Miracle-dz/UniFAR-FTUs huggingface dataset:
Multi-targeted directed ligands for Alzheimer’s disease: design of novel lead coumarin conjugates

Abstract Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by central nervous system insults with progressive cognitive (memory, attention) and non-cognitive (anxiety, depression) impairments. Pathophysiological events affect predominantly cholinergic neuronal loss and dysfunctions of the dopaminergic system. The aim of the current study was to design multi-targeted directed lead structures based on the coumarin scaffold with inhibitory properties at two key enzymes in disease relevant systems, i.e. acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Conventional and microwave synthetic methods were utilized to synthesize coumarin scaffold-based novel morpholino, piperidino, thiophene and erucic acid conjugates. Biological assays indicated that the coumarin–morpholine ether conjugate BPR 10 was the most potent hMAO-B inhibitor. The coumarin–piperidine conjugates BPR 13 and BPR 12 were the most potent inhibitors of eeAChE at 100 μM and 1 μM, respectively. Molecular modelling studies were conducted with Accelrys® Discovery Studio® V3.1. 1 utilising the published hMAO-B (2V61) and hAChE (4EY7) crystal structures. Compound BPR 10 occupies both the entrance and substrate cavities of the active site of MAO-B. BPR 13 resides in both the peripheral anionic site (PAS) and the catalytic anionic site (CAS) of hAChE. This study demonstrated that the coumarin scaffold serves as a promising pharmacophore for MTDLs design.
The Relationship of Excitability to Conduction Velocity in Canine Purkinje Tissue

The relationship between interelectrode conduction time and “take-off” potential (TOP) was studied with microelectrode techniques in isolated canine false tendons. Conduction of regular or test beats initiated during phase 4 depolarization or late phase 3 repolarization speeded as TOP decreased. Similarly, beats initiated during digitalis-induced oscillatory afterpotentials demonstrated more rapid conduction at lower TOP. Because of the frequency-coupled nature of the oscillations, conduction times became rate dependent. Phenytoin antagonized digitalis oscillations and reversed speeding of conduction attributable to the oscillations. No uniform relationship between speed of conduction and maximum upstroke velocity of the action potential could be demonstrated in the above experiments or when speed of conduction was varied by changes in concentration of K+ or Ca2+. However, speed of conduction could be demonstrated to vary directly with changes in excitability as measured by intracellular current injection.
Enabling e cient stencil code generation in penACC

The OpenACC programming model simplifies the programming for accelerator devices such as GPUs. Its abstract accelerator model defines a least common denominator for accelerator devices, thus it cannot represent architectural specifics of these devices without losing portability. Therefore, this general-purpose approach delivers good performance on average, but it misses optimization opportunities for code generation and execution of specific classes of applications. In this paper, we propose stencil extensions to enable efficient code generation in OpenACC. Our results show that our stencil extensions may improve the performance of OpenACC in up to 28% and 45% on GPU and CPU, respectively.
Intralesional PV‐10 for in‐transit melanoma—A single‐center experience

Patients with in‐transit melanoma metastasis have longer median survival than patients with distant metastatic disease. Furthermore, local disease control is an important endpoint for symptom management. The treatment of unresectable loco‐regional recurrence or in‐transit disease has been historically managed with a combination of treatments including surgery, radiotherapy, isolated limb infusion or perfusion as well as systemic therapies. Intralesional PV‐10 has been used at Peter MacCallum Cancer Centre since 2010, and the current report presents a retrospective analysis of patient outcomes, reporting the response rates, durability of responses, and observed toxicities.
Strontium to calcium ratios in the marine gastropod Conus ermineus: Growth rate effects and temperature calibration

