Utility of plasma neurofilament light and total tau for clinical trials in Alzheimer's disease

INTRODUCTION: Several blood‐based biomarkers are associated with neuronal injury, but their utility in interventional clinical trials is unclear. This study retrospectively evaluated the utility of plasma neurofilament light (NfL) and total tau (t‐tau) in an 18‐month trial in mild Alzheimer's disease (AD). METHODS: Correlation and conditional independence analyses and Gaussian graphical models were used to investigate cross‐sectional and longitudinal relations between NfL, t‐tau, and clinical scales. RESULTS: NfL had a stronger association than t‐tau with clinical scales; t‐tau did not hold additional information to that given by NfL (P > 0.05 at all time points). NfL held independent information about shorter‐term (3‐ to 6‐month) progression beyond patient age and clinical scores. However, no meaningful gain in power was found when adjusting a longitudinal analysis of cognitive scores for baseline NfL. DISCUSSION: Plasma NfL is superior to t‐tau in mild AD. The ability of NfL to detect changes before clinical manifestations makes it a promising biomarker of drug response in trials of disease‐modifying drugs

Inducible nitric oxide synthase (iNOS) expression may predict distant metastasis in human melanoma

Expression of inducible nitric oxide synthase (iNOS) and its cellular localization was investigated in subcutaneous or lymph node metastases of human melanoma. Immunohistochemistry revealed that iNOS expression was limited to melanoma cells. In samples of patients without distant metastases, the number of iNOS+ tumour cells/total tumour cells was 55% ± 17% (n = 12) compared with 9% ± 8% when distant metastases of lung, liver or brain occurred within an observation period of 3 years (n = 10) (P < 0.001). Western blotting confirmed the expression of iNOS protein in select cases. Notably, iNOS is expressed in regional melanoma metastases and its expression is inversely related to the tumour's metastatic potential. Thus, iNOS expression may have predictive value for the development of distant metastases of human melanoma. © 1999 Cancer Research Campaig

What you know can influence what you are going to know (especially for older adults)

Stimuli related to an individual's knowledge/experience are often more memorable than abstract stimuli, particularly for older adults. This has been found when material that is congruent with knowledge is contrasted with material that is incongruent with knowledge, but there is little research on a possible graded effect of congruency. The present study manipulated the degree of congruency of study material with participants’ knowledge. Young and older participants associated two famous names to nonfamous faces, where the similarity between the nonfamous faces and the real famous individuals varied. These associations were incrementally easier to remember as the name-face combinations became more congruent with prior knowledge, demonstrating a graded congruency effect, as opposed to an effect based simply on the presence or absence of associations to prior knowledge. Older adults tended to show greater susceptibility to the effect than young adults, with a significant age difference for extreme stimuli, in line with previous literature showing that schematic support in memory tasks particularly benefits older adults

Resolving the extragalactic hard X-ray background

The origin of the hard (2-10 keV) X-ray background has remained mysterious for over 35 years. Most of the soft (0.5-2 keV) X-ray background has been resolved into discrete sources, which are primarily quasars; however, these sources do not have the flat spectral shape required to match the X-ray background spectrum. Here we report the results of an X-ray survey 30 times more sensitive than previous studies in the hard band and four times more sensitive in the soft band. The sources detected in our survey account for at least 75 per cent of the hard X-ray background. The mean X-ray spectrum of these sources is in good agreement with that of the background. The X-ray emission from the majority of the detected sources is unambiguously associated with either the nuclei of otherwise normal bright galaxies or optically faint sources, which could either be active nuclei of dust enshrouded galaxies or the first quasars at very high redshifts.Comment: Nature article in pres

Distant X-ray Galaxies: Insights from the Local Population

A full understanding of the origin of the hard X-ray background requires a complete and accurate census of the distant galaxies that produce it. Unfortunately, distant X-ray galaxies tend to be very faint at all wavelengths, which hinders efforts to perform this census. This chapter discusses the insights that can be obtained through comparison of the distant population to local X-ray galaxies, whose properties are well characterized. Such comparisons will ultimately aid investigations into the cosmic evolution of supermassive black holes and their environments.Comment: 19 pages, 10 figures, to appear as Chapter 7 in "Supermassive Black Holes in the Distant Universe" (2004), ed. A. J. Barger, Kluwer Academic Publishers, in pres

