Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Lipoteichoic Acid in the Phagocyte Response to Group B Streptococcus1

Group B Streptococcus (GBS) cell walls potently activate phagocytes by a largely TLR2-independent mechanism. In contrast, the cell wall component lipoteichoic acid (LTA) from diverse Gram-positive bacterial species has been shown to engage TLR2. In this study we examined the role of LTA from GBS in phagocyte activation and the requirements for TLR-LTA interaction. Using cells from knockout mice and genetic complementation in epithelial cells we found that highly pure LTA from both GBS and Staphylococcus aureus interact with TLR2 and TLR6, but not TLR1, in contrast to previous reports. Furthermore, NF-κB activation by LTA required the integrity of two putative PI3K binding domains within TLR2 and was inhibited by wortmannin, indicating an essential role for PI3K in cellular activation by LTA. However, LTA from GBS proved to be a relatively weak stimulus of phagocytes containing ∼20% of the activity observed with LTA from Staphylococcus aureus. Structural analysis by nuclear magnetic resonance spectrometry revealed important differences between LTA from GBS and S. aureus, specifically differences in glycosyl linkage, in the glycolipid anchor and a lack of N-acetylglucosamine substituents of the glycerophosphate backbone. Furthermore, GBS expressing LTA devoid of d-alanine residues, that are essential within immune activation by LTA, exhibited similar inflammatory potency as GBS with alanylated LTA. In conclusion, LTA from GBS is a TLR2/TLR6 ligand that might contribute to secreted GBS activity, but does not contribute significantly to GBS cell wall mediated macrophage activation.
Mutation at the circadian clock gene EARLY MATURITY 8 adapts domesticated barley (Hordeum vulgare) to short growing seasons

The circadian clock is an autonomous oscillator that produces endogenous biological rhythms with a period of about 24 h. This clock allows organisms to coordinate their metabolism and development with predicted daily and seasonal changes of the environment. In plants, circadian rhythms contribute to both evolutionary fitness and agricultural productivity. Nevertheless, we show that commercial barley varieties bred for short growing seasons by use of early maturity 8 (eam8) mutations, also termed mat-a, are severely compromised in clock gene expression and clock outputs. We identified EAM8 as a barley ortholog of the Arabidopsis thaliana circadian clock regulator EARLY FLOWERING3 (ELF3) and demonstrate that eam8 accelerates the transition from vegetative to reproductive growth and inflorescence development. We propose that eam8 was selected as barley cultivation moved to high-latitude short-season environments in Europe because it allowed rapid flowering in genetic backgrounds that contained a previously selected late-flowering mutation of the photoperiod response gene Ppd-H1. We show that eam8 mutants have increased expression of the floral activator HvFT1, which is independent of allelic variation at Ppd-H1. The selection of independent eam8 mutations shows that this strategy facilitates short growth-season adaptation and expansion of the geographic range of barley, despite the pronounced clock defect.
Wavelet Shrinkage using Cross-validation

SUMMARY Wavelets are orthonormal basis functions with special properties that show potential in many areas of mathematics and statistics. This paper concentrates on the estimation of functions and images from noisy data by using wavelet shrinkage. A modified form of twofold cross-validation is introduced to choose a threshold for wavelet shrinkage estimators operating on data sets of length a power of 2. The cross-validation algorithm is then extended to data sets of any length and to multidimensional data sets. The algorithms are compared with established threshold choosers by using simulation. An application to a real data set arising from anaesthesia is presented.
Defense Technical Information Center Compilation Part Notice ADPO 11998

In the theory of radial basis functions, linear combinations of the translates of a single function 4 are used as interpolants. The space spanned by all of these linear combinations carries an inner product defined via b itself. It can be completed and becomes a Hilbert space, called the native space for P, which is of great importance for further investigation of radial basis functions. The native space will contain abstract elements which are not linear combinations of radial basis functions, and require some work to be recognized as functions. This paper provides some characterizations of native spaces and relates some of the different approaches used to define them. Finally, embedding results for native spaces into Sobolev spaces are proven. §
Optimal step-size of a local voting protocol for differentiated consensuses achievement in a stochastic network with priorities

