234 research outputs found
Single-photon detection and cryogenic reconfigurability in Lithium Niobate nanophotonic circuits
Lithium-Niobate-On-Insulator (LNOI) is emerging as a promising platform for
integrated quantum photonic technologies because of its high second-order
nonlinearity and compact waveguide footprint. Importantly, LNOI allows for
creating electro-optically reconfigurable circuits, which can be efficiently
operated at cryogenic temperature. Their integration with superconducting
nanowire single-photon detectors (SNSPDs) paves the way for realizing scalable
photonic devices for active manipulation and detection of quantum states of
light. Here we report the first demonstration of these two key components
integrated in a low loss (0.2 dB/cm) LNOI waveguide network. As an experimental
showcase of our technology, we demonstrate the combined operation of an
electrically tunable Mach-Zehnder interferometer and two waveguide-integrated
SNSPDs at its outputs. We show static reconfigurability of our system with a
bias-drift-free operation over a time of 12 hours, as well as high-speed
modulation at a frequency up to 1 GHz. Our results provide blueprints for
implementing complex quantum photonic devices on the LNOI platform
Kidney involvement in the Schnitzler syndrome, a rare disease
The Schnitzler syndrome (SS) is a rare and underdiagnosed entity that associates a chronic urticarial rash, monoclonal IgM (or sometimes IgG) gammopathy and signs and symptoms of systemic inflammation. During the past 45 years, the SS has evolved from an elusive little-known disorder to the paradigm of a late-onset acquired auto-inflammatory syndrome. Though there is no definite proof of its precise pathogenesis, it should be considered as an acquired disease involving abnormal stimulation of the innate immune system, which can be reversed by the interleukin-1 receptor antagonist anakinra. It clearly expands our view of this group of rare genetic diseases and makes the concept of auto-inflammation relevant in polygenic acquired diseases as well. Increasing numbers of dermatologists, rheumatologists, allergologists, haematologists and, more recently, nephrologists, recognize the SS. The aim of this review is to focus on kidney involvement in the SS. Although the literature regarding kidney involvement in the SS is very poor it can be severe, as in our own case here reported, leading us to recommend the systematic search for nephropathy markers in the SS
An interactive database for the investigation of high-density peptide microarray guided interaction patterns and antivenom cross-reactivity
Snakebite envenoming is a major neglected tropical disease that affects millions of people every year. The only effective treatment against snakebite envenoming consists of unspecified cocktails of polyclonal antibodies purified from the plasma of immunized production animals. Currently, little data exists on the molecular interactions between venom-toxin epitopes and antivenom-antibody paratopes. To address this issue, high-density peptide microarray (hdpm) technology has recently been adapted to the field of toxinology. However, analysis of such valuable datasets requires expert understanding and, thus, complicates its broad application within the field. In the present study, we developed a user-friendly, and high-throughput web application named “Snake Toxin and Antivenom Binding Profiles” (STAB Profiles), to allow straight-forward analysis of hdpm datasets. To test our tool and evaluate its performance with a large dataset, we conducted hdpm assays using all African snake toxin protein sequences available in the UniProt database at the time of study design, together with eight commercial antivenoms in clinical use in Africa, thus representing the largest venom-antivenom dataset to date. Furthermore, we introduced a novel method for evaluating raw signals from a peptide microarray experiment and a data normalization protocol enabling intra-microarray and even inter-microarray chip comparisons. Finally, these data, alongside all the data from previous similar studies by Engmark et al., were preprocessed according to our newly developed protocol and made publicly available for download through the STAB Profiles web application (http://tropicalpharmacology.com/tools/stab-profiles/). With these data and our tool, we were able to gain key insights into toxin-antivenom interactions and were able to differentiate the ability of different antivenoms to interact with certain toxins of interest.
