Miracle-dz/UniFAR-FTUs huggingface dataset:
VER-246608, a novel pan-isoform ATP competitive inhibitor of pyruvate dehydrogenase kinase, disrupts Warburg metabolism and induces context-dependent cytostasis in cancer cells

Pyruvate dehydrogenase kinase (PDK) is a pivotal enzyme in cellular energy metabolism that has previously been implicated in cancer through both RNAi based studies and clinical correlations with poor prognosis in several cancer types. Here, we report the discovery of a novel and selective ATP competitive pan-isoform inhibitor of PDK, VER-246608. Consistent with a PDK mediated MOA, VER-246608 increased pyruvate dehydrogenase complex (PDC) activity, oxygen consumption and attenuated glycolytic activity. However, these effects were only observed under D-glucose-depleted conditions and required almost complete ablation of PDC E1α subunit phosphorylation. VER-246608 was weakly anti-proliferative to cancer cells in standard culture media; however, depletion of either serum or combined D-glucose/L-glutamine resulted in enhanced cellular potency. Furthermore, this condition-selective cytostatic effect correlated with reduced intracellular pyruvate levels and an attenuated compensatory response involving deamination of L-alanine. In addition, VER-246608 was found to potentiate the activity of doxorubicin. In contrast, the lipoamide site inhibitor, Nov3r, demonstrated sub-maximal inhibition of PDK activity and no evidence of cellular activity. These studies suggest that PDK inhibition may be effective under the nutrient-depleted conditions found in the tumour microenvironment and that combination treatments should be explored to reveal the full potential of this therapeutic strategy.
Cellular toxicity of expanded RNA repeats: focus on RNA foci

Discrete and punctate nuclear RNA foci are characteristic molecular hallmarks of pathogenesis in myotonic dystrophy type 1 and type 2. Intranuclear RNA inclusions of distinct morphology have also been found in fragile X-associated tremor ataxia syndrome, Huntington's disease-like 2, spinocerebellar ataxias type 8, type 10 and type 31. These neurological diseases are associated with the presence of abnormally long simple repeat expansions in their respective genes whose expression leads to the formation of flawed transcripts with altered metabolisms. Expanded CUG, CCUG, CGG, CAG, AUUCU and UGGAA repeats are associated with the diseases and accumulate in nuclear foci, as demonstrated in variety of cells and tissues of human and model organisms. These repeat RNA foci differ in size, shape, cellular abundance and protein composition and their formation has a negative impact on cellular functions. This review summarizes the efforts of many laboratories over the past 15 years to characterize nuclear RNA foci that are recognized as important triggers in the mutant repeat RNA toxic gain-of-function mechanisms of pathogenesis in neurological disorders.
Redefining Clustering for High-Dimensional Applications

Clustering problems are well-known in the database literature for their use in numerous applications, such as customer segmentation, classification, and trend analysis. High-dimensional data has always been a challenge for clustering algorithms because of the inherent sparsity of the points. Recent research results indicate that, in high-dimensional data, even the concept of proximity or clustering may not be meaningful. We introduce a very general concept of projected clustering which is able to construct clusters in arbitrarily aligned subspaces of lower dimensionality. The subspaces are specific to the clusters themselves. This definition is substantially more general and realistic than the currently available techniques which limit the method to only projections from the original set of attributes. The generalized projected clustering technique may also be viewed as a way of trying to redefine clustering for high-dimensional applications by searching for hidden subspaces with clusters which are created by interattribute correlations. We provide a new concept of using extended cluster feature vectors in order to make the algorithm scalable for very large databases. The running time and space requirements of the algorithm are adjustable and are likely to trade-off with better accuracy.
Fuzzy Based Approach for Assessing Amount of Alloy Additives in Steel Production Process