This paper deals with a “differentiated consensuses” problem in a distributed stochastic network system with priorities. The network is considered as a set of heterogeneous agents that process incoming tasks with different importance (priority) levels. The observations about neighbors' states are supposed to be obtained with random noise and delays and the topology could switch over time. Several consensus objectives are to be achieved. To maintain almost balanced load, i.e. approximate consensus for every priority class across the network, a new family of control protocols that use different step-size parameters for each task class is introduced. An instrument for choosing optimal step-sizes for the proposed control strategy is given. In addition, a numerical example that illustrates the proposed control strategy and the results of simulations are provided.
Genetics and the Specificity of the Aging Process

The identification and study of long-lived mutant animals has provided valuable insights into the mechanisms that limit the life-span of organisms. Findings with the gene SIR2suggest that the rate of aging can be regulated under certain conditions. Indeed, increased expression of SIR2 lengthens life-span by acting on biological processes that promote survival under conditions of scarcity. In addition, studies of mutant strains ofCaenorhabditis elegans, in particular daf-2,clk-1, and isp-1 mutants, suggest that the biology of reactive oxygen species in the mitochondria and elsewhere might be the main determinant of life-span in this organism. Thus, the aging process may be more specific than previously anticipated on evolutionary grounds.
Human Drug Metabolism and the Cytochromes P450: Application and Relevance of In Vitro Models

The cytochromes P450 (CYPs) constitute a superfamily of hemoprotein enzymes that are responsible for the biotransformation of numerous xenobiotics, including therapeutic agents. Studies of the biochemical and enzymatic properties of these enzymes and their molecular genetics and regulation of gene expression and activity have greatly enhanced our understanding of several aspects of clinical pharmacology such as pharmacokinetic variability, drug toxicity, and drug interactions. This review evaluates the major human hepatic drug‐metabolizing CYP enzymes and their clinically relevant substrates, inhibitors, and inducers. Also discussed are the molecular bases and clinical implications of genetic polymorphisms that affect the CYPs. Much of the information on the specificity of substrates and inhibitors of the CYP enzymes is derived from in vitro studies using human liver microsomes and heterologously expressed CYP enzymes. These methods are discussed, and guidelines are provided for designing enzyme kinetic and reaction phenotyping studies using multiple approaches. The strengths, weaknesses, and discrepancies among the different approaches are considered using representative examples. The mathematical models used in predicting the pharmacokinetic clearance of a drug from in vitro estimates of intrinsic clearance and the principles of quantitative in vitro‐in vivo scaling of metabolic drug interactions are also discussed.
Psychoeducation and compliance in the treatment of schizophrenia: results of the Munich Psychosis Information Project Study.

OBJECTIVE The present study examined whether psychoeducational groups for patients with schizophrenic disorders and for their families can reduce rehospitalization rates and improve compliance. METHOD 236 inpatients who met DSM-III-R criteria for schizophrenia or schizoaffective disorder and who had regular contact with at least 1 relative or other key person were randomly assigned to 1 of 2 treatment conditions. In the intervention condition, patients and their relatives were encouraged to attend psychoeducational groups over a period of 4 to 5 months. The patients' and relatives' psychoeducational programs were separate, and each consisted of 8 sessions. Patients in the other treatment condition received routine care. Outcomes were compared over 12-month and 24-month follow-up periods. The study was conducted from 1990 to 1994. RESULTS It was possible to significantly reduce the rehospitalization rate after 12 and 24 months in patients who attended psychoeducational groups compared with those receiving routine care (p < .05). Patients who attended psychoeducational groups showed better compliance than patients under routine care without psycho-education. CONCLUSIONS The results suggest that a relatively brief intervention of 8 psychoeducational sessions with systematic family involvement in simultaneous groups can considerably improve the treatment of schizophrenia. Psychoeducation should be routinely offered to all patients with schizophrenia and their families.
A randomized trial comparing the hand‐mounted JoStent with the premounted Multi‐Link Duet stent in patients with coronary artery disease

