HLA-C and HIV-1: friends or foes?

The major histocompatibility complex class I protein HLA-C plays a crucial role as a molecule capable of sending inhibitory signals to both natural killer (NK) cells and cytotoxic T lymphocytes (CTL) via binding to killer cell Ig-like receptors (KIR). Recently HLA-C has been recognized as a key molecule in the immune control of HIV-1. Expression of HLA-C is modulated by a microRNA binding site. HLA-C alleles that bear substitutions in the microRNA binding site are more expressed at the cell surface and associated with the control of HIV-1 viral load, suggesting a role of HLA-C in the presentation of antigenic peptides to CTLs. This review highlights the role of HLA-C in association with HIV-1 viral load, but also addresses the contradiction of the association between high cell surface expression of an inhibitory molecule and strong cell-mediated immunity. To explore additional mechanisms of control of HIV-1 replication by HLA-C, we address specific features of the molecule, like its tendency to be expressed as open conformer upon cell activation, which endows it with a unique capacity to associate with other cell surface molecules as well as with HIV-1 proteins

Trapping in irradiated p-on-n silicon sensors at fluences anticipated at the HL-LHC outer tracker

The degradation of signal in silicon sensors is studied under conditions expected at the CERN High-Luminosity LHC. 200 $\mu$m thick n-type silicon sensors are irradiated with protons of different energies to fluences of up to $3 \cdot 10^{15}$ neq/cm$^2$. Pulsed red laser light with a wavelength of 672 nm is used to generate electron-hole pairs in the sensors. The induced signals are used to determine the charge collection efficiencies separately for electrons and holes drifting through the sensor. The effective trapping rates are extracted by comparing the results to simulation. The electric field is simulated using Synopsys device simulation assuming two effective defects. The generation and drift of charge carriers are simulated in an independent simulation based on PixelAV. The effective trapping rates are determined from the measured charge collection efficiencies and the simulated and measured time-resolved current pulses are compared. The effective trapping rates determined for both electrons and holes are about 50% smaller than those obtained using standard extrapolations of studies at low fluences and suggests an improved tracker performance over initial expectations

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology

NK cells and cancer: you can teach innate cells new tricks

Natural killer (NK) cells are the prototype innate lymphoid cells endowed with potent cytolytic function that provide host defence against microbial infection and tumours. Here, we review evidence for the role of NK cells in immune surveillance against cancer and highlight new therapeutic approaches for targeting NK cells in the treatment of cancer

Quantifying reaeration rates in alpine streams using deliberate gas tracer experiments

Gas exchange across the air-water interface is a critical process that maintains adequate dissolved oxygen (DO) in the water column to support life. Oxygen reaeration rates can be accurately measured using deliberate gas tracers, like sulfur hexafluoride (SF6) or xenon (Xe). Two continuous release experiments were conducted in different creeks in the Sierra Nevada of California: Sagehen Creek in September, 2009, using SF6and Martis Creek in August, 2012, using both SF6and Xe. Measuring gas loss along the creek, which was approximated with the one-dimensional advection-dispersion equation, allows for the estimation of the SF6or Xe reaeration coefficient (KSF6, KXe), which is converted to DO reaeration (KDOor K2) using Schmidt numbers. Mean KSF6for upper and lower Sagehen and Martis Creeks were, respectively, 34 day-1, 37 day-1and 33 day-1, with corresponding KDOsof 61 day-1, 66 day-1and 47 day-1. In Martis Creek, KXewas slightly higher (21%) than KSF6, but the calculated KDOfrom SF6agreed with the calculated KDOfrom Xe within about 15%; this difference may be due to bubble-enhanced gas transfer. Established empirical equations of KDOusing stream characteristics did a poor job predicting KDO for both creeks. © 2014 by the authors

Quantifying reaeration rates in alpine streams using deliberate gas tracer experiments

Gas exchange across the air-water interface is a critical process that maintains adequate dissolved oxygen (DO) in the water column to support life. Oxygen reaeration rates can be accurately measured using deliberate gas tracers, like sulfur hexafluoride (SF6) or xenon (Xe). Two continuous release experiments were conducted in different creeks in the Sierra Nevada of California: Sagehen Creek in September, 2009, using SF6and Martis Creek in August, 2012, using both SF6and Xe. Measuring gas loss along the creek, which was approximated with the one-dimensional advection-dispersion equation, allows for the estimation of the SF6or Xe reaeration coefficient (KSF6, KXe), which is converted to DO reaeration (KDOor K2) using Schmidt numbers. Mean KSF6for upper and lower Sagehen and Martis Creeks were, respectively, 34 day-1, 37 day-1and 33 day-1, with corresponding KDOsof 61 day-1, 66 day-1and 47 day-1. In Martis Creek, KXewas slightly higher (21%) than KSF6, but the calculated KDOfrom SF6agreed with the calculated KDOfrom Xe within about 15%; this difference may be due to bubble-enhanced gas transfer. Established empirical equations of KDOusing stream characteristics did a poor job predicting KDO for both creeks. © 2014 by the authors

The Effect of Inhibitory Signals on the Priming of Drug Hapten–Specific T Cells That Express Distinct Vβ Receptors

Drug hypersensitivity involves the activation of T cells in an HLA allele–restricted manner. Because the majority of individuals who carry HLA risk alleles do not develop hypersensitivity, other parameters must control development of the drug-specific T cell response. Thus, we have used a T cell–priming assay and nitroso sulfamethoxazole (SMX-NO) as a model Ag to investigate the activation of specific TCR Vβ subtypes, the impact of programmed death -1 (PD-1), CTL-associated protein 4 (CTLA4), and T cell Ig and mucin domain protein-3 (TIM-3) coinhibitory signaling on activation of naive and memory T cells, and the ability of regulatory T cells (Tregs) to prevent responses. An expansion of the TCR repertoire was observed for nine Vβ subtypes, whereas spectratyping revealed that SMX-NO–specific T cell responses are controlled by public TCRs present in all individuals alongside private TCR repertoires specific to each individual. We proceeded to evaluate the extent to which the activation of these TCR Vβ–restricted Ag-specific T cell responses is governed by regulatory signals. Blockade of PD-L1/CTLA4 signaling dampened activation of SMX-NO–specific naive and memory T cells, whereas blockade of TIM-3 produced no effect. Programmed death-1, CTLA4, and TIM-3 displayed discrete expression profiles during drug-induced T cell activation, and expression of each receptor was enhanced on dividing T cells. Because these receptors are also expressed on Tregs, Treg-mediated suppression of SMX-NO–induced T cell activation was investigated. Tregs significantly dampened the priming of T cells. In conclusion, our findings demonstrate that distinct TCR Vβ subtypes, dysregulation of coinhibitory signaling pathways, and dysfunctional Tregs may influence predisposition to hypersensitivity