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Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups.
In vivo compatible reactions have a broad range of possible applications in chemical biology and the pharmaceutical sciences. Here we report tetrazines that can be removed by exposure to isonitriles under very mild conditions. Tetrazylmethyl derivatives are easily accessible protecting groups for amines and phenols. The isonitrile-induced removal is rapid and near-quantitative. Intriguingly, the deprotection is especially effective with (trimethylsilyl)methyl isocyanide, and serum albumin can catalyze the elimination under physiological conditions. NMR and computational studies revealed that an imine-tautomerization step is often rate limiting, and the unexpected cleavage of the Si-C bond accelerates this step in the case with (trimethylsilyl)methyl isocyanide. Tetrazylmethyl-removal is compatible with use on biomacromolecules, in cellular environments, and in living organisms as demonstrated by cytotoxicity experiments and fluorophore-release studies on proteins and in zebrafish embryos. By combining tetrazylmethyl derivatives with previously reported tetrazine-responsive 3-isocyanopropyl groups, it was possible to liberate two fluorophores in vertebrates from a single bioorthogonal reaction. This chemistry will open new opportunities towards applications involving multiplexed release schemes and is a valuable asset to the growing toolbox of bioorthogonal dissociative reactions
A resorcinarene for inhibition of Aβ fibrillation.
Amyloid-β peptides (Aβ) fibrillation is the hallmark of Alzheimer's disease (AD). However, it has been challenging to discover potent agents in order to inhibit Aβ fibrillation. Herein, we demonstrated the effect of resorcinarene on inhibiting Aβ fibrillation in vitro via experimental and computational methods. Aβ were incubated with different concentrations of resorcinarene so as to monitor the kinetics by using thioflavin T binding assay. The results, which were further confirmed by far-UV CD spectroscopy and atomic force microscopy, strongly indicated that the higher concentration of resorcinarene, the more effective the inhibition of Aβ fibrillation. A cytotoxicity study showed that when sea urchin embryos were exposed to the resorcinarene, the majority survived due to the resorcinarene low toxicity. In addition, when the resorcinarene was added, the formation of toxic Aβ 42 species was delayed. Computational studies of Aβ fibrillation, including docking simulations and MD simulations, illustrated that the interaction between inhibitor resorcinarene and Aβ is driven by the non-polar interactions. These studies display a novel strategy for the exploration of promising antiamyloiddogenic agents for AD treatments
Few-Shot Single-View 3-D Object Reconstruction with Compositional Priors
The impressive performance of deep convolutional neural networks in
single-view 3D reconstruction suggests that these models perform non-trivial
reasoning about the 3D structure of the output space. However, recent work has
challenged this belief, showing that complex encoder-decoder architectures
perform similarly to nearest-neighbor baselines or simple linear decoder models
that exploit large amounts of per category data in standard benchmarks. On the
other hand settings where 3D shape must be inferred for new categories with few
examples are more natural and require models that generalize about shapes. In
this work we demonstrate experimentally that naive baselines do not apply when
the goal is to learn to reconstruct novel objects using very few examples, and
that in a \emph{few-shot} learning setting, the network must learn concepts
that can be applied to new categories, avoiding rote memorization. To address
deficiencies in existing approaches to this problem, we propose three
approaches that efficiently integrate a class prior into a 3D reconstruction
model, allowing to account for intra-class variability and imposing an implicit
compositional structure that the model should learn. Experiments on the popular
ShapeNet database demonstrate that our method significantly outperform existing
baselines on this task in the few-shot setting
Progression of sleep disturbances in Parkinson’s Disease. A 5-year longitudinal study.