Here we investigate the potential of Sr/Ca ratios in the marine gastropod Conus ermineus for reconstructing seawater temperatures. We present annually resolved records of Sr/Ca and δ18O for four shells collected alive from the Flower Garden Banks National Marine Sanctuary in the Gulf of Mexico. Our results show that variations in Sr/Ca and δ18O covary with the in situ seasonal temperature cycle. Sr/Ca and temperature are positively correlated, in contrast with the inverse relationship found in inorganically precipitated aragonite. The seasonal Sr/Ca variability is superimposed on a long‐term trend of increasing Sr/Ca with age. Both the seasonal and long‐term ontogenetic changes in Sr/Ca are associated with variations in growth rate, defined here as the shell linear extension rate (LER); the seasonal variability in LER is superimposed on a long‐term decrease with ontogeny. Thus the covariance of Sr/Ca ratios with temperature and LER suggests that Sr incorporation is likely driven by temperature influence on growth rate, rather than by thermodynamic effects. Unlike the seasonal variability, the ontogenetic effect is characterized by inverse covariation between Sr/Ca and LER, suggesting that Sr/Ca variability is not controlled by growth rate alone, but probably by two different biomineralization mechanisms, one related to temperature and the other related to age. We use the seasonal Sr/Ca signal of four shells to construct a temperature calibration. To minimize the ontogenetic effects, we separate the records into juvenile and adult growth stages and calculate the Sr/Ca‐temperature (T) relationships: Juvenile: Sr/Ca (mmol mol−1) = 0.042 (±0.008) * T (°C) + 0.24 (±0.21) (R2 = 0.66) Adult: Sr/Ca(mmol mol−1) = 0.072 (±0.014) * T (°C) − 0.05 (±0.34) (R2 = 0.68) Applying the calibration to a single specimen provides mean annual temperature estimates within ±1°C of the in situ temperature record but resolves the seasonal variability only within ±3.5°C. The large error in the seasonal estimates reflects the high variability among specimens. To reduce the uncertainty on seasonal temperatures, we propose combining records from multiple shells to generate an average temperature record. The potential of this approach needs, however, to be validated in other locations.
A deep neural network based hashing for efficient image retrieval

Learning valid similarities is a vital problem in hashing methods, especially in large-scale image search. Similarity pertained hashing method is widely used in image retrieval for its high quality compact binary code mapping. The hashing scheme of most existing hashing methods is that the input data is encoded as a vector of visual features and hashed into binary hash codes via projection functions or quantization methods afterward. However, this separated pipeline may prone to lose accurate similarities of images, since the limited compatible domain between visual feature vectors generation and binary codes mapping process. Encouraged by the extraordinary image representation learning ability of deep neural networks in classification, we propose a structure that merges binary code generation process within deep neural networks for efficient image retrieval. The proposed architecture contains two fundamental blocks. The stacked convolution layers of Network In Network with global average pooling compute effective image representation and the embedded latent layer with binary activation functions learn binary hash codes simultaneously. Experiments show that the proposed method gains improvement over several state-of-the-art hashing methods.
Synthesis, Characterization, and Evaluation of Cytotoxic Effects of Novel Hybrid Steroidal Heterocycles as PEG Based Nanoparticles

Anticancer agents featuring hybrid molecules can improve effectiveness and diminish drug resistance. The current study aimed to introduce newly synthesized heterocyclic steroids of promising anticancer effects loaded in polyethylene glycol (PEG)•based nanoparticles form. Several heterocyclic steroids (1-9) were synthesized via multicomponent reactions (MCRs) and confirmed via the analytical and spectral data. Compounds 1, 2, 3, 4, 5, 6, 7 and 9, were investigated individually in their free and PEG based nano-size hybrid forms as anticancer agents against three human cell lines: hepatocellular carcinoma cells (HepG2); breast cancer cells (MCF-7); and colon cancer cells (HCT116). The neutral red supravital dye uptake assay was employed. Compound 6 in its PEG based nano-size form exhibited the best cytotoxic effects against HepG2 and HCT116 cell lines, with IC50 values of 2.44 µmol/l and 2.59 µmol/l, respectively. In addition, it demonstrated a low IC50 value against MCF-7 (3.46µmol/l) cells. This study introduced promising anticancer agents acting through conversion into PEG-based nanoparticles.
Measuring time to awareness

