Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel Therapy for Atherosclerosis Using Recombinant Immunotoxin Against Folate Receptor β–Expressing Macrophages

Background Folate receptor β (FRβ) is induced during macrophage activation. A recombinant immunotoxin consisting of the truncated Pseudomonas exotoxin A (PE38) conjugated to an anti-FRβ antibody (anti–FRβ-PE38) has been reported to kill activated macrophages in inflammatory diseases. To elucidate the effect of an immunotoxin targeting FRβ on atherosclerosis, we determined the presence of FRβ-expressing macrophages in atherosclerotic lesions and administered the FRβ immunotoxin in apolipoprotein E–deficient mice. Methods and Results The FRβ-expressing macrophages were observed in atherosclerotic lesions of apolipoprotein E–deficient mice. At 15 or 35 weeks of age, the apolipoprotein E–deficient mice were divided into 3 groups and were intravenously administered 0.1 mg/kg of anti–FRβ-PE38 (immunotoxin group), 0.1 mg/kg of PE38 (toxin group), or 0.1 mL of saline (control group) every 3 days, for a total of 5 times for each age group. The mice were analyzed at 21 or 41 weeks of age. Treatment with the immunotoxin resulted in 31% and 22% reductions in atherosclerotic lesions of the 21- and 41-week-old mice, respectively (P<0.05). Administration of immunotoxin reduced the numbers of FRβ- and tumor necrosis factor-α–expressing macrophages, reduced cell proliferation, and increased the number of apoptotic cells (P<0.05). Real-time polymerase chain reaction demonstrated that the expression of FRβ and tumor necrosis factor-α mRNA was significantly decreased in the immunotoxin group (P<0.05). Conclusions These results suggest that FRβ-expressing macrophages exist in the atherosclerotic lesions of apolipoprotein E–deficient mice and that FRβ immunotoxin administration reduces the progression of atherosclerotic lesions in younger and older individuals. The recombinant FRβ immunotoxin targeting activated macrophages could provide a novel therapeutic tool for atherosclerosis. (J Am Heart Assoc. 2012;1:e003079 doi: 10.1161/JAHA.112.003079.)
DNA methylation and hydroxymethylation in stem cells

In mammals, DNA methylation and hydroxymethylation are specific epigenetic mechanisms that can contribute to the regulation of gene expression and cellular functions. DNA methylation is important for the function of embryonic stem cells and adult stem cells (such as haematopoietic stem cells, neural stem cells and germline stem cells), and changes in DNA methylation patterns are essential for successful nuclear reprogramming. In the past several years, the rediscovery of hydroxymethylation and the TET enzymes expanded our insights tremendously and uncovered more dynamic aspects of cytosine methylation regulation. Here, we review the current knowledge and highlight the most recent advances in DNA methylation and hydroxymethylation in embryonic stem cells, induced pluripotent stem cells and several well‐studied adult stems cells. Our current understanding of stem cell epigenetics and new advances in the field will undoubtedly stimulate further clinical applications of regenerative medicine in the future. Copyright © 2015 John Wiley & Sons, Ltd.
Determination of genotoxic and other effects in mice following short term repeated‐dose and subchronic inhalation exposure to phosphine

Phosphine is an important fumigant in the grain industry and has been reported to be genotoxic in occupationally exposed fumigators. This study reports on the effects of phosphine inhalation exposure at up to, and exceeding, occupational relevant levels in a subchronic (0.3, 1.0 and 4.5 ppm, 13 weeks) and a short term repeated‐dose (5.5 ppm, 2 weeks) study in both sexes of Balb‐c mice. The following end‐points were examined: micronucleus induction in bone marrow, peripheral blood, spleen lymphocytes and skin keratinocytes, muat the hypox‐anthine‐guanine phosphoribosyl transferase locus in lymphocytes, and weight gain and relative organ weights (kidneys, lungs, liver, heart, brain and spleen). After subchronic exposure, there was a highly significant negative linear correlation between proportional weight gain and exposure in both sexes (multiple linear regression, r = −0.56, P < 0.0001), with female mice showing a greater effect. Females also showed an increase in relative organ weights at the highest test dose, in contrast to males where there was a slight decrease. A statistically significant increase in micronucleus frequency was seen in the bone marrow and spleen lymphocytes of both sexes, but only at the highest concentration. The short term repeated‐dose study revealed a slight decrease in weight gain in both sexes, with a greater effect in females.
Higher criticism for detecting sparse heterogeneous mixtures

