Editing Woolf

No abstract available

Strain Relaxation in Compositionally Graded InGaAs/GaAs Heterostructures

Epilayer strain relaxation in the InGaAs/GaAs system occurs via two mechanisms, plastic deformation and/or surface roughening. Under conditions of two-dimensional growth, we find that compositionally graded InGaAs/GaAs (001) multi-layer buffer structures will plastically deform with \u3c 110 \u3e misfit dislocations approaching 100% strain relaxation. At higher growth temperatures, large-amplitude roughening is observed preferentially along the [110] direction, and the strain relaxation becomes asymmetric in the \u3c 110 \u3e directions. In single epilayers, the symmetry of the strain relaxation is dependent on the magnitude of the substrate offcut angle. In all cases, the epilayers develop a tilt about an in-plane axis in proportion to and opposite in direction to the substrate offcut. With roughening, there is also a change in the orientation of the tilt axis such that only the dislocations with [110] line directions develop a preferred tilt component. These results illustrate the importance of surface steps and morphologies to strain relaxation and perhaps offer clues to the identification of the dislocation formation mechanisms at these interfaces

Editing Woolf

No abstract available

Thrombocytopenia and disseminated histoplasmosis in immunocompetent adults

Disseminated histoplasmosis among immunocompetent patients is rare, but may be associated with clinically significant refractory thrombocytopenia. Platelet counts often return to normal levels following antifungal therapy. Therefore, the most important management of this refractory thrombocytopenia is the recognition and treatment of histoplasmosis infection

Evaluation of PD-L1 expression on vortex-isolated circulating tumor cells in metastatic lung cancer.

Metastatic non-small cell lung cancer (NSCLC) is a highly fatal and immunogenic malignancy. Although the immune system is known to recognize these tumor cells, one mechanism by which NSCLC can evade the immune system is via overexpression of programmed cell death ligand 1 (PD-L1). Recent clinical trials of PD-1 and PD-L1 inhibitors have returned promising clinical responses. Important for personalizing therapy, patients with higher intensity staining for PD-L1 on tumor biopsies responded better. Thus, there has been interest in using PD-L1 tumor expression as a criterion for patient selection. Currently available methods of screening involve invasive tumor biopsy, followed by histological grading of PD-L1 levels. Biopsies have a high risk of complications, and only allow sampling from limited tumor sections, which may not reflect overall tumor heterogeneity. Circulating tumor cell (CTC) PD-L1 levels could aid in screening patients, and could supplement tissue PD-L1 biopsy results by testing PD-L1 expression from disseminated tumor sites. Towards establishing CTCs as a screening tool, we developed a protocol to isolate CTCs at high purity and immunostain for PD-L1. Monitoring of PD-L1 expression on CTCs could be an additional biomarker for precision medicine that may help in determining response to immunotherapies

Novel variants provide differential stabilisation of human equilibrative nucleoside transporter 1 states

Human equilibrative nucleoside transporters represent a major pharmaceutical target for cardiac, cancer and viral therapies. Understanding the molecular basis for transport is crucial for the development of improved therapeutics through structure-based drug design. ENTs have been proposed to utilise an alternating access mechanism of action, similar to that of the major facilitator superfamily. However, ENTs lack functionally-essential features of that superfamily, suggesting that they may use a different transport mechanism. Understanding the molecular basis of their transport requires insight into diverse conformational states. Differences between intermediate states may be discrete and mediated by subtle gating interactions, such as salt bridges. We identified four variants of human equilibrative nucleoside transporter isoform 1 (hENT1) at the large intracellular loop (ICL6) and transmembrane helix 7 (TM7) that stabilise the apo-state (T-m 0.7-1.5 degrees C). Furthermore, we showed that variants K263A (ICL6) and I282V (TM7) specifically stabilise the inhibitor-bound state of hENT1 (T-m 5.0 +/- 1.7 degrees C and 3.0 +/- 1.8 degrees C), supporting the role of ICL6 in hENT1 gating. Finally, we showed that, in comparison with wild type, variant T336A is destabilised by nitrobenzylthioinosine (T-m -4.7 +/- 1.1 degrees C) and binds it seven times worse. This residue may help determine inhibitor and substrate sensitivity. Residue K263 is not present in the solved structures, highlighting the need for further structural data that include the loop regions.Peer reviewe