An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response.

Inhibitors of the HIV aspartyl protease [HIV protease inhibitors (HIV-PIs)] are the cornerstone of treatment for HIV. Beyond their well-defined antiretroviral activity, these drugs have additional effects that modulate cell viability and homeostasis. However, little is known about the virus-independent pathways engaged by these molecules. Here we show that the HIV-PI Nelfinavir decreases translation rates and promotes a transcriptional program characteristic of the integrated stress response (ISR). Mice treated with Nelfinavir display hallmarks of this stress response in the liver, including α subunit of translation initiation factor 2 (eIF2α) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2α stress kinases and instead relied on the inhibition of the constitutive eIF2α dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2α Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2α-specific phosphatase cofactor activity can be a rheostat of cellular homeostasis that initiates a functional ISR and suggest that the HIV-PIs could be repositioned as therapeutics in human diseases to modulate translation rates and stress responses

Hong-Ou-Mandel interference between independent III-V on silicon waveguide integrated lasers

The versatility of silicon photonic integrated circuits has led to a widespread usage of this platform for quantum information based applications, including Quantum Key Distribution (QKD). However, the integration of simple high repetition rate photon sources is yet to be achieved. The use of weak-coherent pulses (WCPs) could represent a viable solution. For example, Measurement Device Independent QKD (MDI-QKD) envisions the use of WCPs to distill a secret key immune to detector side channel attacks at large distances. Thus, the integration of III-V lasers on silicon waveguides is an interesting prospect for quantum photonics. Here, we report the experimental observation of Hong-Ou-Mandel interference with 46\pm 2% visibility between WCPs generated by two independent III-V on silicon waveguide integrated lasers. This quantum interference effect is at the heart of many applications, including MDI-QKD. Our work represents a substantial first step towards an implementation of MDI-QKD fully integrated in silicon, and could be beneficial for other applications such as standard QKD and novel quantum communication protocols.Comment: 5 pages, 3 figure

An extremely low-noise heralded single-photon source: a breakthrough for quantum technologies

Low noise single-photon sources are a critical element for quantum technologies. We present a heralded single-photon source with an extremely low level of residual background photons, by implementing low-jitter detectors and electronics and a fast custom-made pulse generator controlling an optical shutter (a LiNbO3 waveguide optical switch) on the output of the source. This source has a second-order autocorrelation g^{(2)}(0)=0.005(7), and an "Output Noise Factor" (defined as the ratio of the number of noise photons to total photons at the source output channel) of 0.25(1)%. These are the best performance characteristics reported to date

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity.

Inflammasomes are critical sensors that convey cellular stress and pathogen presence to the immune system by activating inflammatory caspases and cytokines such as IL-1β. The nature of endogenous stress signals that activate inflammasomes remains unclear. Here we show that an inhibitor of the HIV aspartyl protease, Nelfinavir, triggers inflammasome formation and elicits an IL-1R-dependent inflammation in mice. We found that Nelfinavir impaired the maturation of lamin A, a structural component of the nuclear envelope, thereby promoting the release of DNA in the cytosol. Moreover, deficiency of the cytosolic DNA-sensor AIM2 impaired Nelfinavir-mediated inflammasome activation. These findings identify a pharmacologic activator of inflammasome and demonstrate the role of AIM2 in detecting endogenous DNA release upon perturbation of nuclear envelope integrity