BACKGROUND: Sleep disorders can occur in early Parkinson’s disease (PD). However, the relationship between different sleep disturbances and their longitudinal evolution has not been fully explored. OBJECTIVE: To describe the frequency, coexistence and longitudinal change in excessive daytime sleepiness (EDS), insomnia and probable REM sleep behaviour disorder (pRBD) in early PD. METHODS: Data were obtained from the Parkinson’s Progression Markers Initiative (PPMI). EDS, insomnia, and pRBD were defined using the Epworth Sleepiness Scale, MDS-UPDRS Part I sub-item 1.7, and RBD screening questionnaire. RESULTS: 218 PD subjects and 102 controls completed five years of follow up. At baseline, 69 (31.7%) PD subjects reported one type of sleep disturbance, 25 (11.5%) reported two types of sleep disturbances, and three (1.4%) reported all three types of sleep disturbances. At five years, the number of PD subjects reporting one, two and three types of sleep disturbances was 85 (39.0%), 51 (23.4%), and 16 (7.3%), respectively. Only 41(18.8%) patients were taking sleep medications. The largest increase in frequency was seen in insomnia (44.5%), followed by EDS (32.1%) and pRBD (31.2%). Insomnia was the most common sleep problem at any time over the 5-year follow-up. The frequency of sleep disturbances in HCs remained stable. CONCLUSIONS: There is a progressive increase in the frequency of sleep disturbances in PD, with the number of subjects reporting multiple sleep disturbances increasing over time. Relatively few patients reported multiple sleep disturbances, suggesting that they can have different pathogenesis. A large number of patients were not treated for their sleep disturbances
Colorimetric Measurement of Triglycerides Cannot Provide an Accurate Measure of Stored Fat Content in Drosophila
Drosophila melanogaster has recently emerged as a useful model system in which to study the genetic basis of regulation of fat storage. One of the most frequently used methods for evaluating the levels of stored fat (triglycerides) in flies is a coupled colorimetric assay available as a kit from several manufacturers. This is an aqueous-based enzymatic assay that is normally used for measurement of mammalian serum triglycerides, which are present in soluble lipoprotein complexes. In this short communication, we show that coupled colorimetric assay kits cannot accurately measure stored triglycerides in Drosophila. First, they fail to give accurate readings when tested on insoluble triglyceride mixtures with compositions like that of stored fat, or on fat extracted from flies with organic solvents. This is probably due to an inability of the lipase used in the kits to efficiently cleave off the glycerol head group from fat molecules in insoluble samples. Second, the measured final products of the kits are quinoneimines, which absorb visible light in the same wavelength range as Drosophila eye pigments. Thus, when extracts from crushed flies are assayed, much of the measured signal is actually due to eye pigments. Finally, the lipoprotein lipases used in colorimetric assays also cleave non-fat glycerides. The glycerol backbones liberated from all classes of glycerides are measured through the remaining reactions in the assay. As a consequence, when these assay kits are used to evaluate tissue extracts, the observed signal actually represents the amount of free glycerols together with all types of glycerides. For these reasons, findings obtained through use of coupled colorimetric assays on Drosophila samples must be interpreted with caution. We also show here that using thin-layer chromatography to measure stored triglycerides in flies eliminates all of these problems
Quantifying Inactive Lithium in Lithium Metal Batteries
Inactive lithium (Li) formation is the immediate cause of capacity loss and
catastrophic failure of Li metal batteries. However, the chemical component and
the atomic level structure of inactive Li have rarely been studied due to the
lack of effective diagnosis tools to accurately differentiate and quantify Li+
in solid electrolyte interphase (SEI) components and the electrically isolated
unreacted metallic Li0, which together comprise the inactive Li. Here, by
introducing a new analytical method, Titration Gas Chromatography (TGC), we can
accurately quantify the contribution from metallic Li0 to the total amount of
inactive Li. We uncover that the Li0, rather than the electrochemically formed
SEI, dominates the inactive Li and capacity loss. Using cryogenic electron
microscopies to further study the microstructure and nanostructure of inactive
Li, we find that the Li0 is surrounded by insulating SEI, losing the electronic
conductive pathway to the bulk electrode. Coupling the measurements of the Li0
global content to observations of its local atomic structure, we reveal the
formation mechanism of inactive Li in different types of electrolytes, and
