Miracle-dz/UniFAR-FTUs huggingface dataset:
Fibroblast Growth Factor 23 Is Associated With Subclinical Cerebrovascular Damage: The Northern Manhattan Study

Background and Purpose— Elevated fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is linked with mortality, cardiovascular events, and stroke. However, the role of FGF23 as a risk factor for subclinical cerebrovascular damage is unclear. Methods— We used multivariable linear and logistic regression to evaluate associations between FGF23, continuously and by quartiles, with white matter hyperintensity volume, expressed as percent intracranial volume (%ICV), and subclinical brain infarction (SBI) in a community-based stroke-free sample. Results— There were 1170 stroke-free Northern Manhattan Study (NOMAS) participants with FGF23 levels and quantitative magnetic resonance imaging data on white matter hyperintensity volume and SBI. Participants with FGF23 levels in the top quartile (range=85–1425 RU/mL) had greater white matter hyperintensity volume (&bgr;=0.19 %ICV; 95% CI, 0.04–0.33 %ICV; P=0.01) compared with those in the lowest quartile (range=15–49 RU/mL), adjusted for demographics, vascular risk factors, and estimated glomerular filtration rate. These findings remained significant in those without evidence of chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m2). Elevated FGF23 was not associated with SBI overall after adjusting for demographic factors and estimated glomerular filtration rate, but sex modified the effect of FGF23 on odds of SBI (P for interaction=0.03). FGF23 was associated with significantly greater odds of SBI only in men (odds ratio, 1.7; 95% CI, 1.1–2.7; P=0.03) after full adjustment. Conclusions— These cross-sectional community-based data from a diverse urban sample show an association between elevated FGF23 and small vessel disease and magnetic resonance imaging–defined brain infarction in men, independent of chronic kidney disease. Data on elevated FGF23 and subclinical cerebrovascular damage progression are needed.
Structural Basis of Multifunctionality in a Vitamin B12-processing Enzyme*

An early step in the intracellular processing of vitamin B12 involves CblC, which exhibits dual reactivity, catalyzing the reductive decyanation of cyanocobalamin (vitamin B12), and the dealkylation of alkylcobalamins (e.g. methylcobalamin; MeCbl). Insights into how the CblC scaffold supports this chemical dichotomy have been unavailable despite it being the most common locus of patient mutations associated with inherited cobalamin disorders that manifest in both severe homocystinuria and methylmalonic aciduria. Herein, we report structures of human CblC, with and without bound MeCbl, which provide novel biochemical insights into its mechanism of action. Our results reveal that CblC is the most divergent member of the NADPH-dependent flavin reductase family and can use FMN or FAD as a prosthetic group to catalyze reductive decyanation. Furthermore, CblC is the first example of an enzyme with glutathione transferase activity that has a sequence and structure unrelated to the GST superfamily. CblC thus represents an example of evolutionary adaptation of a common structural platform to perform diverse chemistries. The CblC structure allows us to rationalize the biochemical basis of a number of pathological mutations associated with severe clinical phenotypes.
Clozapine users in Australia: their characteristics and experiences of care based on data from the 2010 National Survey of High Impact Psychosis

Aims. Clozapine is the most effective medication for treatment refractory schizophrenia. However, descriptions of the mental health and comorbidity profile and care experiences of people on clozapine in routine clinical settings are scarce. Using data from the 2010 Australian Survey of High Impact Psychosis, we aimed to examine the proportion of people using clozapine, and to compare clozapine users with other antipsychotic users on demographic, mental health, adverse drug reaction, polypharmacy and treatment satisfaction variables. Methods. Data describing 1049 people with a diagnosis of schizophrenia or schizoaffective disorder, who reported taking any antipsychotic medication in the previous 4 weeks, were drawn from a representative Australian survey of people with psychotic disorders in contact with mental health services in the previous 12 months. We compared participants taking clozapine (n = 257, 22.4%) with those taking other antipsychotic medications, on a range of demographic, clinical and treatment-related indicators. Results. One quarter of participants were on clozapine. Of participants with a chronic course of illness, only one third were on clozapine. After adjusting for diagnosis and illness chronicity, participants taking clozapine had significantly lower odds of current alcohol, cannabis and other drug use despite similar lifetime odds. Metabolic syndrome and diabetes were more common among people taking clozapine; chronic pain was less common. Psychotropic polypharmacy did not differ between groups. Conclusions. Consistent with international evidence of clozapine underutilisation, a large number of participants with chronic illness and high symptom burden were not taking clozapine. The lower probabilities of current substance use and chronic pain among clozapine users warrant further study.
ESE-1, an Enterocyte-specific Ets Transcription Factor, Regulates MIP-3α Gene Expression in Caco-2 Human Colonic Epithelial Cells*

