Effect of Naloxone-3-Glucuronide and N -Methylnaloxone on the Motility of the Isolated Rat Colon After Morphine

The effect of the opioid antagonists naloxone-3-glucuronide and N-methylnaloxone on rat colon motility after morphine stimulation was measured. The rat model consisted of the isolated, vascularly perfused colon. The antagonists (10−4 M, intraluminally) and morphine (10−4 M, intra-arterially) were administered from 20 to 30 and from 10 to 50 min, respectively. Colon motility was determined by the luminal outflow. The antagonist concentrations in the luminal and venous outflow were measured by high-performance liquid chromatography. Naloxone-3-glucuronide and N-methylnaloxone reversed the morphine-induced reduction of the luminal outflow to baseline within 10 and 20 min, respectively. These antagonists were then excreted in the luminal outflow and could not be found in the venous samples. Naloxone, produced by hydrolysis or demethylation, was not detectable. In conclusion, highly polar naloxone derivatives peripherally antagonize the motility-lowering effect of morphine in the perfused isolated rat colon, are stable, and are not able to cross the colon-mucosal blood barrie

Editors' introduction: Aligning implicit learning and statistical learning: Two approaches, one phenomenon

In their editors’ introduction, Rebuschat and Monaghan provide the background to the special issue. They outline the rationale for bringing together, in a single volume, leading researchers from two distinct, yet related research strands,implicit learning and statistical learning. The editors then introduce the new contributions solicited for this special issueand provide their perspective on the agenda setting that results from combining these two approaches

Modulating prospective memory and attentional control with high-definition transcranial current stimulation: Study protocol of a randomized, double-blind, and sham-controlled trial in healthy older adults.

The ability to remember future intentions (i.e., prospective memory) is influenced by attentional control. At the neuronal level, frontal and parietal brain regions have been related to attentional control and prospective memory. It is debated, however, whether more or less activity in these regions is beneficial for older adults' performance. We will test that by systematically enhancing or inhibiting activity in these regions with anodal or cathodal high-definition transcranial direct current stimulation in older adults. We will include n = 105 healthy older volunteers (60-75 years of age) in a randomized, double-blind, sham-controlled, and parallel-group design. The participants will receive either cathodal, anodal, or sham high-definition transcranial direct current stimulation of the left or right inferior frontal gyrus, or the right superior parietal gyrus (1mA for 20 min). During and after stimulation, the participants will complete tasks of attentional control and prospective memory. The results of this study will clarify how frontal and parietal brain regions contribute to attentional control and prospective memory in older healthy adults. In addition, we will elucidate the relationship between attentional control and prospective memory in that age group. The study has been registered with ClinicalTrials.gov on the 12th of May 2021 (trial identifier: NCT04882527)

Direct in vitro and in vivo comparison of 161Tb and 177Lu using a tumour-targeting folate conjugate

Purpose: The radiolanthanide 161Tb (T 1/2 = 6.90days, Eβ− av = 154keV) was recently proposed as a potential alternative to 177Lu (T 1/2 = 6.71days, Eβ− av = 134keV) due to similar physical decay characteristics but additional conversion and Auger electrons that may enhance the therapeutic efficacy. The goal of this study was to compare 161Tb and 177Lu in vitro and in vivo using a tumour-targeted DOTA-folate conjugate (cm09). Methods: 161Tb-cm09 and 177Lu-cm09 were tested in vitro on folate receptor (FR)-positive KB and IGROV-1 cancer cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay. In vivo 161Tb-cm09 and 177Lu-cm09 (10MBq, 0.5nmol) were investigated in two different tumour mouse models with regard to the biodistribution, the possibility for single photon emission computed tomography (SPECT) imaging and the antitumour efficacy. Potentially undesired side effects were monitored over 6months by determination of plasma parameters and examination of kidney function with quantitative SPECT using 99mTc-dimercaptosuccinic acid (DMSA). Results: To obtain half-maximal inhibition of tumour cell viability a 4.5-fold (KB) and 1.7-fold (IGROV-1) lower radioactivity concentration was required for 161Tb-cm09 (IC50 ~0.014MBq/ml and ~2.53MBq/ml) compared to 177Lu-cm09 (IC50 ~0.063MBq/ml and ~4.52MBq/ml). SPECT imaging visualized tumours of mice with both radioconjugates. However, in therapy studies 161Tb-cm09 reduced tumour growth more efficiently than 177Lu-cm09. These findings were in line with the higher absorbed tumour dose for 161Tb-cm09 (3.3Gy/MBq) compared to 177Lu-cm09 (2.4Gy/MBq). None of the monitored parameters indicated signs of impaired kidney function over the whole time period of investigation after injection of the radiofolates. Conclusion: Compared to 177Lu-cm09 we demonstrated equal imaging features for 161Tb-cm09 but an increased therapeutic efficacy for 161Tb-cm09 in both tumour cell lines in vitro and in vivo. Further preclinical studies using other tumour-targeting radioconjugates are clearly necessary to draw final conclusions about the future clinical perspectives of 161Tb