Higher criticism, or second-level significance testing, is a multiplecomparisons concept mentioned in passing by Tukey. It concerns a situation where there are many independent tests of significance and one is interested in rejecting the joint null hypothesis. Tukey suggested comparing the fraction of observed significances at a given �-level to the expected fraction under the joint null. In fact, he suggested standardizing the difference of the two quantities and forming a z-score; the resulting z-score tests the significance of the body of significance tests. We consider a generalization, where we maximize this z-score over a range of significance levels 0 < � � �0. We are able to show that the resulting higher criticism statistic is effective at resolving a very subtle testing problem: testing whether n normal means are all zero versus the alternative that a small fraction is nonzero. The subtlety of this “sparse normal means” testing problem can be seen from work of Ingster and Jin, who studied such problems in great detail. In their studies, they identified an interesting range of cases where the small fraction of nonzero means is so small that the alternative hypothesis exhibits little noticeable effect on the distribution of the p-values either for the bulk of the tests or for the few most highly significant tests. In this range, when the amplitude of nonzero means is calibrated with the fraction of nonzero means, the likelihood ratio test for a precisely specified alternative would still succeed in separating the two hypotheses. We show that the higher criticism is successful throughout the same region of amplitude sparsity where the likelihood ratio test
Incidence of Neural Axis Abnormalities in Infantile and Juvenile Patients With Spinal Deformity: Is a Magnetic Resonance Image Screening Necessary?

Study Design. A prospective and retrospective review of patients 10 years and younger with idiopathic scoliosis evaluated with a total spine magnetic resonance imaging (MRI) scan. Objectives. To determine the incidence of neural axis abnormalities in infantile and juvenile patients with idiopathic scoliosis without neurologic findings on history and examination, to determine the need for a screening MRI in this age group. Summary of Background Data. In previous studies, a 19.2% and 26% incidence of neural axis abnormalities were found in infantile and juvenile patients with "idiopathic" scoliosis, respectively, raising the question of routine MRI screening of the spinal canal in these patients. Methods. A prospective study included 34 consecutive patients newborn to 10 years of age treated between 1992 and 1996 at a spinal deformity clinic with idiopathic scoliosis >20° without neurologic findings. In addition, a retrospective review of 64 patients age newborn to 10 years of age with idiopathic scoliosis was performed. All patients were evaluated by a total spine MRI protocol for examination of neural axis abnormalities. Results. The incidence of neural axis abnormalities in the prospective group of 34 patients was 17.6% (6 of 34); the incidence of neural axis abnormalities was 20.3% (13 of 64) in the retrospective group. Of 6 patients in the infantile age range, 3 (50%) had neural axis abnormalities. Conclusions. A total spine MRI is recommended at presentation in patients with juvenile onset idiopathic scoliosis (> 20°) because of the high incidence of neural axis abnormalities. Further study appears warranted to establish the incidence of neural axis abnormalities in infantile idiopathic scoliosis to determine the need for to tal spine MRI screening in this age group.
Convex mathematical programs for relational matching of object views