We have previously shown that colonic epithelial cells are a major site of MIP-3α production in human colon and that enterocyte MIP-3α protein levels are elevated in inflammatory bowel disease. The aim of this study was to determine the molecular mechanisms regulating MIP-3α gene transcription in Caco-2 intestinal epithelial cells. We show that a κB element at nucleotides −82 to −93 of the MIP-3α promoter binds p50/p65 NF-κB heterodimers and is a major regulator of basal and interleukin-1β (IL-1β)-mediated gene activation. Scanning mutagenesis of the MIP-3α 5′-flanking region also identified two additional binding elements: Site X (nucleotides −63 to −69) and Site Y (nucleotides −143 to −154). Site X (CGCCTTC) bound Sp1 and regulated basal MIP-3α gene transcription. Overexpression of Sp1 increased basal luciferase activity, whereas, substitutions in the Sp1 element significantly reduced reporter activity. In contrast, Site Y (AAGCAGGAAGTT) regulated both basal and cytokine-induced gene activation and bound the Ets nuclear factor ESE-1. Substitutions in the Site Y element markedly reduced inducible MIP-3α reporter activity. Conversely, overexpression of ESE-1 significantly up-regulated MIP-3α luciferase levels. Taken together, our findings demonstrate that co-ordinate activation and binding of ESE-1, Sp1, and NF-κB to the MIP-3α promoter is required for maximal gene expression by cytokine-stimulated Caco-2 human intestinal epithelial cells.
Progesterone, Inflammatory Cytokine (TNF-α), and Oxidative Stress (H2O2) Regulate Progesterone Receptor Membrane Component 1 Expression in Fetal Membrane Cells

Progesterone receptor membrane component 1 (PGRMC1) is an important novel mediator of progesterone (P4) function in fetal membrane cells. We demonstrated previously that PGRMC1 is differentially expressed in fetal membranes among pregnancy subjects and diminished in preterm premature rupture of membrane subjects. In the current study, we aim to elucidate whether PGRMC1 expression is regulated by P4, tumor necrosis factor α (TNF-α), and H2O2 in fetal membrane cells. Primary cultured membrane cells were serum starved for 24 hours followed by treatments of P4, 17 hydroxyprogesterone caproate, and medroxyprogesterone 17 acetate (MPA) at 10−7 mol/L with ethanol as vehicle control; TNF-α at 10, 20, and 50 ng/mL with phosphate-buffered saline (PBS) as control; and H2O2 at 10 and 100 μmol/L with culture media as control for 24, 48, and 72 hours. The messenger RNA (mRNA) and protein expression of PGRMC1 was quantified using polymerase chain reaction and Western blotting, respectively. We found that PGRMC1 protein expression was regulated by MPA, TNF-α, and H2O2 in a dose-dependent manner. This regulation is also specific to the type of cell (amnion, chorion, or decidua). The upregulation of PGRMC1 by MPA might be mediated through glucocorticoid receptor (GR) demonstrated using amnion and chorion cells model with GR knockdown by specific small interfering RNA transfection. The mRNA expression of PGRMC1 was decreased by H2O2 (100 μmol/L) treatment in amnion cells, which might ultimately result in downregulation of PGRMC1 protein as our data demonstrated. None of other treatments changed PGRMC1 mRNA level in these cells. We conclude that these stimuli act as regulatory factors of PGRMC1 in a cell-specific manner.
Gene Transfer by Transduction in the Marine Environment

