Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Novel Pax8 Targets in FRTL-5 Thyroid Cells by Gene Silencing and Expression Microarray Analysis

Background The differentiation program of thyroid follicular cells (TFCs), by far the most abundant cell population of the thyroid gland, relies on the interplay between sequence-specific transcription factors and transcriptional coregulators with the basal transcriptional machinery of the cell. However, the molecular mechanisms leading to the fully differentiated thyrocyte are still the object of intense study. The transcription factor Pax8, a member of the Paired-box gene family, has been demonstrated to be a critical regulator required for proper development and differentiation of thyroid follicular cells. Despite being Pax8 well-characterized with respect to its role in regulating genes involved in thyroid differentiation, genomics approaches aiming at the identification of additional Pax8 targets are lacking and the biological pathways controlled by this transcription factor are largely unknown. Methodology/Principal Findings To identify unique downstream targets of Pax8, we investigated the genome-wide effect of Pax8 silencing comparing the transcriptome of silenced versus normal differentiated FRTL-5 thyroid cells. In total, 2815 genes were found modulated 72 h after Pax8 RNAi, induced or repressed. Genes previously reported to be regulated by Pax8 in FRTL-5 cells were confirmed. In addition, novel targets genes involved in functional processes such as DNA replication, anion transport, kinase activity, apoptosis and cellular processes were newly identified. Transcriptome analysis highlighted that Pax8 is a key molecule for thyroid morphogenesis and differentiation. Conclusions/Significance This is the first large-scale study aimed at the identification of new genes regulated by Pax8, a master regulator of thyroid development and differentiation. The biological pathways and target genes controlled by Pax8 will have considerable importance to understand thyroid disease progression as well as to set up novel therapeutic strategies.
Posttranslational Regulation of Human DNA Polymerase ι*

Background: Many proteins are subject to posttranslational regulation, such as ubiquitination. Results: Human DNA polymerase ι (polι) can be monoubiquitinated at >27 unique sites, and exposure to naphthoquinones results in polyubiquitination of polι. Conclusion: Ubiquitination sites are located across the entire polι polypeptide as well as various structural motifs. Significance: Ubiquitination at these sites is likely to alter cellular functions of polι in vivo. Human DNA polymerases (pols) η and ι are Y-family DNA polymerase paralogs that facilitate translesion synthesis past damaged DNA. Both polη and polι can be monoubiquitinated in vivo. Polη has been shown to be ubiquitinated at one primary site. When this site is unavailable, three nearby lysines may become ubiquitinated. In contrast, mass spectrometry analysis of monoubiquitinated polι revealed that it is ubiquitinated at over 27 unique sites. Many of these sites are localized in different functional domains of the protein, including the catalytic polymerase domain, the proliferating cell nuclear antigen-interacting region, the Rev1-interacting region, and its ubiquitin binding motifs UBM1 and UBM2. Polι monoubiquitination remains unchanged after cells are exposed to DNA-damaging agents such as UV light (generating UV photoproducts), ethyl methanesulfonate (generating alkylation damage), mitomycin C (generating interstrand cross-links), or potassium bromate (generating direct oxidative DNA damage). However, when exposed to naphthoquinones, such as menadione and plumbagin, which cause indirect oxidative damage through mitochondrial dysfunction, polι becomes transiently polyubiquitinated via Lys11- and Lys48-linked chains of ubiquitin and subsequently targeted for degradation. Polyubiquitination does not occur as a direct result of the perturbation of the redox cycle as no polyubiquitination was observed after treatment with rotenone or antimycin A, which both inhibit mitochondrial electron transport. Interestingly, polyubiquitination was observed after the inhibition of the lysine acetyltransferase KATB3/p300. We hypothesize that the formation of polyubiquitination chains attached to polι occurs via the interplay between lysine acetylation and ubiquitination of ubiquitin itself at Lys11 and Lys48 rather than oxidative damage per se.
Comparison of the Binax NOW Flu A Enzyme Immunochromatographic Assay and R-Mix Shell Vial Culture for the 2003-2004 Influenza Season

