Change in the molecular properties of CH1641 prions after transmission to wild-type mice: Evidence for a single strain.

AIM: CH1641 was discovered in 1970 as a scrapie isolate that was unlike all other classical strains of scrapie isolated so far. We performed bio-assays of CH1641 in mice in order to further characterise this specific isolate. METHODS: We inoculated the original CH1641 isolate into ovine and bovine prion protein (PrP) transgenic mice as well as wild-type mice. In addition, we performed cross- and back passages between the various mouse lines to examine if one identical prion strain was isolated in all mouse lines or whether multiple prion strains exist in CH1641. RESULTS: We report the first successful transmission of CH1641 to wild-type RIII mice and via RIII mice to wild-type VM mice. Unexpectedly, analysis of the protease-resistant prion protein (PrPres ) in wild-type mice showed a classical scrapie banding pattern differing from the banding pattern of the original CH1641 isolate. Cross- and back passages of CH1641 between the various mouse lines confirmed that the same prion strain had been isolated in all mouse lines. CONCLUSIONS: The CH1641 isolate consists of a single prion strain but its molecular banding pattern of PrPres differs between wild-type mice and PrP transgenic mice. Consequently, molecular banding patterns of PrPres should be used with caution in strain typing since they do not solely depend on the properties of the prion strain but also on the host prion protein.

Abnormal accumulation of lipid droplets in neurons induces the conversion of alpha-Synuclein to proteolytic resistant forms in a Drosophila model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein (αSyn) aggregation and associated with abnormalities in lipid metabolism. The accumulation of lipids in cytoplasmic organelles called lipid droplets (LDs) was observed in cellular models of PD. To investigate the pathophysiological consequences of interactions between αSyn and proteins that regulate the homeostasis of LDs, we used a transgenic Drosophila model of PD, in which human αSyn is specifically expressed in photoreceptor neurons. We first found that overexpression of the LD-coating proteins Perilipin 1 or 2 (dPlin1/2), which limit the access of lipases to LDs, markedly increased triacylglyclerol (TG) loaded LDs in neurons. However, dPlin-induced-LDs in neurons are independent of lipid anabolic (diacylglycerol acyltransferase 1/midway, fatty acid transport protein/dFatp) and catabolic (brummer TG lipase) enzymes, indicating that alternative mechanisms regulate neuronal LD homeostasis. Interestingly, the accumulation of LDs induced by various LD proteins (dPlin1, dPlin2, CG7900 or KlarsichtLD-BD) was synergistically amplified by the co-expression of αSyn, which localized to LDs in both Drosophila photoreceptor neurons and in human neuroblastoma cells. Finally, the accumulation of LDs increased the resistance of αSyn to proteolytic digestion, a characteristic of αSyn aggregation in human neurons. We propose that αSyn cooperates with LD proteins to inhibit lipolysis and that binding of αSyn to LDs contributes to the pathogenic misfolding and aggregation of αSyn in neurons.

Monolithically integrated photonic crystal surface emitters on silicon with a vortex beam by using bound states in the continuum.

Optical resonant cavities with high quality factor (Q-factor) are widely used in science and technology for their capabilities of strong confinement of light and enhanced light-matter interaction. The 2D photonic crystal structure with bound states in the continuum (BICs) is a novel concept for resonators with ultra-compact device size, which can be used to generate surface emitting vortex beams based on symmetry-protected BICs at the Γ point. Here, to the best of our knowledge, we demonstrate the first photonic crystal surface emitter with a vortex beam by using BICs monolithically grown on CMOS-compatible silicon substrate. The fabricated quantum-dot BICs-based surface emitter operates at 1.3 µm under room temperature (RT) with a low continuous wave (CW) optically pumped condition. We also reveal the BIC's amplified spontaneous emission with the property of a polarization vortex beam, which is promising to provide a novel degree of freedom in classical and quantum realms.

Design and Characterization of 5 µm Pitch InGaAs Photodiodes Using In Situ Doping and Shallow Mesa Architecture for SWIR Sensing.