ABSTRACT To determine the potential for bacteriophage-mediated gene transfer in the marine environment, we established transduction systems by using marine phage host isolates. Plasmid pQSR50, which contains transposon Tn5 and encodes kanamycin and streptomycin resistance, was used in plasmid transduction assays. Both marine bacterial isolates and concentrated natural bacterial communities were used as recipients in transduction studies. Transductants were detected by a gene probe complementary to the neomycin phosphotransferase (nptII) gene in Tn5. The transduction frequencies ranged from 1.33 × 10−7 to 5.13 × 10−9transductants/PFU in studies performed with the bacterial isolates. With the mixed bacterial communities, putative transductants were detected in two of the six experiments performed. These putative transductants were confirmed and separated from indigenous antibiotic-resistant bacteria by colony hybridization probed with thenptII probe and by PCR amplification performed with two sets of primers specific for pQSR50. The frequencies of plasmid transduction in the mixed bacterial communities ranged from 1.58 × 10−8 to 3.7 × 10−8transductants/PFU. Estimates of the transduction rate obtained by using a numerical model suggested that up to 1.3 × 1014transduction events per year could occur in the Tampa Bay Estuary. The results of this study suggest that transduction could be an important mechanism for horizontal gene transfer in the marine environment.
Conceptualising Informality: Regulation and Enforcement

The informality discourse is large and vibrant, and is expanding rapidly. But there is a certain conceptual incoherence to the literature. New definitions of informality compete with old definitions leading to a plethora of alternative conceptualisations. While some individual studies may apply a tight definition consistently, the literature as a whole is in a mess. This article proposes that informality and formality should be seen in direct relation to economic activity in the presence of specified regulation(s). Relative to the regulation(s), four conceptual categories that can help frame the analysis are: (A) regulation applicable and compliant, (B) regulation applicable and non-compliant, (C) regulation non-applicable after adjustment of activity, and (D) regulation non-applicable to the activity. Rather than use thegeneric labels â€˜informalâ€™ and â€˜formalâ€™, it would be preferable if the analysis focused on thesefour categories (or even more disaggregated as appropriate). A central determining factor in the impacts of regulation on economic activity across these four categories is the nature and intensity of enforcement. While lack of enforcement is well-documented, an understanding of its determinants − why and to what extent a government would not enforce a regulation that it has itself passed, and why non-enforcement varies from one context to another, is relatively neglected in the literature. Thus, specificity on regulation and on enforcement is the key to achieving conceptual clarity in the analytical literature and in the policy discourse on informality. [IZA Discussion Paper 4186]
Programmable Logic Construction Kits for Hyper-Real-Time Neuronal Modeling

Programmable logic designs are presented that achieve exact integration of leaky integrate-and-fire soma and dynamical synapse neuronal models and incorporate spike-time dependent plasticity and axonal delays. Highly accurate numerical performance has been achieved by modifying simpler forward-Euler-based circuitry requiring minimal circuit allocation, which, as we show, behaves equivalently to exact integration. These designs have been implemented and simulated at the behavioral and physical device levels, demonstrating close agreement with both numerical and analytical results. By exploiting finely grained parallelism and single clock cycle numerical iteration, these designs achieve simulation speeds at least five orders of magnitude faster than the nervous system, termed here hyper-real-time operation, when deployed on commercially available field-programmable gate array (FPGA) devices. Taken together, our designs form a programmable logic construction kit of commonly used neuronal model elements that supports the building of large and complex architectures of spiking neuron networks for real-time neuromorphic implementation, neurophysiological interfacing, or efficient parameter space investigations.
Prefrontal Dynamics Underlying Rapid Instructed Task Learning Reverse with Practice

The ability to rapidly reconfigure our minds to perform novel tasks is important for adapting to an ever-changing world, yet little is understood about its basis in the brain. Furthermore, it is unclear how this kind of task preparation changes with practice. Previous research suggests that prefrontal cortex (PFC) is essential when preparing to perform either novel or practiced tasks. Building upon recent evidence that PFC is organized in an anterior-to-posterior hierarchy, we postulated that novel and practiced task preparation would differentiate hierarchically distinct regions within PFC across time. Specifically, we hypothesized and confirmed using functional magnetic resonance imaging and magnetoencephalography with humans that novel task preparation is a bottom-up process that involves lower-level rule representations in dorsolateral PFC (DLPFC) before a higher-level rule-integrating task representation in anterior PFC (aPFC). In contrast, we identified a complete reversal of this activity pattern during practiced task preparation. Specifically, we found that practiced task preparation is a top-down process that involves a higher-level rule-integrating task representation (recalled from long-term memory) in aPFC before lower-level rule representations in DLPFC. These findings reveal two distinct yet highly inter-related mechanisms for task preparation, one involving task set formation from instructions during rapid instructed task learning and the other involving task set retrieval from long-term memory to facilitate familiar task performance. These two mechanisms demonstrate the exceptional flexibility of human PFC as it rapidly reconfigures cognitive brain networks to implement a wide variety of possible tasks.
The Kap60-Kap95 Karyopherin Complex Directly Regulates Phosphatidylcholine Synthesis*