THE timing of two simultaneous responses to one single visual event, namely the sudden subjective expansion of a real object occurring at the onset of a reaching movement, was measured in normal subjects. The motor response was represented by the earliest sign of correction in trajectory of the movement. The subjective report was represented by a vocal utterance that the subjects were instructed to emit when they became aware of the change in appearance of the object. The subjective report lagged the motor response by 150 ms. Control experiments ruled out a possible interference between the two responses. It is concluded that this temporal dissociation reflects a duality of neural pathways involved in processing object-related information.
Effects of external driving on the coherence time of a Josephson junction qubit in a bath of two-level fluctuators

We study the effect of external driving on the two level systems (TLSs) assumed to be a major obstacle in increasing the coherence time of solid state Josephson-junction qubits. We find, by use of a Bloch-Redfield approach, that external driving has two major effects on the TLS. The first is increased fluctuations between the two states of the TLS, the significance of this effect compared to thermal fluctuations depend on the energy splitting of the TLS compared to temperature. The second effect is a reduction in the intensity of the noise spectrum at low frequencies, and at the same time an increase in intensity around the renormalized Rabi frequency of the TLS, the driving frequency and at beatings between these two frequencies. Finally we study the ensemble averaged noise spectrum for a typical distribution of TLSs known to give origin to $\propto 1/f$ noise. We find that strong driving leads to reduced noise at low frequencies, and therefore to an increased dephasing time $T_2^Q$ of the qubit. However this effect is exponentially suppressed when the driving frequency is large compared to temperature, as we typically find for Josephson qubits. We suggest that external driving at frequencies much lower than the qubit frequency might be used in order to enhance the the qubit coherence time.
A Graphical Query Generator for Clinical Research Databases

Abstract: Clinical research involves recording, storage and retrieval of disease-related patient data, typically using a database system. In order to facilitate ad hoc queries to clinical databases we have developed a query generator with a graphical interface. The query generator uses an object-oriented data model which is visualized by directed graphs. The main focus of our work was the definition of object-oriented user views to the partly complex data structures of a relational database. Furthermore, we tried to define graphical abstractions for all common types of queries. Thus, even for non-expert database users such as clinicians, it is easy to assemble highly complex queries for a thorough examination of the content of large research databases.
Acute Thromboembolic Events during Carotid Artery Angioplasty and Stenting: Etiology and a Technique of Neurorescue

Purpose: To review the protected carotid stenting experience at two major referral centers to evaluate the frequency of clinically significant intraprocedural thromboembolic events, use of neurorescue techniques, and ultimate clinical outcomes. Methods: A retrospective review was conducted of 254 cases of protected transfemoral carotid stenting performed at the Washington University-Barnes Hospital and The Fleni Institute of Buenos Aires in a 6-year period. Medical records of patients with periprocedural thromboembolic events were reviewed to determine the type of complication, method of treatment, and outcome. Results: Among the 254 cases in which a carotid protection device was used, 2 (0.79%) episodes of witnessed, symptomatic thromboembolism occurred. Both patients suffered thromboembolic occlusion of the M1 branch of the middle cerebral artery (MCA) immediately following crossing of the internal carotid lesion with the protection device. Neurological symptoms consisted of agitation, aphasia, and hemiplegia in both patients. After rapid stent deployment across the carotid lesion, the MCA was cannulated and the occlusion treated with balloon angioplasty. This was followed by selective intra-arterial delivery of urokinase and intravenous abciximab. These maneuvers resulted in excellentrestoration of blood flow in the MCA and its branches. With the exception of minor word-finding difficulties in one, both patients demonstrated full neurological recovery within the perioperative period. Conclusions: In our experience, intraprocedural thromboembolic events occur despite the use of cerebral protection devices, but are rare. Notably these complications appeared to occur at the time of lesion crossing by distal cerebral protection devices. These thromboembolic events can be successfully treated if the complication is rapidly identified and the physician is adequately prepared and proficient in neurorescue techniques.
p53-dependent regulation of metabolic function through transcriptional activation of pantothenate kinase-1 gene