ABSTRACT The Binax NOW Flu A enzyme immunochromatographic assay was compared to viral culture with R-Mix shell vials for 455 nasal-wash or nasal-aspirate specimens. The overall sensitivity, specificity, positive predictive value, and negative predictive value of the assay were 64.9%, 98.4%, 89.3%, and 93.2%, respectively. However, the assay sensitivity decreased significantly with increasing patient age.
Non-Intrusive Energy Disaggregation Using Non-Negative Matrix Factorization With Sum-to-k Constraint

Energy disaggregation or non-intrusive load monitoring addresses the issue of extracting device-level energy consumption information by monitoring the aggregated signal at one single measurement point without installing meters on each individual device. Energy disaggregation can be formulated as a source separation problem, where the aggregated signal is expressed as linear combination of basis vectors in a matrix factorization framework. In this paper, an approach based on Sum-to-k constrained non-negative matrix factorization (S2K-NMF) is proposed. By imposing the sum-to-k constraint and the non-negative constraint, S2K-NMF is able to effectively extract perceptually meaningful sources from complex mixtures. The strength of the proposed algorithm is demonstrated through two sets of experiments: Energy disaggregation in a residential smart home; and heating, ventilating, and air conditioning components energy monitoring in an industrial building testbed maintained at the Oak Ridge National Laboratory. Extensive experimental results demonstrate the superior performance of S2K-NMF as compared to state-of-the-art decomposition-based disaggregation algorithms.
SEC14 and Spectrin Domains 1 (Sestd1), Dishevelled 2 (Dvl2) and Dapper Antagonist of Catenin-1 (Dact1) co-regulate the Wnt/Planar Cell Polarity (PCP) pathway during mammalian development

We previously reported that Sestd1 KO phenocopies Dact1 KO in mice, consistent with a model in which Sestd1 and Dact1 act together to form a crucial functional complex that regulates Vangl2 in the Wnt/Planar Cell Polarity (PCP) pathway. Here, we show that Dvl2, a binding partner of Dact1, also forms complexes with Sestd1, and does so independently of both Dact1 and Vangl2. In cell-based assays, whereas Sestd1 does not alter Dvl2 activation of the Wnt/β-catenin signaling pathway, Dvl2 enhances activation of Rho family GTPases by Dact1 and Sestd1, consistent with a role in the PCP pathway. In mice, although Dvl2 KO is recessive in an otherwise wild type background, it leads to dominant embryonic lethality in either the Sestd1 or Dact1 KO background. This genetic synergy stands in contrast to the epistasis we have previously reported between Sestd1 and Dact1 KO, and suggests independent or semi-independent functions for Dvl2 vs. Sestd1/Dact1 in the regulation of the PCP pathway during development. In conclusion, biochemical and genetic interactions between Dvl2, Sestd1, and Dact1, in addition to prior reported interactions between these same molecules and Vangl2, suggest that all these gene products can form complexes together and regulate the PCP pathway during mammalian development. However, Sestd1 and Dact1 have a closely allied function in the post-translational regulation of Vangl2 that is at least partially distinct from the functions of Dvl2 in this pathway.
Context-Dependent Human Extinction Memory Is Mediated by a Ventromedial Prefrontal and Hippocampal Network

In fear extinction, an animal learns that a conditioned stimulus (CS) no longer predicts a noxious stimulus [unconditioned stimulus (UCS)] to which it had previously been associated, leading to inhibition of the conditioned response (CR). Extinction creates a new CS–noUCS memory trace, competing with the initial fear (CS–UCS) memory. Recall of extinction memory and, hence, CR inhibition at later CS encounters is facilitated by contextual stimuli present during extinction training. In line with theoretical predictions derived from animal studies, we show that, after extinction, a CS-evoked engagement of human ventromedial prefrontal cortex (VMPFC) and hippocampus is context dependent, being expressed in an extinction, but not a conditioning, context. Likewise, a positive correlation between VMPFC and hippocampal activity is extinction context dependent. Thus, a VMPFC–hippocampal network provides for context-dependent recall of human extinction memory, consistent with a view that hippocampus confers context dependence on VMPFC.
Beta-lactoglobulin secretion in human milk varies widely after cow's milk ingestion in mothers of infants with cow's milk allergy.

