Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular Pathogenesis of Non-Hodgkin's Lymphoma: the Role of Bcl-6

Non-Hodgkin's lymphomas (NHL) form a heterogeneous group of diseases, with diffuse large B-cell lymphoma (DLBCL) comprising the largest subgroup. The commonest chromosomal translocations found in DLBCL are those affecting band 3q27. In 35% of DLBCL cases, as well as in a small fraction of follicular lymphomas, the normal transcriptional regulation of Bcl-6 is disrupted by these chromosomal translocations. In addition, about three-quarters of cases of DLBCL display multiple somatic mutations in the 5′ non-coding region of Bcl-6, which occur independently of chromosomal translocations and appear to be due to the IgV-associated somatic hypermutation process. Bcl-6 is a 95-kD nuclear phosphoprotein belonging to the BTB/POZ (bric-a-brac, tramtrack, broad complex/Pox virus zinc finger) zinc finger family of transcription factors. It has been suggested that Bcl-6 is important in the repression of genes involved in the control of lymphocyte activation, differentiation, and apoptosis within the germinal center, and that its down-regulation is necessary for normal B-cells to exit the germinal center. Bcl-6 remains constitutively expressed in a substantial proportion of B-cell lymphomas. Recently, acetylation has been identified as a mode for down-regulating Bcl-6 activity by inhibition of the ability of Bcl-6 to recruit complexes containing histone deacetylases (HDAC). The pharmacologic inhibition of two recently identified deacetylation pathways, HDAC- and silent information regulator (SIR)-2-dependent deacetylation, results in the accumulation of inactive acetylated Bcl-6 and thus in cell cycle arrest and apoptosis in B-cell lymphoma cells. These results reveal a new method of regulating Bcl-6, with the potential for therapeutic exploitation. These studies also indicate a novel mechanism by which acetylation promotes transcription, not only by modifying histones and activating transcriptional activators, but also by inhibiting transcriptional repressors.
Real-time Pitched/Unpitched Separation of Monophonic Timbre Components

Described here is a new technique for the real-time separation of a monophonic sound source timbre into its pitched and unpitched components (e.g. violin string vibration vs. bow noise.) This technique differs from preexisting noise extraction and reduction techniques in that it does not rely on a priori knowledge of the signal and does not consider the duration or stability of a component in determining whether that component is pitched, but rather analyzes sinusoidal components based on their harmonic relationship to an estimated fundamental frequency. This has several benefits including independence of time in the determination of un-pitched components and the ability to discern pitched components from unpitched components in situations where the unpitched components may be steady in the time-evolving frequency sense.
An 800 Mhz mixed-VT 4T gain-cell embedded DRAM in 28 nm CMOS bulk process for approximate computing applications

Gain-cell embedded DRAM (GC-eDRAM) is an attractive alternative to traditional SRAM, due to its high-density, low-leakage, and inherent 2-ported operation, yet, its dynamic nature leads to limited retention time that requires periodic, power-hungry refresh cycles. This drawback is further aggravated in scaled technologies, where increased leakage currents and decreased in-cell storage capacitances lead to accelerated data integrity deterioration. However, the emerging approximate computing paradigm utilizes the inherent error resilience of some applications to tolerate data errors. Such error tolerance can be exploited by reducing the refresh rate in GC-eDRAM to achieve a substantial decrease in power consumption, at the cost of an increase in cell failure probability. In this paper, we present the first fabricated and fully functional GC-eDRAM in a 28 nm bulk CMOS technology. The array, which is based on a novel mixed-Vt 4T bitcell, can be used in both traditional and for approximate computing applications, featuring a small silicon footprint and supporting high-performance operation. Silicon measurements demonstrate successful operation at 800 Mhz under a 900 mV supply, while retaining almost 30% lower area than a single-ported 6T SRAM in the same technology.
Supervised Training of Dynamical Neural Networks for Associative Memory Design and Identification of Nonlinear Maps

