Constituents of Lepidium meyenii 'maca'.

The tubers of Lepidium meyenii contain the benzylated derivative of 1,2-dihydro-N-hydroxypyridine, named macaridine, together with the benzylated alkamides (macamides), N-benzyl-5-oxo-6E,8E-octadecadienamide and N-benzylhexadecanamide, as well as the acyclic keto acid, 5-oxo-6E,8E-octadecadienoic acid. The structure elucidation of the isolated compounds was based primarily on 1D and 2D NMR spectroscopic analyses, including 1H-1H COSY, 1H-13C HMQC, 1H-13C HMBC and 1H-1H NOESY experiments, as well as from 1H-15N NMR HMBC correlations for macaridine and N-benzylhexadecanamide.     

Anticentromere antibody positive Sj?gren's Syndrome: a retrospective descriptive analysis

Introduction

A subgroup of patients with primary Sjögren''s Syndrome (SS) and positive anticentromere antibodies (ACA) were recognized as having features intermediate between SS and systemic sclerosis (SSc). Our goal was to describe this group clinically and serologically and define its tendency to evolve to full blown SSc.

Methods

Among 535 patients with primary SS we identified 20 ACA positive (ACA+/SS). We compared them to 61 randomly selected ACA negative SS patients (ACA-/SS), 31 ACA positive SSc patients with sicca manifestations [SSc/(+) sicca] and 20 ACA positive SSc patients without sicca manifestations [SSc/(-) sicca].

Results

Prevalence of ACA among SS patients was 3.7%. Cases and controls did not differ in sex ratio and age at disease onset. ACA+/SS patients had a lower prevalence of dry eyes, hypergammaglobulinaemia, anti-Ro and anti-La antibodies and a higher prevalence of Raynaud''s phenomenon and dysphagia compared to ACA-/SS patients. They also had lower prevalence of telangiectasias, puffy fingers, sclerodactyly, Raynaud''s phenomenon, digital ulcers and gastroesophageal reflux in comparison to both of the SSc subgroups and a lower prevalence of dyspnoea and lung fibrosis compared to the SSc/(+) sicca subgroup. Two patients originally having ACA+/SS evolved to full blown SSc. Four deaths occurred, all among SSc patients. Kaplan Meier analysis showed a significant difference between cases and controls in time from disease onset to development of gastroesophageal reflux, telangiectasias, digital ulcers, arthritis, puffy fingers, xerostomia, hypergammaglobulinaemia and dysphagia.

Conclusions

ACA+/SS has a clinical phenotype intermediate between ACA-/SS and SSc and shows little tendency to evolve to SSc.     

Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis

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Altered Antibody Profiles against Common Infectious Agents in Chronic Disease

Despite the important diagnostic value of evaluating antibody responses to individual human pathogens, antibody profiles against multiple infectious agents have not been used to explore health and disease mainly for technical reasons.  We hypothesized that the interplay between infection and chronic disease might be revealed by profiling antibodies against multiple agents. Here, the levels of antibodies against a panel of 13 common infectious agents were evaluated with the quantitative Luciferase Immunoprecipitation Systems (LIPS) in patients from three disease cohorts including those with pathogenic anti-interferon-γ autoantibodies (IFN-γ AAB), HIV and Sjögren’s syndrome (SjS) to determine if their antibody profiles differed from control subjects.  The IFN-γ AAB patients compared to controls demonstrated statistically higher levels of antibodies against VZV (p=0.0003), EBV (p=0.002), CMV (p=0.003), and C. albicans (p=0.03), but lower antibody levels against poliovirus (p=0.04). Comparison of HIV patients with blood donor controls revealed that the patients had higher levels of antibodies against CMV (p=0.0008), HSV-2 (p=0.0008), EBV (p=0.001), and C. albicans (p=0.01), but showed decreased levels of antibodies against coxsackievirus B4 (p=0.0008), poliovirus (p=0.0005),   and HHV-6B (p=0.002). Lastly, SjS patients had higher levels of anti-EBV antibodies (p=0.03), but lower antibody levels against several enteroviruses including a newly identified picornavirus, HCoSV-A (p=0.004), coxsackievirus B4 (p=0.04), and poliovirus (p=0.02). For the IFN-γ AAB and HIV cohorts, principal component analysis revealed unique antibody clusters that showed the potential to discriminate patients from controls.  The results suggest that antibody profiles against these and likely other common infectious agents may yield insight into the interplay between exposure to infectious agents, dysbiosis, adaptive immunity and disease activity.     

Direct Recycling of Spent NCM Cathodes through Ionothermal Lithiation

Ionic liquids (ILs) are a family of nonconventional molten salts that offer many advantages, such as negligible vapor pressures, negligible flammability, wide liquidus ranges, good thermal stability, and much synthesis flexibility. The unique solvation environment of these ILs provides new reaction or flux media for controlling formation of solid‐state materials with a minimum perturbation of morphologies. A successful lithiation via ionothermal synthesis using a cost‐effective Li halide as Li source and recyclable ILs as solvents is reported here for the direct recycling of LiNi_1/3Co_1/3Mn_1/3O₂ (NCM 111) cathodes. In addition, the ionic liquids can be readily recycled and reused after ionothermal lithiation. The lithiation of spent cathodes can enable the direct recycling of spent cathode materials in lithium‐ion batteries.     

