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Although Pavlovian threat conditioning has proven to be a useful translational model for the development of anxiety disorders, it remains unknown if this procedure can generate intrusive memories - a symptom of many anxiety-related disorders, and whether intrusions persist over time. Social support has been related to better adjustment after trauma however, experimental evidence regarding its effect on the development of anxiety-related symptoms is sparse. We had two aims: to test whether threat conditioning generates intrusive memories, and whether different social support interactions impacted expression of emotional memories. Non-clinical participants (n = 81) underwent threat conditioning to neutral stimuli. Participants were then assigned to a supportive, unsupportive, or no social interaction group, and asked to report intrusive memories for seven days. As predicted, threat conditioning can generate intrusions, with greater number of intrusions of CS+ (M = 2.35, SD = 3.09) than CS- (M = 1.39, SD = 2.17). Contrary to predictions, compared to no social interaction, supportive social interaction did not reduce, and unsupportive interaction did not increase skin conductance of learned threat or number of intrusions. Unsupportive interaction resulted in a relative difference in number of intrusions to CS + vs CS-, suggesting that unsupportive interaction might have increased image-based threat memories. Intrusions were still measurable one year after conditioning (one-year follow-up; n = 54), when individuals with higher trait anxiety and greater number of previous trauma experiences reported more intrusions. Our findings show that threat conditioning can create long-lasting intrusions, offering a novel experimental psychopathology model of intrusive memories with implications for both research on learning and clinical applications.

Past research has shown that attributions of intentions to other's actions determine how we experience these actions and their consequences. Yet, it is unknown how such attributions affect our learning and memory. Addressing this question, we combined neuroimaging with an interactive threat learning paradigm in which two interaction partners (confederates) made choices that had either threatening (shock) or safe (no shock) consequences for the participants. Importantly, participants were led to believe that one partner intentionally caused the delivery of shock, whereas the other did not (i.e. unintentional partner). Following intentional versus unintentional shocks, participants reported an inflated number of shocks and a greater increase in anger and vengeance. We applied a model-based representational similarity analysis to blood-oxygen-level-dependent (BOLD)-MRI patterns during learning. Surprisingly, we did not find any effects of intentionality. The threat value of actions, however, was represented as a trial-by-trial increase in representational similarity in the insula and the inferior frontal gyrus. Our findings illustrate how neural pattern formation can be used to study a complex interaction.

The induction of apoptosis is a direct way to eliminate tumor cells and improve cancer therapy. Apoptosis is tightly controlled by the balance of pro- and antiapoptotic Bcl-2 proteins. BH3 mimetics neutralize the antiapoptotic function of Bcl-2 proteins and are highly promising compounds inducing apoptosis in several cancer entities including pediatric malignancies. However, the clinical application of BH3 mimetics in solid tumors is impeded by the frequent resistance to single BH3 mimetics and the anticipated toxicity of high concentrations or combination treatments. One potential avenue to increase the potency of BH3 mimetics is the development of immune cell-based therapies to counteract the intrinsic apoptosis resistance of tumor cells and sensitize them to immune attack. Here, we describe spheroid cultures of pediatric cancer cells that can serve as models for drug testing. In these 3D models, we were able to demonstrate that activated allogeneic Natural Killer (NK) cells migrated into tumor spheroids and displayed cytotoxicity against a wide range of pediatric cancer spheroids, highlighting their potential as anti-tumor effector cells. Next, we investigated whether treatment of tumor spheroids with subtoxic concentrations of BH3 mimetics can increase the cytotoxicity of NK cells. Notably, the cytotoxic effects of NK cells were enhanced by the addition of BH3 mimetics. Treatment with either the Bcl-XL inhibitor A1331852 or the Mcl-1 inhibitor S63845 increased the cytotoxicity of NK cells and reduced spheroid size, while the Bcl-2 inhibitor ABT-199 had no effect on NK cell-mediated killing. Taken together, this is the first study to describe the combination of BH3 mimetics targeting Bcl-XL or Mcl-1 with NK cell-based immunotherapy, highlighting the potential of BH3 mimetics in immunotherapy.

