julilili42/papers huggingface dataset:
B42 Early olfactory behaviour deficits associated with olfactory bulb atrophy and caspase-8 activation in HD rodent models
2016-09-01

<h3>Background</h3> Olfactory dysfunction and altered neurogenesis are observed in several neurodegenerative disorders including Huntington’s disease (HD). These deficits are an early symptom and correlate with decline in cognitive performance, depression and degeneration of olfactory regions in the brain. <h3>Aims</h3> Despite clear evidence demonstrating olfactory dysfunction in HD patients, only limited details are available in murine models and the cause is unknown. Our goal is to determine if olfactory dysfunction is an early event in the pathogenesis of HD and to delineate the underlying mechanism(s). <h3>Results</h3> We have previously shown decreased olfactory cortical volume in the YAC128 HD model. We now examined odour investigation behaviours and show that at 1 and 3 months YAC128 mice do not habituate to the odour as quickly in trial 2 (p &lt; 0.05), and at 5 months the YAC128 mice investigate trial 1 odours longer than WT littermates (p &lt; 0.05). Initial data also show an increase in GFAP and Iba-1 in the olfactory bulb (OB) in post-symptomatic YAC128 compared to WT. Furthermore, an increase in the active form of caspase-6 and caspase-8 are observed at 3 months in YAC128 OB vs WT. We also assessed the rat BACHD model. In the BACHD model, early increases in NeuN and atrophy of the OB (ANOVA p = 0.02) are observed. In addition, an increase in caspase-8 (ANOVA p = 0.02) expression at 6 months is observed vs. WT. Supporting this, we detect an increase in casp8 activation in the OB at 3 months of age. <h3>Conclusions</h3> As we observe neuronal loss in the HD piriform cortex, a region that receives direct input from the OB and plays a role in odour discrimination and odour memory, this may reflect a loss in neuronal production or increased cell death in this area. The caspase activation studies support that cell death may be increased in both the murine HD piriform cortex and OB. However it cannot be ruled out that problems in neurogenesis are also occurring. Additional studies are required to ascertain the type and progression of olfactory dysfunction in the HD mice and highlight the specific olfactory pathway involved. Identification of early markers for HD will help inform therapeutic approaches and will clarify the utility of olfactory function tests in at risk HD individuals.
C5 Alteration of threat processing in the bachd rat model of huntington’s disease relies on dysfunction of central amygdala
2016-09-01

<h3>Background</h3> In Huntington’s disease (HD), dysfunctional affective processes emerge as key symptoms of disturbances. In human HD and transgenic rat models of the disease, the amygdala was previously shown to have a reduced volume and carry a high load of mutant huntingtin (mHTT) aggregates. In search of the pathophysiology of affective dysregulation in HD, we hypothesised a specific role of the central amygdala (CeA), known to be particularly involved in emotional regulation. <h3>Methods</h3> Using transgenic BACHD rats carrying full-length human mHTT, we first compared behavioural consequences of pharmacological modulation of CeA function by infusing GABAA receptor (GABAAR) antagonist picrotoxinin into ~4.5 month old BACHD and WT rats before confronting them to a threatening stimulus in two tasks: social interaction and signalled active avoidance. <h3>Results</h3> Our results show that modulating the CeA induced differential behaviour between WT and BACHD rats. Second, we analysed amygdala alteration/dysfunction at the cellular level. An age-dependent increase in number and size of mHTT aggregates was observed specifically in the CeA of BACHD rats (between 3 and 6 months). No alteration of GABA and GABAAR expression levels, but an increased neuronal reactivity (Arc labelling) to a threatening stimulus in the medial part of this nucleus in 4.5 months old BACHD rats was found. <h3>Conclusions</h3> These results suggest a basal pathological hyper-activity in the CeA (in particular its medial part) in the transgenic animals. Such amygdala dysfunction could account, at least in part, for affective symptoms in HD patients.
B46 The HD-like type 4/SCA17 disease protein TBP is cleaved by calpains in vitro and in vivo
2016-09-01

