Miracle-dz/UniFAR-FTUs huggingface dataset:
Integrated chip‐based physiometer for automated fish embryo toxicity biotests in pharmaceutical screening and ecotoxicology

Transgenic zebrafish (Danio rerio) models of human diseases have recently emerged as innovative experimental systems in drug discovery and molecular pathology. None of the currently available technologies, however, allow for automated immobilization and treatment of large numbers of spatially encoded transgenic embryos during real‐time developmental analysis. This work describes the proof‐of‐concept design and validation of an integrated 3D microfluidic chip‐based system fabricated directly in the poly(methyl methacrylate) transparent thermoplastic using infrared laser micromachining. At its core, the device utilizes an array of 3D micromechanical traps to actively capture and immobilize single embryos using a low‐pressure suction. It also features built‐in piezoelectric microdiaphragm pumps, embryo‐trapping suction manifold, drug delivery manifold, and optically transparent indium tin oxide heating element to provide optimal temperature during embryo development. Furthermore, we present design of the proof‐of‐concept off‐chip electronic interface equipped with robotic servo actuator driven stage, innovative servomotor‐actuated pinch valves, and embedded miniaturized fluorescent USB microscope. Our results showed that the innovative device has 100% embryo‐trapping efficiency while supporting normal embryo development for up to 72 hr in a confined microfluidic environment. We also showed data that this microfluidic system can be readily applied to kinetic analysis of a panel of investigational antiangiogenic agents in transgenic zebrafish lines. The optical transparency and embryo immobilization allow for convenient visualization of developing vasculature patterns in response to drug treatment without the need for specimen re‐positioning. The integrated electronic interfaces bring the lab‐on‐a‐chip systems a step closer to realization of complete analytical automation. © 2014 International Society for Advancement of Cytometry
Cellular response to empty and palladium‐conjugated amino‐polystyrene nanospheres uptake: A proteomic study

Amino polystyrene nanospheres are shown to be efficient and controllable delivery devices, capable of transporting several bioactive cargoes. Recently, the design of a new device for prodrug activation, using these nanospheres with palladium encapsulated onto them, has been developed successfully. To study the influence of the cellular uptake of these nanodevices, we investigated the cellular response of human embryonic kidney cells (HEK‐293T) and murine fibroblasts (L929) treated with empty or palladium‐conjugated amino polystyrene nanospheres. To identify differentially expressed proteins, we performed an exhaustive proteomic analysis. In accordance with genomic data previously obtained, the uptake of the empty nanospheres did not induce significant variation in protein expression levels. Following the treatment with palladium‐conjugated nanospheres, some changes in protein profiles in both cell lines were observed; these alterations affect proteins involved in cell metabolism and intracellular transport. No key regulator of the cell cycle result was differentially expressed after the treatment, confirming that these innovative drug delivery systems are harmless and well tolerated by the cells.
Recent molecular and therapeutic advances in B‐cell non‐Hodgkin lymphoma in children

Paediatric B‐cell non‐Hodgkin lymphoma (B‐NHL) compromises a heterogeneous group of histological entities of which Burkitt lymphoma is the most common. In resource‐rich countries, the expected cure rate is in excess of 85% with application of risk‐adapted short intensive chemotherapy. In recent years, large paediatric cooperative group trials have sought to improve upon outcomes by decreasing the intensity of cytotoxic treatment as well as introducing targeted therapies, such as rituximab. These efforts have resulted in excellent outcomes, however there remains a group of high‐risk patients for whom novel treatment approaches are needed. In this review, we will summarize the recent paediatric clinical trials in B‐NHL as well as compare treatment approaches across the major cooperative groups. We will also highlight our current understanding of the molecular biology of paediatric B‐NHL with a focus on how this may help guide future rational targeted therapy.
A non‐inferiority test for diagnostic accuracy based on the paired partial areas under ROC curves