This paper presents the complete design, fabrication, and characterization of a shallow-mesa photodiode for short-wave infra-red (SWIR) sensing. We characterized and demonstrated photodiodes collecting 1.55 µm photons with a pixel pitch as small as 3 µm. For a 5 µm pixel pitch photodiode, we measured the external quantum efficiency reaching as high as 54%. With substrate removal and an ideal anti-reflective coating, we estimated the internal quantum efficiency as achieving 77% at 1.55 µm. The best measured dark current density reached 5 nA/cm2 at -0.1 V and at 23 °C. The main contributors responsible for this dark current were investigated through the study of its evolution with temperature. We also highlight the importance of passivation with a perimetric contribution analysis and the correlation between MIS capacitance characterization and dark current performance.

Chronic Exposure to Paraquat Induces Alpha-Synuclein Pathogenic Modifications in Drosophila.

Parkinson's disease (PD) is characterized by the progressive accumulation of neuronal intracellular aggregates largely composed of alpha-Synuclein (αSyn) protein. The process of αSyn aggregation is induced during aging and enhanced by environmental stresses, such as the exposure to pesticides. Paraquat (PQ) is an herbicide which has been widely used in agriculture and associated with PD. PQ is known to cause an increased oxidative stress in exposed individuals but the consequences of such stress on αSyn conformation remains poorly understood. To study αSyn pathogenic modifications in response to PQ, we exposed Drosophila expressing human αSyn to a chronic PQ protocol. We first showed that PQ exposure and αSyn expression synergistically induced fly mortality. The exposure to PQ was also associated with increased levels of total and phosphorylated forms of αSyn in the Drosophila brain. Interestingly, PQ increased the detection of soluble αSyn in highly denaturating buffer but did not increase αSyn resistance to proteinase K digestion. These results suggest that PQ induces the accumulation of toxic soluble and misfolded forms of αSyn but that these toxic forms do not form fibrils or aggregates that are detected by the proteinase K assay. Collectively, our results demonstrate that Drosophila can be used to study the effect of PQ or other environmental neurotoxins on αSyn driven pathology.

Etched-cavity GaSb laser diodes on a MOVPE GaSb-on-Si template.

We report on 2.3-µm etched-cavity GaSb-based laser diodes (LDs) epitaxially integrated on on-axis (001)Si and benchmarked against their cleaved facet counterparts. The LDs were grown in two steps. First, a GaSb-on-Si template was grown by metal-organic vapor phase epitaxy (MOVPE) before the growth of the LD heterostructure by molecular-beam epitaxy. Different etched-facet geometries operate in continuous wave well above room temperature, and their performance are similar to those of cleaved-cavity LDs. These results show that etching mirrors is a viable route to form laser cavities in the GaSb technology and that MOVPE GaSb-on-Si templates are a suitable platform for optoelectronic devices overgrowth.

Seeded propagation of α-synuclein aggregation in mouse brain using protein misfolding cyclic amplification.

α-Synuclein (α-syn) protein aggregation is associated with several neurodegenerative disorders collectively referred to as synucleinopathies, including Parkinson's disease. We used protein misfolding cyclic amplification (PMCA) to study α-syn aggregation in brain homogenates of wild-type or transgenic mice expressing normal (D line) or A53T mutant (M83 line) human α-syn. We found that sonication-incubation cycles of M83 mouse brain gradually produce large quantities of SDS-resistant α-syn aggregates, involving both human and mouse proteins. These PMCA products, containing partially proteinase K-resistant α-syn species, are competent to accelerate the onset of neurologic symptoms after intracerebral inoculation to young M83 mice and to seed aggregate formation of α-syn following PMCA, including in D and wild-type mouse brain substrates. PMCA seeding activity in the M83 diseased brain correlates positively with regions mostly targeted by the α-syn pathology in this model. Our data indicate that similar to prions, PMCA can reproduce some characteristics of α-syn aggregation and seeded propagation in vitro in a complex milieu. This opens new opportunities for the molecular study of synucleinopathies.-Nicot, S., Verchère, J., Bélondrade, M., Mayran, C., Bétemps, D., Bougard, D., Baron, T. Seeded propagation of α-synuclein aggregation in mouse brain using protein misfolding cyclic amplification.

