Synthetic Dimeric Aβ(28–40) Mimics the Complex Epitope of Human Anti-Aβ Autoantibodies against Toxic Aβ Oligomers

Covalently linked carboxyl-terminal segments of the β-amyloid peptide (Aβ) were tested for their qualification as minimal conformational epitopes of the naturally occurring human autoantibodies against β-amyloid (nAbs-Aβ). nAbs-Aβ specifically recognize the toxic oligomers of Aβ and not the monomeric or the fibrillar forms of Aβ. The synthetic dimers of Aβ(28–40) described herein mimic the toxic Aβ oligomers but are not kinetic intermediates with uncertain compositions. CD spectra identified a surprisingly rich conformational behavior of selected miniamyloids. We observed a highly cooperative conformational transition of β-sheet to α-helix upon the addition of the helix enforcing co-solvent hexafluoroisopropanol. The CD curves of dimer 9 resembled, in a completely reversible manner, the CD spectra measured during the irreversible fibrillation of the parent Aβ(1–40). Synthetic peptide epitopes with high affinities for nAbs-Aβ are needed to identify the physiological roles of nAbs-Aβ and are promising epitopes for vaccination experiments.     

Dimeric argininamide-type neuropeptide Y receptor antagonists: Chiral discrimination between Y1 and Y4 receptors

The structurally related peptides neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) are endogenous agonists of the NPY receptor (YR) family, which in humans comprises four functionally expressed subtypes, designated Y₁R, Y₂R, Y₄R and Y₅R. Nonpeptide antagonists with high affinity and selectivity have been described for the Y₁R, Y₂R and Y₅R, but such compounds are still lacking for the Y₄R. In this work, the structures of the high affinity selective (R)-argininamide-type Y₁R antagonists BIBP3226 and BIBO3304 were linked via the guanidine or urea moieties to give homo-dimeric argininamides with linker lengths ranging from 31 to 41 atoms. Interestingly, the twin compounds proved to be by far less selective for the Y₁R than the R-configured monovalent parent compounds. The decrease in selectivity ratio was most pronounced for Y₁R versus Y₄R subtype, resulting in comparable affinities of bivalent ligands for Y₁R and Y₄R (e.g. UR-MK177 ((R,R)-49): K_i = 230 nM (Y₁R) and 290 nM (Y₄R)). With a K_i value of 130 nM and a K_b value of 20 nM, UR-MK188 ((R,R)-51) was superior to all Y₄R antagonists known to date. The S,S-configured optical antipodes of UR-MK177 and UR-MK188 (UR-MEK381 ((S,S)-49) and UR-MEK388 ((S,S)-51)) were synthesized to investigate the stereochemical discrimination by the different receptor subtypes. Whereas preference for R,R-configured argininamides was characteristic of the Y₁R, stereochemical discrimination by the Y₄R was not observed. This may pave the way to selective Y₄R antagonists.     

Design,synthesis and biological evaluation of novel anti-cytokine 1,2,4-triazine derivatives

A series of 16 novel 1,2,4-triazine derivatives bearing hydrazone moiety (7a–7p) have been designed, synthesized and evaluated for their activity to inhibit IL-1β and TNF-α production. All compounds are reported for the first time. The chemical structures of all compounds were confirmed by spectroscopic methods and elemental analyzes. Most of the synthesized compounds were proved to have potent anti-cytokine activity and low toxicity on PBMC and MCF-7 cell lines. Compounds 7f, 7k, 7l and 7j presented simultaneously good levels of inhibition of both cytokines. Moreover, compound 7l exhibited good anti-inflammatory effect in carrageenan-induced rat paw edema. The results of Western blotting demonstrated that the anti-cytokine potential of compound 7l is mainly mediated through the inhibition of p38 MAPK signaling pathway. Molecular docking was performed to position compound 7l into p38α binding site in order to explore the potential target. The information of this work might be helpful for the design and synthesis of novel scaffold toward the development of new therapeutic agent to fight against inflammatory diseases.     