Automatic recognition of objects in images is a difficult and challenging task in computer vision which has been tackled in many different ways. Based on the powerful and widely used concept to represent objects and scenes as relational structures, the problem of graph matching, i.e. to find correspondences between two graphs is a part of the object recognition problem. Belonging to the field of combinatorial optimization graph matching is considered to be one of the most complex problems in computer vision: It is known to be NP-complete in the general case. In this thesis, two novel approaches to the graph matching problem are proposed and investigated. They are based on recent progress in the mathematical literature on convex programming. Starting out from describing the desired matchings by suitable objective functions in terms of binary variables, relaxations of combinatorial constraints and an adequate adaption of the objective function lead to continuous convex optimization problems which can be solved without parameter tuning and in polynomial time. A subsequent post-processing step results in feasible, sub-optimal combinatorial solutions to the original decision problem. In the first part of this thesis, the connection between specific graph-matching problems and the quadratic assignment problem is explored. In this case, the convex relaxation leads to a convex quadratic program , which is combined with a linear program for post-processing. Conditions under which the quadratic assignment representation is adequate from the computer vision point of view are investigated, along with attempts to relax these conditions by modifying the approach accordingly. The second part of this work focuses directly on the matching of subgraphs -- representing a model -- to a considerably larger scene graph. A bipartite matching is extended with a quadratic regularization term to take into account relations within each set of vertices. Based on this convex relaxation, post-processing and the application to computer vision are investigated and discussed. Numerical experiments reveal both the power and the limitations of the approach. For problems of sizes which occur in applications the approach is quite reasonable and often the combinatorial optimal solution is found. For larger instances the intrinsic combinatorial nature of the problem comes out and leads to sub-optimal solutions which, however, are still good.
Inference without Chaining

The problem of specifying, constructing, and understanding specialized, limited inference systems arises in many areas of AI. As a first step towards solving this problem this paper recommends the development of an inference engine that is limited by its inability to chain together two pieces of a representation in order to derive a third. A method for using model theory to specify limited inference is introduced and then used to specify an inference engine via a three valued logic. This inference engine is proved to be the strongest one that does no chaining, modulo the way that it divides the representation into pieces. Thus, the specification captures the set of all inferences that require no chaining. This paper also surveys and compares a number of systems that do no chaining as well as some that allow only selected forms of chaining.
Transcripts of the malaria vector Anopheles gambiae that are differentially regulated in the midgut upon exposure to invasive stages of Plasmodium falciparum

Understanding the interactions between the most deadly malaria parasite, Plasmodium falciparum, and its main vector, Anopheles gambiae, would be of great help in developing new malaria control strategies. The malaria parasite undergoes several developmental transitions in the mosquito midgut and suffers population losses to which mosquito factors presumably contribute. To identify such factors, we analysed An. gambiae midgut transcripts whose expression is regulated upon ingestion of invasive or non‐invasive forms of P. falciparum using a differential display approach. Sixteen cDNA were studied in detail; 12 represent novel genes of An. gambiae including a gene encoding profilin. Four transcripts were specifically regulated by P. falciparum gametocytes (invasive forms), whereas the others were regulated by either non‐invasive or both non‐invasive and invasive forms of the parasite. This differential regulation of some genes may reflect the adaptation of P. falciparum to its natural vector. These genes may be involved in the development of P. falciparum in An. gambiae or in the defence reaction of the mosquito midgut towards the parasite.
Hepatitis c virus and host cell lipids: An intimate connection

Hepatitis C virus (HCV) is a major human pathogen, persistently infecting more than 170 million individuals worldwide. The recent establishment of fully permissive culture systems allowed unraveling the close link between host cell lipids and HCV, at each step of the viral replication cycle. HCV entry is triggered by the timely coordinated interaction of virus particles with cell surface receptors, including the low-density lipoprotein receptor. Viral RNA replication strictly depends on fatty acids and cholesterol biosynthesis. This process occurs on modified intracellular membranes, forming a membranous web. Their biogenesis is induced by the viral nonstructural proteins (NS) 4B and NS5A and requires the activity of cellular lipid kinases belonging to the phosphatidylinositol-4-kinase III family. A hallmark of HCV-induced membranes is thus the presence of phosphatidylinositol-4-phosphate (PI4P), which is synthesized by these kinases. Intriguingly, certain recently identified HCV dependency factors selectively bind to PI derivatives, suggesting a crucial role for PIPs in viral RNA replication and assembly. The latter occurs on the surface of lipid droplets and is tightly connected to the very low density lipoprotein pathway leading to the formation of unique lipoviro particles. Thus, HCV exploits lipid metabolism in many ways and may therefore serve as a model system to gain insights into membrane biogenesis, lipid droplet formation and lipid trafficking.
Molecular Basis of the Extracellular Ligands Mediated Signaling by the Calcium Sensing Receptor