Substrate Binding Mode and Its Implication on Drug Design for Botulinum Neurotoxin A

The seven antigenically distinct serotypes of Clostridium botulinum neurotoxins, the causative agents of botulism, block the neurotransmitter release by specifically cleaving one of the three SNARE proteins and induce flaccid paralysis. The Centers for Disease Control and Prevention (CDC) has declared them as Category A biowarfare agents. The most potent among them, botulinum neurotoxin type A (BoNT/A), cleaves its substrate synaptosome-associated protein of 25 kDa (SNAP-25). An efficient drug for botulism can be developed only with the knowledge of interactions between the substrate and enzyme at the active site. Here, we report the crystal structures of the catalytic domain of BoNT/A with its uncleavable SNAP-25 peptide 197QRATKM202 and its variant 197RRATKM202 to 1.5 Å and 1.6 Å, respectively. This is the first time the structure of an uncleavable substrate bound to an active botulinum neurotoxin is reported and it has helped in unequivocally defining S1 to S5′ sites. These substrate peptides make interactions with the enzyme predominantly by the residues from 160, 200, 250 and 370 loops. Most notably, the amino nitrogen and carbonyl oxygen of P1 residue (Gln197) chelate the zinc ion and replace the nucleophilic water. The P1′-Arg198, occupies the S1′ site formed by Arg363, Thr220, Asp370, Thr215, Ile161, Phe163 and Phe194. The S2′ subsite is formed by Arg363, Asn368 and Asp370, while S3′ subsite is formed by Tyr251, Leu256, Val258, Tyr366, Phe369 and Asn388. P4′-Lys201 makes hydrogen bond with Gln162. P5′-Met202 binds in the hydrophobic pocket formed by the residues from the 250 and 200 loop. Knowledge of interactions between the enzyme and substrate peptide from these complex structures should form the basis for design of potent inhibitors for this neurotoxin

Ionic structure and photoabsorption in medium sized sodium clusters

We present ground-state configurations and photoabsorption spectra of Na-7+, Na-27+ and Na-41+. Both the ionic structure and the photoabsorption spectra of medium-size sodium clusters beyond Na-20 have been calculated self-consistently with a nonspherical treatment of the valence electrons in density functional theory. We use a local pseudopotential that has been adjusted to experimental bulk properties and the atomic 3s level of sodium. Our studies have shown that both the ionic structure of the ground state and the positions of the plasmon resonances depend sensitively on the pseudopotential used in the calculation, which stresses the importance of its consistent use in both steps.Comment: 4 pages, 3 figures. Accepted for publication in PRB, tentatively July 15th, 1998 some typos corrected, brought to nicer forma

CD56 is a pathogen recognition receptor on human natural killer cells

Aspergillus (A.) fumigatus is an opportunistic fungal mold inducing invasive aspergillosis (IA) in immunocompromised patients. Although antifungal activity of human natural killer (NK) cells was shown in previous studies, the underlying cellular mechanisms and pathogen recognition receptors (PRRs) are still unknown. Using flow cytometry we were able to show that the fluorescence positivity of the surface receptor CD56 significantly decreased upon fungal contact. To visualize the interaction site of NK cells and A. fumigatus we used SEM, CLSM and dSTORM techniques, which clearly demonstrated that NK cells directly interact with A. fumigatus via CD56 and that CD56 is re-organized and accumulated at this interaction site time-dependently. The inhibition of the cytoskeleton showed that the receptor re-organization was an active process dependent on actin re-arrangements. Furthermore, we could show that CD56 plays a role in the fungus mediated NK cell activation, since blocking of CD56 surface receptor reduced fungal mediated NK cell activation and reduced cytokine secretion. These results confirmed the direct interaction of NK cells and A. fumigatus, leading to the conclusion that CD56 is a pathogen recognition receptor. These findings give new insights into the functional role of CD56 in the pathogen recognition during the innate immune response