Distance and direction, but not light cues, support response reversal learning.

Across three experiments, we examined the cuing properties of metric (distance and direction) and nonmetric (lighting) cues in different tasks. In Experiment 1, rats were trained on a response problem in a T-maze, followed by four reversals. Rats that experienced a change in maze orientation (Direction group) or a change in the length of the start arm (Distance group) across reversals showed facilitation of reversal learning relative to a group that experienced changes in room lighting across reversals. In Experiment 2, rats learned a discrimination task more readily when distance or direction cues were used than when light cues were used as the discriminative stimuli. In Experiment 3, performance on a go/no-go task was equivalent using both direction and lighting cues. The successful use of both metric and nonmetric cues in the go/no-go task indicates that rats are sensitive to both types of cues and that the usefulness of different cues is dependent on the nature of the task.

Machine learning-based models to predict modes of toxic action of phenols to Tetrahymena pyriformis.

The phenols are structurally heterogeneous pollutants and they present a variety of modes of toxic action (MOA), including polar narcotics, weak acid respiratory uncouplers, pro-electrophiles, and soft electrophiles. Because it is often difficult to determine correctly the mechanism of action of a compound, quantitative structure-activity relationship (QSAR) methods, which have proved their interest in toxicity prediction, can be used. In this work, several QSAR models for the prediction of MOA of 221 phenols to the ciliated protozoan Tetrahymena pyriformis, using Chemistry Development Kit descriptors, are reported. Four machine learning techniques (ML), k-nearest neighbours, support vector machine, classification trees, and artificial neural networks, have been used to develop several models with higher accuracies and predictive capabilities for distinguishing between four MOAs. They showed global accuracy values between 95.9% and 97.7% and area under Receiver Operator Curve values between 0.978 and 0.998; additionally, false alarm rate values were below 8.2% for training set. In order to validate our models, cross-validation (10-folds-out) and external test-set were performed with good behaviour in all cases. These models, obtained with ML techniques, were compared with others previously reported by other researchers, and the improvement was significant.

Mitochondrial-Targeted Catalase: Extended Longevity and the Roles in Various Disease Models.

The free-radical theory of aging was proposed more than 50 years ago. As one of the most popular mechanisms explaining the aging process, it has been extensively studied in several model organisms. However, the results remain controversial. The mitochondrial version of free-radical theory of aging proposes that mitochondria are both the primary sources of reactive oxygen species (ROS) and the primary targets of ROS-induced damage. One critical ROS is hydrogen peroxide, which is naturally degraded by catalase in peroxisomes or glutathione peroxidase within mitochondria. Our laboratory developed mice-overexpressing catalase targeted to mitochondria (mCAT), peroxisomes (pCAT), or the nucleus (nCAT) in order to investigate the role of hydrogen peroxide in different subcellular compartments in aging and age-related diseases. The mCAT mice have demonstrated the largest effects on life span and healthspan extension. This chapter will discuss the mCAT phenotype and review studies using mCAT to investigate the roles of mitochondrial oxidative stresses in various disease models, including metabolic syndrome and atherosclerosis, cardiac aging, heart failure, skeletal muscle pathology, sensory defect, neurodegenerative diseases, and cancer. As ROS has been increasingly recognized as essential signaling molecules that may be beneficial in hormesis, stress response and immunity, the potential pleiotropic, or adverse effects of mCAT are also discussed. Finally, the development of small-molecule mitochondrial-targeted therapeutic approaches is reviewed.

QuBiLs-MAS method in early drug discovery and rational drug identification of antifungal agents.

The QuBiLs-MAS approach is used for the in silico modelling of the antifungal activity of organic molecules. To this effect, non-stochastic (NS) and simple-stochastic (SS) atom-based quadratic indices are used to codify chemical information for a comprehensive dataset of 2478 compounds having a great structural variability, with 1087 of them being antifungal agents, covering the broadest antifungal mechanisms of action known so far. The NS and SS index-based antifungal activity classification models obtained using linear discriminant analysis (LDA) yield correct classification percentages of 90.73% and 92.47%, respectively, for the training set. Additionally, these models are able to correctly classify 92.16% and 87.56% of 706 compounds in an external test set. A comparison of the statistical parameters of the QuBiLs-MAS LDA-based models with those for models reported in the literature reveals comparable to superior performance, although the latter were built over much smaller and less diverse datasets, representing fewer mechanisms of action. It may therefore be inferred that the QuBiLs-MAS method constitutes a valuable tool useful in the design and/or selection of new and broad spectrum agents against life-threatening fungal infections.

Investigating the performance and cost-effectiveness of the simple ultrasound-based rules compared to the risk of malignancy index in the diagnosis of ovarian cancer (SUBSONiC-study): protocol of a prospective multicenter cohort study in the Netherlands.