Complexity of implementation has been a major difficulty in the development of gradient descent learning algorithms for dynamical neural networks with feedback and recurrent connections. Some insights from the stability properties of the equilibrium points of the network, which suggest an appropriate tailoring of the sigmoidal nonlinear functions, can however be utilized in obtaining simplified learning rules, as demonstrated in this paper. An analytical proof of convergence of the learning scheme under specific conditions is given and some upper bounds on the adaptation parameters for an efficient implementation of the training procedure are developed. The performance features of the learning algorithm are illustrated by applying it to two problems of importance, viz., design of associative memories and nonlinear input-output mapping. For the first application, a systematic procedure is given for training a network to store multiple memory vectors as its stable equilibrium points, whereas for the second application, specific training rules are developed for a three-layer network architecture comprising a dynamical hidden layer for the identification of nonlinear input-output maps. A comparison with the performance of a standard backpropagation network provides an illustration of the capabilities of the present network architecture and the learning algorithm.
Determination of structural and functional overlap/divergence of five proto‐type galectins by analysis of the growth‐regulatory interaction with ganglioside GM1 in silico and in vitro on human neuroblastoma cells

The growth‐regulatory interplay between ganglioside GM1 on human SK‐N‐MC neuroblastoma cells and an endogenous lectin provides a telling example for glycan (polysaccharide) functionality. Galectin‐1 is the essential link between the sugar signal and the intracellular response. The emerging intrafamily complexity of galectins raises the question on defining extent of their structural and functional overlap/divergence. We address this problem for proto‐type galectins in this system: ganglioside GM1 as ligand, neuroblastoma cells as target. Using the way human galectin‐1 interacts with this complex natural ligand as template, we first defined equivalent positioning for distinct substitutions in the other tested proto‐type galectins, e.g., Lys63 vs. Leu60/Gln72 in galectins‐2 and ‐5. As predicted from our in silico work, the tested proto‐type galectins have affinity for the pentasaccharide of ganglioside GM1. In contrast to solid‐phase assays, cell surface presentation of the ganglioside did not support binding of galectin‐5, revealing the first level of regulation. Next, a monomeric proto‐type galectin (CG‐14) can impair galectin‐1‐dependent negative growth control by competitively blocking access to the shared ligand without acting as effector. Thus, the quaternary structure of proto‐type galectins is an efficient means to give rise to functional divergence. The identification of this second level of regulation is relevant for diagnostic monitoring. It might be exploited therapeutically by producing galectin variants tailored to interfere with galectin activities associated with the malignant phenotype. Moreover, the given strategy for comparative computational analysis of extended binding sites has implications for the rational design of galectin‐type‐specific ligands. © 2004 Wiley‐Liss, Inc.
Defense Styles, Impulsivity and Suicide Attempts in Major Depression

Background: The aim of our study was to identify if defense mechanisms are associated with impulsivity and lifetime suicide attempts in depressed patients. Sampling and Methods: The Defense Style Questionnaire, the Impulsivity Rating Scale and the Impulse Control Scale were used in 77 depressed inpatients. Results: Impulsivity was correlated positively with immature and neurotic styles and negatively with mature style. Some but not all defense mechanisms were relevant in this respect. The number of lifetime suicide attempts was positively correlated not only with impulsivity, but also with immature style and to a lesser extent with neurotic style. Several defense mechanisms were involved in these correlations: undoing, projection, passive aggression, acting out, splitting and somatization. Conclusions: Like impulsivity, defense styles may be relevant to discriminate recurrent suicide attempters in depression. Prospective assessment of defense styles and suicide attempts in depression is needed.
Predictive Model of Avian Electrocution Risk on Overhead Power Lines