<h3>Background</h3> The Spinocerebellar ataxia type 17 (SCA17) also referred to as HD-like type 4 is a neurodegenerative disease caused by an elongation of the CAG repeat in the gene of the TATA box binding protein (TBP), an ubiquitary transcription factor. Although the underlying pathomechanism is not fully understood, fragmentation of polyglutamine-expanded TBP by yet unidentified proteases might contribute to the toxicity of the mutant protein in affected cerebellar neurons. <h3>Aims</h3> The role of proteolysis of mutant proteins is a hallmark of many neurodegenerative diseases such as Parkinson disease, Huntington’s disease or Spinocerebellar ataxia type 3 and calpains, a family of calcium-dependent proteases, were found to be one of the key players. Thus we sought to investigate the contribution of calpains-dependent TBP cleavage to the pathogenesis in SCA 17. <h3>Methods</h3> TBP fragmentation was investigated <i>in vitro</i> in cell-free and cell-based calpain activation assays. The activation state of the calpain system and the presence of calpain-dependent TBP fragments <i>in vivo</i> was analysed in our SCA17 rat model by western blotting. <h3>Results</h3> Our calpain activation assays showed the occurrence of specific calpain-dependent fragments of wildtype and mutant TBP after addition of exogenous calpains or after triggering activity of endogenous calpains. Furthermore, pharmacologic inhibition of calpains reduced base-line cleavage of the disease protein and we identified corresponding TBP fragments in cerebellar lysates of SCA17 animals. <h3>Conclusions</h3> We could identify TBP as a novel target of calpain-dependent cleavage <i>in vitro</i> and <i>in vivo</i>. Further analyses of cleavage sites, the contribution of specific TBP fragments to the molecular pathomechanism of SCA17 and ways to reduce fragmentation of TBP <i>in vivo</i> stand in the focus of our further investigations and could help to develop a therapeutic approach for this dreadful disease. As Huntingtin is also cleaved by calpains, effective therapeutic approaches in SCA17 could also be transferred to Huntington’s disease.
L10 Two novel mtor and PI3K/mTOR inhibitors induce autophagy and reduce the amount of aggregated mutant huntingtin in cell models of HD
2016-09-01

<h3>Background</h3> The pathogenesis of HD is not entirely understood, but it is clear that the expression of the disease-causing mutant huntingtin protein leads to the disruption of a variety of cellular functions, which ultimately results in cell death. A hallmark of HD is the accumulation of intracellular inclusions of mHTT, the mHTT aggregates. Although the toxicity of mHTT aggregates is still debated, various studies have demonstrated that induction of autophagy, the major pathway for the degradation of mHTT aggregates, leads to increased cell viability. ATP- competitive mTOR inhibitors have been shown to be more efficient in induction of autophagy and reduction of protein aggregates than allosteric mTOR inhibitors, like Rapamycin. <h3>Aim</h3> The ability of catalytic mTOR inhibitors to cross the blood-brain barrier, however, is limited and mTOR inhibition in brain is insufficient. Therefore two novel mTOR inhibitors were evaluated for their efficacy in mTOR inhibition in an HD context, by assessing their potential for inducing autophagy and reducing HTT levels. <h3>Methods</h3> Expression levels of autophagic markers and well-studied mTOR targets were analysed by western blot analysis in STHdhQ7/Q7 and STHdhQ111/Q111 cells and brain samples from mice treated with both compounds. Cytotoxic effects were monitored in STHdh cells. For studying HTT levels HEK293T cells were transiently transfected with HTT- Exon 1- eGFP constructs with either 19 or 51 Q and analysed by fluorescent imaging and filter trap assay. <h3>Results</h3> Treatment with both compounds led to decreased cytotoxicity in STHdh cells. The phosphorylation level of mTOR targets 4EBP1 and ribosomal protein S6 were found to be reduced, while LC3B – II levels increased in vitro and in vivo, indicating inhibition of mTOR activity and induction of autophagy. Furthermore reduction of aggregates was demonstrated upon treatment with both substances. <h3>Conclusion</h3> Originally derived from cancer treatment, these second generation mTOR inhibitors show brain penetrance and effectiveness in cell models of HD, which suggests them as potentially relevant in treatment of neurodegenerative disorders.
An Image-Based Multi-Channel Model for Light Adaptation
2016-09-01