The objective of this multicenter randomized study was to compare the angiographic and clinical results achieved 1 year after coronary placement of two stent models: the hand‐mounted JoStent and the premounted Multi‐Link Duet stent. We included 505 patients who were randomly assigned to receive either the hand‐mounted JoStent (n = 252) or the premounted Multi‐Link Duet stent (n = 253). The primary endpoint of the study, late lumen loss, measured 1.12 mm in the JoStent group and 1.17 mm in the Multi‐Link Duet group. These values were statistically equivalent (P = 0.02 from the equivalence test). No significant difference was observed in the incidence of restenosis, 24.2% in the JoStent and 25.2% in the Multi‐Link Duet stent group, and target vessel revascularization, 13.9% in the JoStent and 15.4% in the Multi‐Link Duet patients. In conclusion, the hand‐mounted JoStent and the premounted Multi‐Link Duet stent enable excellent procedural success rates and equally favorable 1‐year angiographic and clinical outcomes. Cathet Cardiovasc Intervent 2001;54:414–419. © 2001 Wiley‐Liss, Inc.
Asymptotic multiphysics modeling of composite slender structures

An efficient high-fidelity beam model for predicting multiphysics behavior of smart slender structures is developed using the variational asymptotic method. The original three-dimensional variational statement governing the coupled electromagneto-mechanical behavior is asymptotically split into a multiphysics cross-sectional analysis and a multiphysics beam analysis, exploiting the inherent small parameter characterizing the slenderness of the structure. Several examples are used to validate the proposed model by comparing the results available in the literature and three-dimensional finite element analysis.
Selective rescue of heightened anxiety but not gait ataxia in a premutation 90CGG mouse model of Fragile X-associated tremor/ataxia syndrome

A CGG-repeat expansion in the premutation range in the Fragile X mental retardation 1 gene (FMR1) has been identified as the genetic cause of Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder that manifests with action tremor, gait ataxia and cognitive impairments. In this study, we used a bigenic mouse model, in which expression of a 90CGG premutation tract is activated in neural cells upon doxycycline administration-P90CGG mouse model. We, here, demonstrate the behavioural manifestation of clinically relevant features of FXTAS patients and premutation carrier individuals in this inducible mouse model. P90CGG mice display heightened anxiety, deficits in motor coordination and impaired gait and represent the first FXTAS model that exhibits an ataxia phenotype as observed in patients. The behavioural phenotype is accompanied by the formation of ubiquitin/FMRpolyglycine-positive intranuclear inclusions, as another hallmark of FXTAS, in the cerebellum, hippocampus and amygdala. Strikingly, upon cessation of transgene induction the anxiety phenotype of mice recovers along with a reduction of intranuclear inclusions in dentate gyrus and amygdala. In contrast, motor function deteriorates further and no reduction in intranuclear inclusions can be observed in the cerebellum. Our data thus demonstrate that expression of a 90CGG premutation expansion outside of the FMR1 context is sufficient to evoke an FXTAS-like behavioural phenotype. Brain region-specific neuropathology and (partial) behavioural reversibility make the inducible P90CGG a valuable mouse model for testing pathogenic mechanisms and therapeutic intervention methods.
Gene selection: a Bayesian variable selection approach

UNLABELLED Selection of significant genes via expression patterns is an important problem in microarray experiments. Owing to small sample size and the large number of variables (genes), the selection process can be unstable. This paper proposes a hierarchical Bayesian model for gene (variable) selection. We employ latent variables to specialize the model to a regression setting and uses a Bayesian mixture prior to perform the variable selection. We control the size of the model by assigning a prior distribution over the dimension (number of significant genes) of the model. The posterior distributions of the parameters are not in explicit form and we need to use a combination of truncated sampling and Markov Chain Monte Carlo (MCMC) based computation techniques to simulate the parameters from the posteriors. The Bayesian model is flexible enough to identify significant genes as well as to perform future predictions. The method is applied to cancer classification via cDNA microarrays where the genes BRCA1 and BRCA2 are associated with a hereditary disposition to breast cancer, and the method is used to identify a set of significant genes. The method is also applied successfully to the leukemia data. SUPPLEMENTARY INFORMATION http://stat.tamu. edu/people/faculty/bmallick.html.
Fluid role boundaries: exploring the contribution of the advanced nurse practitioner to multi-professional palliative care.