Electrocution on overhead power structures negatively affects avian populations in diverse ecosystems worldwide, contributes to the endangerment of raptor populations in Europe and Africa, and is a major driver of legal action against electric utilities in North America. We investigated factors associated with avian electrocutions so poles that are likely to electrocute a bird can be identified and retrofitted prior to causing avian mortality. We used historical data from southern California to identify patterns of avian electrocution by voltage, month, and year to identify species most often killed by electrocution in our study area and to develop a predictive model that compared poles where an avian electrocution was known to have occurred (electrocution poles) with poles where no known electrocution occurred (comparison poles). We chose variables that could be quantified by personnel with little training in ornithology or electric systems. Electrocutions were more common at distribution voltages (≤33 kV) and during breeding seasons and were more commonly reported after a retrofitting program began. Red‐tailed Hawks (Buteo jamaicensis) (n = 265) and American Crows (Corvus brachyrhynchos) (n = 258) were the most commonly electrocuted species. In the predictive model, 4 of 14 candidate variables were required to distinguish electrocution poles from comparison poles: number of jumpers (short wires connecting energized equipment), number of primary conductors, presence of grounding, and presence of unforested unpaved areas as the dominant nearby land cover. When tested against a sample of poles not used to build the model, our model distributed poles relatively normally across electrocution‐risk values and identified the average risk as higher for electrocution poles relative to comparison poles. Our model can be used to reduce avian electrocutions through proactive identification and targeting of high‐risk poles for retrofitting.
The Relationships of Cardiovascular Disease Risk Factors to Flow-Mediated Dilatation in Japanese Subjects Free of Cardiovascular Disease

We examined the relationship of several cardiovascular disease (CVD) risk factors to flow-mediated vasodilatation of the brachial artery (FMD) and the clustering effect of risk factors on FMD in Japanese subjects free of CVD. In 819 Japanese subjects free of CVD (age 45±10 years, 611 men and 208 women), FMD correlated significantly with the Framingham risk points score (FRS) (r=−0.27, p<0.01). FMD was higher in subjects in the 1st tertile of the FRS range than in patients in either the 2nd or 3rd tertiles of the FRS range, but it was similar between the subjects in the 2nd and 3rd tertiles. FMD was found to have a significant independent negative correlation with age (β=−0.19, p < 0.01), gender (β=−0.024, p < 0.01) and smoking habit (β=−0.08, p = 0.02). In subjects ≥ 50 years of age, the FMD in men with one CVD risk factor, excluding smoking, was similar to that in men with no CVD risk factors. CVD risk factors did not attenuate FMD in women. Thus, in Japanese subjects free of CVD, FMD may be a useful marker of CVD risk, but it may not be a robust marker for endothelial damage related to clusters of CVD risk factors. Age, gender and smoking were independent variables related to the impairment of FMD, which therefore appears to be less applicable in subjects aged 50 or more, and especially in women.
Study of the Rifampin Monoresistance Mechanism in Mycobacterium tuberculosis

ABSTRACT Rifampin (RIF) susceptibility is a key factor in determining the treatment effectiveness of the standardized treatment regimens. In Mycobacterium tuberculosis, both target gene mutation and the efflux pump play major roles in the resistance to antituberculosis drugs. By eliminating RIF-resistant strains with rpoB mutation, the choice of RIF-monoresistant strains may allow us to identify the RIF-specific efflux pump genes. This study explored the RIF monoresistance mechanism in M. tuberculosis. Data from DNA sequencing and MIC measurements revealed that specific mutations, including Ser531Leu and His526Asp in RpoB, show high-level drug resistance. Three-dimensional structure modeling provided further evidence that the affinity between RIF and RpoB mutants was in accordance with the drug resistance level of the corresponding isolates. Furthermore, transcription-level analysis among the nonmutated isolates indicated that three efflux pumps (Rv0783, Rv2936, and Rv0933) might be involved in exporting RIF from the cell. Compared to 8 μg/ml for wild-type Escherichia coli, the MICs for the transgenic E. coli strains with either Rv0783 or Rv2936 were 32 and 16 μg/ml, respectively. In conclusion, our study indicated that several RpoB mutant types, including Ser531Leu and His526Asp, show high-level RIF resistance attributed to low affinity between RpoB mutant proteins and RIF. In addition, this work demonstrates that Rv2936 and Rv0783 may be responsible for low-level resistance to RIF by exporting RIF from cells. The predicted structure of RpoB and the newly identified efflux pumps in this study will provide a novel approach to design new drugs and develop novel diagnosis technologies.
A Review of Pathway-Based Analysis Tools That Visualize Genetic Variants