Accelerated accumulation of retinal α-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by accumulation of misfolded α-synuclein within the central nervous system (CNS). Visual problems in PD patients are common, although retinal pathology associated with PD is not well understood. The purpose of this study was to investigate retinal pathology in a transgenic mouse model (TgM83) expressing the human A53T α-synuclein mutation and assess the effect of α-synuclein "seeding" on the development of retinal pathology. Two-month-old TgM83 mice were intracerebrally inoculated with brain homogenate from old (12-18 months) TgM83 mice. Retinas were then analyzed at 5 months of age. We analyzed retinas from 5-month-old and 8-month-old uninoculated healthy TgM83 mice, and old (12-18 months) mice that were euthanized following the development of clinical signs. Retinas of B6C3H mice (genetic background of the TgM83 mouse) served as control. We used immunohistochemistry and western blot analysis to detect accumulation of α-synuclein, pTauThr231, inflammation, changes in macroautophagy, and cell death. Raman spectroscopy was used to test the potential to differentiate between retinal tissues of healthy mice and diseased mice. This work demonstrates retinal changes associated with the A53T mutation. Retinas of non-inoculated TgM83 mice had accumulation of α-synuclein, "pre-tangle" tau, activation of retinal glial cells, and photoreceptor cell loss by 8 months of age. The development of these changes is accelerated by inoculation with brain homogenate from clinically ill TgM83 mice. Compared to non-inoculated 5-month-old TgM83 mice, retinas of inoculated 5-month-old mice had increased accumulation of α-synuclein (pSer129) and pTauThr231 proteins, upregulated microglial activation, and dysregulated macroautophagy. Raman spectroscopic analysis was able to discriminate between healthy and diseased mice. This study describes retinal pathology resulting from the A53T mutation. We show that seeding with brain homogenates from old TgM83 mice accelerates retinal pathology. We demonstrate that Raman spectroscopy can be used to accurately identify a diseased retina based on its biochemical profile, and that α-synuclein accumulation may contribute to accumulation of pTauThr231 proteins, neuroinflammation, metabolic dysregulation, and photoreceptor cell death. Our work provides insight into retinal changes associated with Parkinson's disease, and may contribute to a better understanding of visual symptoms experienced by patients.

Novel Type of Chronic Wasting Disease Detected in Moose (Alces alces), Norway.

Chronic wasting disease (CWD) persists in cervid populations of North America and in 2016 was detected for the first time in Europe in a wild reindeer in Norway. We report the detection of CWD in 3 moose (Alces alces) in Norway, identified through a large scale surveillance program. The cases occurred in 13-14-year-old female moose, and we detected an abnormal form of prion protein (PrPSc) in the brain but not in lymphoid tissues. Immunohistochemistry revealed that the moose shared the same neuropathologic phenotype, characterized by mostly intraneuronal deposition of PrPSc. This pattern differed from that observed in reindeer and has not been previously reported in CWD-infected cervids. Moreover, Western blot revealed a PrPSc type distinguishable from previous CWD cases and from known ruminant prion diseases in Europe, with the possible exception of sheep CH1641. These findings suggest that these cases in moose represent a novel type of CWD.

'Prion-like' propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum.

