Opposing Mechanisms Support the Voluntary Forgetting of Unwanted Memories

SummaryReminders of the past can trigger the recollection of events that one would rather forget. Here, using fMRI, we demonstrate two distinct neural mechanisms that foster the intentional forgetting of such unwanted memories. Both mechanisms impair long-term retention by limiting momentary awareness of the memories, yet they operate in opposite ways. One mechanism, direct suppression, disengages episodic retrieval through the systemic inhibition of hippocampal processing that originates from right dorsolateral prefrontal cortex (PFC). The opposite mechanism, thought substitution, instead engages retrieval processes to occupy the limited focus of awareness with a substitute memory. It is mediated by interactions between left caudal and midventrolateral PFC that support the selective retrieval of substitutes in the context of prepotent, unwanted memories. These findings suggest that we are not at the mercy of passive forgetting; rather, our memories can be shaped by two opposite mechanisms of mnemonic control

HDAC inhibitors increase NRF2-signaling in tumour cells and blunt the efficacy of co-adminstered cytotoxic agents

The NRF2 signalling cascade provides a primary response against electrophilic chemicals and oxidative stress. The activation of NRF2-signaling is anticipated to have adverse clinical consequences; NRF2 is activated in a number of cancers and, additionally, its pharmacological activation by one compound can reduce the toxicity or efficiency of a second agent administered concomitantly. In this work, we have analysed systematically the ability of 152 research, pre-clinical or clinically used drugs to induce an NRF2 response using the MCF7-AREc32 NRF2 reporter. Ten percent of the tested drugs induced an NRF2 response. The NRF2 activators were not restricted to classical cytotoxic alkylating agents but also included a number of emerging anticancer drugs, including an IGF1-R inhibitor (NVP-AEW541), a PIM-1 kinase inhibitor (Pim1 inhibitor 2), a PLK1 inhibitor (BI 2536) and most strikingly seven of nine tested HDAC inhibitors. These findings were further confirmed by demonstrating NRF2-dependent induction of endogenous AKR genes, biomarkers of NRF2 activity. The ability of HDAC inhibitors to stimulate NRF2-signalling did not diminish their own potency as antitumour agents. However, when used to pre-treat cells, they did reduce the efficacy of acrolein. Taken together, our data suggest that the ability of drugs to stimulate NRF2 activity is common and should be investigated as part of the drug-development process

Disassociation between glomerular hyperfiltration and extracellular volume in diabetic rats

Disassociation between glomerular hyperfiltration and extracellular volume in diabetic rats. The relationship of the development of glomerular hyperfiltration in diabetes to changes in extracellular fluid volume has not been previously examined. To accomplish this task, male Wistar rats were chronically cannulated in the bladder, femoral artery and vein. Control measurements of glomerular filtration rate (GFR), renal plasma flow (RPF), extracellular fluid volume (ECF), and urinary sodium excretion were performed on two separate days prior to infusion of streptozotocin (65 mg/kg body wt i.v.). After infusion of streptozotocin, the IDDM rats were separated into two groups: untreated IDDM group of rats and IDDM rats treated with insulin at doses sufficient to normalize blood glucose (Ultralente, 2 to 8 IU/day). A third group of normal non-diabetic rats served as time controls. Measurements of renal function occurred at 1, 4, 7, 11, and 15 days after infusion of streptozotocin. Blood glucose in the non-diabetic measurement period averaged 137 ± 30 mg/dl and increased from 412 ± 55 after 24 hours in the untreated diabetic rats to 533 ± 33 mg/dl after 15 days of IDDM. The time controls and the insulin-treated diabetic rats did not differ in blood glucose values at the time measurements were performed. Glomerular filtration rate increased from 1.0 ± 0.1 to 1.7 ± 0.1 ml/min/100g body wt by day 15 in the untreated diabetic rats with significant increases in GFR within 24 hours. GFR of both time controls and the insulin-treated IDDM rats did not significantly vary during the time of the study. The increase in GFR in the untreated IDDM group was associated with a concomitant increase in RPF. However, ECF decreased in both the insulin treated and untreated groups by one day after streptozotocin infusion and was less than control throughout the 15 day IDDM measurement period. Therefore, the data indicate that the development of hyperfiltration in IDDM is not caused by ECF expansion and cannot be temporally linked to changes in ECF

A mass spectrometry-guided genome mining approach for natural product peptidogenomics.