Non‐inferiority is a reasonable approach to assessing the diagnostic accuracy of a new diagnostic test if it provides an easier administration or reduces the cost. The area under the receiver operating characteristic (ROC) curve is one of the common measures for the overall diagnostic accuracy. However, it may not differentiate the various shapes of the ROC curves with different diagnostic significances. The partial area under the ROC curve (PAUROC) may present an alternative that can provide additional and complimentary information for some diagnostic tests which require false‐positive rate that does not exceed a certain level. Non‐parametric and maximum likelihood methods can be used for the non‐inferiority tests based on the difference in paired PAUROCs. However, their performance has not been investigated in finite samples. We propose to use the concept of generalized p‐value to construct a non‐inferiority test for diagnostic accuracy based on the difference in paired PAUROCs. Simulation results show that the proposed non‐inferiority test not only adequately controls the size at the nominal level but also is uniformly more powerful than the non‐parametric methods. The proposed method is illustrated with a numerical example using published data. Copyright © 2007 John Wiley & Sons, Ltd.
Automatic head pose estimation with Synchronized sub manifold embedding and Random Regression Forests

Head pose can indicate the eye-gaze direction and face toward which is an important part of human motion estimation and understanding. Due to physical factors of the camera, shooting environment, as well as the appearance change of humanity, the head pose estimation becomes a challenging task. Synchronization sub manifold embedding can find the internal structure of nonlinear data for nonlinear dimensionality reduction and random regression forests can make the nonlinear function mapping for getting the right head pose. In this paper, the advantages of these two algorithms are combined with a method for solving the head pose estimation. Data collection step, the depth data come from the 3D sensor; and training data step, the data is using the local linear structure for label and using a statistical model for synchronization pose samples. Meanwhile the experimental results on a publicly available database prove that the proposed algorithm can achieve state-of-the-art performance while the current estimate has a faster speed and higher robustness when large range of pose changes and outperforms existing.
Impact of Alternaria toxins on CYP1A1-and GST-expression in human tumour cells

Die Alternaria Toxine Alternariol (AOH) und Alternariolmonomethylether (AME) wurden von der EFSA auf die Liste der Mykotoxine gesetzt, die noch einer weitgehenden toxikologische Untersuchungen bedurfen, um eine bessere Risikobewertung fur Mensch und Tier zu ermoglichen. Der Konsum von Alternaria spp. kontaminierten Getreide wurde in Linxian, China in Verbindung mit Osophaguskarzinom gebracht. In bereits veroffentlichten Daten von Fehr (2008) und Schreck et al. (2011) wurde die Induktion von CYP1A1 durch Alternaria Toxine beschrieben, was zu weiteren Untersuchungen uber die Rolle des Arylhydrocarbon Rezeptors (AhR) in der AME- und AOH-vermittelten CYP1A1 Induktion in humanen Osophagus Karzinomzellen (KYSE510) veranlasste. Die Frage, ob die Induktion von CYP1A1 mRNA durch Mykotoxine Ah-Rezeptor vermittelt ablauft, wurde in zwei verschiedene Ansatze geklart. Zuerst wurden AhR-supprimierte Osophagus Karzinomzellen mithilfe der RNAi Technologie generiert, die ein geeignetes Modell fur die Untersuchung des Einfluss der Alternaria Toxine auf CYP1A1 Genexpression darstellten. Zweitens wurde der Ah-Rezeptor in KYSE510 Zellen durch eine Vorbehandlung mit 10 µM MNF inhibiert. Die signifikante Induktion von CYP1A1 in AhR-exprimierenden Zellen (nicht-transfizierte und dsRNA-transfizierte (Negativkontrolle) KYSE510) nach 24 h war abhangig von der applizierten AME- und AOH-Konzentration. Keine Anderungen der CYP1A1 Transkripte wurden bei geringen Mykotoxinkonzentrationen (≤ 0.1 µM) beobachtet, wobei hohere Konzentrationen (≥ 1 µM) eine maximale, 2.5-fache Induktion fur AME und eine 8-fache Induktion fur AOH hervor riefen. Vergleichbare Ergebnisse in beiden Zelltypen lassen auf keinerlei Veranderungen durch die Transfektion der KYSE510, in Hinblick auf ihre Reaktion auf AME und AOH, schliesen. In AhR-supprimierten (AhR-siRNA transfizierten) KYSE510 Zellen waren die CYP1A1 mRNA Level nach der Inkubation mit AME und AOH im Vergleich zu den Kontrollzellen signifikant erniedrigt, was fur die AhR-Abhangigkeit der CYP1A1 Induktion spricht. Das Absinken der CYP1A1 Transkripte unterhalb das endogene Level bei hohen Konzentrationen (10 µM AME, 50 µM AOH) lasst auf die Interferenz eines bisher unbekannten Signalweges vermuten. Die Ergebnisse die mithilfe MNF-inhibierter KYSE510 Zellen ermittelt wurden, sind generell in Einklang mit denen, die mit transient siRNA-transfizierten Zellen erzielt wurden und sprechen fur eine entscheidende Rolle des Ah-Rezeptors in der AME-vermittelten CYP1A1 Induktion. Glutathion-S-Transferasen (GST) gehoren zu den Phase II Enzymen und tragen einen beachtlichen Anteil zur Detoxifizierung von Xenobiotika bei. Nach der Etablierung und Optimierung des GST Assays nach Habig et al. (1973), wurde der Einfluss von AME und AOH auf die GST Aktivitaten in humanen Kolonkarzinomzellen (HT29) untersucht. Ein marginaler, aber doch signifikant erhohter Anstieg der GST Aktivitat bei hohen AOH Konzentrationen (10 µM, 50 µM) lasst auf einen minimalen Beitrag dieser Enzyme in der Detoxifizierung beider Alternaria Toxine schliesen.
Does Long-Term Itraconazole Prophylaxis Result in In Vitro Azole Resistance in Mucosal Candida albicans Isolates from Persons with Advanced Human Immunodeficiency Virus Infection?