Pathway analysis is a powerful method for data analysis in genomics, most often applied to gene expression analysis. It is also promising for single-nucleotide polymorphism (SNP) data analysis, such as genome-wide association study data, because it allows the interpretation of variants with respect to the biological processes in which the affected genes and proteins are involved. Such analyses support an interactive evaluation of the possible effects of variations on function, regulation or interaction of gene products. Current pathway analysis software often does not support data visualization of variants in pathways as an alternate method to interpret genetic association results, and specific statistical methods for pathway analysis of SNP data are not combined with these visualization features. In this review, we first describe the visualization options of the tools that were identified by a literature review, in order to provide insight for improvements in this developing field. Tool evaluation was performed using a computational epistatic dataset of gene–gene interactions for obesity risk. Next, we report the necessity to include in these tools statistical methods designed for the pathway-based analysis with SNP data, expressly aiming to define features for more comprehensive pathway-based analysis tools. We conclude by recognizing that pathway analysis of genetic variations data requires a sophisticated combination of the most useful and informative visual aspects of the various tools evaluated.
A Continuously Infused Microfluidic Radioassay System for the Characterization of Cellular Pharmacokinetics

Measurement of cellular tracer uptake is widely applied to learn the physiologic status of cells and their interactions with imaging agents and pharmaceuticals. In-culture measurements have the advantage of less stress to cells. However, the tracer solution still needs to be loaded, unloaded, and purged from the cell culture during the measurements. Here, we propose a continuously infused microfluidic radioassay (CIMR) system for continuous in-culture measurement of cellular uptake. The system was tested to investigate the influence of the glucose concentration in cell culture media on 18F-FDG uptake kinetics. Methods: The CIMR system consists of a microfluidic chip integrated with a flow-control unit and a positron camera. Medium diluted with radioactive tracer flows through a cell chamber continuously at low speed. Positrons emitted from the cells and from tracer in the medium are measured with the positron camera. The human cell lines SkBr3 and Capan-1 were incubated with media of 3 different glucose concentrations and then measured with 18F-FDG on the CIMR system. In addition, a conventional uptake experiment was performed. The relative uptake ratios between different medium conditions were compared. A cellular 2-compartment model was applied to estimate the cellular pharmacokinetics on CIMR data. The estimated pharmacokinetic parameters were compared with expressions of glucose transporter-1 (GLUT1) and hexokinase-2 measured by quantitative real-time polymerase chain reaction. Results: The relative uptake ratios obtained from CIMR measurements correlated significantly with those from the conventional uptake experiments. The relative SDs of the relative uptake ratios obtained from the CIMR uptake experiments were significantly lower than those from the conventional uptake experiments. The fit of the cellular 2-compartment model to the 18F-FDG CIMR measurements was of high quality. For SkBr3, the estimated pharmacokinetic parameters k1 and k3 were consistent with the messenger RNA expression of GLUT1 and hexokinase-2: culturing with low glucose concentrations led to higher GLUT1 and hexokinase-2 expression as well as higher estimated k1 and k3. For Capan-1, the estimated k1 and k3 increased as the glucose concentration in the culture medium decreased, and this finding did not match the corresponding messenger RNA expression. Conclusion: The CIMR system captures dynamic uptake within the cell culture and enables estimation of the cellular pharmacokinetics.
Physical-layer secret key generation with untrusted relays

In this paper, we propose a physical-layer secret key generation scheme for multi-antenna legitimate nodes with the help from multiple untrusted relays with single antenna. The relays' actions conform to the rules but they passively eavesdrop the information. Different from most previous key generation schemes, where a key is generated based on a channel coefficient, in the proposed scheme, we use the linear combination of channel coefficients to generate a key. Simulation results show that the rate leaked to the untrusted relays is low and the secret key rate is therefore high. We also point out that the relay communication can achieve higher secret key rate than the direct communication in several distance ranges.
Central Cholinergic Challenging of Migraine by Testing Second‐Generation Anticholinesterase Drugs