It is well established that the p53 tumor suppressor plays a crucial role in controlling cell proliferation and apoptosis upon various types of stress. There is increasing evidence showing that p53 is also critically involved in various metabolic pathways, both in tumor and normal cells. Here, we have identified a novel p53 metabolic target pantothenate kinase-1 (PANK1) via ChIP-on-chip. PanK1 catalyzes the rate-limiting step for CoA synthesis and, therefore, controls intracellular CoA content; Pank1-knockout mice exhibit defect in β-oxidation and gluconeogenesis in the liver after starvation due to insufficient CoA levels. We demonstrated that PANK1 gene is a direct transcriptional target of p53. Although DNA damage-induced p53 upregulates PanK1 expression, depletion of PanK1 expression does not affect p53-dependent growth arrest or apoptosis. Interestingly, upon glucose starvation, PanK1 expression is significantly reduced in HCT116 p53 (−/−) but not in HCT116 p53 (+/+) cells, suggesting that p53 is required to maintain PanK1 expression under metabolic stress conditions. Moreover, by using p53-mutant mice, we observed that, similar to the case in Pank1-knockout mice, gluconeogenesis is partially impaired in p53-null mice. Together, our findings show that p53 plays an important role in regulating energy homeostasis through transcriptional control of PANK1, independent of its canonical functions in apoptosis and cell cycle arrest.
Geometric Criteria for the Quasi-Linearization of the Equations of Motion of Mechanical Systems

A linear transformation of velocity for a mechanical system is said to quasi-linearize the equations of motion of the system if it eliminates all terms quadratic in the velocity. It is well-known that controller/observer synthesis becomes tractable when the dynamics of a mechanical system are in quasi-linearized form. In this technical note, we show that the quasi-linearization property is equivalent to the property that the Lie algebra of Killing vector fields is pointwise equal to the tangent space to the configuration manifold with the Riemannian metric induced by the mass tensor of the mechanical system. A sufficient condition for this property is that the Riemannian manifold be locally symmetric. We further show that a necessary and sufficient condition for quasi-linearizability on 2-D Riemannian manifolds is that the scalar curvature is constant. The above results extend the zero Riemannian curvature condition that has been extensively applied since its introduction in 1992. Moreover, the local symmetricity condition and the constant scalar curvature condition can be easily verified using differentiation.
Detecting selection along environmental gradients: analysis of eight methods and their effectiveness for outbreeding and selfing populations

Thanks to genome‐scale diversity data, present‐day studies can provide a detailed view of how natural and cultivated species adapt to their environment and particularly to environmental gradients. However, due to their sensitivity, up‐to‐date studies might be more sensitive to undocumented demographic effects such as the pattern of migration and the reproduction regime. In this study, we provide guidelines for the use of popular or recently developed statistical methods to detect footprints of selection. We simulated 100 populations along a selective gradient and explored different migration models, sampling schemes and rates of self‐fertilization. We investigated the power and robustness of eight methods to detect loci potentially under selection: three designed to detect genotype–environment correlations and five designed to detect adaptive differentiation (based on FST or similar measures). We show that genotype–environment correlation methods have substantially more power to detect selection than differentiation‐based methods but that they generally suffer from high rates of false positives. This effect is exacerbated whenever allele frequencies are correlated, either between populations or within populations. Our results suggest that, when the underlying genetic structure of the data is unknown, a number of robust methods are preferable. Moreover, in the simulated scenario we used, sampling many populations led to better results than sampling many individuals per population. Finally, care should be taken when using methods to identify genotype–environment correlations without correcting for allele frequency autocorrelation because of the risk of spurious signals due to allele frequency correlations between populations.
Three Distinct Fusion Processes during Eosinophil Degranulation

