julilili42/papers huggingface dataset:
Tissue analysis of solitary pulmonary nodules using OCT A-Scan imaging needle probe
2014-09-01

State of the art to specify the entity of solitary pulmonary nodules (SPN) is TTNA or TBNA. Optical coherence tomography (OCT) has the capability to close the gap between confocal microscopy and ultrasound. To investigate OCT imaging in the diagnosis of SPN′s we developed a forward imaging needle probe. Single A-Scan images were taken from different tissue sides manually and consecutive A-Scans while puncturing robotically guided. Histopathology defined the tissue probe as malignant or nonmalignant and characterized the architecture of the lung and SPN along the robotically punctured channel. The A-Scans were classified by a bidirectional long short term memory network. From 15 different tissue specimens 75 datasets of lung tissue and 22 datasets of tumor tissue have been acquired. Results are shown in Figure 1 [1 and 2: A-Scans from the same patient contribute to test set or trainings set. All tumor samples (PatAll), adeno carcinoma (PatAd). 3 and 4: A-Scans from the same record contribute to test set or training set. All carcinoma (RecAll), adeno carcinoma (RecAd)]. Further analysis of the individual patient data showed improved sensitivity, specificity and accuracy. Our results demonstrate that individual OCT A-Scans can provide information for differentiation of malignant and non-malignant lung tissue. Further were we able to align histopathologic features and OCT features of the consecutive data sets.
M12 A769662 Leads to AMPK Activation, Induces Autophagy and has Beneficial Effects IN HD Cells
2014-09-01

&lt;sec&gt;&lt;st&gt;Background&lt;/st&gt; The expansion of a polyglutamine repeat in the HD gene encoding huntingtin (htt) protein causes Huntington disease (HD). Although the exact pathogenesis is not known in its entirety, mutant htt causes disruption of various cellular functions, formation of aggregates and finally cell death. The process of autophagy is the main degradation pathway for mutant htt and various studies demonstrated that the induction of autophagy leads to an improvement of aggregate formation and cell viability. Commonly, the mTor inhibitor rapamycin is used for autophagy induction and has been shown to protect against mutant htt mediated toxicity in several HD models. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Aim/method&lt;/st&gt; As rapamycin, beside autophagy induction, also suppresses mTor mediated protein synthesis, we aimed to characterise AMPK as a new drug target for autophagy induction. In this regard, we analysed AMPK activation by the AMPK inducer A769662 and its effects on autophagic degradation and mutant htt mediated toxicity. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Results&lt;/st&gt; Activation of AMPK by A769662 led to an increased expression of the autophagosomal markers LC3 and p62, suggesting an efficient induction of autophagy. The autophagy induction is accompanied by a decrease of mutant htt expression and cytotoxicity. Additionally, mTor mediated protein synthesis, measured by the S6K1 (ribosomal protein S6 kinase) and RPS6 (ribosomal protein S6) expression is not affected. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Conclusion&lt;/st&gt; Therefore, we identified AMPK as an interesting therapeutic target and A769662 as a potential treatment compound to facilitate the clearance of mutant htt without interfering with mTor mediated protein synthesis. &lt;/sec&gt;
B15 Dysregulation of Gene Expression in the Striatum of Bachd Rats and Abnormalities Involved on Molecular and Protein Levels
2014-09-01