Common gene variants in RAD51, XRCC2 and XPD are not associated with clinical outcome in soft-tissue sarcoma patients

BackgroundDNA repair mechanisms play a major role in cancer risk and progression. Germline variants in DNA repair genes may result in altered gene function and/or activity, thereby causing inter-individual differences in a patient's tumor recurrence capacity. In genes of the DNA repair pathway the gene variants RAD51 rs1801320 G > C, XRCC2 rs3218536 G > A and XPD rs13181 A > C have been previously related to genetic predisposition and prognosis of various cancer entities. In this study we investigated the association between these polymorphisms and time to recurrence (TTR) and overall survival (OS) in soft-tissue sarcoma (STS) patients after curative surgery.MethodsTwo hundred sixty STS patients were included in this retrospective study. Germline DNA was genotyped by 5′-exonuclease (TaqMan) technology. Kaplan Meier curves and multivariate Cox proportional models were calculated for TTR and OS.ResultsA statistically significant association was observed between tumor grade and adjuvant radiotherapy and TTR and between tumor grade and OS. No association was found between RAD51 rs1801320 G > C, XRCC2 rs3218536 G > A and XPD rs13181 A > C and TTR and OS in univariate and multivariate analysis.ConclusionOur results underline a prognostic effect of tumor grade and adjuvant radiotherapy in STS patients but indicate no association between RAD51 rs1801320 G > C, XRCC2 rs3218536 G > A and XPD rs13181 A > C and clinical outcome in STS patients after curative surgery.     

Impact of Early Initiation of Antiretroviral Therapy in Patients with Acute HIV Infection in Vienna,Austria

BackgroundIt is unclear whether antiretroviral therapy (ART) should be initiated during acute HIV infection. Most recent data provides evidence of benefits of early ART.MethodsWe retrospectively compared the clinical and immunological course of individuals with acute HIV infection, who received ART within 3 months (group A) or not (group B) after diagnosis.ResultsAmong the 84 individuals with acute HIV infection, 57 (68%) received ART within 3 months (A) whereas 27 (32%) did not receive ART within 3 months (B), respectively. Clinical progression to CDC stadium B or C within 5 years after the diagnosis of HIV was less common in (A) when compared to (B) (P = 0.002). After twelve months, both the mean increase in CD4+ T cell count and the mean decrease in viral load was more pronounced in (A), when compared to (B) (225 vs. 87 cells/μl; P = 0.002 and -4.19 vs. -1.14 log10 copies/mL; P<0.001). Twenty-four months after diagnosis the mean increase from baseline of CD4+ T cells was still higher in group A compared to group B (251 vs. 67 cells/μl, P = 0.004).ConclusionsInitiation of ART during acute HIV infection is associated with a lower probability of clinical progression to more advanced CDC stages and significant immunological benefits.     

Reduced Recombination in High Efficiency Molecular Nematic Liquid Crystalline: Fullerene Solar Cells

Bimolecular recombination in bulk heterojunction organic solar cells is the process by which nongeminate photogenerated free carriers encounter each other, and combine to form a charge transfer (CT) state which subsequently relaxes to the ground state. It is governed by the diffusion of the slower and faster carriers toward the electron donor–acceptor interface. In an increasing number of systems, the recombination rate constant is measured to be lower than that predicted by Langevin's model for relative Brownian motion and the capture of opposite charges. This study investigates the dynamics of charge generation, transport, and recombination in a nematic liquid crystalline donor:fullerene acceptor system that gives solar cells with initial power conversion efficiencies of >9.5%. Unusually, and advantageously from a manufacturing perspective, these efficiencies are maintained in junctions thicker than 300 nm. Despite finding imbalanced and moderate carrier mobilities in this blend, strongly suppressed bimolecular recombination is observed, which is ≈150 times less than predicted by Langevin theory, or indeed, more recent and advanced models that take into account the domain size and the spatial separation of electrons and holes. The suppressed bimolecular recombination arises from the fact that ground‐state decay of the CT state is significantly slower than dissociation.     