BACKGROUND: Estimating the risk of malignancy is essential in the management of adnexal masses. An accurate differential diagnosis between benign and malignant masses will reduce morbidity and costs due to unnecessary operations, and will improve referral to a gynecologic oncologist for specialized cancer care, which improves outcome and overall survival. The Risk of Malignancy Index is currently the most commonly used method in clinical practice, but has a relatively low diagnostic accuracy (sensitivity 75-80% and specificity 85-90%). Recent reports show that other methods, such as simple ultrasound-based rules, subjective assessment and (Diffusion Weighted) Magnetic Resonance Imaging might be superior to the RMI in the pre-operative differentiation of adnexal masses. METHODS/DESIGN: A prospective multicenter cohort study will be performed in the south of The Netherlands. A total of 270 women diagnosed with at least one pelvic mass that is suspected to be of ovarian origin who will undergo surgery, will be enrolled. We will apply the Risk of Malignancy Index with a cut-off value of 200 and a two-step triage test consisting of simple ultrasound-based rules supplemented -if necessary- with either subjective assessment by an expert sonographer or Magnetic Resonance Imaging with diffusion weighted sequences, to characterize the adnexal masses. The histological diagnosis will be the reference standard. Diagnostic performances will be expressed as sensitivity, specificity, positive and negative predictive values and likelihood ratios. DISCUSSION: We hypothesize that this two-step triage test, including the simple ultrasound-based rules, will have better diagnostic accuracy than the Risk of Malignancy Index and therefore will improve the management of women with adnexal masses. Furthermore, we expect this two-step test to be more cost-effective. If the hypothesis is confirmed, the results of this study could have major effects on current guidelines and implementation of the triage test in daily clinical practice could be a possibility. TRIAL REGISTRATION: ClinicalTrials.gov: registration number NCT02218502.

Monoallelic ABCC8 mutations are a common cause of diazoxide-unresponsive diffuse form of congenital hyperinsulinism.

ABCC8 encodes a subunit of the ß-cell potassium channel (KATP ) whose loss of function is responsible for congenital hyperinsulinism (CHI). Patients with two recessive mutations of ABCC8 typically have severe diffuse forms of CHI unresponsive to diazoxide. Some dominant ABCC8 mutations are responsible for a subset of diffuse diazoxide-unresponsive forms of CHI. We report the analysis of 21 different ABCC8 mutations identified in 25 probands with diazoxide-unresponsive diffuse CHI and carrying a single mutation in ABCC8. Nine missense ABCC8 mutations were subjected to in vitro expression studies testing traffic efficiency and responses of mutant channels to activation by MgADP and diazoxide. Eight of the 9 missense mutations exhibited normal trafficking. Seven of the 8 mutants reaching the plasma membrane had dramatically reduced response to MgADP or to diazoxide (<10% of wild-type response). In our cohort, dominant KATP mutations account for 22% of the children with diffuse unresponsive-diazoxide CHI. Their clinical phenotype being indistinguishable from that of children with focal CHI and diffuse CHI forms due to two recessive KATP mutations, we show that functional testing is essential to make the most reliable diagnosis and offer appropriate genetic counseling.

On the edge: haptic discrimination of edge sharpness.

The increasing ubiquity of haptic displays (e.g., smart phones and tablets) necessitates a better understanding of the perceptual capabilities of the human haptic system. Haptic displays will soon be capable of locally deforming to create simple 3D shapes. This study investigated the sensitivity of our haptic system to a fundamental component of shapes: edges. A novel set of eight high quality shape stimuli with test edges that varied in sharpness were fabricated in a 3D printer. In a two alternative, forced choice task, blindfolded participants were presented with two of these shapes side by side (one the reference, the other selected randomly from the remaining set of seven) and after actively exploring the test edge of each shape with the tip of their index finger, reported which shape had the sharper edge. We used a model selection approach to fit optimal psychometric functions to performance data, and from these obtained just noticeable differences and Weber fractions. In Experiment 1, participants performed the task with four different references. With sharpness defined as the angle at which one surface meets the horizontal plane, the four JNDs closely followed Weber's Law, giving a Weber fraction of 0.11. Comparisons to previously reported Weber fractions from other haptic manipulations (e.g. amplitude of vibration) suggests we are sufficiently sensitive to changes in edge sharpness for this to be of potential utility in the design of future haptic displays. In Experiment 2, two groups of participants performed the task with a single reference but different exploration strategies; one was limited to a single touch, the other unconstrained and free to explore as they wished. As predicted, the JND in the free exploration condition was lower than that in the single touch condition, indicating exploration strategy affects sensitivity to edge sharpness.

Protocol for translabial 3D-ultrasonography for diagnosing levator defects (TRUDIL): a multicentre cohort study for estimating the diagnostic accuracy of translabial 3D-ultrasonography of the pelvic floor as compared to MR imaging.