Phosphatidylcholine is the major phospholipid in eukaryotic cells. There are two main pathways for the synthesis of phosphatidylcholine: the CDP-choline pathway present in all eukaryotes and the phosphatidylethanolamine methylation pathway present in mammalian hepatocytes and some single celled eukaryotes, including the yeast Saccharomyces cerevisiae. In S. cerevisiae, the rate-determining step in the synthesis of phosphatidylcholine via the CDP-choline pathway is catalyzed by Pct1. Pct1 converts phosphocholine and CTP to CDP-choline and pyrophosphate. In this study, we determined that Pct1 is in the nucleoplasm and at endoplasmic reticulum and nuclear membranes. Pct1 directly interacts with the α-importin Kap60 via a bipartite basic region in Pct1, and this region of Pct1 was required for its entry into the nucleus. Pct1 also interacted with the β-importin Kap95 in cell extracts, implying a model whereby Pct1 interacts with Kap60 and Kap95 with this tripartite complex transiting the nuclear pore. Exclusion of Pct1 from the nucleus by elimination of its nuclear localization signal or by decreasing Kap60 function did not affect the level of phosphatidylcholine synthesis. Diminution of Kap95 function resulted in almost complete ablation of phosphatidylcholine synthesis under conditions where Pct1 was extranuclear. The β-importin Kap95 is a direct regulator membrane synthesis.
Modulation of Cell-adhesive Activity of Fibronectin by the Alternatively Spliced EDA Segment

Fibronectin (FN) has a complex pattern of alternative splicing at the mRNA level. One of the alternatively spliced segments, EDA, is prominently expressed during biological processes involving substantial cell migration and proliferation, such as embryonic development, malignant transformation, and wound healing. To examine the function of the EDA segment, we overexpressed recombinant FN isoforms with or without EDA in CHO cells and compared their cell-adhesive activities using purified proteins. EDA+ FN was significantly more potent than EDA− FN in promoting cell spreading and cell migration, irrespective of the presence or absence of a second alternatively spliced segment, EDB. The cell spreading activity of EDA+ FN was not affected by antibodies recognizing the EDA segment but was abolished by antibodies against integrin α5 and β1 subunits and by Gly-Arg-Gly-Asp-Ser-Pro peptide, indicating that the EDA segment enhanced the cell-adhesive activity of FN by potentiating the interaction of FN with integrin α5β1. In support of this conclusion, purified integrin α5β1 bound more avidly to EDA+ FN than to EDA− FN. Augmentation of integrin binding by the EDA segment was, however, observed only in the context of the intact FN molecule, since the difference in integrin-binding activity between EDA+ FN and EDA− FN was abolished after limited proteolysis with thermolysin. Consistent with this observation, binding of integrin α5β1 to a recombinant FN fragment, consisting of the central cell-binding domain and the adjacent heparin-binding domain Hep2, was not affected by insertion of the EDA segment. Since the insertion of an extra type III module such as EDA into an array of repeated type III modules is expected to rotate the polypeptide up to 180° at the position of the insertion, the conformation of the FN molecule may be globally altered upon insertion of the EDA segment, resulting in an increased exposure of the RGD motif in III10 module and/or local unfolding of the module. Our results suggest that alternative splicing at the EDA exon is a novel mechanism for up-regulating integrin-binding affinity of FN operating when enhanced migration and proliferation of cells are required.
Functional Elimination of Excitatory Feedforward Inputs Underlies Developmental Refinement of Visual Receptive Fields in Zebrafish