BACKGROUND Cow's milk proteins secreted in human milk may cause cow's milk allergy (CMA) even during exclusive breast-feeding. We studied beta-lactoglobulin levels in human milk of mothers of infants with CMA. We also studied intestinal absorption of macromolecules in the same mothers to see whether it is related to the secretion of beta-lactoglobulin in human milk. METHODS CMA was verified with oral challenge in 46 of 55 infants assessed. beta-Lactoglobulin levels were assessed in human milk from 53 of 55 mothers of the infants before (basal sample) and 1 and 2 hours after an oral cow's milk load, which was given after a 24-hour milk-free diet. beta-Lactoglobulin was determined by an ELISA with a detection limit of 0.002 microgram/L. The 6-hour urine recovery of a high-molecular-weight polyethylene glycol (PEG) 3000 was assessed after an oral load of PEG in 45 of 55 mothers. RESULTS beta-Lactoglobulin was found in the 1- or 2-hour samples in 75% of the mothers. beta-Lactoglobulin levels were increased in the 1- or 2-hour samples as compared with the basal levels in about half of the mothers. The respective levels were decreased in one third of the mothers whose basal beta-lactoglobulin levels were higher than in the others. beta-Lactoglobulin was found in none of the three human milk samples in 15% of the mothers. After an oral load of a high-molecular-weight PEG 3000, the 6-hour urine recovery of PEG was similar in the mothers of the infants with CMA and the mothers of infants without CMA. Neither was the urinary recovery of PEG related to the beta-lactoglobulin levels in human milk. CONCLUSIONS The results support the view that beta-lactoglobulin in human milk may contribute to, but does not alone explain, the development of CMA in breast-fed infants.
Multiple human single-stranded DNA binding proteins function in genome maintenance: structural, biochemical and functional analysis

DNA exists predominantly in a duplex form that is preserved via specific base pairing. This base pairing affords a considerable degree of protection against chemical or physical damage and preserves coding potential. However, there are many situations, e.g. during DNA damage and programmed cellular processes such as DNA replication and transcription, in which the DNA duplex is separated into two single-stranded DNA (ssDNA) strands. This ssDNA is vulnerable to attack by nucleases, binding by inappropriate proteins and chemical attack. It is very important to control the generation of ssDNA and protect it when it forms, and for this reason all cellular organisms and many viruses encode a ssDNA binding protein (SSB). All known SSBs use an oligosaccharide/oligonucleotide binding (OB)-fold domain for DNA binding. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating strand-exchange proteins and helicases, and mediation of protein–protein interactions. Recently two additional human SSBs have been identified that are more closely related to bacterial and archaeal SSBs. Prior to this it was believed that replication protein A, RPA, was the only human equivalent of bacterial SSB. RPA is thought to be required for most aspects of DNA metabolism including DNA replication, recombination and repair. This review will discuss in further detail the biological pathways in which human SSBs function.
Multiple Type-B Response Regulators Mediate Cytokinin Signal Transduction in Arabidopsisw⃞

Type-B Arabidopsis thaliana response regulators (ARRs) are transcription factors that function in the final step of two-component signaling systems. To characterize their role in plant growth and development, we isolated T-DNA insertions within six of the genes (ARR1, ARR2, ARR10, ARR11, ARR12, and ARR18) from the largest subfamily of type-B ARRs and also constructed various double and triple combinations of these mutations. Higher order mutants revealed progressively decreased sensitivity to cytokinin, including effects on root elongation, lateral root formation, callus induction and greening, and induction of cytokinin primary response genes. The triple mutant arr1,10,12 showed almost complete insensitivity to cytokinin under many of the assay conditions used. By contrast, no significant change in the sensitivity to ethylene was found among the mutants examined. These results indicate that there is functional overlap among the type-B ARRs and that they act as positive regulators of cytokinin signal transduction.
Selection and Rate-Adaptation Schemes for MIMO Multiple-Access Channels With Low-Rate Channel Feedback

