Second-harmonic generation in silicon waveguides strained by silicon nitride

Silicon photonics meets the electronics requirement of increased speed and bandwidth with on-chip optical networks. All-optical data management requires nonlinear silicon photonics. In silicon only third-order optical nonlinearities are present owing to its crystalline inversion symmetry. Introducing a second-order nonlinearity into silicon photonics by proper material engineering would be highly desirable. It would enable devices for wideband wavelength conversion operating at relatively low optical powers. Here we show that a sizeable second-order nonlinearity at optical wavelengths is induced in a silicon waveguide by using a stressing silicon nitride overlayer. We carried out second-harmonic-generation experiments and first-principle calculations, which both yield large values of strain-induced bulk second-order nonlinear susceptibility, up to 40pm/V at 2.300 nm. We envisage that nonlinear strained silicon could provide a competing platform for a new class of integrated light sources spanning the near- to mid-infrared spectrum from 1.2 to 10 micron

AB0578 SUBCLINICAL ENTHESITIS IN PSORIASIS patiEntS AS prediCtor OF ARTHRITIS (EPESCA STUDY): PRELIMINARY RESULTS

Background:Enthesitis is one of the typical pathological signs of spondyloarthritis such as psoriatic arthritis (PsA) and it seems to be the Primum movens of the disease. Clinical assessment of enthesitis showed to be less sensitive, compared to ultrasound (US) evaluation, in identifying enthesitis in patients with PsA [1].OMERACT defined US enthesitis as: "hypoechoic and/or thickened insertion of the tendon close to the bone (within 2 mm from the bony cortex), which exhibits Doppler signal if active and that may show erosions, enthesophytes/calcifications as a sign of structural damage" [3]The reported prevalence of subclinical enthesitis in psoriasis (PsO) patients in different countries ranges between 7% and 20% [2].Objectives:The main objective of this study was to estimate, by US evaluation, the prevalence of subclinical enthesitis in PsO patients without any clinical signs of enthesitis. Secondary objectives were to analyze differences, in terms of age, sex, BMI, PsO onset and diagnosis, among patients with enthesitis (active or not active), enthesopathy and without any alteration of enthesis.According to the OMERACT definition of ultrasound enthesitis, patients were divided into 4 groups: patients with active enthesitis (AE) defined as the presence of power-Doppler signal in a hypoechoic and/or thickened insertion of the tendon close to the bone; patient with enthesitis (En) defined as hypoechoic and/or thickened insertion of the tendon close to the bone without PD signal; patients with enthesopathy (Ep) defined as the presence of structural damage (erosions, enthesophytes/calcifications); patients without any alteration of enthesis (WE).Methods:Patients with at least 18 years and a diagnosis of PsO made by a Dermatologist were included. Exclusion criteria were the presence of clinical symptoms or signs of articular or entheseal involvement, diagnosis of arthritis and therapy with bDMARDs or tsDMARDs.All patients underwent US examination on grey scale and Power Doppler (PD) ultrasonography of 6 sites (Achilles, quadriceps, distal and proximal patellar, plantar fascia and triceps enthesis) bilaterally. Ultrasound was performed by an experienced sonographer, using a Logiq P9 equipped with 6-12 MHz broad band linear transducer. Data were reported as frequencies and median with interquartile range. To check differences among these four groups, we used chi-square test or Kruskall-Wallis test. P-value ≤ 0.05 is considered statistically significant.Results:We enrolled 124 consecutive psoriasis patients (47 [37.9%] female) with median age 57.7 (45.3-66.5) years, median disease duration 20.4 (10.1-30.8) years, median BMI 27 [24-29]. Patients with AE, En, Ep were 20.2% (25/124), 49.2% (61/124) and 18.5% (23/124), respectively.Patients WE (12.1%, 15/124) showed significantly lower BMI, younger age and shorter diagnostic delay compared to the other patients.All signs of enthesopathy/enthesitis were more frequently observed at Achilles (33.1%, 41/124), triceps (23.4%, 29/124), quadriceps (20.2%, 25/124), distal patellar (18.5%, 23/124) and proximal patellar (4.8%, 6/124) enthesis.Conclusion:Subclinical enthesitis is quite common in PsO patients, and about 20% showed active enthesitis. The enthesopathy seems to be more frequent in patients with increased delay in PsO diagnosis, older age and higher BMI.References:[1]Bandinelli F. et al. Ultrasound detects occult entheseal involvement in early psoriatic arthritis independently of clinical features and psoriasis severity. Clin Exp Rheumatology. Mar-Apr 2013;31(2):219-24.[2]Zuliani F. et al. Ultrasonographic detection of subclinical enthesitis and synovitis: a possible stratification of psoriatic patients without clinical musculoskeletal involvement. Clin Exp Rheumatol Jul-Aug 2019;37(4):593-599.[3]Balint P. V. et al. Reliability of a consensus-based ultrasound definition and scoring for enthesitis in spondyloarthritis and psoriatic arthritis: an OMERACT US initiative. Ann Rheum Dis 2018 Dec;77(12):1730-1735.Disclosure of Interests:None declared

