Miracle-dz/UniFAR-FTUs huggingface dataset:
The PAI‐1 4G/5G polymorphism is not associated with an increased risk of adverse pregnancy outcome in asymptomatic nulliparous women

Summary. Background: Plasminogen activator inhibitor type 1 (PAI‐1) is an important regulator of fibrinolysis. A common deletion polymorphism that results in a sequence of 4G instead of 5G in the promoter region of the gene is associated with a small increase in the risk of venous thromboembolism. Its potential association with adverse pregnancy events remains controversial.
Requirement of 3-Phosphoinositide-Dependent Protein Kinase-1 for BDNF-Mediated Neuronal Survival

Although PDK1 regulates several signaling pathways that respond to neurotrophins, direct evidence for its involvement in neurotrophin-mediated survival has not yet been reported. Here we show high neuronal expression of active PDK1 in the rat cortex and hippocampus at the developmental stages with pronounced dependence on extracellular survival signals. Also, in cultured cortical neurons from newborn rats, BDNF resulted in PDK1- and extracellular signal-regulated kinase-1/2 (ERK1/2)-mediated activation of their direct target, the p90 ribosomal S6 kinase 1/2 (RSK1/2). In trophic-deprived cortical neurons, knockdown of endogenous PDK1 attenuated the antiapoptotic survival response to 10 ng/ml BDNF, whereas an overexpressed active mutant form of PDK1 reduced apoptosis. The neuroprotection by BDNF or active PDK1 required RSK1/2. Conversely, PDK1 knockdown reversed the survival effects of combining the overexpressed RSK1 with a low, subprotective BDNF concentration of 2 ng/ml. Likewise, the protection by the overexpressed, active PDK1 was enhanced by coexpression of an active RSK1 mutant. Consistent with the observations that in BDNF-stimulated neurons RSK1/2 activation required both PDK1 and ERK1/2, ERK1/2 knockdown removed BDNF-mediated survival. Selective activation of ERK1/2 with an overexpressed active mutant form of MKK1 resulted in RSK1/2- and PDK1-dependent neuroprotection. Finally, at subprotective plasmid DNA dosage, overexpression of the active MKK1 and PDK1 mutants produced synergistic effect on survival. Our findings indicate a critical role for PDK1-RSK1/2 signaling in BDNF-mediated neuronal survival. Thus, the PDK1 is indispensable for the antiapoptotic effects of the ERK1/2 pathway offering previously unrecognized layer of survival signal processing and integration.
The Rules of Standard Setting Organizations: An Empirical Analysis

This paper empirically explores the procedures employed by standard-setting organizations. Consistent with Lerner-Tirole (2004), we find (a) a negative relationship between the extent to which an SSO is oriented to technology sponsors and the concession level required of sponsors and (b) a positive correlation between the sponsor-friendliness of the selected SSO and the quality of the standard. We also develop and test two extensions of the earlier model: the presence of provisions mandating royalty-free licensing is negatively associated with disclosure requirements, and when there are only a limited number of SSOs, the relationship between concessions and user friendliness is weaker.
Induced liver injury after high-dose methylprednisolone in a patient with multiple sclerosis

A 33-year-old woman with multiple sclerosis, medicated with high doses of methylprednisolone, cyclophosphamide and glatiramer acetate, was referred to our department due to acute liver injury. The laboratory investigation was normal except for weakly positive antinuclear antibodies. Cyclophosphamide and glatiramer acetate were suspended, and intravenous immunoglobulin with maintenance of high doses of methylprednisolone was initiated. The patient developed another episode of acute hepatitis so the immunoglobulin was stopped. After that, she had three more episodes of elevation of liver enzymes with no hepatic insufficiency while medicated only with high doses of methylprednisolone. At this time, liver biopsy showed focal centrilobubar hepatocyte necrosis with minimal interface hepatitis. After the high doses of methylprednisolone were suspended, the patient remained asymptomatic, with normal hepatic enzymes. This case emphasises that, although rare, induced liver injury after high doses of methylprednisolone can occur.
A separation‐free assay for the detection of mutations: Combination of homogeneous time‐resolved fluorescence and minisequencing

