBS showed false-positive retention of I-131 in various locations. SUMMARY: False-positive accumulations of I-131 on WBS may be classified according to the underlying pathophysiological mechanisms: external and internal contaminations by body secretions, ectopic normal thyroid and gastric tissues, inflammatory and infectious diseases, benign and malignant tumors, cysts and effusions of serous cavities, thymic uptake, and other non classified causes. CONCLUSIONS: Clinicians must be aware of possible false-positive findings to avoid misinterpretations of the I-131 WBS, which could lead to inappropriate treatments

The micrometeoroid complex and evolution of the lunar regolith

The interaction of the micrometeoroid complex with the lunar surface is evidenced by numerous glass-lined microcraters on virtually every lunar surface exposed to space. Such craters range in size from less than .1 micron to approximately 2 sq cm diameter. Using small scale laboratory cratering experiments for calibration, the observed crater-sized frequency distributions may be converted into micrometeoroid mass distributions. These lunar mass distributions are in essential agreement with satellite data. Some physical properties of micrometeoroids may be deduced by comparing lunar crater geometries with those obtained in laboratory experiments. The proponderance of circular outlines of lunar microcraters necessitates equidimensional, if not spherical, micrometeoroids

Scalable Substrate Development for Aqueous Biological Samples for Atom Probe Tomography

Reliable and consistent preparation of atom probe tomography (APT) specimens from aqueous and hydrated biological specimens remains a significant challenge. One particularly difficult process step is the use of a focused ion beam (FIB) instrument for preparing the required needle-shaped specimen, typically involving a "lift-out" procedure of a small sample of material. Here, two alternative substrate designs are introduced that enable using FIB only for sharpening, along with example APT datasets. The first design is a laser-cut FIB-style half-grid close to those used for transmission-electron microscopy, that can be used in a grid holder compatible with APT pucks. The second design is a larger, standalone self-supporting substrate called a "crown", with several specimen positions that self-aligns in APT pucks, prepared by electrical discharge machining (EDM). Both designs are made nanoporous, to provide strength to the liquid-substrate interface, using chemical and vacuum dealloying. We select alpha brass a simple, widely available, lower-cost alternative to previously proposed substrates. We present the resulting designs, APT data, and provide suggestions to help drive wider community adoption

Facilitating the systematic nanoscale study of battery materials by atom probe tomography through in-situ metal coating

Through its capability for 3D mapping of Li at the nanoscale, atom probe tomography (APT) is poised to play a key role in understanding the microstructural degradation of lithium-ion batteries (LIB) during successive charge and discharge cycles. However, APT application to materials for LIB is plagued by the field induced delithiation (deintercalation) of Li-ions during the analysis itself that prevents the precise assessment of the Li distribution. Here, we showcase how a thin Cr-coating, in-situ formed on APT specimens of NMC811 in the focused-ion beam (FIB), preserves the sample's integrity and circumvent this deleterious delithiation. Cr-coated specimens demonstrated remarkable improvements in data quality and virtually eliminated premature specimen failures, allowing for more precise measurements via. improved statistics. Through improved data analysis, we reveal substantial cation fluctuations in commercial grade NMC811, including complete grains of LiMnO. The current methodology stands out for its simplicity and cost-effectiveness and is a viable approach to prepare battery cathodes and anodes for systematic APT studies

Changes in the Ultrastructure of Beef Muscle as Influenced by Acidic Conditions Below the Ultimate pH

Ultrastructural changes in meat incubated with different concentrations of acetic acid were investigated by transmission electron microscopy. Discs of bovine M. longissimus dorsi (48 h postmortem) were incubated at 46 C for 48 h in various acetlc acid solutions, giving discs with pH values ranging from 5.1 to 3.9 . Below pH 4. 5 , the volume of the discs increased markedly due to water absorption. Discs incubated in 0.01M acetic acid had a pH of 5.1, lower swelling ratios and shorter sarcomeres than control samples at pH 5. 5. Structural studies of the samples at pH 5.1 revealed that A-band length decreased whereas I-band length increased . There was fragmentation of thin filaments in the Z-line region and disorganization of Z-line structure. In discs treated with O.O5M acetic acid (meat pH 4.5), complete loss of M-lines was observed. Noticeable swelling also occurred across the muscle fibre axis , mainly in the A-band region, and myosin filaments were partially extracted. Z-lines were swollen, disorganized and slightly fragmented. Below pH 4. 5 , swelling became much more pronounced with further extraction of myosin filaments. Most of the actin filaments were extracted and myofibrils fused together giving an amorphous, coagulated appearance. Z-lines were partially extracted. In general, the greatest amount of swelling occurred across the muscle fibre axis although significant in creases in sarcomere length were observed at pH 4.5 and below. Cooking of control and O.01M acid treated meat discs at 80°C increased the space between myofibrils whereas minimal shrinkage was not iced in samples below pH 4.5