In recent years, histopathological characterization of intrahepatic cholangiocarcinoma revealed small duct type (SD-iCCA) and large duct type (LD-iCCA). Data on the prevalence of the subtypes are limited and highly varying. The aim of this study was to assess the prevalence of SD-iCCA and LD-iCCA and their impact on survival for the first time in a European cohort.All patients with surgically resected iCCA diagnosed between December 2005 and December 2021 at the University Hospital Frankfurt were analyzed by an expert hepatobiliary pathologist. For overall survival (OS) and progression-free survival (PFS), Kaplan-Meier curves and Cox-regression analyses were performed.In total, 116 patients with surgically resected iCCA treated in our tertiary hospital were classified as SD-iCCA (73.3%, n = 85) and LD-iCCA (26.7%, n = 31). Subgroup analyses revealed median OS of 54.4 months (95% CI = 38.3 - 70.4 months) and 25.4 months (95% CI = 15.1 - 35.7 months) for SD-iCCA and LD-iCCA, respectively (p = 0.027). The median PFS for patients receiving gemcitabine-based chemotherapy with SD- and LD-iCCA was 8.4 months (95% CI = 4.7 - 12 months) and 3.3 months (95% CI = 1.8 - 4.7 months), respectively (p = 0.011). While LD-iCCA was as a significant risk factor of OS (HR = 1.7, 95% CI = 1 - 2.8, p = 0.031) in univariate analysis, it was not significant in multivariate analysis.In contrast to data from Asia, SD-iCCA is more prevalent than LD-iCCA in our cohort. LD-iCCA is associated with impaired OS after surgical resection and decreased PFS for patients receiving chemotherapy. These findings may suggest including the histological subtype in clinical routine diagnostics.

Previous research shows that associative memory declines more than item memory in aging. Although the underlying mechanisms of this selective impairment remain poorly understood, animal and human data suggest that dopaminergic modulation may be particularly relevant for associative binding. We investigated the influence of dopamine (DA) receptor genes on item and associative memory in a population-based sample of older adults (n = 525, aged 60 years), assessed with a face–scene item associative memory task. The effects of single-nucleotide polymorphisms of DA D1 (DRD1; rs4532), D2 (DRD2/ANKK1/Taq1A; rs1800497), and D3 (DRD3/Ser9Gly; rs6280) receptor genes were examined and combined into a single genetic score. Individuals carrying more beneficial alleles, presumably associated with higher DA receptor efficacy (DRD1 C allele; DRD2 A2 allele; DRD3 T allele), performed better on associative memory than persons with less beneficial genotypes. There were no effects of these genes on item memory or other cognitive measures, such as working memory, executive functioning, fluency, and perceptual speed, indicating a selective association between DA genes and associative memory. By contrast, genetic risk for Alzheimer disease (AD) was associated with worse item and associative memory, indicating adverse effects of APOE ε4 and a genetic risk score for AD (PICALM, BIN1, CLU) on episodic memory in general. Taken together, our results suggest that DA may be particularly important for associative memory, whereas AD-related genetic variations may influence overall episodic memory in older adults without dementia.

Functional magnetic resonance imaging (MRI) studies have demonstrated a critical role of hippocampus and inferior frontal gyrus (IFG) in associative memory. Similarly, evidence from structural MRI studies suggests a relationship between gray-matter volume in these regions and associative memory. However, how brain volume and activity relate to each other during associative-memory formation remains unclear. Here, we used joint independent component analysis (jICA) to examine how gray-matter volume and brain activity would be associated during associative encoding, especially in medial-temporal lobe (MTL) and IFG. T1-weighted images were collected from 27 young adults, and functional MRI was employed during intentional encoding of object pairs. A subsequent recognition task tested participants' memory performance. Unimodal analyses using voxel-based morphometry revealed that participants with better associative memory showed larger gray-matter volume in left anterior hippocampus. Results from the jICA revealed one component that comprised a covariance pattern between gray-matter volume in anterior and posterior MTL and encoding-related activity in IFG. Our findings suggest that gray matter within the MTL modulates distally distinct parts of the associative encoding circuit, and extend previous studies that demonstrated MTL-IFG functional connectivity during associative memory tasks.

