While the pathophysiological changes induced by the loss of dopamine innervation in the basal ganglia by Parkinson's disease (PD) are well studied, little is known about functional changes in the ...neural circuitry of this area during normal aging. Here we report the first survey of age-associated changes in the basal ganglia of behaviorally characterized, awake rhesus monkeys, using pharmacological MRI to map responses to dopaminergic stimulation. Apomorphine, a mixed D1/D2 dopamine receptor agonist, evoked little change in the substantia nigra (SN) of aged animals while significantly reducing activation in young adult monkeys. Compared to young animals, both apomorphine and d-amphetamine (which increases synaptic dopamine levels) significantly increased activation of the aged rhesus globus pallidus externa (GPe). In addition, the aged animals showed decreased activity in the putamen in response to d-amphetamine administration. Although the responses in the SN and putamen of the aged monkeys differed from those in animal models of PD, the apomorphine-evoked activation of their GPe corresponded with apomorphine-induced increases in neuronal activity seen in Parkinson's patients and animal models. Given the major role of the GPe in regulating motor behavior, the altered responses in the aged GPe may contribute significantly to the motor slowing and movement dysfunctions characterizing advanced age.
PurposeTo investigate targeting of indoleamine 2.3 dioxygenase (IDO) enzyme using a synthetic peptide vaccine administered to patients with metastatic non small-cell lung cancer (NSCLC).Experimental ...designIn a clinical phase I study we treated 15 HLA-A2 positive patients with stage III-IV NSCLC in disease stabilization (SD) after standard chemotherapy. Patients were treated with Imiquimod ointment and subcutaneous vaccinations (100 µg IDO5 peptide, sequence ALLEIASCL, formulated in 900 µL Montanide). Primary end point was toxicity. Clinical benefit and immunity were assessed as secondary endpoints.ResultsNo severe toxicity was observed. One patient developed a partial response (PR) after 1 year of vaccine treatment while long-lasting disease stabilization (SD≥8.5 months) was demonstrated in another 6 patients. The median overall survival (OS) was 25.9 months. Patients demonstrated significant improved OS (P=0.03) when compared to the group of patients excluded due to HLA-A2 negativity. IDO specific CD8+ T cell immunity was demonstrated by IFN-γ Elispot and Tetramer staining. FACS analyses demonstrated a significant reduction of the Treg population (P=0.03) and a significant increase in NK cell population (P=0.05) after the 6th vaccine (2.5 months) compared to pre-treatment levels. Furthermore, expression of IDO was detected in 9/10 tumour biopsies by immunohistochemistry. HPLC analyses of Kynurenine/Tryptophan (Kyn/Trp) ratio in sera were performed. In long term analyses of two clinical responding patients the ratio of Kyn/Trp remained stable.ConclusionThe vaccine was well-tolerated with no severe toxicity occurring. A median OS of 25.9 months was demonstrated and long-lasting PR+SD were seen in 47% of the patients.
Extended tetrathiafulvalenes with central diindenothienoacene cores were prepared and studied for their redox and spectroelectrochemical properties, which depended strongly on the orientation of the ...thiophene rings. The cations undergo remarkably strong associations, rendering them attractive as redox-controllable tectons in supramolecular chemistry, and in one case crystals were grown by electrocrystallization.
The redox properties and cation associations of extended tetrathiafulvalenes with diindenothienoacene cores are strongly dependent on the number and regioisomeric structural orientation of the central thiophene units.
Three series of ionic self-assembled materials based on anionic azo-dyes and cationic benzalkonium surfactants were synthesized and thin films were prepared by spin-casting. These thin films appear ...isotropic when investigated with polarized optical microscopy, although they are highly anisotropic. Here, three series of homologous materials were studied to rationalize this observation. Investigating thin films of ordered molecular materials relies to a large extent on advanced experimental methods and large research infrastructure. A statement that in particular is true for thin films with nanoscopic order, where X-ray reflectometry, X-ray and neutron scattering, electron microscopy and atom force microscopy (AFM) has to be used to elucidate film morphology and the underlying molecular structure. Here, the thin films were investigated using AFM, optical microscopy and polarized absorption spectroscopy. It was shown that by using numerical method for treating the polarized absorption spectroscopy data, the molecular structure can be elucidated. Further, it was shown that polarized optical spectroscopy is a general tool that allows determination of the molecular order in thin films. Finally, it was found that full control of thermal history and rigorous control of the ionic self-assembly conditions are required to reproducibly make these materials of high nanoscopic order. Similarly, the conditions for spin-casting are shown to be determining for the overall thin film morphology, while molecular order is maintained.