The human visual system is sensitive to luminances ranging from 10-6 to 108 cd/sqm (Hood & Finkelstein, 1986, Handbook of Perception and Human Performance, Vol 1). Given the more limited dynamic range of the photoreceptors and subsequent neurons, effective light adaptation must thus be an essential property of the visual system. In an important study Kortum & Geisler (1995, Vision Research) measured contrast increment thresholds for increment-Gabor probes on flashed backgrounds in the presence of steady-state backgrounds, exploring how the spatial frequency of the increment-Gabor affects thresholds, i.e. how light adaptation and spatial vision interact. In addition to their experiments, Kortum & Geisler presented a successful model in which the incoming signal undergoes multiplicative and subtractive adapting stages followed by non-linear transduction and late noise. Here we significantly expand and modify their model: First, our model is image-based and thus accepts any image as input, whereas the original model is only applicable to the putative scalar activations of sine wave stimuli. Second, our model has a single set of parameters for the multiplicative and subtractive adaptation stages, followed by a multi-scale pyramid decomposition (Simoncelli & Freeman, 1995, IEEE International Conference on Image Processing, Vol. III). The spatial frequency dependence of the thresholds is modelled via the DC components' selective influence on the variance of the late noise in the decision stage of the model. In the original model by Kortum & Geisler the parameters of the multiplicative and subtractive adaptation stages are all spatial frequency dependent, which is problematic if one believes adaptation to happen very early in the visual system, before the signal is split into separate spatial frequency channels. Our image-based multi-channel light adaptation model not only accounts well for the data of Kortum & Geisler (1995), but in addition captures, for example, the effects of test patches of different size (Geisler, 1979, Vision Research). Meeting abstract presented at VSS 2016
Does Event Perception Depend on IQ, Expertise, and Repetition?
2016-09-01

Event Segmentation Theory (EST) explains the perceptual organization of an ongoing activity into meaningful events. Classical event segmentation task involves watching an online video and indicating with keypress, the event boundaries i.e., when one event ends and the next one begins. The resulting hierarchical organization of object-based coarse-events and action-based fine-events provide insight about various cognitive processes. We studied event perception in the domain of assistance and training systems development for assembly workers in industrial settings. We investigated event segmentation performance of 32 intellectually-disabled people (mean IQ = 64.4) compared to 30 controls (IQ>100). Stimuli: One "breakfast-making" video and three assembly task videos. 38% Intellectually-disabled participants defined more coarse-events than fine-events, indicating misconception of higher- and lower-level content. The remaining 62% showed diminished hierarchical alignment compared to controls. We suggest that simple event segmentation task can serve as diagnostic assessment for intellectually disabled workers' cognitive potential. Furthermore, we investigated how repeated practice of sequential assembly tasks in virtual training influences learning of the task's coarse and fine assembly steps in car door assembly for domain experts (N = 18) and novices (N = 19). Stimuli: A video of car door assembly task. The video stopped at time points associated with the coarse-event boundaries; either before a coarse-event boundary – this tested memory for coarse-events - or after a coarse-event boundary – this tested memory for fine-events. We found virtual training enhances ability to predict object-based coarse-event from nearest fine-event boundary. It did not improve memory for action-based fine-event from the nearest coarse-event boundary. Expertise had a positive effect on memory for fine assembly steps. Our research in event perception can help improve the quality of life of workers at various levels- experts, new hires, and intellectually-disabled workers, by identifying gaps in existing assistance systems for the different user groups. Meeting abstract presented at VSS 2016
The Scope of Auctions in the Presence of Downstream Interactions and Information Externalities
2016-09-01