In this paper, two selection schemes are proposed for coded transmission over multiple-input multiple-output (MIMO) multiple-access channels (MAC) to yield a much higher diversity-multiplexing gain tradeoff (DMT) performance. These schemes require a channel feedback, but at an extremely low rate. The first scheme is based on user selection and can be easily implemented in the existing MIMO-MAC systems. Upper bounds on the minimal computational complexity required by sphere decoders to decode DMT-optimal codes for this scheme as well as for MIMO MAC without feedback are given. It is shown that this scheme can offer both a much larger DMT and an exponential reduction on decoding complexity, compared with the latter. The second scheme selects jointly the users and their transmit antennas. It requires an additional design of rate assignments for performance optimization. A very general framework on the design of optimal rate assignments is thus provided. It is shown that this scheme can yield DMT performances far superior to the optimal MIMO-MAC DMT without channel feedback. The simulation results confirm that in some cases, this scheme can provide an astonishing SNR gain of 14.64 dB at outage probability 10-6 compared with the optimal MIMO-MAC coding schemes without feedback.
A Network Formation Model Based on Subgraphs

We develop a new class of random-graph models for the statistical estimation of network formation that allow for substantial correlation in links. Various subgraphs (e.g., links, triangles, cliques, stars) are generated and their union results in a network. The challenge in estimating the frequencies with which subgraphs 'truly' form is that subgraphs can overlap and may also incidentally generate new subgraphs, and so the true rate of formation of the subgraphs cannot generally be inferred just by counting their presence in the resulting network. We provide estimation techniques for recovering the rates at which the underlying subgraphs were formed from the observation of a single (large) network. We provide results on identification of the true underlying rates of subgraph formation from various statistics, as well as a new Central Limit Theorem for correlated random variables that establishes asymptotic normality for our estimators. We also show that if the network is sparse enough then direct counts of subgraphs are consistent and asymptotically normal estimators. We illustrate the models with applications.
Transfer Learning with Cluster Ensembles

Traditional supervised learning algorithms typically assume that the training data and test data come from a common underlying distribution. Therefore, they are challenged by the mismatch between training and test distributions encountered in transfer learning situations. The problem is further exacerbated when the test data actually comes from a different domain and contains no labeled example. This paper describes an optimization framework that takes as input one or more classifiers learned on the source domain as well as the results of a cluster ensemble operating solely on the target domain, and yields a consensus labeling of the data in the target domain. This framework is fairly general in that it admits a wide range of loss functions and classification/clustering methods. Empirical results on both text and hyperspectral data indicate that the proposed method can yield superior classification results compared to applying certain other transductive and transfer learning techniques or naively applying the classifier (ensemble) learnt on the source domain to the target domain.
Safety and Efficacy of an Oral Inhibitor of the Purinergic Receptor P2X7 in Adult Patients with Moderately to Severely Active Crohn's Disease: A Randomized Placebo-controlled, Double-blind, Phase IIa Study