Ca2+-sensing receptors (CaSRs) play a central role in regulating extracellular calcium concentration ([Ca2+]o) homeostasis and many (patho)physiological processes in multiple organs. This regulation is orchestrated by a cooperative response to extracellular stimuli such as small changes in Ca2+, Mg2+, amino acids, and other ligands. In addition, CaSR is a pleiotropic receptor regulating several intracellular signaling pathways, including calcium mobilization and intracellular calcium oscillation. Nearly 200 mutations and polymorphisms have been found in CaSR in relation to a variety of human disorders associated with abnormal Ca2+ homeostasis. In this review, we summarize efforts directed at identifying binding sites for calcium and amino acids. Both homotropic cooperativity among multiple calcium binding sites and heterotropic cooperativity between calcium and amino acid were revealed using computational modeling, predictions, and site-directed mutagenesis coupled with functional assays. The hinge region of the bilobed Venus flytrap (VFT) domain of CaSR plays a pivotal role in coordinating multiple extracellular stimuli, leading to cooperative responses from the receptor. We further highlight the extensive number of disease-associated mutations that have also been shown to affect CaSR's cooperative action via several types of mechanisms. These results provide insights into the molecular bases of the structure and functional cooperativity of this receptor and other members of family C of the G protein-coupled receptors (cGPCRs) in health and disease states, and may assist in the prospective development of novel receptor-based therapeutics.
Interactions Between Zinc Transporter-8 Gene (SLC30A8) and Plasma Zinc Concentrations for Impaired Glucose Regulation and Type 2 Diabetes

Although both SLC30A8 rs13266634 single nucleotide polymorphism and plasma zinc concentrations have been associated with impaired glucose regulation (IGR) and type 2 diabetes (T2D), their interactions for IGR and T2D remain unclear. Therefore, to assess zinc-SLC30A8 interactions, we performed a case-control study in 1,796 participants: 218 newly diagnosed IGR patients, 785 newly diagnosed T2D patients, and 793 individuals with normal glucose tolerance. After adjustment for age, sex, BMI, family history of diabetes, and hypertension, the multivariable odds ratio (OR) of T2D associated with a 10 µg/dL higher plasma zinc level was 0.87 (95% CI 0.85–0.90). Meanwhile, the OR of SLC30A8 rs13266634 homozygous genotypes CC compared with TT was 1.53 (1.11–2.09) for T2D. Similar associations were found in IGR and IGR&T2D groups. Each 10 µg/dL increment of plasma zinc was associated with 22% (OR 0.78 [0.72–0.85]) lower odds of T2D in TT genotype carriers, 17% (0.83 [0.80–0.87]) lower odds in CT genotype carriers, and 7% (0.93 [0.90–0.97]) lower odds in CC genotype carriers (P for interaction = 0.01). Our study suggested that the C allele of rs13266634 was associated with higher odds of T2D, and higher plasma zinc was associated with lower odds. The inverse association of plasma zinc concentrations with T2D was modified by SLC30A8 rs13266634. Further studies are warranted to confirm our findings and clarify the mechanisms underlying the interaction between plasma zinc and the SLC30A8 gene in relation to T2D.
Circulating Dipeptidyl Peptidase IV Activity Correlates With Cardiac Dysfunction in Human and Experimental Heart Failure