identify the true underlying cause of low Coulombic efficiency in Li metal
deposition and stripping. We ultimately propose strategies to enable the highly
efficient Li deposition and stripping to enable Li metal anode for next
generation high energy batteries
A Functional Henipavirus Envelope Glycoprotein Pseudotyped Lentivirus Assay System
<p>Abstract</p> <p>Background</p> <p>Hendra virus (HeV) and Nipah virus (NiV) are newly emerged zoonotic paramyxoviruses discovered during outbreaks in Queensland, Australia in 1994 and peninsular Malaysia in 1998/9 respectively and classified within the new <it>Henipavirus </it>genus. Both viruses can infect a broad range of mammalian species causing severe and often-lethal disease in humans and animals, and repeated outbreaks continue to occur. Extensive laboratory studies on the host cell infection stage of HeV and NiV and the roles of their envelope glycoproteins have been hampered by their highly pathogenic nature and restriction to biosafety level-4 (BSL-4) containment. To circumvent this problem, we have developed a henipavirus envelope glycoprotein pseudotyped lentivirus assay system using either a luciferase gene or green fluorescent protein (GFP) gene encoding human immunodeficiency virus type-1 (HIV-1) genome in conjunction with the HeV and NiV fusion (F) and attachment (G) glycoproteins.</p> <p>Results</p> <p>Functional retrovirus particles pseudotyped with henipavirus F and G glycoproteins displayed proper target cell tropism and entry and infection was dependent on the presence of the HeV and NiV receptors ephrinB2 or B3 on target cells. The functional specificity of the assay was confirmed by the lack of reporter-gene signals when particles bearing either only the F or only G glycoprotein were prepared and assayed. Virus entry could be specifically blocked when infection was carried out in the presence of a fusion inhibiting C-terminal heptad (HR-2) peptide, a well-characterized, cross-reactive, neutralizing human mAb specific for the henipavirus G glycoprotein, and soluble ephrinB2 and B3 receptors. In addition, the utility of the assay was also demonstrated by an examination of the influence of the cytoplasmic tail of F in its fusion activity and incorporation into pseudotyped virus particles by generating and testing a panel of truncation mutants of NiV and HeV F.</p> <p>Conclusions</p> <p>Together, these results demonstrate that a specific henipavirus entry assay has been developed using NiV or HeV F and G glycoprotein pseudotyped reporter-gene encoding retrovirus particles. This assay can be conducted safely under BSL-2 conditions and will be a useful tool for measuring henipavirus entry and studying F and G glycoprotein function in the context of virus entry, as well as in assaying and characterizing neutralizing antibodies and virus entry inhibitors.</p
Catastrophic total costs in tuberculosis-affected households and their determinants since Indonesia’s implementation of universal health coverage
Structural analysis and corrosion studies on an ISO 5832-9 biomedical alloy with TiO2 sol–gel layers
The aim of this study was to demonstrate the
relationship between the structural and corrosion properties
of an ISO 5832-9 biomedical alloy modified with titanium
dioxide (TiO2) layers. These layers were obtained via the
sol–gel method by acid-catalyzed hydrolysis of titanium
isopropoxide in isopropanol solution. To obtain TiO2 layers
with different structural properties, the coated samples
were annealed at temperatures of 200, 300, 400, 450, 500,
600 and 800 C for 2 h. For all the prepared samples,
accelerated corrosion measurements were performed in
Tyrode’s physiological solution using electrochemical
methods. The most important corrosion parameters were
determined: corrosion potential, polarization resistance,
corrosion rate, breakdown and repassivation potentials.
Corrosion damage was analyzed using scanning electron
microscopy. Structural analysis was carried out for selected
TiO2 coatings annealed at 200, 400, 600 and 800 C. In
addition, the morphology, chemical composition, crystallinity,
thickness and density of the deposited TiO2 layers
were determined using suitable electron and X-ray measurement
methods. It was shown that the structure and
character of interactions between substrate and deposited
TiO2 layers depended on annealing temperature. All the
obtained TiO2 coatings exhibit anticorrosion properties, but
these properties are related to the crystalline structure and
character of substrate–layer interaction. From the point of
view of corrosion, the best TiO2 sol–gel coatings for stainless steel intended for biomedical applications seem to
be those obtained at 400 C.This study was supported by Grant No. N N507
501339 of the National Science Centre. The authors wish to express
their thanks to J. Borowski (MEDGAL, Poland) for the Rex 734 alloy
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