Single nucleotide primer extension reaction has been widely used in DNA testing, and several detection methods based on this core allelic discrimination have been developed. Most of the reported formats are based on a two step protocol involving first, a liquid phase extension reaction, then a physical separation process (chromatography, electrophoresis, capture on solid support, mass spectrometry). Here we describe a new strategy based on homogeneous time‐resolved fluorescence (HTRF), which does not involve any separation process and which allows a simple “mix and measure” protocol. In this approach, a 5′‐(europium) cryptate–labeled primer is elongated by a biotinylated dideoxynucleoside‐triphosphate, followed by the addition of a streptavidin‐acceptor conjugate, which gives rise to a long‐life fluorescence resonance energy transfer (FRET) signal between the cryptate donor and the acceptor. We present the development of HTRF® technology as applied to the diagnosis of tumor suppressor gene p53 (TP53) mutations, and its application to the analysis of genomic DNA from human tumoral samples. The sensitivity of the reported method is compared to the corresponding fluorescent polarization assay. Hum Mutat 25:468–475, 2005. © 2005 Wiley‐Liss, Inc.
The Effects of Harvesting Media on Biological Characteristics and Repair Potential of Neural Stem Cells after Traumatic Brain Injury

Various solutions are utilized widely for the isolation, harvesting, sorting, testing and transplantation of neural stem cells (NSCs), whereas the effects of harvesting media on the biological characteristics and repair potential of NSCs remain unclear. To examine some of these effects, NSCs were isolated from cortex of E14.5 mice and exposed to the conventional harvesting media [0.9% saline (Saline), phosphate-buffered saline (PBS) or artificial cerebrospinal fluid (ACSF)] or the proliferation culture medium (PCM) for different durations at 4°C. Treated NSCs were grafted by in situ injection into the lesion sites of traumatic brain injury (TBI) mice. In vitro, harvesting media-exposed NSCs displayed time-dependent reduction of viability and proliferation. S phase entry decreased in harvesting media-exposed cells, which was associated with upregulation of p53 protein and downregulation of cyclin E1 protein. Moreover, harvesting media exposure induced the necrosis and apoptosis of NSCs. The levels of Fas-L, cleaved caspase 3 and 8 were increased, which suggests that the death receptor signaling pathway is involved in the apoptosis of NSCs. In addition, exposure to Saline did not facilitate the neuronal differentiation of NSCs, suggesting that Saline exposure may be disadvantageous for neurogenesis. In vivo, NSC-mediated functional recovery in harvesting media-exposed NSC groups was notably attenuated in comparison with the PCM-exposed NSC group. In conclusion, harvesting media exposure modulates the biological characteristics and repair potential of NSCs after TBI. Our results suggest that insight of the effects of harvesting media exposure on NSCs is critical for developing strategies to assure the successful long-term engraftment of NSCs.
Tumor Targeting and Drug Delivery by Anthrax Toxin

Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery.
Plasma Adrenomedullin Levels in Type 1 Diabetes: Relationship with clinical parameters

OBJECTIVE To assess the relationship between plasma adrenomedullin (AM) levels and the presence of microvascular complications in type 1 diabetic patients. RESEARCH DESIGN AND METHODS We measured plasma AM and cAMP levels in 103 type 1 diabetic patients (46 without complications, 24 with retinopathy only, 14 with microalbuminuria but normal kidney function, and 19 with renal insufficiency) and 41 matched healthy control subjects. RESULTS Patients with renal insufficiency had higher levels of AM and cAMP than all other groups. Patients with only retinopathy showed a trend to have higher levels than patients without complications. There were no differences among all other groups. There was a significant correlation between AM and cAMP in the total diabetic group (rs = 0.36, P < 0.001) but not in the control group. In multiple regression analysis, plasma AM demonstrated significant relationships with creatinine clearance (β = −0.31, P = 0.004) and duration of the disease (β = 0.28, P = 0.008). CONCLUSIONS Plasma AM and cAMP are increased in type 1 diabetic patients with renal insufficiency. Creatinine clearance (CrClc) and duration of the disease are related to plasma AM levels in these patients.
Publicly Verifiable Non-Interactive Arguments for Delegating Computation