&lt;sec&gt;&lt;st&gt;Background&lt;/st&gt; Huntington disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by an expansion of CAG repeats in the gene coding for the huntingtin protein (htt). Mutant htt has been proposed to cause neuronal dysfunction and neuronal loss through multiple mechanisms. Transcriptional changes may be a core pathogenic feature of HD. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Methods&lt;/st&gt; Utilising the Affymetrix platform we performed a genome-wide RNA expression analysis in two BACHD transgenic rat lines (TG5 and TG9) at 12 months of age, which carry full-length human mutant htt with different expression levels. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Results&lt;/st&gt; Applying a threshold of significance of 0.01, we found 1608 genes and 871 genes differently expressed in TG5 and TG9 rats compared to wild type littermates, respectively. We only chose highly up/down regulated genes for further analysis by setting an additional threshold of 1.5 for fold change. Comparison with data from human HD brains revealed a high concordance in involved functional and IPA (Ingenuity Pathway Analysis) canonical pathways relevant in HD. In addition, we investigated the causes leading to gene expression changes on molecular and protein levels in BACHD rats including the amount of wild type htt, interaction of mhtt with polyQ containing transcription factors as well as chromatin structure. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Conclusions&lt;/st&gt; Results of this study demonstrate that this BACHD rat model recapitulates accurately gene expression changes of the human disease and therefore supports its application in preclinical research. Analysis of causative events in BACHD rats confirmed some findings in &lt;it&gt;in vitro&lt;/it&gt;test, and also provides a novel insight into initiators of perturbed gene transcription in HD. &lt;/sec&gt;
M06 Olesoxime Treatment Inhibits The Formation Of Mhtt Fragments Through Suppression Of Calpain Activity, And Leads To Behavioural And Neurological Improvements In The Bachd Rat
2014-09-01

&lt;sec&gt;&lt;st&gt;Background&lt;/st&gt; Proteolytic cleavage of the mutant huntingtin protein (mHtt) leads to toxic N-terminal mHtt fragments, which are known to disrupt mitochondrial function. Olesoxime, a small cholesterol-like molecule, targets mitochondria and has demonstrated therapeutic efficacy in a variety of disease models. Recent clinical investigations revealed exciting results in spinal muscular atrophy patients, where olesoxime was found to be the first drug to efficiently block the progression of motor deficits in a clinical type II study. Furthermore, it was found to increase the survival of primary striatal neurons overexpressing mHtt, suggesting therapeutic potential also for HD. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Aims&lt;/st&gt; To evaluate the therapeutic potential of olesoxime in the BACHD rat model of HD. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Methods&lt;/st&gt; Olesoxime was supplied to BACHD rats via drug-loaded food pellets from the age of 5 weeks on, and the rats’ behaviour was studied for 12 months. Brain atrophy was investigated with MRI at 13 months. Mitochondrial parameters, mHtt cleavage and aggregation were measured in brain lysates &lt;it&gt;ex vivo&lt;/it&gt;. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Results&lt;/st&gt; We found olesoxime to specifically ameliorate psychiatric and cognitive disturbances of BACHD rats, to increase frontal cortex thickness and to improve mitochondrial function. Very interestingly, the beneficial effects seemed to be mediated by a downregulation of calpain activity, thereby drastically reducing the formation of mHtt fragments and aggregates, and increasing soluble mHtt levels. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Conclusions&lt;/st&gt; Our study reveals new insights into olesoxime’s mechanism of action and highlights olesoxime as a novel tool for reducing toxic mHtt fragments. &lt;/sec&gt;
C06 Motor, Emotional And Cognitive Phenotyping Of Bachd Rats
2014-09-01

&lt;sec&gt;&lt;st&gt;Background&lt;/st&gt; Huntington disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. Patients affected by HD are impaired in motor and cognitive abilities and present neuropsychiatric symptoms. BACHD rats are a model of HD expressing the full length mutant human HTT under the control of the human HTT promoter.AimThe purpose of this study was to phenotype BACHD rats for anxiety, cognition and motor functionality. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Methods&lt;/st&gt; BACHD rats and WT controls, between 1 and 6 months of age, were subjected to open field (OF), elevated plus maze (EPM), passive avoidance (PA), and rotarod tests. Body weight measurements were taken once a month. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Results&lt;/st&gt; BACHD rats, compared to controls, showed: decreased time spent in the inner area as well as lower number of zone transitions in OF at 1 and 3 months; decreased distance and speed in OF at 3 months; alterations in EPM behaviour at 4 months; unchanged emotional and associative learning at 6 months and progressively impaired motor coordination starting from month 2. Body weight did not change throughout the experiment. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Conclusions&lt;/st&gt; The impairment in motor function as well as the behavioural alterations indicates that BACHD rats may be a model representative of the human disease. &lt;/sec&gt;
Different roles for PI3Kγ and δ in asthma
2014-09-01