Characterization of the HIV protease inhibitor Nelfinavir cellular targets

The HIV protease inhibitors (HIV-PIs) are among the most potent antiviral drugs for the HIV infection. Treatment of patients with HIV-PIs has been linked with development of side effects including dyslipidemia, lipodystrophy syndrome and cardiovascular complications. Moreover, these drugs have shown anti-tumoral activity in non-infected patients but little is known about the involved molecular mechanism for these off-target effects. Here we propose that the HIV-PI Nelfinavir could block a cellular protease thus causing the observed phenotypes. We firstly focus our attention on a cellular protein, DDI2, showing sequence and structural conservation with the HIV protease. We applied cellular and in vitro approaches to produce a correctly folded recombinant protein in order to investigate the presence of a proteolytic activity. Despite the fact that we could identify two techniques that can be applied to produce a folded recombinant DDI2, no proteolytic activity has been identified in the present study. However, we could observe that decreasing the DDI2 levels recapitulated some phenotype observed in presence of HIV-PIs, including the phosphorylation of the protein translation regulators eIF2a and eEF2. As an alternative approach to identify cellular targets for HIV-PIs, we applied a proteomic screening called Slice-SILAC. We focused our attention on the defective maturation of Lamin A, a member of the nuclear lamina, induced by the block of the cellular protease Zmpste24. We demonstrated that Nelfinavir induced accumulation of Prelamin A and nuclear shape defects and in addition caused presence of cytosolic DNA, probably due to TREX1 downregulation. We showed that these phenotypes correlated with activation of the AIM2 inflammasome and IL-lß release. These findings suggest that DDI2 and Zmpste24 are direct or indirect cellular targets for the HIV-PIs and indicate a possible role for these proteins in promoting off-target effects and anti¬tumoral activity observed in HIV-PI treated patients. -- Les inhibiteurs de la protéase du VIH (IP-VIH) sont parmi les médicaments antiviraux les plus efficaces pour l'infection par le VIH. Le traitement des patients avec les IP-VIH cause des effets secondaires comprenant la dyslipidémie, le syndrome de lipodystrophie et les complications cardio-vasculaires. De plus, ces médicaments ont montré une activité anti-tumorale chez les patients non infectés, toutefois le mécanisme moléculaire impliqué dans ces effets hors-cible reste inconnu. Nous proposons que l'IP-VIH Nelfinavir puisse bloquer une protéase cellulaire provoquant les phénotypes observés. De ce fait, nous avons concentré notre attention sur une protéine cellulaire, DDI2, qui possède une séquence et une structure proche de celle de la protéase du VIH. Nous avons appliqué des approches cellulaire et in vitro pour produire une protéine recombinante correctement repliée afin d'étudier son activité protéolytique. Malgré le fait que nous avons pu identifier deux techniques qui peuvent être appliquées pour produire une protéine DDI2 recombinante correctement repliée, aucune activité protéolytique n'a été identifiée dans la présente étude. De plus, nous avons pu observer que la réduction de DDI2 récapitule les phénotypes observé avec le IP-VIH, y compris les phosphorylations de eIF2a et eEF2, impliquées dans la régulation de la traduction protéique. Une approche alternative, appelée Slice-SILAC, a été utilisée afin d'identifier de nouvelles cibles cellulaires du Nelfinavir. Nous avons concentré notre attention sur la maturation défectueuse de la Lamine A, un membre de la lamine nucléaire, induite par l'inhibition de la protéase cellulaire Zmpste24. Nous avons démontré que le Nelfinavir induit une accumulation de Prélamine A déformant la membrane nucléaire et la présence d'ADN cytosolique, probablement en raison de la régulation négative de TREX1. Nous avons montré que ces phénotypes causent l'activation de l'inflammasome AIM2 et la sécrétion d'IL-lß. Ces résultats suggèrent que DDI2 et Zmpste24 sont des cibles cellulaires pour les IP-VIH et indiquent un possible rôle pour ces protéines dans l'apparition d'effets secondaires ainsi que dans l'activité anti-tumorale observée chez les patients traités avec les IP-VIH

CMOS SPAD Pixels for Indirect Time-of-Flight Ranging

We present two 0.35μm CMOS pixels for indirect time-of-flight range-finding, with single-photon avalanche diode (SPAD) and processing electronics, representing the building blocks for 2D and 3D single-photon imaging cameras

Hong–Ou–Mandel interference between independent III–V on silicon waveguide integrated lasers

The versatility of silicon photonic integrated circuits has led to a widespread usage of this platform for quantum information-based applications, including quantum key distribution (QKD). However, the integration of simple high-repetition-rate photon sources is yet to be achieved. The use of weak-coherent pulses (WCPs) could represent a viable solution. For example, measurement device independent QKD (MDI-QKD) envisions the use of WCPs to distill a secret key immune to detector side channel attacks at large distances. Thus, the integration of III-V lasers on silicon waveguides is an interesting prospect for quantum photonics. Here we report the experimental observation of Hong-Ou-Mandel interference with 46 +/- 2% visibility between WCPs generated by two independent III-V on silicon waveguide integrated lasers. This quantum interference effect is at the heart of many applications, including MDI-QKD. This Letter represents a substantial first step towards an implementation of MDI-QKD fully integrated in silicon and could be beneficial for other applications such as standard QKD and novel quantum communication protocols. (C) 2019 Optical Society of Americ

Entanglement in a Bragg ReflectionWaveguide

We demonstrate that an integrated photonic Bragg Reflection waveguide (BRW) inherently produces polarization entangled photons.2 page(s

An extremely low-noise heralded single-photon source: a breakthrough for quantum technologies

Low noise single-photon sources are a critical element for quantum technologies. We present a heralded single-photon source with an extremely low level of residual background photons, by implementing low-jitter detectors and electronics and a fast custom-made pulse generator controlling an optical shutter (a LiNbO3 waveguide optical switch) on the output of the source. This source has a second-order autocorrelation g((2))(0) = 0.005(7), and an output noise factor (defined as the ratio of the number of noise photons to total photons at the source output channel) of 0.25(1)%. These are the best performance characteristics reported to date