The M83 transgenic mouse is a model of human synucleinopathies that develops severe motor impairment correlated with accumulation of the pathological Ser129-phosphorylated α-synuclein (α-synP ) in the brain and spinal cord. M83 disease can be accelerated by intracerebral inoculation of brain extracts from sick M83 mice. This has also recently been described using peripheral routes, injecting recombinant preformed α-syn fibrils into the muscle or the peritoneum. Here, we inoculated homozygous and/or hemizygous M83 neonates via the intraperitoneal and/or intracerebral routes with two different brain extracts: one from sick M83 mice inoculated with brain extract from other sick M83 mice, and the other derived from a human multiple system atrophy source passaged in M83 mice. Detection of α-synP using ELISA and western blot confirmed the disease in mice. The distribution of α-synP in the central nervous system was similar, independently of the inoculum or inoculation route, consistent with previous studies describing M83 disease. ELISA tests revealed higher levels of α-synP in homozygous than in hemizygous sick M83 mice, at least after IC inoculation. Interestingly, the immunoreactivity of α-synP detected by ELISA was significantly lower in M83 mice inoculated with the multiple system atrophy inoculum than in M83 mice inoculated with the M83 inoculum, at the first two passages. 'Prion-like' propagation of the synucleinopathy up to the clinical disease was accelerated by both intracerebral and intraperitoneal inoculations of brain extracts from sick mice. This acceleration, however, depends on the levels of α-syn expression by the mouse and the type of inoculum.

Electrically pumped continuous-wave 1.3 µm InAs/GaAs quantum dot lasers monolithically grown on on-axis Si (001) substrates.

We report on the first electrically pumped continuous-wave (cw) InAs/GaAs quantum dot (QD) lasers monolithically grown on on-axis Si (001) substrates without any intermediate buffer layers. A 400 nm antiphase boundary (APB) free epitaxial GaAs film with a small root-mean-square (RMS) surface roughness of 0.86 nm was first deposited on a 300 mm standard industry-compatible on-axis Si (001) substrate by metal-organic chemical vapor deposition (MOCVD). The QD laser structure was then grown on this APB-free GaAs/Si (001) virtual substrate by molecular beam epitaxy (MBE). Room-temperature cw lasing at ~1.3 µm has been achieved with a threshold current density of 425 A/cm2 and single facet output power of 43 mW. Under pulsed operation, lasing operation up to 102 °C has been realized, with a threshold current density of 250 A/cm2 and single facet output power exceeding 130 mW at room temperature.

pH driven addressing of silicon nanowires onto Si3N4/SiO2 micro-patterned surfaces.

pH was used as the main driving parameter for specifically immobilizing silicon nanowires onto Si3N4 microsquares at the surface of a SiO2 substrate. Different pH values of the coating aqueous solution enabled to experimentally distribute nanowires between silicon nitride and silicon dioxide: at pH 3 nanowires were mainly anchored on Si3N4; they were evenly distributed between SiO2 and Si3N4 at pH 2.8; and they were mainly anchored on SiO2 at pH 2. A theoretical model based on DLVO theory and surface protonation/deprotonation equilibria was used to study how, in adequate pH conditions, Si nanowires could be anchored onto specific regions of a patterned Si3N4/SiO2 surface. Instead of using capillary forces, or hydrophilic/hydrophobic contrast between the two types of materials, the specificity of immobilization could rely on surface electric charge contrasts between Si3N4 and SiO2. This simple and generic method could be used for addressing a large diversity of nano-objects onto patterned substrates.

Adjustable continence therapy (ProACT™) after male sling failure for patients with post-radical prostatectomy urinary incontinence: a prospective study with one-year follow-up.