Effects of heat and drought stress on post‐illumination bursts of volatile organic compounds in isoprene‐emitting and non‐emitting poplar

Over the last decades, post‐illumination bursts (PIBs) of isoprene, acetaldehyde and green leaf volatiles (GLVs) following rapid light‐to‐dark transitions have been reported for a variety of different plant species. However, the mechanisms triggering their release still remain unclear. Here we measured PIBs of isoprene‐emitting (IE) and isoprene non‐emitting (NE) grey poplar plants grown under different climate scenarios (ambient control and three scenarios with elevated CO₂ concentrations: elevated control, periodic heat and temperature stress, chronic heat and temperature stress, followed by recovery periods). PIBs of isoprene were unaffected by elevated CO₂ and heat and drought stress in IE, while they were absent in NE plants. On the other hand, PIBs of acetaldehyde and also GLVs were strongly reduced in stress‐affected plants of all genotypes. After recovery from stress, distinct differences in PIB emissions in both genotypes confirmed different precursor pools for acetaldehyde and GLV emissions. Changes in PIBs of GLVs, almost absent in stressed plants and enhanced after recovery, could be mainly attributed to changes in lipoxygenase activity. Our results indicate that acetaldehyde PIBs, which recovered only partly, derive from a new mechanism in which acetaldehyde is produced from methylerythritol phosphate pathway intermediates, driven by deoxyxylulose phosphate synthase activity.     

Modeling immune response and its effect on infectious disease outbreak dynamics

Background

In recent epidemiological models, immunity is incorporated as a simplified value that determines the capacity of an individual to become infected or to transmit the disease. Moreover, the quality of the immune response determines the chances of infection and the length of time an individual is capable to infect others. We present a model that incorporates individuals’ immune responses to, further, examine the role of the collective immune response of individuals in a population during an infectious outbreak.

Methods

We constructed a contagion model that incorporates the collective immune response of individuals represented by the superposition of individual immune responses (PIR). Multiple probability distributions are used to represent the immunocompetence of different age groups, thereby modeling the concept of Population Immune Response (PIR). Multiple experiments were conducted in which the population is divided in different age groups for which each group has a unique immune response quality and thus a different length for its immune periods. Finally, we explored the effects of implementing different vaccination strategies in the population.

Results

The experiments displayed important variations in the outbreak dynamics as a consequence of incorporating PIR in homogeneous and mixed populations. The experiments showed that individuals with weak immune responses and those who are immune to the pathogen play a significant role in shaping the outbreak dynamics. Finally, after implementing different vaccination strategies, the results suggest that if vaccination resources are limited, the vaccination should be targeted towards individuals that spread the disease for a longer period of time.

Conclusions

Our results suggest that it is essential for the public health establishment to increase their understanding of the characteristics of regional demographics that could impact the quality of the immune response of the individuals. The results indicate that it is necessary to further investigate mitigation strategies to limit the capacity to transmit the disease by individuals that spread the pathogen for extended periods of time. Ultimately, this study suggests that it is crucial for public health researchers to identify appropriate targeted vaccination regimes and to explore the link between PIR and outbreak dynamics to improve the monitoring and mitigating efforts of ongoing and future epidemics.

     

Organization of the subumbrellar musculature in the ephyra,juvenile, and adult stages of Aurelia aurita Medusae

We used fluorescently labeled phalloidin to examine the subumbrellar musculature of the scyphozoan jellyfish Aurelia aurita in a developmental series from ephyra to adult medusa. In the ephyra, the swim musculature includes a disc‐like sheet of circular muscle, in addition to two radial bands of muscle in each of the eight ephyral arms. The radial muscle bands join with the circular muscle, and both circular and radial muscle act together during each swim contraction. As the ephyra grows into a juvenile medusa, arms tissue is resorbed as the bell tissue grows outward, so eventually, the ephyral arms disappear. During this process, the circular muscle disc also grows outward and the radial muscle bands of the arms also disappear. At this time, a marginal gap appears at the bell margin, which is devoid of circular muscle cells, but has a loose arrangement of radial muscle fibers. This marginal gap is preserved as the medusa grows, and contributes to the floppy nature of the bell margin. Radial distortions in the circular muscle layer involve muscle fibers that run in random directions, with a primarily radial orientation. These are believed to be remnants of the radial muscle of the ephyral arms, and the distortions decrease in number and extent as the medusa grows. Since the mechanics of swimming changes from drag‐based paddling in the ephyra to marginal rowing in the adult medusa, the development of the marginal gap and the presence of radial distortions should be considered in terms of this mechanical transition.     

Sowing of margin strips rich in floral resources improves herbivore control in adjacent crop fields

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