Background Anemia is linked to impaired outcome in patients with cardiovascular diseases. We sought to characterize the impact of baseline anemia on mid-term outcome after transcatheter aortic valve implantation (TAVI). Methods and results Data of 1201 consecutive TAVI patients were retrospectively analyzed. Baseline anemia was defined according to the WHO (hemoglobin

Evidence from neuroimaging studies suggests a critical role of hippocampus and inferior frontal gyrus (IFG) in associative relative to item encoding. Here, we investigated similarities and differences in functional brain correlates for associative and item memory as a function of encoding instruction. Participants received either incidental (animacy judgments) or intentional encoding instructions while fMRI was employed during the encoding of associations and items. In a subsequent recognition task, memory performance of participants receiving intentional encoding instructions was higher compared with those receiving incidental encoding instructions. Furthermore, participants remembered more items than associations, regardless of encoding instruction. Greater brain activation in the left anterior hippocampus was observed for intentionally compared with incidentally encoded associations, although activity in this region was not modulated by the type of instruction for encoded items. Furthermore, greater activity in the left anterior hippocampus and left IFG was observed during intentional associative compared with item encoding. The same regions were related to subsequent memory of intentionally encoded associations and were thus task relevant. Similarly, connectivity of the anterior hippocampus to the right superior temporal lobe and IFG was uniquely linked to subsequent memory of intentionally encoded associations. Our study demonstrates the differential involvement of anterior hippocampus in intentional relative to incidental associative encoding. This finding likely reflects that the intent to remember triggers a specific binding process accomplished by this region.

This study deals with the synthesis of tert-O-alkyl thiohydroxamates and their use as tert-alkoxyl radical precursors. tert-Alkoxyl radicals were applied in mechanistic studies to determine rate constants of (i) p-chlorocumyloxyl radical addition to bicyclo[2.2.1]heptene (k=1×107 M−1 s−1), (ii) 2-phenylhex-5-en-2-oxyl radical 5-exo-trig-cyclization (kcis=3×109 s−1, ktrans=1×109 s−1), and (iii) 2-methyl-5-phenylpent-2-oxyl to 2-hydroxy-2-methyl-5-phenylpent-5-yl radical isomerization (1,5-H-atom shift; k=0.4–1.5×108 s−1). The reactions pose key steps in synthesis of 2,2,5-substituted tetrahydrofurans and 2-bromo-3-alkoxybicyclo[2.2.1]heptanes. Stereoselectivity in 5-exo-trig cyclization (2,5-cis) and intermolecular addition (exo/endo>99:1), originates from torsional strain in transition structures of alkoxyl radical reactions.

Background: Polymorphonuclear, neutrophil granulocytes (PMN) play a major role in the control of infections, and people who abuse alcohol are susceptible to infections. Resistance against infections ensues intracellularly following initial phagocytosis of microorganisms with the oxygen-dependent respiratory burst, the key enzyme of which is the respiratory burst oxidase, whereby oxygen radicals are produced for microbial destruction. To date there is insufficient information available in connection with the process of impaired defence against infection in patients suffering from alcohol dependence. Therefore, our investigation was carried out to determine the influence of alcohol exposition on the formation of oxygen radicals and the respiratory burst. Methods: 4.5 ml of whole blood was taken from 10 healthy adults and 10 patients suffering from alcohol dependence. An additional 3.5 ml of whole blood was taken from the alcoholic patients for determination of the blood alcohol concentration. The respiratory burst of PMN was tested using the Four-Colour-Continuous Flow Cytometer. Each experimental procedure consisted of 4 test samples [negative controls, Escherichia coli, FMLP-supplement (N-formyl-l-methionyl-l-leucyl-l-phenylalanin), PMA-supplement (phorbol-12-myristate-13-acetate)]. Differing concentrations of ethanol were also introduced to each of the tests performed (0.20 to 4.00 g/l). Results: Ethanol revealed a marked decrease of burst activity in those patients suffering from alcoholism with increased alcohol concentration. A dependence between the burst activity and the ethanol concentration was seen to be statistically significant. This effect was only evident after stimulation with E. coli and FMLP in those patients with alcohol dependence. Conclusion: The results presented in this study show an impairment in the function of PMN in those patients addicted to alcohol due to the decrease in burst activity. In view of the results of the different stimuli, the second-messenger effects were not evident. A clarification of this phenomenon could well be assumed as an allosteric receptor effect on the burst oxidase, namely, a direct effect on the phagocytosis interaction between circulating granulocytes and causative organisms.