Background:AZD9056 is a selective orally active inhibitor of the purinergic receptor P2X7, which is a key player in the generation and secretion of several proinflammatory cytokines involved in the pathogenesis of Crohn's disease (CD). The aim of this phase IIa study was to assess the efficacy and safety of AZD9056 for the treatment of moderately to severely active CD. Methods:We conducted a placebo-controlled, multicenter, double-blind phase IIa study in patients with moderately to severely active CD as defined by a CD Activity Index (CDAI) of at least 220. Patients were randomized in a 2:1 mode either to 200 mg of AZD9056 administered orally as a tablet once daily for 28 days or matching placebo. Primary endpoint was the change in CDAI from baseline at day 28, and secondary endpoints included clinical remission (CDAI < 150) and CDAI 70 response and improvement in the quality of life measures Short Form 36 and Inflammatory Bowel Disease Questionnaire. Changes in serum C-reactive protein and fecal calprotectin were assessed. Results:In total, 34 patients were enrolled, 24 to AZD9056 and 10 to placebo. The CDAI dropped in AZD9056-treated subjects from a baseline mean of 311 to 242 and from 262 to 239 in placebo-treated subjects (P = 0.049). Remission and response rates were numerically higher with AZD9056 versus placebo, (n = 5, 24% versus n = 1, 11%, P = 0.43 and n = 11, 52% versus n = 2, 22%, P = 0.13, respectively). Marked decrease in disease activity was observed for the CDAI subcomponents, pain and general well-being. Apart from a statistically significant improvement in the Mental Component Score of Short Form 36 for AZD9056 versus placebo (P = 0.017), no other differences in measurements of quality of life could be observed. There was no decrease in concentrations of serum C-reactive protein and fecal calprotectin during treatment. AZD9056 was well-tolerated, and no serious adverse events were reported. Conclusions:Our data suggest that the purinergic receptor P2X7 antagonist AZD9056 has the potential to improve symptoms in patients with moderate-to-severe CD combined with a beneficial risk profile. Although the lack in change of inflammatory biomarkers questions its anti-inflammatory potential, the results obtained in this study rather suggest P2X7 antagonism for the treatment of chronic abdominal pain.
Brain and central haemodynamics and oxygenation during maximal exercise in humans

During maximal exercise in humans, fatigue is preceded by reductions in systemic and skeletal muscle blood flow, O2 delivery and uptake. Here, we examined whether the uptake of O2 and substrates by the human brain is compromised and whether the fall in stroke volume of the heart underlying the decline in systemic O2 delivery is related to declining venous return. We measured brain and central haemodynamics and oxygenation in healthy males (n= 13 in 2 studies) performing intense cycling exercise (360 ± 10 W; mean ±s.e.m.) to exhaustion starting with either high (H) or normal (control, C) body temperature. Time to exhaustion was shorter in H than in C (5.8 ± 0.2 versus 7.5 ± 0.4 min, P < 0.05), despite heart rate reaching similar maximal values. During the first 90 s of both trials, frontal cortex tissue oxygenation and the arterial–internal jugular venous differences (a‐v diff) for O2 and glucose did not change, whereas middle cerebral artery mean flow velocity (MCA Vmean) and cardiac output increased by ∼22 and ∼115%, respectively. Thereafter, brain extraction of O2, glucose and lactate increased by ∼45, ∼55 and ∼95%, respectively, while frontal cortex tissue oxygenation, MCA Vmean and cardiac output declined ∼40, ∼15 and ∼10%, respectively. At exhaustion in both trials, systemic declined in parallel with a similar fall in stroke volume and central venous pressure; yet the brain uptake of O2, glucose and lactate increased. In conclusion, the reduction in stroke volume, which underlies the fall in systemic O2 delivery and uptake before exhaustion, is partly related to reductions in venous return to the heart. Furthermore, fatigue during maximal exercise, with or without heat stress, in healthy humans is associated with an enhanced rather than impaired brain uptake of O2 and substrates.
Percolation for the vacant set of random interlacements

We investigate random interlacements on ℤd, d ≥ 3. This model, recently introduced in [8], corresponds to a Poisson cloud on the space of doubly infinite trajectories modulo time shift tending to infinity at positive and negative infinite times. A nonnegative parameter u measures how many trajectories enter the picture. Our main interest lies in the percolative properties of the vacant set left by random interlacements at level u. We show that for all d ≥ 3 the vacant set at level u percolates when u is small. This solves an open problem of [8], where this fact has only been established when d ≥ 7. It also completes the proof of the nondegeneracy in all dimensions d ≥ 3 of the critical parameter u* of [8]. © 2008 Wiley Periodicals, Inc.