Miracle-dz/UniFAR-FTUs huggingface dataset:
The effect of the pathological V72I, D109N and T190M missense mutations on the molecular structure of α-dystroglycan

Dystroglycan (DG) is a highly glycosylated protein complex that links the cytoskeleton with the extracellular matrix, mediating fundamental physiological functions such as mechanical stability of tissues, matrix organization and cell polarity. A crucial role in the glycosylation of the DG α subunit is played by its own N-terminal region that is required by the glycosyltransferase LARGE. Alteration in this O-glycosylation deeply impairs the high affinity binding to other extracellular matrix proteins such as laminins. Recently, three missense mutations in the gene encoding DG, mapped in the α-DG N-terminal region, were found to be responsible for hypoglycosylated states, causing congenital diseases of different severity referred as primary dystroglycanopaties.To gain insight on the molecular basis of these disorders, we investigated the crystallographic and solution structures of these pathological point mutants, namely V72I, D109N and T190M. Small Angle X-ray Scattering analysis reveals that these mutations affect the structures in solution, altering the distribution between compact and more elongated conformations. These results, supported by biochemical and biophysical assays, point to an altered structural flexibility of the mutant α-DG N-terminal region that may have repercussions on its interaction with LARGE and/or other DG-modifying enzymes, eventually reducing their catalytic efficiency.
Outcomes of matched sibling donor hematopoietic stem cell transplantation for severe sickle cell disease with myeloablative conditioning and intermediate‐dose of rabbit anti‐thymocyte globulin

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD) in children. Despite excellent outcomes of matched sibling donor (MSD) HSCT, there is still 5–10% chance of rejection and transplant related mortality (TRM) with 12–23% incidence of graft versus host disease (GVHD). We postulated that an intermediate dose of rabbit anti‐thymocyte globulin (r‐ATG, 10 mg/kg cumulative) would be effective in preventing both rejection and GVHD.
A Coevolutionary Residue Network at the Site of a Functionally Important Conformational Change in a Phosphohexomutase Enzyme Family

Coevolution analyses identify residues that co-vary with each other during evolution, revealing sequence relationships unobservable from traditional multiple sequence alignments. Here we describe a coevolutionary analysis of phosphomannomutase/phosphoglucomutase (PMM/PGM), a widespread and diverse enzyme family involved in carbohydrate biosynthesis. Mutual information and graph theory were utilized to identify a network of highly connected residues with high significance. An examination of the most tightly connected regions of the coevolutionary network reveals that most of the involved residues are localized near an interdomain interface of this enzyme, known to be the site of a functionally important conformational change. The roles of four interface residues found in this network were examined via site-directed mutagenesis and kinetic characterization. For three of these residues, mutation to alanine reduces enzyme specificity to ∼10% or less of wild-type, while the other has ∼45% activity of wild-type enzyme. An additional mutant of an interface residue that is not densely connected in the coevolutionary network was also characterized, and shows no change in activity relative to wild-type enzyme. The results of these studies are interpreted in the context of structural and functional data on PMM/PGM. Together, they demonstrate that a network of coevolving residues links the highly conserved active site with the interdomain conformational change necessary for the multi-step catalytic reaction. This work adds to our understanding of the functional roles of coevolving residue networks, and has implications for the definition of catalytically important residues.
Forage Species Swarm in Response to Coastal Upwelling

We observed the distribution and identity of forage species to infer behavioral changes in response to intraseasonal variation in the coastal upwelling ecosystem of Monterey Bay, California. While the biomass of forage species remained comparable, the small‐scale distribution of krill and anchovies was strongly affected by upwelling conditions. When regional upwelling influences were strong in the Bay, both species formed numerous discrete swarms and schools. During relaxation, both species were more diffusely distributed. Rather than gross changes in spatial distribution, a process that could take a long time for these relatively small animals, forage species responded to the short time scale dynamics that occur between days in the upwelling season with changes in their aggregative behavior. The behavioral responses observed highlight the need to study within‐season dynamics in upwelling systems in addition to their cumulative influence in order to understand the ecological processes of these productive systems.
Centre De Referència En Economia Analítica Barcelona Economics Working Paper Series a Theory of Reference-dependent Behavior a Theory of Reference-dependent Behavior

Extensive field and experimental evidence in a variety of environments show that behavior depends on a reference point. This paper provides an axiomatic characterization of this dependence. We proceed by imposing gradually more structure on both choice correspondences and preference relations, requiring increasingly higher levels of rationality, and freeing the decision-maker from certain types of inconsistencies. The appropriate degree of behavioral structure will depend on the phenomenon that is to be modeled. Lastly, we provide two applications of our work: one to model the status-quo bias, and another to model addictive behavior.
Uncertainty Analysis in Photovoltaic Cell Parameter Estimation

