Miracle-dz/UniFAR-FTUs huggingface dataset:
Discovery of New Sites for Drug Binding to the Hypertension‐Related Renin–Angiotensinogen Complex

Renin (REN) is a key drug target to stop the hypertension cascade, but thus far only one direct inhibitor has been made commercially available. In this study, we assess an innovative REN inhibition strategy, by targeting the interface of the renin:angiotensinogen (REN:ANG) complex. We characterized the energetic role of interfacial residues of REN:ANG and identified the ones responsible for protein:protein binding, which can serve as drug targets for disruption of the REN:ANG association. For this purpose, we applied a computational alanine scanning mutagenesis protocol, which measures the contribution of each side chain for the protein:protein binding free energy with an accuracy of ≈ 1 kcal/mol. As a result, in REN and ANG, six and eight residues were found to be critical for binding, respectively. The leading force behind REN:ANG complexation was found to be the hydrophobic effect. The binding free energy per residue was found to be proportional to the buried area. Residues responsible for binding were occluded from water at the complex, which promotes an efficient pairing between the two proteins. Two druggable pockets involving critical residues for binding were found on the surface of REN, where small drug‐like molecules can bind and disrupt the ANG:REN association that may provide an efficient way to achieve REN inhibition and control hypertension.
Chemotaxis of Capacitated Rabbit Spermatozoa to Follicular Fluid Revealed by a Novel Directionality-Based Assay1

Abstract Precontact communication between gametes is established by chemotaxis. Sperm chemotaxis toward factor(s) in follicular fluid (FF) has been demonstrated in humans and mice. In humans, the chemotactic responsiveness is restricted to capacitated spermatozoa. Here, we investigated whether sperm chemotaxis to factor(s) present in FF also occurs in rabbits and, if so, whether only capacitated spermatozoa are chemotactically responsive. Chemotaxis assays were performed by videomicroscopy in a Zigmond chamber. We measured chemotactic responsiveness as a function of FF dilution by means of a novel directionality-based method that considers the ratio between the distances traveled by the spermatozoa both parallel to the chemoattractant gradient and perpendicular to it. A peak of maximal response was observed at 10−4 dilution of FF, resulting in a typical chemotactic concentration-dependent curve in which 23% of the spermatozoa were chemotactically responsive. In contrast, the percentage of cells exhibiting FF-dependent enhanced speed of swimming increased with the FF concentration, whereas the percentage of cells maintaining linear motility decreased with the FF concentration. The percentages of chemotactically responsive cells were very similar to those of capacitated spermatozoa. Depletion of the latter by stimulation of the acrosome reaction resulted in a total loss of the chemotactic response, whereas the reappearance of capacitated cells resulted in a recovery of chemotactic responsiveness. We conclude that rabbit spermatozoa, like human spermatozoa, are chemotactically responsive to FF factor(s) and acquire this responsiveness as part of the capacitation process.
Gender‐specific activity of chemotherapy correlates with outcomes in chemosensitive cancers of young adulthood

Good evidence indicates that adolescents and young adults (AYAs) with cancer do badly compared with children with similar cancers. The reasons are poorly understood. Australian registry data on 14,824 cancers of adolescence and young adulthood seen between 1982 and 2002 were reviewed. A detailed substudy of clinical characteristics was analyzed from 179 AYAs with Hodgkin lymphoma (HL), Ewing sarcoma (ES) or osteosarcomas (OS) treated at a single institution. Despite significant improvements in survival for both groups over the period in question, for acute lymphoblastic leukaemia, rhabdomyosarcoma, ES, OS and HL, survival for AYAs was worse than for children. For ES, OS and HL, the survival gap occurred almost entirely in males (Hazard ratios compared with female AYAs of 1.8 [p < 0.01], 1.4 [p = 0.03] and 1.5 [p < 0.01] respectively). Survival outcomes from ES, OS and HL for female AYAs were not significantly different from children of either sex. For brain tumors and thyroid cancers, which are primarily treated surgically, there were no gender‐related differences in outcomes. Although no differences in tumor stage or compliance were identified, male AYAs experienced less toxicity and lower response rates to chemotherapy (p = 0.008). Young males account almost entirely for excess mortality from chemosensitive cancers of adolescence and young adulthood compared to children, which may be due to relative underdosing with current chemotherapy dosing algorithms. © 2009 UICC
Phase edge match algorithm for phase unwrapping based on combination of gray-code and phase-shift light projection