We construct publicly verifiable non-interactive arguments that can be used to delegate polynomial time computations. These computationally sound proof systems are completely non-interactive in the common reference string model. The verifier’s running time is nearly-linear in the input length, and poly-logarithmic in the complexity of the delegated computation. Our protocol is based on graded encoding schemes, introduced by Garg, Gentry and Halevi (Eurocrypt 2012). Security is proved under a falsifiable and arguably simple cryptographic assumption about graded encodings. All prior publicly verifiable non-interactive argument systems were based on non-falsifiable knowledge assumptions. Our new result builds on the beautiful recent work of Kalai, Raz and Rothblum (STOC 2014), who constructed privately verifiable 2-message arguments. While building on their techniques, our protocols avoid no-signaling PCPs, and we obtain a simplified and modular analysis. As a second contribution, we also construct a publicly verifiable non-interactive argument for (logspace-uniform) computations of bounded depth. The verifier’s complexity grows with the depth of the circuit. This second protocol is adaptively sound, and its security is based on a falsifiable assumption about the hardness of a search problem on graded encodings (a milder cryptographic assumption). This result builds on the interactive proof of Goldwasser, Kalai and Rothblum (STOC 2008), using graded encodings to construct a non-interactive version of their protocol. ∗Boston University. Email: omer@bu.edu. Supported by the Simons award for graduate students in theoretical computer science and an NSF Algorithmic foundations grant 1218461. †Stanford University. Email: rothblum@alum.mit. edu. Part of this work was done at Microsoft Research, Silicon Valley. This work was supported by the DARPA PROCEED program. Opinions, findings and conclusions or recommendations expressed in this material are those of the author and do not necessarily reflect the views of DARPA.
Global Hypomethylation Identifies Loci Targeted for Hypermethylation in Head and Neck Cancer

Purpose: The human epigenome is profoundly altered in cancers, with a characteristic loss of methylation in repetitive regions and concomitant accumulation of gene promoter methylation. The degree to which these processes are coordinated is unclear so we investigated both in head and neck squamous cell carcinomas. Experimental Design: Global methylation was measured using the luminometric methylation assay (LUMA) and pyrosequencing of LINE-1Hs and AluYb8 repetitive elements in a series of 138 tumors. We also measured methylation of more than 27,000 CpG loci with the Illumina HumanMethylation27 Microarray (n = 91). Results:LINE-1 methylation was significantly associated with LUMA and Infinium loci methylation (Spearman's ρ = 0.52/ρ = 0.56, both P < 0.001) but not that of AluYb8. Methylation of LINE-1, AluYb8, and Infinium loci differed by tumor site (each Kruskal–Wallis, P < 0.05). Also, LINE-1 and LUMA methylation were associated with HPV16 E6 serology (each Mann–Whitney, P < 0.05). Comparing LINE-1 methylation to gene-associated methylation, we identified a distinct subset of CpG loci with significant hypermethylation associated with LINE-1 hypomethylation. An investigation of sequence features for these CpG loci revealed that they were significantly less likely to reside in repetitive elements (Gene Set Enrichment Analysis, P < 0.02), enriched in CpG islands (P < 0.001) and were proximal to transcription factor–binding sites (P < 0.05). We validated the top CpG loci that had significant hypermethylation associated with LINE-1 hypomethylation (at EVI2A, IFRD1, KLHL6, and PTPRCAP) by pyrosequencing independent tumors. Conclusions: These data indicate that global hypomethylation and gene-specific methylation processes are associated in a sequence-dependent manner, and that clinical characteristics and exposures leading to HNSCC may be influencing these processes. Clin Cancer Res; 17(11); 3579–89. ©2011 AACR.
Low-Complexity Channel Estimation and Detection for MIMO-OFDM Receiver With ESPAR Antenna