This paper describes a theoretical approach to evaluate the uncertainty on the series and shunt resistances estimated by the seven-parameter (double diode) model of a photovoltaic (PV) cell using data commonly provided by panel manufacturers, measured environmental parameters, and semiempirical equations. After a brief survey on the state of the art and the treatment of the double-diode model, the procedure proposed by the authors, to estimate the unknown parameters, is illustrated. The theoretical expression of the uncertainty, which affects the estimation of the series and shunt resistances (namely, and ) of a PV cell, is then derived. A statistical analysis performed by means of a Monte Carlo simulation is in agreement with the theoretical expression of the uncertainty.
The effect of a 16% carbamide peroxide gel on mercury and silver ion release from admixed and spherical dental amalgams.

AIM The aim of this study was to investigate the effect of 16 percent carbamide peroxide gel on mercury and silver ions released from admixed and spherical dental amalgams. METHODS AND MATERIALS A total of 96 amalgam discs were prepared from two different types and brands of dental amalgam (admixed and spherical). The samples were stored at room temperature in glass tubes containing distilled water for 24 hours. The specimens were then polished and again immersed in distilled water at room temperature and stored for one month. Samples of both types of dental amalgam were treated with carbamide peroxide 16 percent gel (Nite White, Discus Dental, Inc., Culver City, CA, USA) for 14 and 28 hours (experimental group) and compared to samples not exposed to the bleaching agent but stored continuously in distilled water. Mercury and silver levels of each solution were measured using the VAV-440 analyzer system. RESULTS Mercury and silver ions released from the experimental group were significantly greater than from the control group (p<0.001). There was no significant difference between the mean levels of mercury and silver ions in the two kinds of amalgams after treatment with 16 percent carbamide peroxide (p=0.119 for mercury and p=0.199 for silver). Increasing the storage time in the carbamide peroxide gel from 14 to 28 hours did not result in significant changes in the amount of ions released (p=0.329 for mercury and p=0.082 for silver). Also, the interaction effect between amalgam particles' shape (admixed and spherical) versus storage time (14 versus 28 hours) was not statistically significant (p=0.901 for mercury and p=0.951 for silver). CONCLUSION Treatment with 16 percent carbamide peroxide gel increased mercury and silver ions released from admixed and spherical amalgams, compared to samples in the control group, but the difference between the two amalgams was not statistically significant. CLINICAL SIGNIFICANCE The amount of mercury and silver ions released from high-copper dental amalgams during bleaching with 16 percent carbamide peroxide is in the safe range of mercury intake for patients.
Analysis of risk factors for the occurrence of feather pecking in laying hen growers.

1. Potential risk factors for the occurrence of feather pecking in laying hen growers raised under commercial conditions were investigated on Swiss farms with more than 500 rearing places. On-farm interviews were conducted on a sample of 64 flocks which represented 42.6% of all farms concerned. 2. All variables considered were dichotomised and their univariate correlation with the occurrence of feather pecking was tested for significance at P <0.20 using chi2 tests. Logistic regression with backward elimination was then used with the significant variables to identify the potentially most important factors influencing feather pecking. These variables included stocking density, light intensity, intensity of care, access to elevated perches, access to a roofed and littered outdoor area ('bad weather run'), time of access to the feeding facilities of the housing system, stocking density in the restricted area at the beginning of the rearing period, additional open feeding areas in the beginning and air quality. 3. The final model contained stocking density and access to elevated perches as significant factors (P<0.05). Flocks kept in high density (> or = 10 birds per m2) and with no access to elevated perches were 6.4 (95% Confidence interval 1.7 to 24.2) and 4.0 (95% Confidence interval 1.2 to 12.9) times more likely to be affected by feather pecking, respectively. 4. The study identified 2 risk factors for the occurrence of feather pecking in flocks of laying hen growers reared under commercial conditions. It is concluded that in order to reduce feather pecking chicks should be reared at low density and with access to elevated perches.
Repeated Treatment with Subtoxic Doses of TRAIL Induces Resistance to Apoptosis through Its Death Receptors in MDA-MB-231 Breast Cancer Cells