ABSTRACT The effects of prolonged itraconazole exposure on the susceptibility of Candida albicans isolates to itraconazole and fluconazole have not been well characterized. A recent placebo-controlled study of long-term itraconazole antifungal prophylaxis in persons with advanced human immunodeficiency virus infection afforded the opportunity to address this question. MucosalCandida sp. isolates were obtained from subjects who developed oropharyngeal or esophageal candidiasis, and in vitro susceptibilities of the last isolate obtained at removal from the study as a prophylaxis failure were compared in itraconazole and placebo recipients. More subjects in the placebo group (74 of 146 [51%]) than in the itraconazole group (51 of 149 [34%]) developed mucosal candidiasis (P = 0.004). A total of 112 isolates were recovered from 56 of the 74 (76%) subjects with mucosal candidiasis assigned to the placebo group, compared to 97 isolates from 45 of the 51 (88%) subjects in the itraconazole group. C. albicansaccounted for 98% of isolates in the placebo group and 89% of isolates in the itraconazole group. The itraconazole MIC at which 50% of the isolates tested were inhibited (MIC50) for last-episode isolates from the itraconazole group was 0.125 μg/ml compared to 0.015 μg/ml for the placebo group subjects,P = 0.0001. The MIC50 of fluconazole for the last isolates from the itraconazole group was 1.5 μg/ml compared to 0.5 μg/ml for the placebo subjects (P = 0.005). A lower proportion of isolates recovered from subjects on itraconazole therapy were classified as susceptible to itraconazole (63%) compared to isolates from the placebo group (96%) (P = 0.001). Similarly, a lower proportion of C. albicans isolates from subjects on itraconazole therapy were susceptible to fluconazole (78%) compared to isolates from the placebo group (96%) (P= 0.01). Also, the proportion of isolates that were not fully susceptible to itraconazole or fluconazole was greater in patients assigned to the itraconazole group than the placebo group (itraconazole susceptibility, 37 and 4%, respectively (P = 0.001); fluconazole susceptibility, 23 and 4%, respectively (P = 0.01). In conclusion, long-term itraconazole prophylaxis in patients with AIDS is associated with reduction in susceptibility to itraconazole and cross-resistance to fluconazole.
The rise and fall of the mountain hare (Lepus timidus) during Pleistocene glaciations: expansion and retreat with hybridization in the Iberian Peninsula