The data, as well as the web application, we present in this article should be of significant value to the venom-antivenom research community. Knowledge gained from our current and future analyses of this dataset carry the potential to guide the improvement and optimization of current antivenoms for maximum patient benefit, as well as aid the development of next-generation antivenoms.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP
Envenomations by Bothrops and Crotalus Snakes Induce the Release of Mitochondrial Alarmins
Skeletal muscle necrosis is a common manifestation of viperid snakebite envenomations. Venoms from snakes of the genus Bothrops, such as that of B. asper, induce muscle tissue damage at the site of venom injection, provoking severe local pathology which often results in permanent sequelae. In contrast, the venom of the South American rattlesnake Crotalus durissus terrificus, induces a clinical picture of systemic myotoxicity, i.e., rhabdomyolysis, together with neurotoxicity. It is known that molecules released from damaged muscle might act as ‘danger’ signals. These are known as ‘alarmins’, and contribute to the inflammatory reaction by activating the innate immune system. Here we show that the venoms of B. asper and C. d. terrificus release the mitochondrial markers mtDNA (from the matrix) and cytochrome c (Cyt c) from the intermembrane space, from ex vivo mouse tibialis anterior muscles. Cyt c was released to a similar extent by the two venoms whereas B. asper venom induced the release of higher amounts of mtDNA, thus reflecting hitherto some differences in their pathological action on muscle mitochondria. At variance, injection of these venoms in mice resulted in a different time-course of mtDNA release, with B. asper venom inducing an early onset increment in plasma levels and C. d. terrificus venom provoking a delayed release. We suggest that the release of mitochondrial ‘alarmins’ might contribute to the local and systemic inflammatory events characteristic of snakebite envenomations
Cross-recognition of a pit viper (Crotalinae) polyspecific antivenom explored through high-density peptide microarray epitope mapping
Snakebite antivenom is a 120 years old invention based on polyclonal mixtures of antibodies
purified from the blood of hyper-immunized animals. Knowledge on antibody recognition
sites (epitopes) on snake venom proteins is limited, but may be used to provide molecular
level explanations for antivenom cross-reactivity. In turn, this may help guide antivenom
development by elucidating immunological biases in existing antivenoms. In this study, we
have identified and characterized linear elements of B-cell epitopes from 870 pit viper venom
protein sequences by employing a high-throughput methodology based on custom designed
high-density peptide microarrays. By combining data on antibody-peptide interactions with
multiple sequence alignments of homologous toxin sequences and protein modelling, we
have determined linear elements of antibody binding sites for snake venom metalloproteases
(SVMPs), phospholipases A2s (PLA2s), and snake venom serine proteases (SVSPs). The
studied antivenom antibodies were found to recognize linear elements in each of the three
enzymatic toxin families. In contrast to a similar study of elapid (non-enzymatic) neurotoxins,
these enzymatic toxins were generally not recognized at the catalytic active site responsible
for toxicity, but instead at other sites, of which some are known for allosteric inhibition or for
interaction with the tissue target. Antibody recognition was found to be preserved for several
minor variations in the protein sequences, although the antibody-toxin interactions could
often be eliminated completely by substitution of a single residue. This finding is likely to have
large implications for the cross-reactivity of the antivenom and indicate that multiple different
antibodies are likely to be needed for targeting an entire group of toxins in these recognized
sites.Novo Nordisk Foundation/[NNF13OC0005613]/NNF/DinamarcaNovo Nordisk Foundation/[NNF16OC0019248]/NNF/DinamarcaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP
Delayed oral LY333013 rescues mice from highly neurotoxic, lethal doses of Papuan Taipan (Oxyuranus scutellatus) venom
There is an unmet need for economical snakebite therapies with long shelf lives
that are effective even with delays in treatment. The orally bioavailable, heat-stable, secretory
phospholipase A2 (sPLA2) inhibitor, LY333013, demonstrates antidotal characteristics for severe
snakebite envenoming in both field and hospital use. A murine model of lethal envenoming
by a Papuan taipan (Oxyuranus scutellatus) demonstrates that LY333013, even with delayed oral
administration, improves the chances of survival. Furthermore, LY333013 improves the performance
of antivenom even after it no longer reverses neurotoxic signs. Our study is the first demonstration
that neurotoxicity from presynaptic venom sPLA2S can be treated successfully, even after the window
of therapeutic antivenom has closed. These results suggest that sPLA2 inhibitors have the potential
to reduce death and disability and should be considered for the initial and adjunct treatment of
snakebite envenoming. The scope and capacity of the sPLA2 inhibitors ability to achieve these
endpoints requires further investigation and development effortsUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP)UCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiologí
Behavior and Impact of Zirconium in the Soil–Plant System: Plant Uptake and Phytotoxicity
Because of the large number of sites they pollute, toxic metals that contaminate terrestrial ecosystems are increasingly of environmental and sanitary concern (Uzu et al. 2010, 2011; Shahid et al. 2011a, b, 2012a). Among such metals is zirconium (Zr), which has the atomic number 40 and is a transition metal that resembles titanium in physical and chemical properties (Zaccone et al. 2008). Zr is widely used in many chemical industry processes and in nuclear reactors (Sandoval et al. 2011; Kamal et al. 2011), owing to its useful properties like hardness, corrosion-resistance and permeable to neutrons (Mushtaq 2012). Hence, the recent increased use of Zr by industry, and the occurrence of the Chernobyl and Fukashima catastrophe have enhanced environmental levels in soil and waters (Yirchenko and Agapkina 1993; Mosulishvili et al. 1994 ; Kruglov et al. 1996)
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