Recombinant human tumor necrosis factor–related apoptosis–inducing ligand (rhTRAIL) is being evaluated clinically in treating various malignancies. Previous studies have shown that repeated application of high doses of rhTRAIL results in a subpopulation of parental cells that is unresponsive to the death ligand. However, it is not clear whether TRAIL-sensitive cancer cells could acquire resistance to TRAIL treatment. Here, we found that MDA-MB-231 breast cancer cells, which are highly sensitive to TRAIL-induced apoptosis, became resistant to TRAIL killing after a prolonged exposure to subtoxic doses of rhTRAIL. The resulting TRAIL-resistant cells were cross-resistant to antibodies against its death receptors (DR4 and DR5); however, they retained sensitivity to several clinically relevant chemotherapies. Surface expression of DR4 and DR5 was significantly reduced in the selected cells, resulting in failure in death-inducing signaling complex formation and caspase activation. In addition, real-time PCR analysis revealed an upregulation in multiple apoptosis-regulator genes, including c-FLIP, Stat5a, and Stat5b. Inhibition of Janus-activated kinase, an upstream activator of signal transducer and activator of transcription 5 (Stat5), or knockdown of Stat5 itself partially restored cellular sensitivity to TRAIL-induced apoptosis, suggesting that Stat5 signaling is also involved in the development of TRAIL resistance. Furthermore, we showed that acquired TRAIL resistance was effectively eliminated by combination with etoposide, doxorubicin, or paclitaxel. These results suggest that tumor cells could acquire resistance to TRAIL therapy especially when they are repeatedly exposed to low levels of the death ligand, highlighting the necessity of combination with therapies that target the resistance mechanisms. (Mol Cancer Res 2009;7(11):1835–44)
The Hippocampus and Imagining the Future: Where Do We Stand?

Recent neuroimaging work has demonstrated that the hippocampus is engaged when imagining the future, in some cases more than when remembering the past. It is possible that this hippocampal activation reflects recombining details into coherent scenarios and/or the encoding of these scenarios into memory for later use. However, inconsistent findings have emerged from recent studies of future simulation in patients with memory loss and hippocampal damage. Thus, it remains an open question as to whether the hippocampus is necessary for future simulation. In this review, we consider the findings from patient studies and the neuroimaging literature with respect to a new framework that highlights three component processes of simulation: accessing episodic details, recombining details, and encoding simulations. We attempt to reconcile these discrepancies between neuroimaging and patient studies by suggesting that different component processes of future simulation may be differentially affected by hippocampal damage.
Automation of system building for state-of-the-art large vocabulary speech recognition using evolution strategy

When building a state-of-the-art speech recognition system, the laborious effort required by human experts in tuning numerous parameters remains a prominent obstacle. The goal of this paper is to automate the process. We propose to tune DNN-HMM based large vocabulary speech recognition systems using the covariance matrix adaptation evolution strategy (CMA-ES) with a multi-objective Pareto optimization. This optimizes systems to achieve both high-accuracy and compact model size. An additional advantage of our approach is that it is efficiently parallelizable and easily adapted to cloud computing services. We performed experiments on the Corpus of Spontaneous Japanese (CSJ) using the TSUBAME 2.5 supercomputer. Compared with a strong manually tuned configuration borrowed from a similar system, our approach automatically discovered systems with lower WER by 0.48%, and systems with 59% smaller model size while keeping WER constant. The optimized training script is released in the Kaldi speech recognition toolkit as the first publicly available recipe for Japanese large vocabulary speech recognition.
Chaotic mixing deep in the lung

Our current understanding of the transport and deposition of aerosols (viruses, bacteria, air pollutants, aerosolized drugs) deep in the lung has been grounded in dispersive theories based on untested assumptions about the nature of acinar airflow fields. Traditionally, these have been taken to be simple and kinematically reversible. In this article, we apply the recently discovered fluid mechanical phenomenon of irreversible low-Reynolds number flow to the lung. We demonstrate, through flow visualization studies in rhythmically ventilated rat lungs, that such a foundation is false, and that chaotic mixing may be key to aerosol transport. We found substantial alveolar flow irreversibility with stretched and folded fractal patterns, which lead to a sudden increase in mixing. These findings support our theory that chaotic alveolar flow—characterized by stagnation saddle points associated with alveolar vortices—governs gas kinematics in the lung periphery, and hence the transport, mixing, and ultimately the deposition of fine aerosols. This mechanism calls for a rethinking of the relationship of exposure and deposition of fine inhaled particles.
Experimental Axonal Injury Triggers Interleukin-6 mRNA, Protein Synthesis and Release into Cerebrospinal Fluid