An edge match algorithm for phase unwrapping based on combination of gray-code and phase-shift light projection is presented, which is indispensable to retrieve the object absolute phase. The algorithm is made up of two consecutive steps: the phase jump edges are firstly thinned, and then the phase jump edges are matched. When thinning, the blurred edge pixels are Incorporated Into a unique edge pixel employing a suitable estimated rule, the real edge pixel is kept, the pseudo one is discarded, and the originally unique edge pixel is directly regarded as the real edge pixel. When matching, firstly, all the coordinates of wrapped phase edge and gray-code phase edge are taken out, and then the two corresponding match pixels are searched out and the coordinates of gray-code edge pixel are rectified based on edge position of wrapped phase map. The validity of proposed algorithm has been testified by lots of experiments.
Bioinfo Analyse Discriminante des données micropuces

Exemples didactiques pour la comprehension de l’analyse discriminante utilisant le logiciel R. Ensembles d’apprentissage sont utilisés pour se donner une regle d’attribution a un groupe par toute observation. Liens utilies: http://www.bioconductor. org/workshops/Milan/Lectures/MachineLearning.pdf http://www.bioconductor. org/workshops/Milan/Lectures/classif.pdf
Randomized consensus algorithms over large scale networks

Suppose we have a directed graph G with set of nodes V = {1,. ,N} and a measure xi for every node i euro V. The average consensus problem consists in computing the average xA= N-1Sigmai xi in an iterative way, exchanging information among nodes exclusively along the available edges in G. This problem appears in a number of different contexts since the 80's (decentralized computation, load balancing, clock syncronization) and, recently, has attracted much attention for possible applications to sensor networks (data fusion problems) and to coordinated control for mobile autonomous agents. Several algorithms for average consensus can be found in the literature: they differentiate on the basis of the amount of communication and computation they use, on their scalability with respect to the number of nodes, on their adaptability to time-varying graphs, and, finally, they can be deterministic or random. In this presentation we will focus on random algorithms: we will review some algorithms present in the literature and we will propose some new ones. We will present some performance results which will allow to make some comparison. Finally, we will establish some probabilistic concentration results which will give a stronger significance to previous results.
Efficiency comparison of the full bridge converters in considered magnetic saturation

The operating efficiency of the full bridge converters via one and two output inductors was evaluated and analyzed based on the same power devices, magnetic components, output voltage ripple and switching frequency, is presented in this paper. Since the core losses of the output inductor and primary MOSFET ZVS performance will be affected by the output inductance at different load currents, the operating efficiency of the full bridge converter will be deteriorated without proper consideration the magnetic saturation characteristics of the core material. In order to take account the magnetic saturated effects of the core material, a nonlinear inductance model is used. As a result, the output current ripple and AC flux density variation at a different load current can be estimated more accurately in the design evaluation stage. After formulating the power losses of the key components, the operating efficiency of the 800W/12V/66A full bridge converter is estimated. From the estimated results, the one output inductor scheme has smaller power losses in the full CCM load range through proper design output inductance based on the output voltage ripple. Furthermore, the converters were further built and the experimental results were coincident with previous estimation. Finally, some simulation and experimental results are provided to demonstrate the effectiveness of this study.
A Survey on Internet Multipath Routing and Provisioning