Transport by molecular motors in the presence of static defects

The transport by molecular motors along cytoskeletal filaments is studied theoretically in the presence of static defects. The movements of single motors are described as biased random walks along the filament as well as binding to and unbinding from the filament. Three basic types of defects are distinguished, which differ from normal filament sites only in one of the motors' transition probabilities. Both stepping defects with a reduced probability for forward steps and unbinding defects with an increased probability for motor unbinding strongly reduce the velocities and the run lengths of the motors with increasing defect density. For transport by single motors, binding defects with a reduced probability for motor binding have a relatively small effect on the transport properties. For cargo transport by motors teams, binding defects also change the effective unbinding rate of the cargo particles and are expected to have a stronger effect.Comment: 20 pages, latex, 7 figures, 1 tabl

Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells

Dendritic cell (DC) migration in peripheral tissues serves two main functions: antigen sampling by immature DCs, and chemokine-guided migration towards lymphatic vessels (LVs) on maturation. These migratory events determine the efficiency of the adaptive immune response. Their regulation by the core cell locomotion machinery has not been determined. Here, we show that the migration of immature DCs depends on two main actin pools: a RhoA mDial-dependent actin pool located at their rear, which facilitates forward locomotion; and a Cdc42 Arp2/3-dependent actin pool present at their front, which limits migration but promotes antigen capture. Following TLR4 MyD88-induced maturation, Arp2/3-dependent actin enrichment at the cell front is markedly reduced. Consequently, mature DCs switch to a faster and more persistent mDial-dependent locomotion mode that facilitates chemotactic migration to LVs and lymph nodes. Thus, the differential use of actin-nucleating machineries optimizes the migration of immature and mature DCs according to their specific function

Testing the theory of immune selection in cancers that break the rules of transplantation

Modification of cancer cells likely to reduce their immunogenicity, including loss or down-regulation of MHC molecules, is now well documented and has become the main support for the concept of immune surveillance. The evidence that these modifications, in fact, result from selection by the immune system is less clear, since the possibility that they may result from reorganized metabolism associated with proliferation or from cell de-differentiation remains. Here, we (a) survey old and new transplantation experiments that test the possibility of selection and (b) survey how transmissible tumours of dogs and Tasmanian devils provide naturally evolved tests of immune surveillance

Hormonal signaling in cnidarians : do we understand the pathways well enough to know whether they are being disrupted?

Author Posting. © The Author, 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Ecotoxicology 16 (2007): 5-13, doi:10.1007/s10646-006-0121-1.Cnidarians occupy a key evolutionary position as basal metazoans and are ecologically important as predators, prey and structure-builders. Bioregulatory molecules (e.g., amines, peptides and steroids) have been identified in cnidarians, but cnidarian signaling pathways remain poorly characterized. Cnidarians, especially hydras, are regularly used in toxicity testing, but few studies have used cnidarians in explicit testing for signal disruption. Sublethal endpoints developed in cnidarians include budding, regeneration, gametogenesis, mucus production and larval metamorphosis. Cnidarian genomic databases, microarrays and other molecular tools are increasingly facilitating mechanistic investigation of signaling pathways and signal disruption. Elucidation of cnidarian signaling processes in a comparative context can provide insight into the evolution and diversification of metazoan bioregulation. Characterizing signaling and signal disruption in cnidarians may also provide unique opportunities for evaluating risk to valuable marine resources, such as coral reefs