The majority of microRNAs detectable in serum and saliva is concentrated in exosomes

There is an increasing interest in using microRNAs (miRNA) as biomarkers in autoimmune diseases. They are easily accessible in many body fluids but it is controversial if they are circulating freely or are encapsulated in microvesicles, particularly exosomes. We investigated if the majority of miRNas in serum and saliva are free-circulating or concentrated in exosomes. Exosomes were isolated by ultracentrifugation from fresh and frozen human serum and saliva. The amount of selected miRNAs extracted from the exosomal pellet and the exosome-depleted serum and saliva was compared by quantitative RT-PCR. Some miRNAs tested are ubiquitously expressed, others were previously reported as biomarkers. We included miRNAs previously reported to be free circulating and some thought to be exosome specific. The purity of exosome fraction was confirmed by electronmicroscopy and western blot. The concentration of miRNAs was consistently higher in the exosome pellet compared to the exosome-depleted supernatant. We obtained the same results using an equal volume or equal amount of total RNA as input of the RT-qPCR. The concentration of miRNA in whole, unfractionated serum, was between the exosomal pellet and the exosome-depleted supernatant. Selected miRNAs, which were detectable in exosomes, were undetectable in whole serum and the exosome-depleted supernantant. Exosome isolation improves the sensitivity of miRNA amplification from human biologic fluids. Exosomal miRNA should be the starting point for early biomarker studies to reduce the probability of false negative results involving low abundance miRNAs that may be missed by using unfractionated serum or saliva.     

Functional expression of a costimulatory B7.2 (CD86) protein on human salivary gland epithelial cells that interacts with the CD28 receptor, but has reduced binding to CTLA4

B7 molecules expressed on classic APC play a critical role in the regulation of immune responses by providing activation or inhibitory signals to T cells, through the ligation with CD28 or CTLA4 receptors, respectively. We have recently described the expression of B7 molecules by the salivary gland epithelial cells (SGEC) of patients with Sj?gren's syndrome (also termed autoimmune epithelitis). The role of such expression needs to be clarified. Thus, in the present study, we sought to address the existence and function of B7.2 proteins on cultured nonneoplastic SGEC lines derived from Sj?gren's syndrome patients. The occurrence of B7.2 proteins on SGEC was verified by flow cytometry, immunocytochemistry, immunoprecipitation, and immunoblotting. The assessment of several cell lines in costimulation assays had revealed that the constitutive expression of B7.2 molecules is sufficient to provide costimulatory signals to anti-CD3-stimulated T cells. SGEC-derived costimulation induced IL-2-dependent proliferation of CD4(+) T cells, which was associated with low production of IL-2, but probably also with the secretion of yet undefined autocrine T cell growth factor(s). B7.2 proteins expressed by SGEC were found to display distinctive binding properties denoted by the functional interaction with CD28 receptor and reduced binding to CTLA4. Finally, the detection of a functional soluble form of B7.2 protein in cell-free culture supernatants of both SGEC and EBV-transformed B cell lines is demonstrated. These findings imply a critical role for epithelial cells in the regulation of local immune responses in the salivary glands.     

Peptide carriers: A helicoid-type sequential oligopeptide carrier (SOC(n)) for multiple anchoring of antigenic/immunogenic peptides.

A new peptide carrier with three-dimensional predetermined structural motif has been constructed by the repetitive Lys-Aib-Gly moiety. The sequential oligopeptide carrier (SOC(n)), (Lys-Aib-Gly)(n), adopts a distorted 3(10)-helical conformation and the Lys-N(epsilon)H(2) anchoring groups exhibit defined spatial orientations. Conformational analysis of the SOC(n) conjugates showed that the coupled peptides retain their initial "active" structure, while prevalence of one conformer was also observed. It is concluded that the beneficial structural elements of SOC(n) induce a favorable arrangement of the conjugated peptides, so that potent antigens and immunogens are generated.     

Neutron scattering measurements of intact cells show changes after heat shock consistent with an increase in molecular crowding

Molecular crowding has been shown to be important in many cellular processes. The crowded environment in the cell results in a significant proportion of the cellular water being in contact with macromolecules such as proteins and DNA. These interfacial water molecules show a reduced dynamic motion that has been observed with isolated macromolecules using several biophysical techniques. Previously we investigated the inelastic neutron scattering properties of water closely associated with isolated biomolecules, and showed that interfacial water is strongly perturbed, as judged by its energy transfer spectrum. Here we have probed living cells using inelastic and quasielastic neutron scattering. We have found that mild heat stress ('heat shock'), which causes some proteins to become unfolded in the cell, results in changes in the inelastic neutron scattering in the librational region (45-130 meV). Heat shock also causes a narrowing of the quasielastic scattering peak. These changes can be understood in terms of an increase in the proportion of interfacial water molecules, and a net reduction in proton dynamics.     

A lifetime perspective on foraging and mortality

Food intake carries many potential risks which may impair an animal's reproductive success not only in the current breeding cycle, but also for the rest of its lifetime. We examine the lifetime trade-off between the costs and benefits of food intake by presenting a simple animal foraging model, where each unit of food eaten carries with it a risk of mortality. We show that the optimal food intake rate over an animal's lifetime, for both semelparous and iteroparous animals, is not maximal. Instead, animals are required to strike a balance between the immediate reproductive benefits of gathering food and the future reproductive costs incurred by the food's mortality risk. This balance depends upon the lifespan of the animal as well as the nature of the risk. Different mortality risks are compared and it is shown that a mortality risk per unit time spent foraging is not, in general, equivalent to a mortality risk per unit of food consumed. The results suggest that a mortality risk per unit of food consumed, such as that presented by the presence of a toxin or of a parasite in the diet, has important consequences for feeding behaviour and is a possible factor involved in food intake regulation.