Background: The predominantly haematopoeticaly expressed class I PI3-kinases γ and δ have been shown to be important in the development of asthma bronchiale. So far, it is not clear which specific roles these two PI3Ks play in asthma. Aim: To determine the biological function of PI3Kγ and PI3Kδ in asthma. Methods: We examined C57BL/6N mice deficient for the catalytic subunit of PI3Kγ and δ, i.e. p110γ and p110δ, together with their WT littermates in an experimental ovalbumin-induced asthma model. Severity of asthma was analysed by measuring lung functions using the isolated perfused mouse lung. Cellular changes were analysed by collecting BAL fluid (BALf) and lung tissue by flow cytometry. Results: Ovalbumin-induced asthma resulted in a significant increase in AHR upon methacholine challenge in WT mice and a significant inflammation in WT lungs. Interestingly, measurement of AHR in both KO mouse models revealed no reduction. However, analysis of BALf showed a significant reduction of eosinophils, neutrophils and T cells in p110γ and p110δ KO mice. Analysis of lung tissue of asthmatic mice revealed elevated cell counts in p110γ KO lungs only. In p110γ KO mice levels of neutrophils were significantly increased in comparison to WT, whereas in p110δ KO neutrophils and eosinophils were significantly reduced. IgE levels were elevated in asthmatic p110γ KO mice. Conclusion: Despite our observation, that deficiency for p110γ or p110δ in asthmatic mice produces different inflammatory patterns the AHR is not reduced in both models. Reduced cell counts in BALf of p110γ KO mice seemed to be caused by an interference with diapedesis, whereas reduced cell counts in p110δ KO mice may be caused by a reduced differentiation of inflammatory cells in our model.
Modulation of neutrophil functionalities by indacaterol and their relevance for chronic lung diseases
2014-09-01

Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), severe asthma and cystic fibrosis (CF), are characterized by an infiltration of neutrophils into the airways. Long-acting inhaled bronchodilators (long-acting β2-agonists, LABAs) in a regularly scheduled regimen are recommended as first-line therapy in symptomatic patients with COPD. Traditionally, a potential effect of LABAs on neutrophils has been rather neglected. Recent studies, however, revealed that LABAs may represent key modulators of neutrophil effector responses by exerting a “neutrophil-stabilising” effect, but the underlying modes of actions, in particular in the context of COPD, are poorly understood. Therefore, we comprehensively studied the effect of the LABA indacaterol on homeostasis and effector functionalities of human neutrophils. These studies demonstrate that indacaterol modulates neutrophilic surface marker expression profiles, particularly downregulates CD11b/integrin surface expression, while upregulating CD62L and preventing PMA-induced CD62L shedding. These results were validated by analysing the effect of indacaterol on COPD airway fluid-induced neutrophil activation. These studies confirmed the “neutrophil dampening” effect of indacaterol. At the cellular level, indacaterol did not impair the anti-bacterial neutrophil functions, such as phagocytosis or granule release. When viewed in combination, these data support the notion that indacterol modulates neutrophilic inflammation by dampening, but not impairing, neutrophil responses, which may have implications for the neutrophilic inflammation in COPD and other chronic lung diseases.
A grain boundary Josephson junction as a mixer to evaluate terahertz emission from intrinsic Josephson junctions
2014-09-01

To evaluate terahertz emission from intrinsic Josephson junctions, we used a YBa <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> Cu <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sub> O <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">7-δ</sub> (YBCO) grain boundary Josephson junction as a terahertz detector. Shapiro steps have been clearly seen on the current-voltage curves of the YBCO junction irradiated with the emission from either a VDI-Tx-S140 transmitter (tens of μW at 620 GHz) or a Bi <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> Sr <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> CaCu <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sub> O <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">8-x</sub> stack (25 μW at 500 GHz). While the harmonic mixing has been successfully performed with the VDI transmitter as the signal source, the evaluation of the intrinsic Josephson junctions is still undergoing.
Continuous wave terahertz radiation above 1 THz from Josephson junction arrays
2014-09-01