Background—The present study addresses the hypothesis that the activity of dipeptidyl peptidase IV (DPPIV), an enzyme that inactivates peptides that possess cardioprotective actions, correlates with adverse outcomes in heart failure (HF). The therapeutic potential of DPPIV inhibition in preventing cardiac dysfunction is also investigated. Methods and Results—Measurements of DPPIV activity in blood samples obtained from 190 patients with HF and 42 controls demonstrated that patients with HF exhibited an increase of ≈130% in circulating DPPIV activity compared with healthy subjects. Furthermore, an inverse correlation was observed between serum DPPIV activity and left ventricular (LV) ejection fraction in patients with HF. Similarly, radiofrequency LV ablation-induced HF rats displayed higher DPPIV activity in the plasma (≈50%) and heart tissue (≈3.5-fold) compared with sham-operated rats. Moreover, positive correlations were observed between the plasma DPPIV activity and LV end-diastolic pressure and lung congestion. Two days after surgery, 1 group of LV ablation-induced HF rats was treated with the DPPIV inhibitor sitagliptin (40 mg/kg BID) for 6 weeks, whereas the remaining rats were administered water. Hemodynamic measurements demonstrated that radiofrequency LV-ablated rats treated with sitagliptin exhibited a significant attenuation of HF-related cardiac dysfunction, including LV end-diastolic pressure, systolic performance, and chamber stiffness. Sitagliptin treatment also attenuated cardiac remodeling and cardiomyocyte apoptosis and minimized pulmonary congestion. Conclusions—Collectively, the results presented herein associate circulating DPPIV activity with poorer cardiovascular outcomes in human and experimental HF. Moreover, the results demonstrate that long-term DPPIV inhibition mitigates the development and progression of HF in rats.
Interventions to improve breastfeeding outcomes: a systematic review and meta‐analysis

To provide comprehensive evidence of the effect of interventions on early initiation, exclusive, continued and any breastfeeding rates when delivered in five settings: (i) Health systems and services (ii) Home and family environment (iii) Community environment (iv) Work environment (v) Policy environment or a combination of any of above.
Route flap damping exacerbates internet routing convergence

Route flap damping is considered to be a widely deployed mechanism in core routers that limits the widespread propagation of unstable BGP routing information. Originally designed to suppress route changes caused by link flaps, flap damping attempts to distinguish persistently unstable routes from routes that occasionally fail. It is considered to be a major contributor to the stability of the Internet routing system.We show in this paper that, surprisingly, route flap damping can significantly exacerbate the convergence times of relatively stable routes. For example, a route to a prefix that is withdrawn exactly once and re-announced can be suppressed for up to an hour (using the current RIPE recommended damping parameters). We show that such abnormal behavior fundamentally arises from the interaction of flap damping with BGP path exploration during route withdrawal. We study this interaction using a simple analytical model and understand the impact of various BGP parameters on its occurrence using simulations. Finally, we outline a preliminary proposal to modify route flap damping scheme that removes the undesired interaction in all the topologies we studied.
Development of a High Sensitivity Giant Magneto-Impedance Magnetometer: Comparison With a Commercial Flux-Gate

Two versions of an operational giant magnetoimpedance (GMI)-based magnetometer, one of which is capable of working in an unshielded geomagnetic field, has been design, built and benchmarked against a commercial fluxgate magnetometer. The sensing element consists of a detection coil, strongly coupled to the GMI wire, in a two-port configuration. Its optimization is based on the surface impedance tensor of the sensing element, in which we include parasitic capacitance and geometric parameters of the coil. Conditions for optimizing the electronic noise level are deduced from the model recently published in (IEEE Sensors Journal, vol. 11, no. 6, pp. 1317-1324, 2011.). The optimized sensor and its conditioning electronics are operated in a field-locked loop, using an external coil or the detection coil for feedback. Experimental noise performance correlates well with that expected from the sensitivity and noise models and are comparable to those of a commercial Flux-Gate magnetometer, offering a low-cost solution for high sensitivity magnetometry. However, the proposed GMI magnetometers still exhibit significant 1/f noise.