Diffuse axonal injury is a frequent pathologic sequel of head trauma, which, despite its devastating consequences for the patients, remains to be fully elucidated. Here we studied the release of interleukin-6 (IL-6) into CSF and serum, as well as the expression of IL-6 messenger ribonucleic acid (mRNA) and protein in a weight drop model of axonal injury in the rat. The IL-6 activity was elevated in CSF within 1 hour and peaked between 2 and 4 hours, reaching maximal values of 82,108 pg/mL, and returned to control values after 24 hours. In serum, the levels of IL-6 remained below increased CSF levels and did not exceed 393 pg/mL. In situ hybridization demonstrated augmented IL-6 mRNA expression in several regions including cortical pyramidal cells, neurons in thalamic nuclei, and macrophages in the basal subarachnoid spaces. A weak constitutive expression of IL-6 protein was shown by immunohistochemical study in control brain. After injury, IL-6 increased at 1 hour and remained elevated through the first 24 hours, returning to normal afterward. Most cells producing IL-6 were cortical, thalamic, and hippocampal neurons as confirmed by staining for the neuronal marker NeuN. These results extend our previous studies showing IL-6 production in the cerebrospinal fluid of patients with severe head trauma and demonstrate that neurons are the main source of IL-6 after experimental axonal injury.
Identification of two nuclear factor-binding domains on the chicken cardiac actin promoter: implications for regulation of the gene

The cis-acting regions that appear to be involved in negative regulation of the chicken alpha-cardiac actin promoter both in vivo and in vitro have been identified. A nuclear factor(s) binding to the proximal region mapped over the TATA element between nucleotides -50 and -25. In the distal region, binding spanned nucleotides -136 to -112, a region that included a second CArG box (CArG2) 5' to the more familiar CCAAT-box (CArG1) consensus sequence. Nuclear factors binding to these different domains were found in both muscle and nonmuscle preparations but were detectable at considerably lower levels in tissues expressing the alpha-cardiac actin gene. In contrast, concentrations of the beta-actin CCAAT-box binding activity were similar in all extracts tested. The role of these factor-binding domains on the activity of the cardiac actin promoter in vivo and in vitro and the prevalence of the binding factors in nonmuscle extracts are consistent with the idea that these binding domains and their associated factors are involved in the tissue-restricted expression of cardiac actin through both positive and negative regulatory mechanisms. In the absence of negative regulatory factors, these same binding domains act synergistically, via other factors, to activate the cardiac actin promoter during myogenesis.
Advances in Brief Endogenous Galectin-3 Determines the Routing of CD 95 Apoptotic Signaling Pathways

Studies of CD95 (APO-1/Fas), a member of the death receptor family, have revealed that it is involved in two primary CD95 apoptotic signaling pathways, one regulated by the large amount of active caspase-8 (type I) formed at the death-inducing signaling complex and the other by the apoptogenic activity of mitochondria (type II). To date, it is still unclear which pathway will be activated in response to an apoptotic insult. Here, we demonstrate that the antiapoptotic molecule galectin-3, which contains the four amino acid-anti-death-motif (NWGR) conserved in the BH1 domain of the Bcl-2 member proteins, is expressed only in type I cells. Transfection of galectin-3 cDNA into galectin-3 null cells (type II) resulted converting them to type I apoptotic phenotype. In addition, we show that galectin-3 is complexed with CD95 in vivo identifying galectin-3 as a novel CD95-binding partner that determines which of the CD95 apoptotic signaling pathways the cell will select.
A variationally consistent fractional time‐step integration method for incompressible and nearly incompressible Lagrangian dynamics

In this paper we present a fractional time‐step method for Lagrangian formulations of solid dynamics problems. The method can be interpreted as belonging to the class of variational integrators which are designed to conserve linear and angular momentum of the entire mechanical system exactly. Energy fluctuations are found to be minimal and stay bounded for long durations.
2 Cognitive Networks 1

Current data networking technology limits a network’s ability to adapt, often resulting in sub-optimal performance. Limited in state, scope, and response mechanisms, the network elements (consisting of nodes, protocol layers, policies, and behaviors) are unable to make intelligent adaptations. Communication of network state information is stifled by the layered protocol architecture, making individual elements unaware of the network status experienced by other elements. Any response that an element may make to network stimuli can only be made in the context of its limited scope. The adaptations that are performed are typically reactive, taking place after a problem has occurred. In this chapter, we advance the idea of cognitive networks, which have the promise to remove these limitations by allowing networks to observe, act, and learn in order to optimize their performance. Cognitive networks are motivated by complexity. Particularly in wireless networks, there has been a trend towards increasingly complex, heterogeneous, and dynamic environments. While wired networks can also take on any of these characteristics (and are not excluded from potential cognitive network applications) wireless networks are a natural target because of their inter-node interactions and the size of their system state space. Previous research into cognitive radio and cross-layer design have addressed some of these issues but have shortcomings from the network perspective. Cognitive networks represent a new scope and approach to dealing with this complexity. This chapter provides the reader with a primer on the cognitive network concept, as envisioned by the authors. It begins by explaining the need for cognitive networks, how they are defined, and possible applications for the technology. Then the chapter examines how cognitive networks are related