Anemia is linked to impaired outcome in patients with cardiovascular diseases. We sought to characterize the impact of baseline anemia on mid-term outcome after transcatheter aortic valve implantation (TAVI).Data of 1201 consecutive TAVI patients were retrospectively analyzed. Baseline anemia was defined according to the WHO (hemoglobin12g/dl [female],13g/dl [male]). It was prevalent in 59.0% of patients and associated with a higher preoperative risk (STS-PROM 7.8 ± 5.7 vs. 6.2 ± 4.1%, P 0.001). Survival was similar at 30 days (90.5 vs. 91.2%, P = 0.626) but NYHA functional capacity was impaired in patients with baseline anemia (classes III/IV: 20.6 vs. 15.6%, P = 0.006). Low baseline hemoglobin (OR 0.85, CI 0.73-0.98, P = 0.025), blood transfusion (OR 2.42, CI 1.38-4.28, P = 0.002), and bleeding complications (OR 2.21, CI 1.27-3.81, P = 0.005) were in addition associated with acute kidney injury after TAVI. Three-year survival was reduced (49.6 vs. 64.9%, P = 0.002) and baseline anemia was linked to increased mid-term mortality (HR 1.43, CI 1.13-1.82, P = 0.003), however its effect was surpassed by the adverse impact of periprocedural complications.Baseline anemia was associated with increased morbidity and mortality after TAVI. Preprocedural hemoglobin levels need to be assessed for risk stratification and blood conservation management seems essential. As a potentially modifiable target, the role of pretreatment of anemia prior to TAVI remains to be determined. © 2016 Wiley Periodicals, Inc.

Associative memory involves binding two or more items into a coherent memory episode. Relative to memory for single items, associative memory declines greatly in aging. However, older individuals vary substantially in their ability to memorize associative information. Although functional studies link associative memory to the medial temporal lobe (MTL) and prefrontal cortex (PFC), little is known about how volumetric differences in MTL and PFC might contribute to individual differences in associative memory. We investigated regional gray-matter volumes related to individual differences in associative memory in a sample of healthy older adults (n=54; age=60years). To differentiate item from associative memory, participants intentionally learned face-scene picture pairs before performing a recognition task that included single faces, scenes, and face-scene pairs. Gray-matter volumes were analyzed using voxel-based morphometry region-of-interest (ROI) analyses. To examine volumetric differences specifically for associative memory, item memory was controlled for in the analyses. Behavioral results revealed large variability in associative memory that mainly originated from differences in false-alarm rates. Moreover, associative memory was independent of individuals' ability to remember single items. Older adults with better associative memory showed larger gray-matter volumes primarily in regions of the left and right lateral PFC. These findings provide evidence for the importance of PFC in intentional learning of associations, likely because of its involvement in organizational and strategic processes that distinguish older adults with good from those with poor associative memory.

Diastereoselective cycloaddition reactions between a nitrile oxide and cyclic allylic alcohols are reported. The products isolated are densely functionalized building blocks that are not otherwise easily accessed with existing methods and concepts previously established for the construction of acyclic polyketides.