In recent years coherent terahertz (THz) radiation from stacks containing nearly 1000 Bi <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> Sr <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> CaCu <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> O <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">8</inf> (BSCCO) intrinsic Josephson junctions (IJJs) has attracted a lot of research interest. However, in most cases, reported have been frequencies well below 1 THz, or typically around 500 GHz, which obviously can be a bottleneck for many applications. In our experiments, by optimizing sample structures and material doping levels, we successfully observed THz radiation at fundamental frequencies above 1 THz. Reported at the conference will be the fabrication process, 600 GHz tunability, and other latest experimental results.
C07 The Influence Of Obesity And Reduced Food Intake On The Behavioural Characterisation Of The Bachd Rat Model Of Huntington Disease
2014-09-01

&lt;sec&gt;&lt;st&gt;Background&lt;/st&gt; Transgenic animals that carry the full-length HD-causing gene are generally heavier than their wild type (WT) littermates, which can be problematic during behavioural characterisation. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Aims&lt;/st&gt; To assess food intake and body composition of the BACHD rat model of Huntington disease, as well as investigating how the apparent phenotypes could affect performance in operant conditioning tests. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Methods&lt;/st&gt; Food consumption was measured longitudinally in a large group of animals housed in genotype-matched pairs. Animals under the same housing conditions were subjected to thorough dissections for body composition analysis. Further, performance in a progressive ratio test was investigated using two different food restriction protocols. In this test, rats are prompted to lever-push for a small food reward. The number of lever pushes required for reward delivery gradually increases and rats eventually lose interest, giving a measurement of motivation. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Results&lt;/st&gt; BACHD rats consumed less food compared to WT rats during most of the food consumption study, but still developed obesity. In the progressive ratio test, BACHD rats were less motivated than WT rats when both were deprived to 85% of their respective free-feeding body weights. Such a phenotype is of interest, as it could be an indicator of apathy, a common symptom among HD patients. However, the rats were equally motivated when the deprivation level of the WT rats has been adjusted so that their apparent food interest was equal to that of the BACHD rats. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Conclusions&lt;/st&gt; The reduced motivation initially seen among BACHD rats was most likely caused by a difference in hunger, rather than a psychological deficit. This was in turn probably connected to their obesity and lower food intake. This should be taken into consideration when working with behavioural characterisation of BACHD rats and other disease models with similar body composition and food intake phenotypes. &lt;/sec&gt;
B21 Characterisation Of Mice Overexpressing Mutant Huntingtin Lacking The Spine Morphogenesis Regulator Kalirin-7
2014-09-01

&lt;sec&gt;&lt;st&gt;Background&lt;/st&gt; Kalirin-7, a postsynaptic density protein which interacts with the huntingtin-associated-protein-1, has several common interactors with huntingtin as PSD95 and NMDAR2B. Kalirin-7 is important for the generation and maintenance of synaptic dendrites and glutamatergic synapses. Glutamatergic N-methyl-D-aspartate receptor (NMDAR)-mediated excitotoxicity has been implicated in Huntington’s disease (HD) pathophysiology for a long time. But the mechanisms mediating NMDAR toxicity in HD are still not clear. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Aim&lt;/st&gt; In this study,we investigated the effect of kalirin-7 deficiency in a HD mouse model &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Methods&lt;/st&gt; Kalirin-7 knockout (Kal7KO) mice were crossbred with a transgenic huntington mouse model (YAC128) carrying a YAC construct with the fulllength human huntingtin with 128CAG repeats. Male mice underwent a behavioural characterisation including activity, motor learning, cognition and anxiety testing. Protein biochemistry and histology were used to assess effects of kalirin-7-deficiency on huntingtin aggregation, glutamate receptor subunit levels and synapse morphology in cortex and striatum. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Results&lt;/st&gt; Kalirin-7 deficiency does not affect the motor performance of YAC128 mice on the rotarod nor does it influence activity in an automated home cage system. Interestingly, Kalirin-7 deficiency reduces anxiety of YAC128 on the elevated plus maze. Spatial learning, memory or relearning in YAC128 mice in a simple swimming test are not modulated by the lack of Kalirin-7. On protein level, Kalirin-7 deficiency leads to the upregulation of larger Kalirin isoforms in YAC128 mice whereas levels of NMDAR subunits are not affected. The aggregate load of YAC128 mice is not changed by lack of kalirin-7. Moreover, the absence of Kalirin-7 does not change nor cause a difference in synapse morphology of YAC128 mice. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Conclusions&lt;/st&gt; Kalirin-7 deficiency specifically influences the anxiety phenotype of YAC128 mice but does not affect aggregate load or NMDAR toxicity linked parameters. &lt;/sec&gt;
B05 New Light On The Role Of Calpain-mediated Proteolysis Of Mutant Huntingtin
2014-09-01