Steel production involves three basic steps. At first, the heat source is to be produced to melt the iron ore. Next in a furnace iron is melted. Lastly, to produce steel the molten iron is processed. The advantage of steel over iron is greatly enhanced strength. The properties of steel are highly reliant on the amount of alloying elements, so that their levels are carefully controlled during its manufacture. The addition of alloying elements is usually made based on the professional experience of experts and thus an operator determines the amount of alloying elements to be added to produce the steel of a particular kind. This paper presents the K-Means clustering method to assess the proportion of alloying elements that has a fuzzy nature. The simulation results show that the proposed method can be applied effectually in steel making. Keywords—alloying elements, clustering, fuzzy, steel.
Magnetic islands in the heliosheath: Properties and implications

Title of dissertation: MAGNETIC ISLANDS IN THE HELIOSHEATH: PROPERTIES AND IMPLICATIONS Kevin Schoeffler, Doctor of Philosophy, 2012 Dissertation directed by: Professor James F. Drake Department of Physics In the heliosheath there are sectors of magnetic fields separated by current sheets thinner than the ion inertial length and thus subject to the tearing instability. This instability allows the development of magnetic islands that grow due to magnetic reconnection. Using PIC (particle-in-cell) simulations, we show that these islands are relevant because they quickly grow to fill up the space between the sectors and in the meanwhile generate temperature anisotropies, accelerate particles, and form instabilities based on the anisotropies. The plasma β (the ratio of the plasma pressure to the magnetic pressure) of a system can have a large effect on its dynamics since high β enhances the effects of pressure anisotropies. In our PIC simulations, we investigate a system of stacked current sheets that break up into magnetic islands due to magnetic reconnection, which is analogous to the compressed heliospheric current sheet in the heliosheath. We find that for high β, and for realistic ion-to-electron mass ratios, only highly elongated islands reach finite size. The anisotropy within these islands prevents full contraction, leading to a final state of highly elongated islands in which further reconnection is suppressed. In the heliosheath there is evidence that these elongated islands are present. We performing a scaling of the growth of magnetic islands versus the system size. We thus determine that the islands, although reaching a final elongated state, can continue growing via the merging process until they reach the sector width. The islands achieve this size in much less time than it takes for the islands to convect through the heliosheath. We also find that the electron heating in our simulations has a strong β dependence. Particles are dominantly heated through Fermi reflection in contracting islands during island growth and merging. However, electron anisotropies support the development of a Weibel instability which impedes the Fermi acceleration of the electrons. In the heliosheath, we predict that energization of particles in general is limited by interaction with anisotropy instabilities such as the firehose instability, and by the the Weibel instability for electrons in particular. MAGNETIC ISLANDS IN THE HELIOSHEATH: PROPERTIES AND IMPLICATIONS
Automatic Sequences and Zip-Specifications

We consider infinite sequences of symbols, also known as streams, and the decidability question for equality of streams defined in a restricted format. (Some formats lead to undecidable equivalence problems.) This restricted format consists of prefixing a symbol at the head of a stream, of the stream function `zip', and recursion variables. Here `zip' interleaves the elements of two streams alternatingly. The celebrated Thue- Morse sequence is obtained by the succinct `zip-specification' M = 0 : X X = 1 : zip(X, Y) Y = 0 : zip(Y, X) The main results are as follows. We establish decidability of equivalence of zip-specifications, by employing bisimilarity of observation graphs based on a suitably chosen cobasis. Furthermore, our analysis, based on term rewriting and coalgebraic techniques, reveals an intimate connection between zip-specifications and automatic sequences. This leads to a new and simple characterization of automatic sequences. The study of zip-specifications is placed in a wider perspective by employing observation graphs in a dynamic logic setting, yielding yet another alternative characterization of automatic sequences. By the first characterization result, zip-specifications can be perceived as a term rewriting syntax for automatic sequences. For streams σ the following are equivalent: (a) σ can be specified using zip; (b) σ is 2-automatic; and (c) σ has a finite observation graph using the cobasis (hd, even, odd). Here even and odd are defined by even(a : s) = a : odd(s), and odd(a : s) = even(s). The generalization to zip-k specifications (with zip-k interleaving k streams) and to k-automaticity is straightforward. As a natural extension of the class of automatic sequences, we also consider `zip-mix' specifications that use zips of different arities in one specification. The corresponding notion of automaton employs a state-dependent input-alphabet, with a number representation (n)A = dm . d0 where the base of digit di is determined by the automaton A on input di-1 . d0. Finally we show that equivalence is undecidable for a simple extension of the zip-mix format with projections analogous to even and odd.
Effectiveness of Maintenance Electroconvulsive Therapy in Rapid-Cycling Bipolar Disorder

