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Microwave-Assisted Synthesis, Structure, and Preliminary Biological Evaluation of Novel 6-Methoxy-5,6-dihydro-5-azapurines
No full textWe herein disclose the microwave-assisted synthesis of previously unreported 6-methoxy-5,6-dihydro-5-azapurines, whose purine-like scaffold is promising for drug discovery. The method is simple, fast, and relies on easily accessible reagents such as trimethyl orthoformate, acetic acid, and aminotriazole-derived N,N'-disubstituted formamidines. The preliminary biological evaluation revealed that selected representatives of synthesized 6-methoxy-5,6-dihydro-5-azapurines dose-dependently reduce the viability of HepG2 and A549 cancer cells having little to no influence on five tested purinergic receptors
Monoidal structures in orthogonal calculus
No full textDer "Orthogonal Calculus", zuerst beschrieben von Michael Weiss in 1991, ist ein Funktorkalkül für Funktoren von euklidischen Vektorräumen nach Räumen. Viele der Funktoren auf die der Orthogonal Calculus angewendet wurde lassen sich mit einer lax symmetrisch monoidalen Struktur ausstatten, die bisher keine Beachtung fand. Beispielsweise lässt sich der Funktor BO(V) mit Abbildungen BO(V) x BO(W) -> BO(V + W) ausstatten die eine lax symmetrisch monoidale Struktur bilden. Eines der Hauptresultate dieser Dissertation besagt, dass auch die Taylorapproximationen eines lax symmetrisch monoidalen Funktors selbst lax symmetrisch monoidal sind. Außerdem studieren wir die Ableitungsspektren lax symmetrisch monoidaler Funktoren und beweisen die Existenz von O(n)-äquivarianten Abbildungen der Form Theta(F) (x) Theta(F) -> Theta(F) (x) DO(n). Hier bezeichnet DO(n) das dualisierende Spektrum der topologischen Gruppe O(n).Orthogonal Calculus, first developed by Weiss in 1991, provides a calculus of functors for functors from real inner product spaces to spaces. Many of the functors to which Orthogonal Calculus has been applied since carry an additional lax symmetric monoidal structure which has so far been ignored. For instance, the functor BO(V) admits maps BO(V) x BO(W) -> BO(V + W) which determine a lax symmetric monoidal structure. One of the main results of this thesis is that the Taylor approximations of a lax symmetric monoidal functor are themselves lax symmetric monoidal as well. We also study the derivative spectra of lax symmetric monoidal functors, and prove that they admit O(n)-equivariant structure maps of the form Theta(F) (x) Theta(F) -> Theta(F) (x) DO(n) where DO(n) is the Klein-Spivak dualising spectrum of the topological group O(n). We also formulate Orthogonal Calculus in the infinity-categorical language before proving our results
Multivariate analysis of speech envelope tracking reveals coupling beyond auditory cortex
No full textThe systematic alignment of low-frequency brain oscillations with the acoustic speech envelope signal is well established and has been proposed to be crucial for actively perceiving speech. Previous studies investigating speech-brain coupling in source space are restricted to univariate pairwise approaches between brain and speech signals, and therefore speech tracking information in frequency-specific communication channels might be lacking. To address this, we propose a novel multivariate framework for estimating speech-brain coupling where neural variability from source-derived activity is taken into account along with the rate of envelope's amplitude change (derivative). We applied it in magnetoencephalographic (MEG) recordings while human participants (male and female) listened to one hour of continuous naturalistic speech, showing that a multivariate approach outperforms the corresponding univariate method in low- and high frequencies across frontal, motor, and temporal areas. Systematic comparisons revealed that the gain in low frequencies (0.6 - 0.8 Hz) was related to the envelope's rate of change whereas in higher frequencies (from 0.8 to 10 Hz) it was mostly related to the increased neural variability from source-derived cortical areas. Furthermore, following a non-negative matrix factorization approach we found distinct speech-brain components across time and cortical space related to speech processing. We confirm that speech envelope tracking operates mainly in two timescales (delta and theta frequency bands) and we extend those findings showing shorter coupling delays in auditory-related components and longer delays in higher-association frontal and motor components, indicating temporal differences of speech tracking and providing implications for hierarchical stimulus-driven speech processing
On the Importance of Using Directional Information in the Search for Lower Mantle Reflectors
No full textThe SS precursor signals are a powerful tool for mapping topography of mantle discontinuities, which are sensitive to the thermal and compositional structure of the mantle. The depth of mantle discontinuities is usually estimated using the differential travel time between the main arrival and its precursor. However, this method ignores potential travel path deviations that influence the travel time of precursor signals. Here, we use an approach that considers directivity information as well as travel‐time measurements. Applying seismic array techniques, we measure slowness, back azimuth, and travel time of the signals, and use this information to backproject to the point of reflection. In our test dataset, we observe deviations from the predicted values in slowness and back azimuth in the range of 0.1–2.3 s/° and 1–20°, respectively. These values lead to reflection locations that can differ considerably from theoretical reflection points calculated with great circle plane paths as well as depths different from the depth calculated for in‐plane propagation, with differences up to ∼150 km. Our results indicate that the travel‐path deviations should be considered to avoid misinterpretation of mantle discontinuities and potentially reduce previously observed scatter in discontinuity depth
Oxidation Products of Tryptophan and Proline in Adipokinetic Hormones—Artifacts or Post-Translational Modifications?