In many cases, exocytosis is a directed process where the secreted material is directed to a certain target. At synapses, the released neurotransmitter has to reach the postsynaptic receptor rapidly and the synaptic vesicles are arranged in highly specialized regions, the active zones. ' The site of exocytosis is thus spatially very well defined and the transmitter only needs to diffuse across the narrow synaptic cleft. Eosinophilic granulocytes (eosinophils) are exocytotic cells that play an important role in the defense of a host against parasites. The cells synthesize cytotoxic proteins and store these proteins in secretory granules, where they are ready to be released onto the surface of a parasite. The release is thus also a directed process, but the site where exocytosis is to occur is not known in advance. It becomes only defined when the cell makes contact with the target. In neurosecretion, only a minor fraction of secretory vesicles fuse with the plasma membrane in response to the stimulus. In contrast, for an eosinophil, it is desirable that the cell discharges the contents of all its granules during parasite killing. It is spatially impossible that all granules fuse with a small section of the plasma membrane. However, nondirected degranulation all over the cell's surface would be inefficient because most of the granular material will be released on the wrong side and will never hit the target. Furthermore, the cytotoxic proteins may eventually get into contact with intact cells of the host and will damage these cells. Host cell damage by eosinophil degranulation is apparently an important problem in certain types of asthma where epithelial cells are destroyed. ' We have investigated the membrane fusion processes in single degranulating eosinophils by electrical impedance analysis using the whole-cell patch-clamp technique to determine how these cells direct the contents of most of their granules to a single site.
High‐Resolution Melting Analysis as a Developed Method for Genotyping the PD Susceptibility Loci in LRRK2 Gene

Single‐nucleotide polymorphisms (SNPs) have been reported as a highly relevant point for the mechanisms of Parkinson's disease (PD). The invention of saturating dye makes it possible to identify heteroduplex DNA without redistribution during melting, which allows using high‐resolution melting (HRM) to detect SNPs. However, the HRM analysis for detection of those SNPs associated with PD was rarely applied.
Do You Know How Much Is Delivered to Your Patient's Lungs? Accurate Measurement of Effective Tidal Volumes Should Be Standard of Care in Infants and Children.

890 www.pccmjournal. org November 2015 • Volume 16 • Number 9 During mechanical ventilation, the ventilator-delivered tidal volume (VTdel) is distributed between the ventilator circuit and the patient. The portion that is distributed to the circuit is referred to as “compressible volume” (CV), and the portion that is distributed to the patient is referred to as the “effective tidal volume” (VTeff) (1). CV can be estimated by multiplying the compliance of the ventilator circuit by the change in pressure during inspiration. VTeff is then estimated by subtracting CV from VTdel. Modern ventilators incorporate software which estimates VTeff by correcting for CV. Alternatively, VTeff can be directly measured at the hub of the endotracheal tube (ETT) by a pneumotachometer.
Gap analysis of future energy grids

Based on existing low and medium voltage grids from distribution system operators and future scenarios of PV and EV penetration, critical load scenarios which lead to violations of relevant KPIs are to be developed in the scope of PlanGridEV. In the course of the gap analysis the expected limits of DER hosting capacities were identified. The method for developing and simulating the different scenarios is following a state-of-the-art approach. Results for each power grid and scenario are addressing specific KPIs. The main goal of this analysis was to assess the current EV and PV hosting capacity of existing low voltage and medium voltage grids and identify the factors which limit this hosting capacity. It is shown that European DSOs share similar structures. Depending on voltage level and topology type, specific KPIs were violated by increasing numbers of RES or EVs. Indications for synergies between PV and EVs could be identified due to an increased hosting capacity in the extra PV scenario.
Golden Handshakes: Separation Pay for Retired and Dismissed CEOS

This paper studies separation payments made when CEOs leave their firms. In a sample of 179 exiting Fortune 500 CEOs, more than half receive severance pay and the mean separation package is worth $5.4 million. The large majority of severance pay is awarded on a discretionary basis by the board of directors and not according to terms of an employment agreement. For the subset of exiting CEOs who are dismissed, separation pay generally conforms to theories related to bonding and damage control. Shareholders react negatively when separation agreements are disclosed, but only in cases of voluntary CEO turnover.