Objectives: To evaluate the effectiveness of maintenance electroconvulsive therapy (m-ECT) in rapid-cycling (RC) bipolar disorder (BPD) patients. Methods: A population sample of 14 patients with BPD (type I or II) and an RC course were treated with m-ECT. Patients had not responded to previous treatments. Sessions of m-ECT were administered monthly and then gradually decreased in frequency upon amelioration of the course. Response to treatment was evaluated as the difference between days of illness before and after the treatment for the same 2 periods in a 2-year time frame. Results: We treated 14 patients with RC BPD (mean age, 46 years; 71% women; 64% with BPD type I). Mean treatment duration was 21 months. All patients improved during treatment. Eight (58%) did not relapse during the 2-year follow-up period, and 6 (42%) relapsed one time each year. Illness duration decreased 13-fold from 304 to 24 days of illness per year, and illness-free intervals increased from 52 to 334 d/yr (all P < 0.0001). A multivariate analysis showed that the factors independently associated with improvement were male sex, diagnosis of type II BPD, hyperthymic temperament, and younger age. Conclusions: Despite patients' clinical severity, we recorded a highly significant reduction of illness morbidity. The m-ECT had a real, long-term prophylactic effect in treating a severe clinical course such as that with rapid cycles. Notwithstanding, our study has to be considered preliminary and carries some limitations, such as its naturalistic design and relatively low number of patients recruited.
Left ventricular longitudinal strain in soccer referees

Along the years, the analysis of soccer referees perfomance has interested the experts and we can find several types of studies in literature using in particular cardiac imaging. The aim of this retrospective study was to observe relationship between VO2max uptake and some conventional and not-conventional echocardiographic parameters. In order to perform this evaluation, we have enrolled 20 referees, belonging to Italian Soccer Referees' Association and we have investigated cardiovascular profile of them. We found a strong direct relationship between VO2max and global longitudinal strain of left ventricle assessed by means of speckle tracking echocardiographic analysis (R2=0.8464). The most common classic echocardiographic indexes have showed mild relations (respectively, VO2max vs EF: R2=0.4444; VO2max vs LV indexed mass: R2=0.2268). Therefore, our study suggests that longitudinal strain could be proposed as a specific echocardiographic parameter to evaluate the soccer referees performance.
Determination of mode number using two laser combs with large difference in repetition rate

Two Er-fiber laser combs with repetition frequency of 500 MHz and 400 MHz are used to measure the frequency of a free-running external cavity diode laser. The mode number is determined by operating the 500 MHz comb at two different repetition rates while keeping the repetition rate of the 400 MHz comb unchanged. A monochromator measures the wavelength of the ECDL to offers an approximate mode number to help determining the mode number shift between the two repetition rates of the 500 MHz comb. The mode number of the beating comb line can be determined with short average time of 1 s.
Lyrics-to-Audio Alignment and its Application

Automatic lyrics-to-audio alignment techniques have been drawing attention in the last years and various studies have been made in this field. The objective of lyrics-to-audio alignment is to estimate a temporal relationship between lyrics and musical audio signals and can be applied to various applications such as Karaoke-style lyrics display. In this contribution, we provide an overview of recent development in this research topic, where we put a particular focus on categorization of various methods and on applications.
Long-term follow-up after weight management in obese cats*