The driving force behind the transition from a foraging to
a farming lifestyle in prehistoric Europe (Neolithization)
has been debated for more than a century 1–3. Of particular
interest is whether ...population replacement or cultural
exchange was responsible 3–5. Scandinavia holds a unique
place in this debate, for it maintained one of the last major
hunter-gatherer complexes in Neolithic Europe, the Pitted
Ware culture 6. Intriguingly, these late hunter-gatherers
existed in parallel to early farmers for more than a millennium
before they vanished some 4,000 years ago 7, 8. The prolonged
coexistence of the two cultures in Scandinavia has
been cited as an argument against population replacement
between the Mesolithic and the present 7, 8. Through analysis
of DNA extracted from ancient Scandinavian human
remains, we show that people of the Pitted Ware culture
were not the direct ancestors of modern Scandinavians
(including the Saami people of northern Scandinavia) but
are more closely related to contemporary populations of
the eastern Baltic region. Our findings support hypotheses
arising from archaeological analyses that propose
a Neolithic or post-Neolithic population replacement in
Scandinavia 7. Furthermore, our data are consistent with
the view that the eastern Baltic represents a genetic refugia
for some of the European hunter-gatherer populations.
This study investigates the effects of developmental stage and muscle type on the mobility and distribution of water within skeletal muscles, using low-field
1H-NMR transverse relaxation measurements
...in vitro on four different porcine muscles (
M. longissimus dorsi, M. semitendinosus, M. biceps femoris, M. vastus intermedius) from a total of 48 pigs slaughtered at various weight classes between 25 kg and 150 kg. Principal component analysis (PCA) revealed effects of both slaughter weight and muscle type on the transverse relaxation decay. Independent of developmental stage and muscle type, distributed exponential analysis of the NMR T
2 relaxation data imparted the existence of three distinct water populations, T
2b, T
21, and T
22, with relaxation times of approximately 1–10, 45–120, and 200–500 ms, respectively. The most profound change during muscle growth was a shift toward faster relaxation in the intermediate time constant, T
21. It decreased by approx. 24% in all four muscle types during the period from 25 to 150 kg live weight. Determination of dry matter, fat, and protein content in the muscles showed that the changes in relaxation time of the intermediate time constant, T
21, during growth should be ascribed mainly to a change in protein content, as the protein content explained 77% of the variation in the T
21 time constant. Partial least squares (PLS) regression revealed validated correlations in the region of 0.58 to 0.77 between NMR transverse relaxation data and muscle development for all the four muscle types, which indicates that NMR relaxation measurements may be used in the prediction of muscle developmental stage.
Retinal Schiff bases serve as chromophores in many photoactive proteins that carry out functions such as signalling and light-induced ion translocation. The retinal Schiff base can be found as ...neutral or protonated, as all-trans, 11-cis or 13-cis isomers and can adopt different conformations in the protein binding pocket. Here we present the synthesis and characterisation of isomeric retinylidene iminium salts as mimics blocked towards isomerisation at the C11 position and conformationally restrained. The intrinsic chromophoric properties are elucidated by gas phase absorption studies. These studies reveal a small blue-shift in the S0-->S1 absorption for the 11-locked derivative as compared to the unlocked one. The gas phase absorption spectra of all the cationic mimics so far investigated show almost no absorption in the blue region. This observation stresses the importance of protein interactions for colour tuning, which allows the human eye to perceive blue light.
The distribution of lymphocyte subpopulations in cerebrospinal fluid (CSF) and their phenotypic characteristics were extensively investigated in a group of 18 healthy individuals using two- and ...three-color flow cytometry. Generally, CDS
+ T lymphocytes constituted the vast majority of CSF lymphocytes while the number of B lymphocytes and NK cells were low. Most T lymphocytes exhibited the phenotype of memory /primed cells in both the CD4
+ and CD8
+ subpopulations. Two markers for recent activation, HLA-DR and interleukin-2 receptor (CD25) were not upregulated when compared with peripheral blood (PB) in the majority of CSF T lymphocytes. However, a fraction of T lymphocytes co-expressing the NK cell markers CD56 and/or CD16 showed a pronounced upregulation of HLA-DR in CSF as compared with PB. This study documents that the cellular composition of the normal CSF differs profoundly from PB regarding all major lymphocyte subpopulations. This has to be taken into account in studies addressing questions regarding cellular immune reactions in the central nervous system under pathological conditions.
Epiphyseal development was investigated on X‐rays of flippers from 158 harbour porpoises from Danish waters. Development followed a proximodistal pattern similar to what is known in other cetacean ...species. Ossification of epiphyses was rare in the phalanges of the first and fifth digits and in the more distal phalanges of the second, third and fourth digits. Along with the morphology of the first metacarpal and the more distal phalanges this suggested paedomorphosis relative to delphinids. Male and female porpoises showed similar progression of epiphyseal development until approximately the sixth year. From then on, female porpoises showed more progressed development than males. This suggests a higher level of paedomorphosis in the male porpoise. The mechanism behind phocoenid paedomorphosis seems to be progenesis, probably as an adaptation towards a high reproductive rate relative to the delphinids.
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