PURPOSE: To assess the effects of the ProACT™ device as a second-line treatment for persistent incontinence after male sling insertion. METHODS: Twenty consecutive patients were treated with the ProACT™ device due to persistent urinary incontinence following male sling insertion (9 AdVance™, 9 TOMS™, 2 InVance™). All balloons were implanted using a combination of fluoroscopic imaging and fibroscopic retrovision. Urinary symptoms were assessed prior to male sling insertion (T0) and before (T1) and 1 year after the ProACT™ insertion (T2) using questionnaires (ICIQ, USP, and ULCA-PCI-urinary bother) and by determining the number of pads used daily. RESULTS: The mean age of the study population at T1 was 68.6 ± 9 years. The mean volume of adjustment at T2 was 4.5 ± 2.7 mL. The previous sling did not cause any technical difficulties during ProACT™ insertion. Late wound infections occurred in the two patients who had been previously treated with the InVance sling and required removal of all implanted materials (Clavien-Dindo classification IIIb). Improvement in mean urinary scores was noted in the remaining patients (n = 18) through T0, T1, and T2, respectively: The ICIQ scores were 16.8 ± 2.6, 13.1 ± 3.4, and 5.7 ± 5.7 (P < 0.0001); USP stress urinary incontinence scores were 8 ± 1.8, 5.6 ± 2.2, and 2.4 ± 2.8, (P < 0.0001); USP overactive bladder symptom scores were 6.8 ± 4.3, 7.6 ± 4.3, and 4.1 ± 3.5 (P = 0.008), UCLA-PCI urinary bother scores were 7.1 ± 11.3, 28.6 ± 12.9, and 69.6 ± 31.6 (P < 0.0001), and number of pads used were 2.9 ± 1, 2 ± 1, and 0.3 ± 0.9 (P < 0.0001). USP obstructive symptoms were 0.4 ± 1, 1 ± 1.6, and 1.3 ± 1.4 (P = 0.19). CONCLUSIONS: The Pro-ACT™ device may provide additional benefits for improving continence in case of persistent incontinence following male sling insertion.

Percolating silicon nanowire networks with highly reproducible electrical properties.

Here, we report the morphological and electrical properties of self-assembled silicon nanowires networks, also called Si nanonets. At the macroscopic scale, the nanonets involve several millions of nanowires. So, the observed properties should result from large scale statistical averaging, minimizing thus the discrepancies that occur from one nanowire to another. Using a standard filtration procedure, the so-obtained Si nanonets are highly reproducible in terms of their morphology, with a Si nanowire density precisely controlled during the nanonet elaboration. In contrast to individual Si nanowires, the electrical properties of Si nanonets are highly consistent, as demonstrated here by the similar electrical properties obtained in hundreds of Si nanonet-based devices. The evolution of the Si nanonet conductance with Si nanowire density demonstrates that Si nanonets behave like standard percolating media despite the presence of numerous nanowire-nanowire intersecting junctions into the nanonets and the native oxide shell surrounding the Si nanowires. Moreover, when silicon oxidation is prevented or controlled, the electrical properties of Si nanonets are stable over many months. As a consequence, Si nanowire-based nanonets constitute a promising flexible material with stable and reproducible electrical properties at the macroscopic scale while being composed of nanoscale components, which confirms the Si nanonet potential for a wide range of applications including flexible electronic, sensing and photovoltaic applications.

Multimode silicon nanowire transistors.

The combined capabilities of both a nonplanar design and nonconventional carrier injection mechanisms are subject to recent scientific investigations to overcome the limitations of silicon metal oxide semiconductor field effect transistors. In this Letter, we present a multimode field effect transistors device using silicon nanowires that feature an axial n-type/intrinsic doping junction. A heterostructural device design is achieved by employing a self-aligned nickel-silicide source contact. The polymorph operation of the dual-gate device enabling the configuration of one p- and two n-type transistor modes is demonstrated. Not only the type but also the carrier injection mode can be altered by appropriate biasing of the two gate terminals or by inverting the drain bias. With a combined band-to-band and Schottky tunneling mechanism, in p-type mode a subthreshold swing as low as 143 mV/dec and an ON/OFF ratio of up to 10(4) is found. As the device operates in forward bias, a nonconventional tunneling transistor is realized, enabling an effective suppression of ambipolarity. Depending on the drain bias, two different n-type modes are distinguishable. The carrier injection is dominated by thermionic emission in forward bias with a maximum ON/OFF ratio of up to 10(7) whereas in reverse bias a Schottky tunneling mechanism dominates the carrier transport.

Composition-dependent interfacial abruptness in Au-catalyzed Si(1-x)Ge(x)/Si/Si(1-x)Ge(x) nanowire heterostructures.