Utilizing the dormant path diversity through multipath routing in the Internet to reach end users-thereby fulfilling their QoS requirements-is rather logical. While offering better resource utilization, better reliability, and often even much better quality of experience (QoE), multipath routing and provisioning was shown to help network and data center operators achieve traffic engineering in the form of load balancing. In this survey, we first highlight the benefits and basic Internet multipath routing components. We take a top-down approach and review various multipath protocols, from application to link and physical layers, operating at different parts of the Internet. We also describe the mathematical foundations of the multipath operation, as well as highlight the issues and challenges pertaining to reliable data delivery, buffering, and security in deploying multipath provisioning in the Internet. We compare the benefits and drawbacks of these protocols operating at different Internet layers and discuss open issues and challenges.
Alzheimer's β-Secretase (BACE1) Regulates the cAMP/PKA/CREB Pathway Independently of β-Amyloid

β-Amyloid protein (Aβ), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from proteolytic cleavages of the amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. BACE1 is the rate-limiting enzyme for Aβ production, and an increase in BACE1 level/activity contributes to the pathogenesis of sporadic AD. In addition to cleaving APP for Aβ generation, BACE1 plays multiple physiological roles including the regulation of synaptic functions. Here, we found that overexpression of BACE1 reduces cAMP response element binding protein (CREB) phosphorylation, protein kinase A (PKA) activity, and cAMP levels, whereas downregulation of BACE1 has the opposite effect. We showed that BACE1's effect is independent of its activity for Aβ production, which is corroborated by the observation that BACE1 transgenic mice have impaired learning/memory in the absence of neurotoxic human Aβ. Furthermore, we demonstrated that BACE1 interacts via its transmembrane domain with adenylate cyclase, resulting in reduction of cellular cAMP levels and thus PKA inactivation and reduced CREB phosphorylation. Our study suggests that in addition to its function as the β-secretase to produce Aβ, BACE1 may contribute to the memory and cognitive deficits typical of AD by regulating the cAMP/PKA/CREB pathway, which is important for memory functions.
An essential role for a mammalian SWI/SNF chromatin-remodeling complex during male meiosis

Germ cell development and gametogenesis require genome-wide transitions in epigenetic modifications and chromatin structure. These changes include covalent modifications to the DNA and histones as well as remodeling activities. Here, we explore the role of the mammalian SWI/SNF chromatin-remodeling complex during spermatogenesis using a conditional allele of the ATPase subunit, brahma-related gene 1 (Brg1, or Smarca4). Not only do BRG1 levels peak during the early stages of meiosis, genetic ablation of Brg1 in murine embryonic gonocytes results in arrest during prophase of meiosis I. Coincident with the timing of meiotic arrest, mutant spermatocytes accumulate unrepaired DNA and fail to complete synapsis. Furthermore, mutant spermatocytes show global alterations to histone modifications and chromatin structure indicative of a more heterochromatic genome. Together, these data demonstrate a requirement for BRG1 activity in spermatogenesis, and suggest a role for the mammalian SWI/SNF complex in programmed recombination and repair events that take place during meiosis.
Reduced Excitatory Neurotransmission and Mild Autism-Relevant Phenotypes in Adolescent Shank3 Null Mutant Mice

Mutations in the synaptic scaffolding protein gene SHANK3 are strongly implicated in autism and Phelan–McDermid 22q13 deletion syndrome. The precise location of the mutation within the Shank3 gene is key to its phenotypic outcomes. Here, we report the physiological and behavioral consequences of null and heterozygous mutations in the ankyrin repeat domain in Shank3 mice. Both homozygous and heterozygous mice showed reduced glutamatergic transmission and long-term potentiation in the hippocampus with more severe deficits detected in the homozygous mice. Three independent cohorts were evaluated for magnitude and replicability of behavioral endophenotypes relevant to autism and Phelan–McDermid syndrome. Mild social impairments were detected, primarily in juveniles during reciprocal interactions, while all genotypes displayed normal adult sociability on the three-chambered task. Impaired novel object recognition and rotarod performance were consistent across cohorts of null mutants. Repetitive self-grooming, reduced ultrasonic vocalizations, and deficits in reversal of water maze learning were detected only in some cohorts, emphasizing the importance of replication analyses. These results demonstrate the exquisite specificity of deletions in discrete domains within the Shank3 gene in determining severity of symptoms.
Modeling dynamic virtualized resource landscapes