AIMS AND OBJECTIVES To evaluate the introduction of Advanced Nurse Practitioners in a specialist, multi-professional palliative care context. The objective is to explore the core domains and competencies of the advanced nurse practitioner role in a multi-professional palliative care context. BACKGROUND New models of health care and service delivery are emerging alongside expanded levels of autonomy, skills and decision-making for nurses and midwives. This has resulted in some confusion in the health service community internationally about the professional role and scope of the advanced nurse practitioner. DESIGN A qualitative evaluation study (n = 21). METHODS Three phases of data collection were conducted over 10 months. Twenty-one participants took part from a specialist palliative care unit in one health board in a U.K. region spanning ANPs (n = 2) multi-professional staff (n = 14) and patients/carers (n = 5). Data collection methods included individual and focus group interviews with key stakeholders and observation of the advanced nurse practitioners at work and their reflexive diaries. RESULTS The findings of this evaluation demonstrate that if the advanced nurse practitioner role can flourish it has the potential to shape 'new identities', re-construct the boundaries of nursing roles and emphasise the relationship based elements of excellent nursing work. CONCLUSIONS The advanced nurse practitioner has the potential to enhance specialist palliative care service delivery through fluid role boundaries. The context in which advanced nurse practitioner roles are developed is important as acceptance of the role is linked to the co-construction of a different nursing identity. Our findings support the need to define, defend and name the work of advanced nursing roles. RELEVANCE TO CLINICAL PRACTICE The advanced nurse practitioner roles were regarded as providing a unique contribution to service delivery and were characterised by fluid role boundaries which crossed the traditional disciplinary boundaries between nursing and medicine.
Logic decomposition during technology mapping

A problem in technology mapping is that quality of the final implementation depends significantly on the initially provided circuit structure. To resolve this problem, conventional techniques iteratively but separately apply technology independent transformations and technology mapping. In this paper, we propose a procedure which performs logic decomposition and technology mapping simultaneously. We show that the procedure effectively explores all possible algebraic decompositions. It finds an optimal tree implementation over all the circuit structures examined, while the run time is typically logarithmic in the number of decompositions.
Immunoglobulin free light chains are biomarkers of poor prognosis in basal-like breast cancer and are potential targets in tumor-associated inflammation

Inflammation is an important component of various cancers and its inflammatory cells and mediators have been shown to have prognostic potential. Tumor-infiltrating mast cells can promote tumor growth and angiogenesis, but the mechanism of mast cell activation is unclear. In earlier studies, we demonstrated that immunoglobulin free light chains (FLC) can trigger mast cells in an antigen-specific manner. Increased expression of FLC was observed within stroma of various human cancers including those of breast, colon, lung, pancreas, kidney and skin, and FLC expression co-localized with areas of mast cell infiltration. In a large cohort of breast cancer patients, FLC expression was shown associated with basal-like cancers with an aggressive phenotype. Moreover, lambda FLC was found expressed in areas of inflammatory infiltration and its expression was significantly associated with poor clinical outcome. Functional importance of FLCs was shown in a murine B16F10 melanoma model, where inhibition of FLC-mediated mast cell activation strongly reduced tumor growth. Collectively, this study identifies FLCs as a ligand in the pro-tumorigenic activation of mast cells. Blocking this pathway may open new avenues for the inhibition of tumor growth, while immunohistochemical staining of FLC may be helpful in the diagnosis and prognosis of cancer.
TACC3 mediates the association of MBD2 with histone acetyltransferases and relieves transcriptional repression of methylated promoters