The antinociceptive activity of donepezil, a novel cholinesterase inhibitor, was investigated in the mouse hot plate test. Donepezil (5 to 10 mg kg− 1 i.p.) induced a dose‐dependent antinociception that reached its maximum effect 15 minutes after injection. Donepezil antinociception was prevented by the antimuscarinic drug scopolamine. At analgesic doses, donepezil did not alter gross animal behavior. These results indicate that donepezil is endowed by muscarinic antinociceptive properties, suggesting this compound as a potential therapeutic approach for the treatment of painful pathologies. Therefore, we investigated donepezil's effect in migraine. Donepezil (5 mg per os, evening assumption) was effective as a prophylatic agent in patients suffering from migraine with or without aura by reducing the number of hours with pain, the number of attacks, and the severity of the pain attack. The efficacy of donepezil was compared with that of the β‐blocker propranolol (40 mg bid per os), showing higher activity. Response rates of a large‐sized open study devoid of entry criteria regarding migraine subtypes suggest the drug as an excellent prophylactic compound for migraine in general practice. Clinical results also indicate that the activation of the cholinergic system can represent a novel prophylactic approach to migraine.
X‐linked cardioskeletal myopathy and neutropenia (Barth syndrome): An update

X‐linked cardioskeletal myopathy and neutropenia (Barth syndrome, MIM302060, BTHS) is a disorder with mitochondrial functional impairments and 3‐methylglutaconic aciduria that maps to Xq28. The associated G4.5 or TAZ gene has been identified but the encoded proteins have not yet been characterized. Following the prediction that the gene encodes one or more acyltransferases, lipid studies have shown a deficiency of cardiolipin, especially its tetralinoleoyl form (L4‐CL). Deficiency of L4‐CL was subsequently demonstrated in a variety of tissues, and determination in thrombocytes or cultured skin fibroblasts is now the most specific biochemical test available. BTHS is the first identified inborn error of metabolism that directly affects cardiolipin, a component of the inner mitochondrial membrane, necessary for proper functioning of the electron transport chain. We report here the finding of deficient docosahexaenoic acid and arachidonic acid in a proportion of patients with BTHS. The initial impression of a uniformly lethal infantile disease has to be modified. Age distribution in 54 living patients ranges between 0 and 49 years and peaks around puberty. Mortality is the highest in the first 4 years. The apex of the survival curve around puberty and the emergence of adults may reflect a dynamic shift towards increased survival. This trend is exemplified in a large pedigree previously published. © 2004 Wiley‐Liss, Inc.
Intratemporal facial nerve blood flow in guinea pigs.

HYPOTHESIS To investigate the effect of interruption of the stylomastoid artery and the petrosal artery on the facial nerve blood flow with the use of a laser Doppler flowmeter. BACKGROUND Ischemia of the facial nerve is thought to be one of the most possible causes in idiopathic facial palsy. The blood supply in the facial nerve has been studied morphologically in considerable detail; however, we have little information on its hemodynamics. METHODS The animals used were 20 guinea pigs. The blood flow in the facial nerve at the geniculate ganglion was measured using a laser Doppler flowmeter, and the change in the facial nerve blood flow between before and after interruption of the stylomastoid artery and the petrosal artery was investigated. The interruption of both arteries was carried out by electrical cauterization with a bipolar coagulator. RESULTS Interruption of the petrosal artery resulted in almost complete ischemia of the facial nerve at the geniculate ganglion. This decrease in the facial nerve blood flow was significant statistically (p < 0.001). But, interruption of the stylomastoid artery caused no change. CONCLUSIONS The blood flow in the geniculate ganglion of the facial nerve is thought to come not from the stylomastoid artery but mainly from the petrosal artery. Peripheral facial palsy following ligation of the middle meningeal artery or embolization of the maxillary artery or intra-arterial infusion of anticancer drug into the maxillary artery is likely to be attributed to facial nerve ischemia at the level of the geniculate ganglion.