The climatic fluctuations during glaciations have affected differently arctic and temperate species. In the northern hemisphere, cooling periods induced the expansion of many arctic species to the south, while temperate species were forced to retract in southern refugia. Consequently, in some areas the alternation of these species set the conditions for competition and eventually hybridization. Hares in the Iberian Peninsula appear to illustrate this phenomenon. Populations of Iberian hare (Lepus granatensis), brown hare (Lepus europaeus) and broom hare (Lepus castroviejoi) in Northern Iberia harbour mitochondrial haplotypes from the mountain hare (Lepus timidus), a mainly boreal and arctic species presently absent from the peninsula. To understand the history of this past introgression we analysed sequence variation and geographical distribution of mitochondrial control region and cytochrome b haplotypes of L. timidus origin found in 378 specimens of these four species. Among 124 L. timidus from the Northern Palaearctic and the Alps we found substantial nucleotide diversity (2.3%) but little differentiation between populations. Based on the mismatch distribution of the L. timidus sequences, this could result from an expansion at a time of temperature decrease favourable to this arctic species. The nucleotide diversity of L. timidus mtDNA found in Iberian L. granatensis, L. europaeus and L. castroviejoi (183, 70 and 1 specimens, respectively) was of the same order as that in L. timidus over its range (1.9%), suggesting repeated introgression of multiple lineages. The structure of the coalescent of L. granatensis sequences indicates that hybridization with L. timidus was followed by expansion of the introgressed haplotypes, as expected during a replacement with competition, and occurred when temperatures started to rise, favouring the temperate species. Whether a similar scenario explains the introgression into Iberian L. europaeus remains unclear but it is possible that it hybridized with already introgressed L. granatensis.
Purification and characterization of detergent stable alkaline protease from Bacillus amyloliquefaciens SP1 isolated from apple rhizosphere

A thermostable extracellular alkaline protease producing Bacillus amyloliquefaciens SP1 was isolated from apple rhizosphere having multifarious plant growth promoting activities. Strain SP1 was purified to 6.48‐fold using four‐step purification protocol and characterized in detail for its robustness and ecofriendly application in leather and detergent industries. Structural analysis revealed that the protease was monomeric and had a molecular weight of 43 kDa. It exhibited optimum activity at 60°C in alkaline environment (pH 8.0) and stable in the presence of surfactants and oxidizing agents. Enzyme was thermostable at 50°C and retained more than 70% activity after 30 min incubation. It has shown stain removal property and dehairing of goat skin without chemical assistance and hydrolyzing fibrous proteins. This protease showed Km of 0.125 mg ml−1 and Vmax of 12820 μg ml−1 indicating its excellent affinity and catalytic role. Thermal inactivation of the pure enzyme followed first‐order kinetics. The half life of the pure enzyme at 50, 60, and 65°C was 77, 19.80, and 13.33 min, respectively. The activation energy was 37.19 KJ mol−1. The results suggest that the B. amyloliquefaciens SP1 has a potential application in different industries.
Observation of Fine Structure in Nuclear Level Densities and gamma -Ray Strength Functions.

An iterative procedure for simultaneous extraction of fine structure in the level density and the {gamma}-ray strength function from a set of primary {gamma}-ray spectra has been developed. Data from the reactions {sup 163}Dy({sup 3}He,{alpha}{gamma}){sup 162}Dy and {sup 173}Yb({sup 3}He,{alpha}{gamma}){sup 172}Yb reveal steplike enhancements in the level density in the region below 5 MeV and peaks in the {gamma}-ray strength function at low {gamma} energy ({ital E}{sub {gamma}}{approx_equal}2{endash}3.5 MeV). Tentative physical interpretations are presented. {copyright} {ital 1996 The American Physical Society. }
On-line load test for induction machine stator inter-turn fault detection under stator electrical asymmetries