BACKGROUND: Pelvic organ prolapse (POP) is a condition affecting more than half of the women above age 40. The estimated lifetime risk of needing surgical management for POP is 11%. In patients undergoing POP surgery of the anterior vaginal wall, the re-operation rate is 30%. The recurrence risk is especially high in women with a levator ani defect. Such defect is present if there is a partially or completely detachment of the levator ani from the inferior ramus of the symphysis. Detecting levator ani defects is relevant for counseling, and probably also for treatment. Levator ani defects can be imaged with MRI and also with Translabial 3D ultrasonography of the pelvic floor. The primary aim of this study is to assess the diagnostic accuracy of translabial 3D ultrasonography for diagnosing levator defects in women with POP with Magnetic Resonance Imaging as the reference standard. Secondary goals of this study include quantification of the inter-observer agreement about levator ani defects and determining the association between levator defects and recurrent POP after anterior repair. In addition, the cost-effectiveness of adding translabial ultrasonography to the diagnostic work-up in patients with POP will be estimated in a decision analytic model. METHODS/DESIGN: A multicentre cohort study will be performed in nine Dutch hospitals. 140 consecutive women with a POPQ stage 2 or more anterior vaginal wall prolapse, who are indicated for anterior colporapphy will be included. Patients undergoing additional prolapse procedures will also be included. Prior to surgery, patients will undergo MR imaging and translabial 3D ultrasound examination of the pelvic floor. Patients will be asked to complete validated disease specific quality of life questionnaires before surgery and at six and twelve months after surgery. Pelvic examination will be performed at the same time points. Assuming a sensitivity and specificity of 90% of 3D ultrasound for diagnosing levator defects in a population of 120 women with POP, with a prior probability of levator ani defects of 40%, we will be able to estimate predictive values with good accuracy (i.e. confidence limits of at most 10% below or above the point estimates of positive and negative predictive values).Anticipating 3% unclassifiable diagnostic images because of technical reasons, and a further safety margin of 10% we plan to recruit 140 patients. TRIAL REGISTRATION: Nederlands trial register NTR2220.

A Novel LMNA Mutation Causes Altered Nuclear Morphology and Symptoms of Familial Partial Lipodystrophy (Dunnigan Variety) with Progeroid Features.

Dunnigan-type partial lipodystrophy (familial partial lipodystrophy, Dunnigan variety, FPLD2) can be caused by LMNA mutations. We identified a novel heterozygous LMNA mutation, P485R, in a patient referred to the International Registry of Werner Syndrome because of features consistent with that of progeroid disorder but who was wild type at the WRN locus. The novel mutation is located 2 amino acids away from the canonical FPLD mutations in exon 8 of the LMNA gene. Immunocytochemical analysis revealed abnormal nuclear morphology characteristic of laminopathies within primary fibroblast cultures, but not in a lymphoblastoid cell line, in keeping with previous observations. Our findings indicate that FPLD2 should be considered in the differential diagnosis of the Werner syndrome.

Patient-related and centre-related factors influencing technique survival of peritoneal dialysis in The Netherlands.

BACKGROUND: Although technique failure occurs relatively frequently in peritoneal dialysis (PD), few data have been published on differences in technique failure between centres. METHODS: Using data from RENINE, the comprehensive dialysis registry of The Netherlands, we analysed PD technique failure rates in the period 1994-1999, with life table methods and Cox multiple regression analysis. Patient age, sex, and the presence or absence of diabetes were included in the analysis, as well as time of initiation of PD and the following centre characteristics: number of PD patients treated in the centre and percentage of patients on PD. RESULTS: Technique failure was higher in older patients: 2-year technique survival was 75% in those younger than 45 years, 68% in the group aged 45-64 years, and 60% in those over 64 years (P<0.0001). Sex and diabetes made no difference in technique survival. Mean annual technique failure rates varied greatly between centres (10-59%) and correlated with the number of patients on PD in the centre (r=-0.396, P=0.009) and with the fraction of patients on PD (r=-0.410, P=0.006). Low technique survival rates occurred mainly in centres with less than 20 patients on PD: relative risk for technique failure 1.68 as compared with larger centres. Patients starting PD in the period 1997-1999 had better technique survival than those starting in 1994-1996 (P=0.001). CONCLUSION: PD technique survival in The Netherlands has increased in recent years. Having less than 20 PD patients in a centre or having a small fraction of patients on PD carries an increased risk of technique failure. The variability in PD technique survival between centres indicates that in many centres further improvements should be possible.

Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces.