As MOSFETs are scaled down, power dissipation remains the most challenging bottleneck for nanoelectronic devices. To circumvent this challenge, alternative devices such as tunnel field effect transistors are potential candidates, where the carriers are injected by a much less energetically costly quantum band to band tunneling mechanism. In this context, axial nanowire heterointerfaces with well-controlled interfacial abruptness offer an ideal structure. We demonstrate here the effect of tuning the Ge concentration in a Si1-xGex part of the nanowire on the Si/Si1-xGex and Si1-xGex/Si interfacial abruptness in axial Si-Si1-xGex nanowire heterostructures grown by the Au-catalyzed vapor-liquid-solid method. The two heterointerfaces are always asymmetric irrespective of the Ge concentration or nanowire diameter. For a fixed diameter, the value of interface abruptness decreases with increasing the Ge content for the Si/Si1-xGex interface but shows no strong Ge dependence at the Si1-xGex/Si interface where it features a linear correlation with the nanowire diameter. To rationalize these findings, a kinetic model for the layer-by-layer growth of nanowire heterostructures from a ternary Au-Ge-Si alloy is established that predicts a discrepancy in Ge concentration in the layer and the catalyst droplet. The Ge concentration in each layer is predicted to be dependent on the composition of the preceding layer. The most abrupt heterointerface (∼5 nm) is achieved by growing Si1-xGex with x = 0.85 on Si in a 25 nm diameter nanowire.

L-type bovine spongiform encephalopathy in genetically susceptible and resistant sheep: changes in prion strain or phenotypic plasticity of the disease-associated prion protein?

BACKGROUND: Sheep with prion protein (PrP) gene polymorphisms QQ171 and RQ171 were shown to be susceptible to the prion causing L-type bovine spongiform encephalopathy (L-BSE), although RQ171 sheep specifically propagated a distinctive prion molecular phenotype in their brains, characterized by a high molecular mass protease-resistant PrP fragment (HMM PrPres), distinct from L-BSE in QQ171 sheep. METHODS: The resulting infectious and biological properties of QQ171 and RQ171 ovine L-BSE prions were investigated in transgenic mice expressing either bovine or ovine PrP. RESULTS: In both mouse lines, ovine L-BSE transmitted similarly to cattle-derived L-BSE, with respect to survival periods, histopathology, and biochemical features of PrPres in the brain, as well as splenotropism, clearly differing from ovine classic BSE or from scrapie strain CH1641. Nevertheless and unexpectedly, HMM PrPres was found in the spleen of ovine PrP transgenic mice infected with L-BSE from RQ171 sheep at first passage, reminiscent, in lymphoid tissues only, of the distinct PrPres features found in RQ171 sheep brains. CONCLUSIONS: The L-BSE agent differs from both ovine classic BSE or CH1641 scrapie maintaining its specific strain properties after passage in sheep, although striking PrPres molecular changes could be found in RQ171 sheep and in the spleen of ovine PrP transgenic mice.

Presence of subclinical infection in gene-targeted human prion protein transgenic mice exposed to atypical bovine spongiform encephalopathy.

The transmission of bovine spongiform encephalopathy (BSE) to humans, leading to variant Creutzfeldt-Jakob disease has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health. Until recently, TSE disease in cattle was thought to be caused by a single agent strain, BSE, also known as classical BSE, or BSE-C. However, due to the initiation of a large-scale surveillance programme throughout Europe, two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H have since been discovered. To model the risk to human health, we previously inoculated these two forms of atypical BSE (BASE and BSE-H) into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP) (HuTg) but were unable to detect any signs of TSE pathology in these mice. However, despite the absence of TSE pathology, upon subpassage of some BASE-challenged HuTg mice, a TSE was observed in recipient gene-targeted bovine PrP Tg (Bov6) mice but not in HuTg mice. Disease transmission from apparently healthy individuals indicates the presence of subclinical BASE infection in mice expressing human PrP that cannot be identified by current diagnostic methods. However, due to the lack of transmission to HuTg mice on subpassage, the efficiency of mouse-to-mouse transmission of BASE appears to be low when mice express human rather than bovine PrP.