The stator inter-turn faults and stator electrical asymmetries such as stator resistance and inductance unbalance generate similar negative sequence current signatures in the induction machine. Hence the stator inter-turn fault is one of the most difficult faults to discriminate and detect in an induction machine. Discrimination of the stator inter-turn fault from stator electrical asymmetry essentially helps to arrange maintenance in a proper schedule. In this paper, a simple on-line load test is proposed to detect the presence of stator inter-turn fault under stator electric asymmetrical condition of the machine. The proposed test is based on the observation of steady-state stator current locus with change in load. The test procedure does not require additional sensors, training and database, past history of the machine and speed measurement. It is also applicable to any unknown machine. This paper presents analytical studies and experiments on a faulted and electrically asymmetrical motors to confirm the simplicity and effectiveness of the proposed load test.
Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells

The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer has generated an opportunity for a novel target-based therapy. Here, we explore the therapeutic potential of 2 FGFR inhibitors, the multikinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of endometrial cancer. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle, and apoptosis using a panel of 20 molecularly characterized human endometrial cancer cell lines. Anchorage-independent growth was studied using soft agar assays. In vivo studies were conducted using endometrial cancer xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared with their FGFR2 wild-type counterparts (P = 0.073 and P = 0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell-cycle arrest, and significantly increased apoptosis in FGFR2-mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2-mutant endometrial cancer cells, but the activity of dovitinib was less restricted to FGFR2-mutant lines when compared with NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2-mutated endometrial cancer xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type endometrial cancer xenograft models including complete tumor regressions in a long-term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2-mutated endometrial cancer. Dovitinib may have antitumor activity in endometrial cancer beyond FGFR2-mutated cases and may permit greater flexibility in patient selection. Mol Cancer Ther; 12(5); 632–42. ©2013 AACR.
Crocetin from the tubular calyx of Nyctanthes arbor-tristis

A carotenoid aglycone Ag-NY1 was isolated from the orange coloured tubular calyx of flowers of Nyctanthes arbor-tristis. The elucidation of the structure through a detailed spectroscopic study revealed that the carotenoid molecule is crocetin, which is the major aglycone present in the stigma of Crocus sativus. The compound exhibited a good membrane stabilising activity as compared to the corresponding glycoside crocin.
Decomposing a Graph Into Expanding Subgraphs Guy Moshkovitz

A paradigm that was successfully applied in the study of both pure and algorithmic problems in graph theory can be colloquially summarized as stating that any graph is close to being the disjoint union of expanders. Our goal in this paper is to show that in several of the instantiations of the above approach, the quantitative bounds that were obtained are essentially best possible. Three examples of our results are the following: • A classical result of Lipton, Rose and Tarjan from 1979 states that if F is a hereditary family of graphs and every graph in F has a vertex separator of size n/(log n), then every graph in F has O(n) edges. We construct a hereditary family of graphs with vertex separators of size n/(log n)1−o(1) such that not all graphs in the family have O(n) edges. • Trevisan and Arora-Barak-Steurer have recently shown that given a graph G, one can remove only 1% of its edges to obtain a graph in which each connected component has good expansion properties. We show that in both of these decomposition results, the expansion properties they guarantee are essentially best possible, even when one is allowed to remove 99% of G’s edges. • Sudakov and the second author have recently shown that every graph with average degree d contains an n-vertex subgraph with average degree at least (1−o(1))d and vertex expansion 1/(log n). We show that one cannot guarantee a better vertex expansion even if allowing the average degree to be O(1). The above results are obtained as corollaries of a new family of graphs which we construct in this paper. These graphs have a super-linear number of edges and nearly logarithmic girth, yet each of their subgraphs has (optimally) poor expansion properties.
Total synthesis of syringolin A and improvement of its biological activity.

The development process for syringolin A analogues having improved proteasome inhibitory and antitumor activity is described. The strategy was to first establish a convergent synthesis of syringolin A using a rare intramolecular Ugi three-component reaction in the last stage of the synthesis, so as to gain access toa set of structure-based analogues. The inhibitory activity of chymotrypsin-like activity of 20S proteasome was largely improved by targeting the S3 subsite of the β5 subunit. Cytotoxic activity was also improved by installing the membrane-permeable substituent. These biological properties are comparable to those of bortezomib, a clinically used first-line proteasome inhibitor.