To examine the in vivo function of presenilin-1 (PS1), we selectively deleted the PS1 gene in excitatory neurons of the adult mouse forebrain. These conditional knockout mice were viable and grew normally, but they exhibited a pronounced deficiency in enrichment-induced neurogenesis in the dentate gyrus. This reduction in neurogenesis did not result in appreciable learning deficits, indicating that addition of new neurons is not required for memory formation. However, our postlearning enrichment experiments lead us to postulate that adult dentate neurogenesis may play a role in the periodic clearance of outdated hippocampal memory traces after cortical memory consolidation, thereby ensuring that the hippocampus is continuously available to process new memories. A chronic, abnormal clearance process in the hippocampus may conceivably lead to memory disorders in the mammalian brain.

Exceptional cellular resistance to oxidative damage in long-lived birds requires active gene expression.

Previous studies indicated that renal tubular epithelial cells from some long-lived avian species exhibit robust and/or unique protective mechanisms against oxidative stress relative to murine cells. Here we extend these studies to investigate the response of primary embryonic fibroblast-like cells to oxidative challenge in long- and short-lived avian species (budgerigar, Melopsittacus undulatus, longevity up to 20 years, vs Japanese quail, Coturnix coturnix japonica, longevity up to 5 years) and short- and long-lived mammalian species (house mouse, Mus musculus, longevity up to 4 years vs humans, Homo sapiens, longevity up to 122 years). Under the conditions of our assay, the oxidative-damage resistance phenotype appears to be associated with exceptional longevity in avian species, but not in mammals. Furthermore, the extreme oxidative damage resistance phenotype observed in a long-lived bird requires active gene transcription and translation, suggesting that specific gene products may have evolved in long-lived birds to facilitate resistance to oxidative stress.

Spatial problem solving and hippocampal place cell firing in rats: control by an internal sense of direction carried across environments.

Rats learned to find the baited corner of a box surrounded by a curtain, regardless of whether they had a fixed or random point of entry (POE) through the curtain. On probe trials, rats used an internal direction sense carried from outside the curtain to solve the problem, and only used the visual cue inside the curtain if disoriented and denied access to a view of the room en route. Similar disorientation procedures were required to obtain cue control of hippocampal place fields. The results suggest that: (1) POE effects previously found in the water maze may be task-specific; (2) an undisrupted internal sense of direction carried from one environment to another may provide the preferred solution to spatial problems in the second environment, even when this second environment is a familiar one with stable visual cues; and (3) choice behaviour is sometimes, but not always, representative of the hippocampal representation of space.

The moving fire hydrant experiment: movement of objects to a new location reelicits marking in rats.

Three experiments were carried out to investigate the influence of object relocation on object marking in an open field by hooded and albino rats. Object marking was reelicited when an object was moved to a new location in the second half of an open field test. Control conditions revealed that an object briefly moved and returned to the original location elicited no more marking than a stationary object. The higher level of marking of the relocated object suggests that object marking may provide an index of spatial knowledge. The implication of spatial knowledge in controlling marking behavior is congruent with observations that rats with hippocampal damage show increased marking.

A two-platform task reveals a deficit in the ability of rats to return to the start location in the water maze.

The ability of rats to return to the start location was examined with a 4-arm radial water maze. The task required rats to find 2 hidden platforms in sequence. Rats were released from 1 of 3 arms and there was a platform located in the fourth arm. Once a rat found this platform, a 2nd platform was raised in another location, which was either the start location, for 1 group, or another fixed location, for a control group. Across 3 experiments, all rats learned the location of the 1st fixed platform in 80 to 120 trials. However, rats had difficulty finding a 2nd platform if it was at the start location. Control groups revealed that rats could learn 2 platform locations and that the difficulty in learning to return to the start location did not seem to be attributable to its aversive nature. In separate groups, exposure to the start location was increased by starting the rats from an initially stable platform. Rats still did not readily learn to return to the start location. The authors suggest that start location, when varied, cannot readily be used to define the location of a hidden platform.

DNA double-strand breaks in mouse kidney cells with age.

A Biojector device fitted with a CO2 cartridge was used to prepare single cell suspensions from kidneys of 12-month- (middle-aged) and 24-month-old (old) C57B1/6 mice. Microgel electrophoresis of DNA from these cells revealed a modest but significant 7.3% increase (P = 0.04) in DNA double-strand breaks in old mice. This increase is equivalent to the DNA damage induced by 0.1 Gray of X-rays (5 double-strand breaks) in kidney cells of 10-month-old mice, as determined by a standard calibration curve. Greater DNA damage with aging was also positively correlated with higher levels of pathology in the kidneys.

Lessons from human progeroid syndromes.

A number of human genes have been identified in which mutations can lead to the accelerated emergence of features of senescence. Studies of these genes, and of the functions of their protein products, may lead to a clearer understanding of the nature of senescence, and could provide clues for ways in which ageing might be retarded.