Multiple-input-multiple-output orthogonal frequency-division multiplexing (MIMO-OFDM) receivers with an electronically steerable passive array radiator (ESPAR) antenna can improve bit error rate (BER) performance and obtain additional diversity gain without increasing the number of radio-frequency (RF) front-end circuits. In this scheme, a minimum-mean-square-error (MMSE) channel estimator is employed for obtaining the channel state information. However, its drawbacks include insufficient estimation accuracy and high computational complexity due to the inverse matrix calculation. In this paper, we propose using a low-complexity compressed-sensing-based channel estimation for the MIMO-OFDM receiver with an ESPAR antenna. We also propose a low-complexity detection scheme to further reduce the computational cost required for the detection. The simulation results show that with using the proposed channel estimation method, the BER performance is improved, while its complexity is reduced. The simulations also show that the proposed detection scheme successfully reduces the required computational cost while minimizing the degradation in the BER.
Production, biodistribution assessment and dosimetric evaluation of 177Lu-TTHMP as an agent for bone pain palliation

Objective(s): Recently, bone-avid radiopharmaceuticals have been shown to have potential benefits for the treatment of widespread bone metastases. Although 177Lu-triethylene tetramine hexa methylene phosphonic acid (abbreviated as 177Lu-TTHMP), as an agent for bone pain palliation, has been evaluated in previous studies, there are large discrepancies between the obtained results. In this study, production, quality control, biodistribution, and dose evaluation of 177Lu-TTHMP have been investigated and compared with the previously reported data. Methods: TTHMP was synthesized and characterized, using spectroscopic methods. Radiochemical purity of the 177Lu-TTHMP complex was determined using instant thin-layer chromatography (ITLC) and high performance liquid chromatography (HPLC) methods. The complex was injected to wild-type rats and biodistribution was studied for 7 days. Preliminary dose evaluation was investigated based on biodistribution data in rats. Results: 177Lu was prepared with 2.6-3 GBq/mg specific activity and radionuclide purity of 99.98%. 177Lu-TTHMP was successfully prepared with high radiochemical purity (>99%). The complex showed rapid bone uptake, while accumulation in other organs was insignificant. Dosimetric results showed that all tissues received almost insignificant absorbed doses in comparison with bone tissues. Conclusion: Based on the obtained results, this radiopharmaceutical can be a good candidate for bone pain palliation therapy in skeletal metastases.
Repeated cocaine administration differentially affects NMDA receptor subunit (NR1, NR2A‐C) mRNAs in rat brain

We investigated the effects of intermittent intraperitoneal (i.p.) injections of cocaine (20 mg/kg) on subunit mRNAs of N‐methyl‐D‐aspartate (NMDA) receptors (NR1/NR2A‐2C) in the rat brain by in situ hybridization using phosphor screen analysis. The level of NR1 subunit mRNA significantly increased in hippocampal complexes 1 h after a single i.p. injection of cocaine. After repeated cocaine injection, the mean scores of stereotyped behavior were increased with the number of injections. The level of NR1 subunit mRNA was obviously decreased in the striatum and cortices 24 h (early withdrawal) after a final injection following 14 days of subchronic administration. During the early withdrawal period, the amount of the NR1 subunit decreased in the nucleus accumbens, globus pallidus, and subiculum. In the dentate gyrus, the NR1 mRNA level significantly increased during early withdrawal in rats subchronically treated with cocaine. Levels of NR2B subunit mRNA were reduced in the cortices and striatum. During late withdrawal from cocaine, the level of NR2C subunit mRNA in the cerebellum was also reduced. These findings suggest that the disruption of NR1, NR2B, and NR2C subunits in the discrete brain regions occurs under the cocaine‐related behavioral abnormalities and would be closely implicated in the initiation and expression of behavioral sensitization induced by repeated cocaine administration. Further studies on the changes in non‐NMDA receptors are required to elucidate the biological significance of glutamate receptors for the mechanisms underlying the development of behavioral sensitization. Synapse 46:157–169, 2002. © 2002 Wiley‐Liss, Inc.
Calcium currents, charge movement and dihydropyridine binding in fast‐ and slow‐twitch muscles of rat and rabbit.