No full textBackground: Adipokinetic hormones (AKHs) regulate important physiological processes in insects. AKHs are short peptides with blocked termini and Trp in position 8. Often, proline occupies position 6. Few post-translational modifications have been found, including hydroxyproline ([Hyp6]) and kynurenine. Our recent data suggest that the Hyp- and Kyn-containing AKHs occur more often than originally thought and we here investigate if they are natural or artifactual. Methods: From crude extracts of the corpora cardiaca (CC) of various insect species, AKHs were analyzed using liquid chromatography coupled to high-resolution mass spectrometry (LC-MS). Synthetic [Hyp6]-AKHs were tested in an in vivo metabolic assay. Freshly dissected Periplaneta americana and Blaberus atropos CCs (with precautions taken against oxidation) were analyzed. B. atropos CC were placed into a depolarizing saline and the released AKHs were measured. Results: Hyp was detected in several decapeptides from cockroaches. The modified form accompanied the AKH at concentrations below 7%. The [Hyp6]-AKHs of B. atropos were present in fresh CC preparations and were shown to be releasable from the CC ex vivo. Synthetic [Hyp6]-containing peptides tested positively in a hypertrehalosemic bioassay. Hydroxyprolination was also detected for Manto-CC from the termite Kalotermes flavicollis and for Tetsu-AKH of the grasshopper, Tetrix subulata. Oxidized Trp-containing forms of Nicve-AKH were found in species of the burying beetle genus Nicrophorus. Conclusions: Trp oxidation is known to occur easily during sample handling and is likely the reason for the present findings. For hydroxyprolination, however, the experimental evidence suggests endogenous processes
Pharmacological Targeting of the RAGE-NFκB Signalling Axis Impedes Monocyte Activation under Diabetic Conditions through the Repression of SHP-2 Tyrosine Phosphatase Function
No full textMonocytes play a vital role in the development of cardiovascular diseases. Type 2 diabetes mellitus (T2DM) is a major CVD risk factor, and T2DM-induced aberrant activation and enhanced migration of monocytes is a vital pathomechanism that leads to atherogenesis. We recently reported the upregulation of SHP-2 phosphatase expression in mediating the VEGF resistance of T2DM patient-derived monocytes or methylglyoxal- (MG, a glucose metabolite and advanced glycation end product (AGE) precursor) treated monocytes. However, the exact mechanisms leading to SHP-2 upregulation in hyperglycemic monocytes are unknown. Since inflammation and accumulation of AGEs is a hallmark of T2DM, we hypothesise that inflammation and AGE-RAGE (Receptor-for-AGEs) signalling drive SHP-2 expression in monocytes and blockade of these pathways will repress SHP-2 function. Indeed, monocytes from T2DM patients revealed an elevated SHP-2 expression. Under normoglycemic conditions, the serum from T2DM patients strongly induced SHP-2 expression, indicating that the T2DM serum contains critical factors that directly regulate SHP-2 expression. Activation of pro-inflammatory TNFα signalling cascade drove SHP-2 expression in monocytes. In line with this, linear regression analysis revealed a significant positive correlation between TNFα expression and SHP-2 transcript levels in T2DM monocytes. Monocytes exposed to MG or AGE mimetic AGE-BSA, revealed an elevated SHP-2 expression and co-treatment with an NFκB inhibitor or genetic inhibition of p65 reversed it. The pharmacological inhibition of RAGE was sufficient to block MG- or AGE-BSA-induced SHP-2 expression and activity. Confirming the importance of RAGE-NFκB signalling in regulating SHP-2 expression, the elevated binding of NFκB to the SHP-2 promoter—induced by MG or AGE-BSA—was reversed by RAGE and NFκB inhibition. Besides, we detected elevated RAGE levels in human and murine T2DM monocytes and monocytes exposed to MG or AGE-BSA. Importantly, MG and AGE-BSA treatment of non-T2DM monocytes phenocopied the aberrant pro-migratory phenotype of T2DM monocytes, which was reversed entirely by either SHP-2- or RAGE inhibition. In conclusion, these findings suggest a new therapeutic approach to prevent accelerated atherosclerosis in T2DM patients since inhibiting the RAGE-NFκB-SHP-2 axis impeded the T2DM-driven, SHP-2-dependent monocyte activation
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No full textRespiratory motion correction in F-18-FDG PET/CT impacts lymph node assessment in lung cancer patients
No full textBackgrounds: Elastic motion correction in PET has been shown to increase image quality and quantitative measurements of PET datasets affected by respiratory motion. However, little is known on the impact of respiratory motion correction on clinical image evaluation in oncologic PET. This study evaluated the impact of motion correction on expert readers’ lymph node assessment of lung cancer patients. Methods: Forty-three patients undergoing F-18-FDG PET/CT for the staging of suspected lung cancer were included. Three different PET reconstructions were investigated: non-motion-corrected ("static"), belt gating-based motion-corrected (“BG-MC”) and data-driven gating-based motion-corrected ("DDG-MC"). Assessment was conducted independently by two nuclear medicine specialists blinded to the reconstruction method on a six-point scale s ranging from "certainly negative" (1) to "certainly positive" (6). Differences in s between reconstruction methods, accounting for variation caused by readers, were assessed by nonparametric regression analysis of longitudinal data. From s, a dichotomous score for N1, N2, and N3 ("negative," "positive") and a subjective certainty score were derived. SUV and metabolic tumor volumes (MTV) were compared between reconstruction methods.
Results: BG-MC resulted in higher scores for N1 compared to static (p = 0.001), whereas DDG-MC resulted in higher scores for N2 compared to static (p = 0.016). Motion correction resulted in the migration of N1 from tumor free to metastatic on the dichotomized score, consensually for both readers, in 3/43 cases and in 2 cases for N2. SUV was significantly higher for motion-corrected PET, while MTV was significantly lower (all p < 0.003). No significant differences in the certainty scores were noted. Conclusions: PET motion correction resulted in significantly higher lymph node assessment scores of expert readers. Significant effects on quantitative PET parameters were seen; however, subjective reader certainty was not improved