Modern data centers are subject to an increasing demand for flexibility. Increased flexibility and dynamics, however, also result in a higher system complexity. This complexity carries on to run-time resource management for Quality-of-Service (QoS) enforcement, rendering design-time approaches for QoS assurance inadequate. In this paper, we present a set of novel meta-models that can be used to describe the resource landscape, the architecture and resource layers of dynamic virtualized data center infrastructures, as well as their run-time adaptation and resource management aspects. With these meta-models we introduce new modeling concepts to improve model-based run-time QoS assurance. We evaluate our meta-models by modeling a representative virtualized service infrastructure and using these model instances for run-time resource allocation. The results demonstrate the benefits of the new meta-models and show how they can be used to improve model-based system adaptation and run-time resource management in dynamic virtualized data centers.
Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging

Protein damage contributes prominently to cellular aging. To address whether this occurs at a specific period during aging or accumulates gradually, we monitored the biochemical, cellular, and physiological properties of folding sensors expressed in different tissues of C. elegans. We observed the age-dependent misfolding and loss of function of diverse proteins harboring temperature-sensitive missense mutations in all somatic tissues at the permissive condition. This widespread failure in proteostasis occurs rapidly at an early stage of adulthood, and coincides with a severely reduced activation of the cytoprotective heat shock response and the unfolded protein response. Enhancing stress responsive factors HSF-1 or DAF-16 suppresses misfolding of these metastable folding sensors and restores the ability of the cell to maintain a functional proteome. This suggests that a compromise in the regulation of proteostatic stress responses occurs early in adulthood and tips the balance between the load of damaged proteins and the proteostasis machinery. We propose that the collapse of proteostasis represents an early molecular event of aging that amplifies protein damage in age-associated diseases of protein conformation.
Dissociable Interference-Control Processes in Perception and Memory

Control over interference is a pervasive feature of cognitive life. Central to research on interference control has been the identification of its underlying mechanisms. Investigations have focused on processes that filter out distracting perceptual information, leading to negative priming, and processes that discard intruding memories that cause proactive interference. Theories differ regarding whether or not a single process during episodic retrieval underlies both negative priming and the resolution of proactive interference. Using functional magnetic resonance imaging, we combined both phenomena into a single paradigm and found that occipital cortex shows activation uniquely related to negative priming, whereas activation increases in left lateral prefrontal cortex are uniquely associated with proactive interference. This pattern of results contradicts theories that rely on a single process to account for both phenomena. However, results also showed common recruitment of right dorsolateral prefrontal cortex and parietal regions and therefore suggest that some control processes are shared.
Outflow Boundary Conditions for Blood Flow in Arterial Trees

In the modeling of the pulse wave in the systemic arterial tree, it is necessary to truncate small arterial crowns representing the networks of small arteries and arterioles. Appropriate boundary conditions at the truncation points are required to represent wave reflection effects of the truncated arterial crowns. In this work, we provide a systematic method to extract parameters of the three-element Windkessel model from the impedance of a truncated arterial tree or from experimental measurements of the blood pressure and flow rate at the inlet of the truncated arterial crown. In addition, we propose an improved three-element Windkessel model with a complex capacitance to accurately capture the fundamental-frequency time lag of the reflection wave with respect to the incident wave. Through our numerical simulations of blood flow in a single artery and in a large arterial tree, together with the analysis of the modeling error of the pulse wave in large arteries, we show that both a small truncation radius and the complex capacitance in the improved Windkessel model play an important role in reducing the modeling error, defined as the difference in dynamics induced by the structured tree model and the Windkessel models.
Imaging TOF‐SIMS of rat kidney prepared by high‐pressure freezing