1. The Vaseline‐gap technique was used to record slow calcium currents and asymmetric charge movement in single fibres of fast‐twitch muscles (extensor digitorum longus (e.d.l.) and sternomastoid) and slow‐twitch muscles (soleus) from rat and rabbit, at a holding potential of ‐90 mV. 2. The slow calcium current in soleus fibres was about one‐third of the size of the current in e.d. l. fibres, but was very similar otherwise. In both e.d. l. and soleus fibres, the dihydropyridine (DHP), nifedipine, suppressed the calcium current entirely. 3. In these normally polarized fibres, nifedipine suppressed only part (qns) of the asymmetric charge movement. The proportion of qns suppressed by various concentrations of nifedipine was linearly related to the associated reduction of the calcium current. Half‐maximal suppression of both parameters was obtained with about 0.5 microM‐nifedipine. The calcium current and the qns component of the charge movement also were suppressed over the same time course by nifedipine. Another DHP calcium antagonist, (+)PN200/110, was indistinguishable from nifedipine in its effects of suppressing calcium currents and qns. 4. In all muscle types, the total amount of qns in each fibre was linearly related to the size of the calcium current (in the absence of DHP). On average, qns was 3.3 times larger in e.d. l. fibres than in soleus fibres. 5. In contrast to the other dihydropyridines, (‐)bay K8644, a calcium channel agonist, did not suppress any asymmetric charge movement. 6. The potential dependence of the slow calcium current implied a minimum gating charge of about five or six electronic charges. The movement of qns occurred over a more negative potential range than the change in calcium conductance. 7. Experiments on the binding of (+)PN200/110 indicated that e.d. l. muscles had between about 2 and 3 times more specific DHP binding sites than did soleus muscle. 8. These results point to a close relationship between slow calcium channels, the qns component of the charge movement and DHP binding sites, in both fast‐ and slow‐twitch mammalian muscle. qns appears to be part of the gating current of the T‐system calcium channels.
Implications of Observed and Simulated Ambient Flow in Monitoring Wells

A recent paper by Hutchins and Acree (2000) has called attention to ground water sampling bias due to ambient (natural gradient‐induced) flows in monitoring wells. Data collected with borehole flowmeters have shown that such ambient flows are ubiquitous in both confined and unconfined aquifers. Developed herein is a detailed three‐dimensional model of flow and transport in the vicinity of a fully penetrating monitoring well. The model was used to simulate a measured ambient flow distribution around a test well in a heterogeneous aquifer at the Savannah River Site (SRS) near Aiken, South Carolina. Simulated ambient flows agreed well with measurements. Natural flow was upward, so water entered the well mainly through high K layers in the lower portion of the aquifer and exited through similar layers in the upper portion. The maximum upward discharge in the well was about 0.28 L/min, which implied an induced exchange of 12 m3/month from the bottom half of the aquifer to the upper half. Tracer transport simulations then illustrated how a contaminant located initially in a lower portion of the aquifer was continuously transported into the upper portion and diluted throughout the entire well by in‐flowing water. Even after full purging or micropurging, samples from such a well will yield misleading and ambiguous data concerning solute concentrations, location of a contaminant source, and plume geometry. For all of these reasons, use of long‐screened monitoring wells should be phased out, unless an appropriate multilevel sampling device prevents vertical flow.
Using compressive sensing to reduce fingerprint collection for indoor localization

Many WLAN-based indoor localization techniques estimate a target's location by comparing received signal strength indicator (RSSI) with stored fingerprints. However, the collection of fingerprints is notoriously tedious and time-consuming. It is challenging to reduce the fingerprint collection and recover absent data without introducing errors. In this article, a new approach based on compressive sensing is presented for recovering absent fingerprints. The hidden structure and redundancy characteristics of fingerprints are revealed in the Merging Matrix. The spatial and temporal relativity of fingerprints leads the rank of the Merging Matrix to be small. But the multipath effect in indoor environments conceals the nature of the matrix. The algorithm Sparsity Rank Singular Value Decomposition (SRSVD) can clear away the interference. Experiment results show that using 10% of the data can recover all of the fingerprint information with error rate less than 16%. The localization accuracy with the recovered fingerprints is similar to the one with the original complete fingerprints.