In many sensory systems, receptive fields (RFs) measured by spike responses undergo progressive refinement during development. It has been proposed that elimination of excitatory synaptic inputs underlies such functional refinement. However, despite many extracellular recording and anatomical studies, direct in vivo intracellular evidence has remained limited. In this study, by cell-attached recordings in the developing optic tectum of zebrafish, we found that during a short period after the initial formation of retinotectal synapses, spike visual RFs of tectal neurons underwent a two-stage developmental modulation: from an initial expansion to a later refinement. Whole-cell voltage-clamp recordings revealed that the underlying excitatory synaptic RF exhibited a similar developmental progression, with its spatial extent first increased and then reduced, and its spatial tuning profile gradually sharpened. The inhibitory RF was initially larger than the excitatory RF but became matched with the excitatory RF at later stages. Simulation with the integrate-and-fire neuron model suggested that the developmental changes of excitatory RFs primarily accounted for the initial enlargement and later refinement of spike RFs, whereas inhibitory inputs generally reduced the size of the spike RF without affecting its developmental progression. In addition, spike RF of individual retinal ganglion cells did not significantly change in size during the same period, and the spatial extent and tuning profile of the tectal excitatory RF barely changed after intratectal excitatory connections were silenced. Together, our results demonstrate that the functional refinement of tectal visual RFs results primarily from a selective elimination of feedforward retinotectal inputs.
The Effect of Shape and Arrangement of End Sill Stepped Cascade Weirs on Water Quality

Hydraulic structures can be accepted as the key components in improving aeration efficiency because of the strong turbulent mixing associated with substantial air bubble entrainment at these structures. Different hydraulic structures have been designed to enhance aeration such as stepped cascades. A laboratory model of stepped cascade weir with five different shapes of end sill (normal, triangle, rectangle1, rectangle2 and rectangle3) have been installed at Al- Mustansiriya University, College of Engineering to evaluate treatment system and reduced pollutants in marginal water for different flow rates (35,60 and 80 L/min). Results indicate that high removal efficiency of all pollutants parameter (Cu, Cr, Mo, Br, Fe, Mn, Zn, PO4, Cl-, ClO2, Hardness as CaCO3, NH3, NO2, Toxic matter) is for rectangle1 shape at Q=60L/min. High aeration efficiency is 45.7% for rectangle1 shape at Q=80L/min. High removal efficiency for BOD5 and COD are 48% and 47% respectively for rectangle 1 at Q=80 L/min.
Anchoring fibrils form a complex network in human and rabbit cornea.

Anchoring fibril distribution, depth of penetration into the stroma, and pattern of histochemical localization of type VII collagen (the anchoring fibril collagen) were studied in normal human and rabbit corneas. Electron micrographs of cross sections and sections taken parallel to the basement membrane demonstrate that anchoring fibrils insert into the basal lamina and then splay out laterally. They are more readily seen in sections taken parallel to the basal lamina, where they are observed to form a complex branching and anastomosing network below the basal lamina. Distal to the basal lamina, anchoring fibrils appear to insert into patches of dense extracellular matrix termed "anchoring plaques. " Average depth of penetration of anchoring fibrils into stroma is 0.60 and 0.54 microns for human and rabbit, respectively. Monoclonal antibodies to type VII collagen localize only to the basement membrane-anchoring fibril zone of both human and rabbit corneas. No obvious differences in anchoring fibril structure or distribution were observed between human corneas, which have a Bowman's layer, and rabbit corneas, which do not.
Time-frequency-autoregressive random processes: modeling and fast parameter estimation

We present a novel formulation of nonstationary autoregressive (AR) models in terms of time-frequency (TF) shifts. The parameters of the proposed TFAR model are determined by "TF Yule-Walker equations" that involve the expected ambiguity function and can be solved efficiently due to their block-Toeplitz structure. For moderate model orders, we also propose approximate TF Yule-Walker equations that have Toeplitz/block-Toeplitz structure and thus allow a further reduction of computational complexity. Simulation results demonstrate that the TFAR model is parsimonious and accurate and that the performance of our parameter estimation methods compares favorably with that of Y. Grenier's method (see IEEE Trans. Acoust., Speech, Sig. Processing, vol.31, p.899-911, 1983).