TWe scrutinize the scope of auctions for firm acquisitions in the presence of downstream interactions and information externalities. We Show that no mechanism exists that allows an investor to acquire a low-cost firm under incomplete information: a separating auction implies adverse selection and relies substantially on commitment to allocation and transfer rules. A pooling auction serves as a commitment device against ex-post opportunistic behavior and alleviates adverse selection. It can earn the investor a higher expected payoff than a separating auction, even when consistency is required as to qualify for a sequential equilibrium.
Using Recursive Partitioning to Account for Parameter Heterogeneity in Multinomial Processing Tree Models
2016-09-01

In multinomial processing tree (MPT) models, individual differences between the participants in a study lead to heterogeneity of the model parameters. While subject covariates may explain these differences, it is often unknown in advance how the parameters depend on the available covariates, that is, which variables play a role at all, interact, or have a nonlinear influence, etc. Therefore, a new approach for capturing parameter heterogeneity in MPT models is proposed based on the machine learning method MOB for model-based recursive partitioning. This recursively partitions the covariate space, leading to an MPT tree with subgroups that are directly interpretable in terms of effects and interactions of the covariates. The pros and cons of MPT trees as a means of analyzing the effects of covariates in MPT model parameters are discussed based on a simulation experiment as well as on two empirical applications from memory research. Software that implements MPT trees is provided via the mpttree function in the psychotree package in R.
Dopamine D2 Receptors Enhance Population Dynamics in Primate Prefrontal Working Memory Circuits
2016-09-02

Working memory is associated with persistent activity in the prefrontal cortex (PFC). The neuromodulator dopamine, which is released by midbrain neurons projecting into the frontal lobe, influences PFC neurons and networks via the dopamine D1 (D1R) and the D2 receptor (D2R) families. Although behavioral, clinical and computational evidence suggest an involvement of D2Rs in working memory, a neuronal explanation is missing. We report an enhancement of persistent working memory responses of PFC neurons after iontophoretically stimulating D2Rs in monkeys memorizing the number of items in a display. D2R activation improved working memory representation at the population level and increased population dynamics during the transition from visual to mnemonic representations. Computational modeling suggests that D2Rs act by modulating interneuron-to-pyramidal signaling. By increasing the population's response dynamics, D2Rs might put PFC networks in a more flexible state and enhance the neurons' working memory coding, thereby controlling dynamic cognitive control.
The clinical relevance of birch pollen profilin cross-reactivity in sensitized patients
2016-09-02

Identification of the clinically relevant and sensitizing allergen needs correlation of actual pollen counts with clinical symptoms and sensitization status to major allergens. Semiquantitative analysis of SPT or BAT and determining profilin-specific IgE can contribute to making the diagnosis.
Zero‐dead‐volume interfaces for two–dimensional electrophoretic separations
2016-09-02

We present the study on the sample transfer characteristics of two different microfluidic interfaces for 2D‐CE . These interfaces were manufactured using two different microfabrication technologies: one was obtained via the classical photolithography—wet etching—anodic‐bonding process; and the other was obtained via the selective laser‐induced etching process. The comparison of the two interfaces, and an intact capillary as a reference, was made via the CE separation of amino acids (arginine and lysine) under different bulk flow conditions, with and without applying bias potential to the secondary channels. The influence on peak shapes, migration times, and repeatabiliy were evaluated.
Sustained Treatment with Insulin Detemir in Mice Alters Brain Activity and Locomotion
2016-09-02

The data suggest that permanently-increased insulin detemir levels in the brain convert its hyperstimulatory effects and finally mediate impairments in brain activity and locomotion. This observation might be considered when human studies with insulin detemir are designed to target the brain in order to optimize treatment regimens.
Deregulation of Apoptosis - Is it Still an Important Issue in Pathogenesis of Chronic Lymphocytic Leukemia?
2016-09-02