We have recently reported that a novel MBD2 interactor (MBDin) has the capacity to reactivate transcription from MBD2-repressed methylated promoters even in the absence of demethylation events. Here we show that another unrelated protein, TACC3, displays a similar activity on methylated genes. In addition the data reported here provide possible molecular mechanisms for the observed phenomenon. Immunoprecipitation experiments showed that MBD2/TACC3 form a complex in vivo with the histone acetyltransferase pCAF. MBD2 could also associate with HDAC2, a component of MeCP1 repression complex. However, we found that the complexes formed by MBD2 with TACC3/pCAF and with HDAC2 were mutually exclusive. Moreover, HAT enzymatic assays demonstrated that HAT activity associates with MBD2 in vivo and that such association significantly increased when TACC3 was over-expressed. Overall our findings suggest that TACC3 can be recruited by MBD2 on methylated promoters and is able to reactivate transcription possibly by favoring the formation of an HAT-containing MBD2 complex and, thus, switching the repression potential of MBD2 in activation even prior to eventual demethylation.
Identification of Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in meso-diencephalic dopamine neurons

The orphan nuclear receptor Nurr1 is essential for the development of meso-diencephalic dopamine (mdDA) neurons and is required, together with the homeobox transcription factor Pitx3, for the expression of genes involved in dopamine metabolism. In order to elucidate the molecular mechanisms that underlie the neuronal deficits in Nurr1-/- mice, we performed combined gene expression microarrays and ChIP-on-chip analysis and thereby identified Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in vivo. In line with the previously described cooperativity between Nurr1 and Pitx3, we show that the expression of Ptpru and Klhl1 in mdDA neurons is also dependent on Pitx3. Furthermore, we demonstrate that Nurr1 interacts with the Ptpru promoter directly and requires Pitx3 for full expression of Ptpru in mdDA neurons. By contrast, the expression of Dlk1 is maintained in Pitx3-/- embryos and is even expanded into the rostral part of the mdDA area, suggesting a unique position of Dlk1 in the Nurr1 and Pitx3 transcriptional cascades. Expression analysis in Dlk1-/- embryos reveals that Dlk1 is required to prevent premature expression of Dat in mdDA neuronal precursors as part of the multifaceted process of mdDA neuronal differentiation driven by Nurr1 and Pitx3. Taken together, the involvement of Nurr1 and Pitx3 in the expression of novel target genes involved in important neuronal processes such as neuronal patterning, axon outgrowth and terminal differentiation, opens up new avenues to study the properties of mdDA neurons during development and in neuronal pathology as observed in Parkinson's disease.
Influence of a niosomal formulation on the oral bioavailability of acyclovir in rabbits

The purpose of this research was to prepare acyclovir niosomes in a trial to improve its poor and variable oral bioavailability. The nonionic surfactant vesicles were prepared by the conventional thin film hydration method. The lipid mixture consisted of cholesterol, span 60, and dicetyl phosphate in the molar ratio of 65:60:5, respectively. The percentage entrapment was ∼11% of acyclovir used in the hydration process. The vesicles have an average size of 0.95 µm, a most probable size of 0.8 µm, and a size range of 0.4 to 2.2 µm. Most of the niosomes have unilamellar spherical shape. In vitro drug release profile was found to follow Higuchi’s equation for free and niosomal drug. The niosomal formulation exhibited significantly retarded release compared with free drug. The in vivo study revealed that the niosomal dispersion significantly improved the oral bioavailability of acyclovir in rabbits after a single oral dose of 40 mg kg−1. The average relative bioavailability of the drug from the niosomal dispersion in relation to the free solution was 2.55 indicating more than 2-fold increase in drug bioavailability. The niosomal dispersion showed significant increase in the mean residence time (MRT) of acyclovir reflecting sustained release characteristics. In conclusion, the niosomal formulation could be a promising delivery system for acyclovir with improved oral bioavailability and prolonged drug release profiles.