Peptide natural products show broad biological properties and are commonly produced by orthogonal ribosomal and nonribosomal pathways in prokaryotes and eukaryotes. To harvest this large and diverse resource of bioactive molecules, we introduce here natural product peptidogenomics (NPP), a new MS-guided genome-mining method that connects the chemotypes of peptide natural products to their biosynthetic gene clusters by iteratively matching de novo tandem MS (MS(n)) structures to genomics-based structures following biosynthetic logic. In this study, we show that NPP enabled the rapid characterization of over ten chemically diverse ribosomal and nonribosomal peptide natural products of previously unidentified composition from Streptomycete bacteria as a proof of concept to begin automating the genome-mining process. We show the identification of lantipeptides, lasso peptides, linardins, formylated peptides and lipopeptides, many of which are from well-characterized model Streptomycetes, highlighting the power of NPP in the discovery of new peptide natural products from even intensely studied organisms

Rapid evolution in response to introduced predators I: rates and patterns of morphological and life-history trait divergence

BACKGROUND: Introduced species can have profound effects on native species, communities, and ecosystems, and have caused extinctions or declines in native species globally. We examined the evolutionary response of native zooplankton populations to the introduction of non-native salmonids in alpine lakes in the Sierra Nevada of California, USA. We compared morphological and life-history traits in populations of Daphnia with a known history of introduced salmonids and populations that have no history of salmonid introductions. RESULTS: Our results show that Daphnia populations co-existing with fish have undergone rapid adaptive reductions in body size and in the timing of reproduction. Size-related traits decreased by up to 13 percent in response to introduced fish. Rates of evolutionary change are as high as 4,238 darwins (0.036 haldanes). CONCLUSION: Species introductions into aquatic habitats can dramatically alter the selective environment of native species leading to a rapid evolutionary response. Knowledge of the rates and limits of adaptation is an important component of understanding the long-term effects of alterations in the species composition of communities. We discuss the evolutionary consequences of species introductions and compare the rate of evolution observed in the Sierra Nevada Daphnia to published estimates of evolutionary change in ecological timescales

Quadrupedal Robots with Stiff and Compliant Actuation

In the broader context of quadrupedal locomotion, this overview article introduces and compares two platforms that are similar in structure, size, and morphology, yet differ greatly in their concept of actuation. The first, ALoF, is a classically stiff actuated robot that is controlled kinematically, while the second, StarlETH, uses a soft actuation scheme based on Changedhighly compliant series elastic actuators. We show how this conceptual difference influences design and control of the robots, compare the hardware of the two systems, and show exemplary their advantages in different application

Potential of in vivo stress reporter models to reduce animal use and provide mechanistic insights in toxicity studies

Chemical risk assessment ensures protection from the toxic effects of drugs and manmade chemicals. To comply with regulatory guidance, studies in complex organisms are required, as well as mechanistic studies to establish the relevance of any toxicities observed to man. Although in vitro toxicity models are improving, in vivo studies remain central to this process. Such studies are invariably time-consuming and often involve large numbers of animals. New regulatory frameworks recommend the implementation of “smart” in vivo approaches to toxicity testing that can effectively assess safety for humans and comply with societal expectations for reduction in animal use. A major obstacle in reducing the animals required is the time-consuming and complexity of the pathological endpoints used as markers of toxicity. Such endpoints are prone to inter-animal variability, subjectivity and require harmonisation between testing sites. As a consequence, large numbers of animals per experimental group are required. To address this issue, we propose the implementation of sophisticated stress response reporter mice that we have developed. These reporter models provide early biomarkers of toxic potential in a highly reproducible manner at single-cell resolution, which can also be measured non-invasively and have been extensively validated in academic research as early biomarkers of stress responses for a wide range of chemicals at human-relevant exposures. In this report, we describe a new and previously generated models in our lab, provide the methodology required for their use and discuss how they have been used to inform on toxic risk. We propose our in vivo approach is more informative (refinement) and reduces the animal use (reduction) compared to traditional toxicity testing. These models could be incorporated into tiered toxicity testing and used in combination with in vitro assays to generate quantitative adverse outcome pathways and inform on toxic potential

Identification of a rare de novo three-way complex t(5;20;8)(q31;p11.2;p21) with microdeletions on 5q31.2, 5q31.3, and 8p23.2 in a patient with hearing loss and global developmental delay: case report

<p>Abstract</p> <p>Background</p> <p>Complex chromosome rearrangements (CCRs), which involve more than two breakpoints on two or more chromosomes, are uncommon occurrences. Although most CCRs appear balanced at the level of the light microscope, many demonstrate cryptic, submicroscopic imbalances at the translocation breakpoints.</p> <p>Results</p> <p>We report a female with hearing loss and global developmental delay with a complex three-way unbalanced translocation (5;20;8)(q31;p11.2;p21) resulting in microdeletions on 5q31.2, 5q31.3, and 8p23.2 identified by karyotyping, microarray analysis and fluorescence in situ hybridization.</p> <p>Discussion</p> <p>The microdeletion of bands 8p23.2 may be associated with the hearing impairment. Furthermore, the characterization of this patient's chromosomal abnormalities demonstrates the importance of integrated technologies within contemporary cytogenetics laboratories.</p