Measuring category intuitiveness in unconstrained categorization tasks

What makes a category seem natural or intuitive? In this paper, an unsupervised categorization task was employed to examine observer agreement concerning the categorization of nine different stimulus sets. The stimulus sets were designed to capture different intuitions about classification structure. The main empirical index of category intuitiveness was the frequency of the preferred classification, for different stimulus sets. With 169 participants, and a within participants design, with some stimulus sets the most frequent classification was produced over 50 times and with others not more than two or three times. The main empirical finding was that cluster tightness was more important in determining category intuitiveness, than cluster separation. The results were considered in relation to the following models of unsupervised categorization: DIVA, the rational model, the simplicity model, SUSTAIN, an Unsupervised version of the Generalized Context Model (UGCM), and a simple geometric model based on similarity. DIVA, the geometric approach, SUSTAIN, and the UGCM provided good, though not perfect, fits. Overall, the present work highlights several theoretical and practical issues regarding unsupervised categorization and reveals weaknesses in some of the corresponding formal models

Timing of retreat of the Reuss Glacier (Switzerland) at the end of the Last Glacial Maximum

We used cosmogenic 10Be and 36Cl to establish the timing of the onset of deglaciation after the Last Glacial Maximum of the Reuss Glacier, one of the piedmont lobes of the Alpine ice cap that reached the northern Alpine foreland in Switzerland. In this study, we sampled erratic boulders both at the frontal position in the foreland (Lenzburg and Wohlen, canton Aargau) and at the lateral Alpine border position (Seeboden moraine, Rigi, canton Schwyz). The minimum age for the beginning of retreat is 22.2±1.0ka at the frontal (terminal) position and 20.4±1.0ka at the lateral position. These ages are directly comparable with exposure ages from the other piedmont lobes in the northern Alpine foreland. Our data from the mountain called Rigi, do not support the hypothesis that boulders located external to the Seeboden moraine were deposited prior to the last glacial cycle. We present a first exposure age from an erratic boulder in a retreat position in the Alpine foreland. The Reuss Glacier was approximately 12km behind the maximal extent no later than at 18.6±0.9ka

Auditory but Not Audiovisual Cues Lead to Higher Neural Sensitivity to the Statistical Regularities of an Unfamiliar Musical Style

It is still a matter of debate whether visual aids improve learning of music. In a multisession study, we investigated the neural signatures of novel music sequence learning with or without aids (auditory-only: AO, audiovisual: AV). During three training sessions on 3 separate days, participants (nonmusicians) reproduced (note by note on a keyboard) melodic sequences generated by an artificial musical grammar. The AV group (n = 20) had each note color-coded on screen, whereas the AO group (n = 20) had no color indication. We evaluated learning of the statistical regularities of the novel music grammar before and after training by presenting melodies ending on correct or incorrect notes and by asking participants to judge the correctness and surprisal of the final note, while EEG was recorded. We found that participants successfully learned the new grammar. Although the AV group, as compared to the AO group, reproduced longer sequences during training, there was no significant difference in learning between groups. At the neural level, after training, the AO group showed a larger N100 response to lowprobability compared to high-probability notes, suggesting an increased neural sensitivity to statistical properties of the grammar; this effect was not observed in the AV group. Our findings indicate that visual aids might improve sequence reproduction while not necessarily promoting better learning, indicating a potential dissociation between sequence reproduction and learning. We suggest that the difficulty induced by auditory-only input during music training might enhance cognitive engagement, thereby improving neural sensitivity to the underlying statistical properties of the learned material

Promiscuous Binding of Invariant Chain-Derived CLIP Peptide to Distinct HLA-I Molecules Revealed in Leukemic Cells

Antigen presentation by HLA class I (HLA-I) and HLA class II (HLA-II) complexes is achieved by proteins that are specific for their respective processing pathway. The invariant chain (Ii)-derived peptide CLIP is required for HLA-II-mediated antigen presentation by stabilizing HLA-II molecules before antigen loading through transient and promiscuous binding to different HLA-II peptide grooves. Here, we demonstrate alternative binding of CLIP to surface HLA-I molecules on leukemic cells. In HLA-II-negative AML cells, we found plasma membrane display of the CLIP peptide. Silencing Ii in AML cells resulted in reduced HLA-I cell surface display, which indicated a direct role of CLIP in the HLA-I antigen presentation pathway. In HLA-I-specific peptide eluates from B-LCLs, five Ii-derived peptides were identified, of which two were from the CLIP region. In vitro peptide binding assays strikingly revealed that the eluted CLIP peptide RMATPLLMQALPM efficiently bound to four distinct HLA-I supertypes (-A2, -B7, -A3, -B40). Furthermore, shorter length variants of this CLIP peptide also bound to these four supertypes, although in silico algorithms only predicted binding to HLA-A2 or -B7. Immunization of HLA-A2 transgenic mice with these peptides did not induce CTL responses. Together these data show a remarkable promiscuity of CLIP for binding to a wide variety of HLA-I molecules. The found participation of CLIP in the HLA-I antigen presentation pathway could reflect an aberrant mechanism in leukemic cells, but might also lead to elucidation of novel processing pathways or immune escape mechanisms