Feline obesity is a prevalent medical disease and the main therapeutic strategy is dietary energy restriction. However, at present there are no data regarding long-term outcome in this species. The purpose of the present study was to investigate if, as in other species, some cats regain weight following successful weight loss, and to identify any influencing factors in a cohort of client-owned cats with naturally occurring obesity. Twenty-six cats were included, all of which had successfully completed a weight management programme. After weight loss, cats were periodically monitored. The median duration of follow-up was 954 d (72–2162 d). Ten cats (39 %) maintained their completion weight (±5 %), four (15 %) lost >5 % additional weight and 12 (46 %) gained >5 % weight. Seven of the rebounding cats (58 %) regained over 50 % of their original weight lost. Older cats were less likely to regain weight than younger cats (P = 0·024); with an approximately linear negative association between the cat's age and the amount of weight regained (Kendall's τ = −0·340, P = 0·016). Furthermore, cats whose energy intake during weight loss was greater were also more likely to regain weight (P = 0·023). When the characteristics of weight regain in cats were compared with those from a similar cohort of dogs, cats that rebounded were more likely to regain >50 % of the weight they had lost. These results suggest that weight regain, after successful weight loss, is common in obese cats, and that young cats (<7 years of age) are most at risk.
Supportive Interaction Between Cell Survival Signaling and Angiocompetent Factors Enhances Donor Cell Survival and Promotes Angiomyogenesis for Cardiac Repair

Akt is a major cell survival and angiogenic mediator downstream of angiopoietin-1 (Ang-1)/Tie-2 signaling pathway. We hypothesize that transplantation of mesenchymal stem cells (MSCs) co-overexpressing Ang-1 and Akt lead to better prognosis. Ang-1 and Akt genes were adenovirally transduced into MSCs from male Fischer rats. Cytoprotective effects of transgene overexpression in vitro were assessed by exposure of cells to 8 hours of anoxia. TUNEL and measurement of lactate dehydrogenase showed that MSCs co-overexpressing Ang-1 and Akt (MAAs) were more resistant to anoxia as compared with the nontransduced MSCs or those transduced with Ang-1 or Akt alone. For in vivo studies, after permanent coronary artery occlusion, animals were grouped (n=20/group) to receive intramyocardial injections of 70 &mgr;L of basal medium without cells (group 1) or containing 3×106 nontransduced MSCs (group 2) or MAAs (group 3). Four animals per group were euthanized on 4, 7, and 14 days after cell transplantation for molecular studies. Extensive survival of MAAs was observed in group 3, which continued to co-overexpress transgenes in rat heart at 2 weeks after cell transplantation. Immunohistology at 4 weeks revealed myogenic differentiation of donor cells at the site of cell graft. Blood vessel density was highest in the infarct and periinfarct regions in group 3 (P<0.05). Echocardiography at 4 weeks showed that heart function indices were significantly improved in group 3 (P<0.05), including ejection fraction and fractional shortening as compared with groups 1 and 2. We conclude that supportive interaction between Ang-1 and Akt during MSC transplantation gave better prognosis via enhanced cell survival, improved angiomyogenesis, and restored global cardiac function.
Role of abd-A and Abd-B in Development of Abdominal Epithelia Breaks Posterior Prevalence Rule

Hox genes that determine anteroposterior body axis formation in all bilaterians are often found to have partially overlapping expression pattern. Since posterior genes dominate over anterior Hox genes in the region of co-expression, the anterior Hox genes are thought to have no function in such regions. In this study we show that two Hox genes have distinct and essential functions in the same cell. In Drosophila, the three Hox genes of the bithorax complex, Ubx, abd-A and Abd-B, show coexpression during embryonic development. Here, we show that in early pupal abdominal epithelia, Ubx does not coexpress with abd-A and Abd-B, while abd-A and Abd-B continue to coexpress in the same nuclei. The abd-A and Abd-B are expressed in both histoblast nest cells and larval epithelial cells of early pupal abdominal epithelia. Further functional studies demonstrate that abd-A is required in histoblast nest cells for their proliferation and suppression of Ubx to prevent first abdominal segment like features in posterior segments while in larval epithelial cells it is required for their elimination. We also observed that these functions of abd-A are required in its exclusive as well as the coexpression domain with that of Abd-B. The expression of Abd-B is required in histoblast nest cells for their identity while it is dispensable in the larval epithelial cells. The higher level of Abd-B in the seventh abdominal segment, that down-regulates abd-A expression, leads this segment to be absent in males or of smaller size in females. We also show that abd-A in histoblast nest cells positively regulates expression of wingless for the formation of the abdominal epithelia. Our study reveals an exception to the rule of posterior prevalence and shows that two different Hox genes have distinct functions in the same cell, which is essential for the development of abdominal epithelia.
Prospective registration, bias risk and outcome-reporting bias in randomised clinical trials of traditional Chinese medicine: an empirical methodological study