Chronic lymphocytic leukemia (CLL), a clonal expansion of B CD5+ cells, is the most common type of adult leukemia in western countries. The accumulation of neoplastic B-cells is primarily caused by prolonged life-span of these cells due to deregulation of apoptosis, and only marginally due to a higher proliferation rate. In spite of numerous reports characterizing particular mechanisms of B-CLL cell apoptosis, still relatively little is known about the complex regulation of this process. Therefore, more detailed research is required to understand the complicated mechanisms and regulatory processes of apoptosis in neoplastic B lymphocytes.
Insight into the ten-penny problem: guiding search by constraints and maximization
2016-09-03

For a long time, insight problem solving has been either understood as nothing special or as a particular class of problem solving. The first view implicates the necessity to find efficient heuristics that restrict the search space, the second, the necessity to overcome self-imposed constraints. Recently, promising hybrid cognitive models attempt to merge both approaches. In this vein, we were interested in the interplay of constraints and heuristic search, when problem solvers were asked to solve a difficult multi-step problem, the ten-penny problem. In three experimental groups and one control group (N = 4 × 30) we aimed at revealing, what constraints drive problem difficulty in this problem, and how relaxing constraints, and providing an efficient search criterion facilitates the solution. We also investigated how the search behavior of successful problem solvers and non-solvers differ. We found that relaxing constraints was necessary but not sufficient to solve the problem. Without efficient heuristics that facilitate the restriction of the search space, and testing the progress of the problem solving process, the relaxation of constraints was not effective. Relaxing constraints and applying the search criterion are both necessary to effectively increase solution rates. We also found that successful solvers showed promising moves earlier and had a higher maximization and variation rate across solution attempts. We propose that this finding sheds light on how different strategies contribute to solving difficult problems. Finally, we speculate about the implications of our findings for insight problem solving.
The Drosophila KIF1A Homolog unc-104 Is Important for Site-Specific Synapse Maturation
2016-09-04

Mutations in the kinesin-3 family member KIF1A have been associated with hereditary spastic paraplegia (HSP), hereditary and sensory autonomic neuropathy type 2 (HSAN2) and non-syndromic intellectual disability (ID). Both autosomal recessive and autosomal dominant forms of inheritance have been reported. Loss of KIF1A or its homolog unc-104 causes early postnatal or embryonic lethality in mice and Drosophila, respectively. In this study, we use a previously described hypomorphic allele of unc-104, unc-104(bris) , to investigate the impact of partial loss-of-function of kinesin-3 on synapse maturation at the Drosophila neuromuscular junction (NMJ). Unc-104(bris) mutants exhibit structural defects where a subset of synapses at the NMJ lack all investigated active zone (AZ) proteins, suggesting a complete failure in the formation of the cytomatrix at the active zone (CAZ) at these sites. Modulating synaptic Bruchpilot (Brp) levels by ectopic overexpression or RNAi-mediated knockdown suggests that the loss of AZ components such as Ca(2+) channels and Liprin-α is caused by impaired kinesin-3 based transport rather than due to the absence of the key AZ organizer protein, Brp. In addition to defects in CAZ assembly, unc-104(bris) mutants display further defects such as depletion of dense core and synaptic vesicle (SV) markers from the NMJ. Notably, the level of Rab3, which is important for the allocation of AZ proteins to individual release sites, was severely reduced at unc-104(bris) mutant NMJs. Overexpression of Rab3 partially ameliorates synaptic phenotypes of unc-104(bris) larvae, suggesting that lack of presynaptic Rab3 contributes to defects in synapse maturation.
PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS
2016-09-05

Background The rarity of mutations in PALB2 , CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2 , CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T&gt;G and c.3113G&gt;A, CHEK2 c.349A&gt;G, c.538C&gt;T, c.715G&gt;A, c.1036C&gt;T, c.1312G&gt;T, and c.1343T&gt;G and ATM c.7271T&gt;G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10 −5 ), PALB2 c.3113G&gt;A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10 −8 ) and ATM c.7271T&gt;G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2 , c.349A&gt;G OR 2.26 (95% CI 1.29 to 3.95), c.1036C&gt;T OR 5.06 (95% CI 1.09 to 23.5) and c.538C&gt;T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T&gt;G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G&gt;T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.