Phosphocholine, potassium ions, and sodium ions were localized in rat kidney with imaging TOF‐SIMS. Tissue preparation was performed with high‐pressure freezing, freeze‐fracturing and freeze‐drying. The distribution of sodium ions was visualized by imaging the signal at m/z 23 of positively charged secondary ions, and the distribution of potassium ions was visualized by imaging the signal at m/z 39. Potassium was found localized within cells of the proximal tubulus epithelium and within cells of the glomeruli. High signals of sodium ions were seen in the interstitial tissue and also in epithelial cells of the collecting ducts and in glomeruli. The overlay image showed that the distribution of sodium ions and potassium ions were largely complementary with color mixing in glomeruli and in the interstitium surrounding proximal tubules. The ion distribution was further analyzed by correlation analysis. Phosphocholine‐containing phospholipids were visualized by imaging the phosphocholine head group at m/z 184 of positively charged ions. The m/z 184 signal shows a ubiquitous distribution with a high intensity of phosphocholine in epithelial cells. Overlay image of m/z 184, m/z 39, and m/z 23 and multivariate analysis showed that the localization of high levels of phosphocholine colocalizes with high levels of potassium ions, as expected for an ion with intracellular localization. Microsc. Res. Tech. 68:329–334, 2005. © 2005 Wiley‐Liss, Inc.
Perceived Image Contrast and Observer Preference I. The Effects of Lightness, Chroma, and Sharpness Manipulations on Contrast Perception

A large-scale investigation into the perception of contrast in color images was performed. Psychophysical experiments were performed to determine the influence of image lightness, chroma, and sharpness transforms on perceived image contrast and observer preference. The influence of these transforms on perceived contrast was investigated separately by independent soft copy, paired comparison tests of contrast perception and image preference. The perception of contrast across transformations was also investigated, as was the perception of image contrast relative to the most preferred image manipulation. In all, four experiments of contrast perception and image preference were performed by at least thirty-two observers each. Results of the lightness, chroma, and sharpness-contrast experiments indicate perceived image contrast is a function of multiple image characteristics as opposed to simply being a function of the dynamic range of image intensity. In the lightness-contrast experiments, images of identical white and black points were scaled to have significant differences in contrast based on their manipulations from the original image. In the chroma-contrast experiments, images of identical lightness channels were scaled to have significant differences in perceived contrast due to relative chroma amount. In the sharpness-contrast experiments, images of identical white and black points were scaled to have significantly different levels of perceived contrast due to sharpness. In the scale-linking experiment, it was found that images of the above manipulations could be scaled similarly for perceived contrast. All scales of perceived contrast and image preference were found to be image independent among pictorial images, regardless of observer experience.
Reviews: Effects of Transdermal Rivastigmine on ADAS-Cog Items in Mild-to-Moderate Alzheimer’s Disease

Alzheimer’s disease (AD) patients treated with rivastigmine transdermal patch have shown statistically significant differences versus placebo on the AD Assessment scale-cognitive subscale (ADAS-cog). In this retrospective analysis of a double-blind, placebo- and active-controlled, 24-week clinical trial, the specific effects of rivastigmine patch on individual ADAS-cog items and cognitive domains (memory, language, and praxis) were explored. The mean baseline to week 24 changes were calculated for each ADAS-cog item and domain in this exploratory, hypothesis-generating analysis. Patients on 9.5 mg/24 h rivastigmine patch, 17.4 mg/24 h rivastigmine patch, and 3 to 12 mg/d rivastigmine capsules showed improvements over placebo on the memory and praxis ADAS-cog subscales. The rivastigmine patch groups also showed improvements on the language subscale. Significant differences versus placebo were seen on several individual item scores in the rivastigmine-treated groups. Rivastigmine patch was associated with improvements on the memory, praxis, and language domains of cognition in patients with mild-to-moderate AD.