Background Clinical trials on Traditional Chinese Medicine (TCM) should be registered in a publicly accessible international trial register and report on all outcomes. We systematically assessed and evaluated TCM trials in registries with their subsequent publications. Objective To describe the characteristics of TCM trials, estimate bias risk and outcome-reporting bias in clinical trials. Data sources and study selection Fifteen trial registries were searched from their inception to July 2012 to identify randomised trials on TCM including Chinese herbs, acupuncture and/or moxibustion, cupping, tuina, qigong, etc. Data extraction We extracted data including TCM specialty and treated disease/conditions from the registries and searched for subsequent publications in PubMed and Chinese databases. We compared information in the registries of completed trials with any publications focusing on study design, sample size, randomisation, bias risk including reporting bias from the register protocol. Results 1096 registered randomised trials were identified evaluating TCM, of which 505 were completed studies (46.1%). The most frequent conditions were pain (13.3%), musculoskeletal (11.7%), nervous (8.7%), digestive (7.1%), circulatory (6.5%), respiratory (6.3%), mental and behavioural disorders (6.2%) and cancer (6.0%). The trial register data identified parallel, phase II/III randomised trials with sample size estimations and blinding, but limited information about randomisation (sequence generation and allocation concealment). Comparing trial registration data of 115 completed trials (22.8%) with their subsequent 136 publications, inconsistencies were identified in one or more of the following: sample size (11%), outcome assessor blinding (37.5%), primary outcomes (29%) and safety (28%) reporting. Conclusions Increasing numbers of clinical trials investigating a variety of TCM interventions have been registered in international trial registries. The study design of registered TCM trials has improved in estimating sample size, use of blinding and placebos. However, selective outcome reporting is widespread and similar to conventional medicine and therefore study conclusions should be interpreted with caution.
Multiple Fault Diagnosis Based on Multiple Fault Simulation Using Particle Swarm Optimization

Fault diagnosis is extremely important to ramp up the manufacturing yield and in some cases to reduce the product debug time as well. In this paper, we have proposed a novel technique to analyze multiple fault diagnosis based on multiple fault injection. Almost all the conventional fault diagnosis method simulate one fault (among the candidate faults) at a time and based on the number of failed patterns the fault can explain, a ranking is proposed for all candidate faults. But, a single fault injection cannot manifest the effect of multiple faults that are present in the actual failed circuit. Thus, in this paper, we have injected multiple faults simultaneously, and perform an effect-cause analysis to find the possible list of faults. Experimental results prove the validation of our approach as it has high diagnosability and resolution. The proposed method runs within moderate CPU time. We have been able to run simulations to diagnose upto 10 faults in a reasonable time. However, the scheme does not put any restrictions on the number of simultaneous faults.
Influence of external optical feedback on threshold and spectral characteristics of vertical-cavity surface-emitting lasers

We report a study of the effects of external optical feedback on the threshold and spectral characteristics of VCSELs with feedback levels in the range from /spl minus/25 dB to 0 dB. A large threshold current reduction and multi-extended-cavity-mode operation have been observed. The experimental results are in good agreement with the theoretical calculations based on a compound cavity laser model. <<ETX>>