The consolidation of implicit sequence memory in obstructive sleep apnea

Obstructive Sleep Apnea (OSA) Syndrome is a relatively frequent sleep disorder characterized by disrupted sleep patterns. It is a well-established fact that sleep has beneficial effect on memory consolidation by enhancing neural plasticity. Implicit sequence learning is a prominent component of skill learning. However, the formation and consolidation of this fundamental learning mechanism remains poorly understood in OSA. In the present study we examined the consolidation of different aspects of implicit sequence learning in patients with OSA. We used the Alternating Serial Reaction Time task to measure general skill learning and sequence-specific learning. There were two sessions: a learning phase and a testing phase, separated by a 10-hour offline period with sleep. Our data showed differences in offline changes of general skill learning between the OSA and control group. The control group demonstrated offline improvement from evening to morning, while the OSA group did not. In contrast, we did not observe differences between the groups in offline changes in sequence-specific learning. Our findings suggest that disrupted sleep in OSA differently affects neural circuits involved in the consolidation of sequence learning

Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers

We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at low doses in cell line, organoid, and rat models of PDAC, whereas each inhibitor alone is only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA) pathway mapping and RNA sequencing (RNA-seq) show that RAFi/ERKi induced insensitivity to loss of negative feedback and system failures including loss of ERK signaling, FOSL1, and MYC; shutdown of the MYC transcriptome; and induction of mesenchymal-to-epithelial transition. We conclude that low-dose vertical inhibition of the RAF-MEK-ERK cascade is an effective therapeutic strategy for KRAS mutant PDAC.Peer reviewe

CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment

We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine. To assess how CHK1 inhibition-induced ERK activation promotes PDAC survival, we perform a CRISPR-Cas9 loss-of-function screen targeting direct/indirect ERK substrates and identify RIF1. A key component of non-homologous end joining repair, RIF1 suppression sensitizes PDAC cells to CHK1 inhibition-mediated apoptotic growth suppression. Furthermore, ERK inhibition alone decreases RIF1 expression and phenocopies RIF1 depletion. We conclude that concurrent DDR suppression enhances the efficacy of ERK and/or autophagy inhibitors in KRAS mutant PDAC

Neuroactive substances specifically modulate rhythmic body contractions in the nerveless metazoon Tethya wilhelma (Demospongiae, Porifera)

BACKGROUND: Sponges (Porifera) are nerve- and muscleless metazoa, but display coordinated motor reactions. Therefore, they represent a valuable phylum to investigate coordination systems, which evolved in a hypothetical Urmetazoon prior to the central nervous system (CNS) of later metazoa. We have chosen the contractile and locomotive species Tethya wilhelma (Demospongiae, Hadromerida) as a model system for our research, using quantitative analysis based on digital time lapse imaging. In order to evaluate candidate coordination pathways, we extracorporeally tested a number of chemical messengers, agonists and antagonists known from chemical signalling pathways in animals with CNS. RESULTS: Sponge body contraction of T. wilhelma was induced by caffeine, glycine, serotonine, nitric oxide (NO) and extracellular cyclic adenosine monophosphate (cAMP). The induction by glycine and cAMP followed patterns varying from other substances. Induction by cAMP was delayed, while glycine lead to a bi-phasic contraction response. The frequency of the endogenous contraction rhythm of T. wilhelma was significantly decreased by adrenaline and NO, with the same tendency for cAMP and acetylcholine. In contrast, caffeine and glycine increased the contraction frequency. The endogenous rhythm appeared irregular during application of caffeine, adrenaline, NO and cAMP. Caffeine, glycine and NO attenuated the contraction amplitude. All effects on the endogenous rhythm were neutralised by the washout of the substances from the experimental reactor system. CONCLUSION: Our study demonstrates that a number of chemical messengers, agonists and antagonists induce contraction and/or modulate the endogenous contraction rhythm and amplitude of our nerveless model metazoon T. wilhelma. We conclude that a relatively complex system of chemical messengers regulates the contraction behaviour through auto- and paracrine signalling, which is presented in a hypothetical model. We assume that adrenergic, adenosynergic and glycinergic pathways, as well as pathways based on NO and extracellular cAMP are candidates for the regulation and timing of the endogenous contraction rhythm within pacemaker cells, while GABA, glutamate and serotonine are candidates for the direct coordination of the contractile cells