&lt;sec&gt;&lt;st&gt;Background&lt;/st&gt; Calpains (CAPNs), a class of intracellular calcium-dependent cysteine proteases, belong to the group of proteolytic enzymes which have been associated with the cleavage of mutant huntingtin (Htt), the source for toxic fragments of the disease protein. As excitation-induced calcium influx occurring in neurons can activate CAPNs and excitotoxicity represents an important factor in the pathomechanism of Huntington’s disease (HD), these proteases might explain the neuronal determination of the disease. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Aims&lt;/st&gt; To improve our knowledge on the involvement of CAPNs in the molecular mechanism of HD pathogenesis by examining the impact of different members of the CAPN system and by dissecting linked activation pathways. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Methods&lt;/st&gt; The CAPN system and proteolytic fragmentation of Htt were analysed in different &lt;it&gt;in vitro&lt;/it&gt;and &lt;it&gt;in vivo&lt;/it&gt;models of HD via protein biochemical and calcium imaging techniques. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Results&lt;/st&gt; We observed an over-activation of the CAPN system in cell and mouse models of HD. Activation of CAPNs in cell-free and cell-based assays promoted the fragmentation of wild type and mutant Htt generating specific N- and C-terminal fragments. Conversely, suppressing CAPN activity using specific inhibitors improved the viability of STHdh Q111 cells. These results stress the importance of CAPNs on mutant Htt cleavage and disease development. &lt;/sec&gt; &lt;sec&gt;&lt;st&gt;Conclusions&lt;/st&gt; Our enhanced understanding of calpain-mediated proteolysis as a key event in the molecular pathogenesis of HD, will promote the quest for new therapeutical targets as a treatment for this fatal disease. &lt;/sec&gt;
C05 Differential-reinforcement-of-low-rates-of-responding-task Performance In A Transgenic Rat Model Of Huntington Disease
2014-09-01

&lt;sec&gt; Psychiatric changes, dementia and motor dysfunction are hallmarks of Huntington disease (HD), a neurodegenerative disorder genetically characterised by the presence of expanded CAG repeats in the HTT gene.The behavioural characterisation of a valid rodent model for HD is critical, especially in light of the development of therapeutic strategies for HD. BACHD transgenic rats, carrying the human full length mutated HTT (97 CAG-CAA repeats) display a robust, early onset and progressive HD-like phenotype including motor deficits and anxiety-related symptoms. We evaluated the impulsive action (IA), defined as the inability to withhold a prepotent motor response.IA of 5 months old BACHD rats was assessed using the DRL (Differential Reinforcement of Low rates of responding task). Rats were trained progressively through a series of two reinforcement schedules (DRL-5 and -10 s) that required them to withhold responding for the appropriate amount of time before a lever press was reinforced. Relative to controls, BACHD rats displayed a decrease in response efficiency during DRL-10. This lack was not present during the DRL-5 schedule, showing that BACHD rats can withhold an instrumental response only for short periods of time. We also observed that BACHD rats displayed deficits in behavioural inhibition (i.e. increased responding during non-reinforced periods) that were mainly evident during the ‘burst’ (0–2s inter response time, IRT) in the DRL-10 schedule.Taken together, these data suggest that deficits in the ability to inhibit lever press responding at increasing IRTs predict greater impulsive action of this transgenic rat model of Huntington’s disease. &lt;/sec&gt;