Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke.

AIMS To assess the safety and feasibility of intra-arterial transplantation of autologous bone marrow mononuclear cells in patients with middle cerebral artery ischemic stroke within 90 days of symptom onset. PATIENTS & METHODS Six patients were included in the study, and they received 1-5 × 10(8) bone marrow mononuclear cell and were evaluated using blood tests, neurological and imaging examination before treatment, and 1, 3, 7, 30, 60, 90, 120 and 180 days after transplantation. Scintigraphies were carried out 2 and 24 h after the procedure to analyze the biodistribution of labeled cells. Electroencephalogram was conducted within 7 days after transplantation. RESULTS No patients exhibited any complication or adverse events during the procedure. There was no worsening in the neurological scales until the end of the follow-up. CONCLUSION Intra-arterial bone marrow mononuclear cell transplantation is feasible and safe in patients with nonacute ischemic strokes of the middle cerebral artery. Further studies are required to evaluate the efficacy of this therapy.
Disparity between Levels of In Vitro Neutralization of Vaccinia Virus by Antibody to the A27 Protein and Protection of Mice against Intranasal Challenge

ABSTRACT Immunization with recombinant proteins may provide a safer alternative to live vaccinia virus for prophylaxis of poxvirus infections. Although antibody protects against vaccinia virus infection, the mechanism is not understood and the selection of immunogens is daunting as there are dozens of surface proteins and two infectious forms known as the mature virion (MV) and the enveloped virion (EV). Our previous studies showed that mice immunized with soluble forms of EV membrane proteins A33 and B5 and MV membrane protein L1 or passively immunized with antibodies to these proteins survived an intranasal challenge with vaccinia virus. The present study compared MV protein A27, which has a role in virus attachment to glycosaminoglycans on the cell surface, to L1 with respect to immunogenicity and protection. Although mice developed similar levels of neutralizing antibody after immunizations with A27 or L1, A27-immunized mice exhibited more severe disease upon an intranasal challenge with vaccinia virus. In addition, mice immunized with A27 and A33 were not as well protected as mice receiving L1 and A33. Polyclonal rabbit anti-A27 and anti-L1 IgG had equivalent MV-neutralizing activities when measured by the prevention of infection of human or mouse cells or cells deficient in glycosaminoglycans or by adding antibody prior to or after virus adsorption. Nevertheless, the passive administration of antibody to A27 was poorly protective compared to the antibody to L1. These studies raise questions regarding the basis for antibody protection against poxvirus disease and highlight the importance of animal models for the early evaluation of vaccine candidates.
Forum on bone and skeletal muscle interactions: Summary of the proceedings of an ASBMR workshop

Annual costs are enormous for musculoskeletal diseases such as osteoporosis and sarcopenia and for bone and muscle injuries, costing billions annually in health care. Although it is clear that muscle and bone development, growth, and function are connected, and that muscle loads bone, little is known regarding cellular and molecular interactions between these two tissues. A conference supported by the National Institutes of Health (NIH) and the American Society for Bone and Mineral Research (ASBMR) was held in July 2012 to address the enormous burden of musculoskeletal disease. National and international experts in either bone or muscle presented their findings and their novel hypotheses regarding muscle‐bone interactions to stimulate the exchange of ideas between these two fields. The immediate goal of the conference was to identify critical research themes that would lead to collaborative research interactions and grant applications focusing on interactions between muscle and bone. The ultimate goal of the meeting was to generate a better understanding of how these two tissues integrate and crosstalk in both health and disease to stimulate new therapeutic strategies to enhance and maintain musculoskeletal health.
Novel Virulent and Broad-Host-Range Erwinia amylovora Bacteriophages Reveal a High Degree of Mosaicism and a Relationship to Enterobacteriaceae Phages

ABSTRACT A diverse set of 24 novel phages infecting the fire blight pathogen Erwinia amylovora was isolated from fruit production environments in Switzerland. Based on initial screening, four phages (L1, M7, S6, and Y2) with broad host ranges were selected for detailed characterization and genome sequencing. Phage L1 is a member of the Podoviridae, with a 39.3-kbp genome featuring invariable genome ends with direct terminal repeats. Phage S6, another podovirus, was also found to possess direct terminal repeats but has a larger genome (74.7 kbp), and the virus particle exhibits a complex tail fiber structure. Phages M7 and Y2 both belong to the Myoviridae family and feature long, contractile tails and genomes of 84.7 kbp (M7) and 56.6 kbp (Y2), respectively, with direct terminal repeats. The architecture of all four phage genomes is typical for tailed phages, i.e., organized into function-specific gene clusters. All four phages completely lack genes or functions associated with lysogeny control, which correlates well with their broad host ranges and indicates strictly lytic (virulent) lifestyles without the possibility for host lysogenization. Comparative genomics revealed that M7 is similar to E. amylovora virus ΦEa21-4, whereas L1, S6, and Y2 are unrelated to any other E. amylovora phage. Instead, they feature similarities to enterobacterial viruses T7, N4, and ΦEcoM-GJ1. In a series of laboratory experiments, we provide proof of concept that specific two-phage cocktails offer the potential for biocontrol of the pathogen.
Inhibition of Plasma Kallikrein by a Highly Specific Active Site Blocking Antibody

Background: Unregulated plasma kallikrein proteolytic activity can result from C1-inhibitor deficiency, causing excessive and potentially fatal edema. Results: The antibody DX-2930 potently and specifically inhibits plasma kallikrein and exhibits a long plasma half-life. Conclusion: An antibody protease inhibitor can lead to potent and specific bioactivity. Significance: DX-2930 could be an effective therapeutic for the prophylactic inhibition of plasma kallikrein-mediated diseases. Plasma kallikrein (pKal) proteolytically cleaves high molecular weight kininogen to generate the potent vasodilator and the pro-inflammatory peptide, bradykinin. pKal activity is tightly regulated in healthy individuals by the serpin C1-inhibitor, but individuals with hereditary angioedema (HAE) are deficient in C1-inhibitor and consequently exhibit excessive bradykinin generation that in turn causes debilitating and potentially fatal swelling attacks. To develop a potential therapeutic agent for HAE and other pKal-mediated disorders, we used phage display to discover a fully human IgG1 monoclonal antibody (DX-2930) against pKal. In vitro experiments demonstrated that DX-2930 potently inhibits active pKal (Ki = 0.120 ± 0.005 nm) but does not target either the zymogen (prekallikrein) or any other serine protease tested. These findings are supported by a 2.1-Å resolution crystal structure of pKal complexed to a DX-2930 Fab construct, which establishes that the pKal active site is fully occluded by the antibody. DX-2930 injected subcutaneously into cynomolgus monkeys exhibited a long half-life (t½ ∼12.5 days) and blocked high molecular weight kininogen proteolysis in activated plasma in a dose- and time-dependent manner. Furthermore, subcutaneous DX-2930 reduced carrageenan-induced paw edema in rats. A potent and long acting inhibitor of pKal activity could be an effective treatment option for pKal-mediated diseases, such as HAE.
Cardioversion and Digitalis: IV. Effect of Beta Adrenergic Blockade

Experiments were performed in anesthetized dogs to study some effects of propranolol, dextro-propranolol and ICI50,172 on digitalis-induced arrhythmias and digitalis-induced sensitization to electrical shock. When given in beta-blocking doses, propranolol did not abbreviate ouabain-induced ventricular tachycardia (VT) or decrease ouabain-induced sensitization to electrical shock. In larger doses, propranolol first controlled the arrhythmia without affecting shock sensitivity and then abolished both arrhythmia and shock sensitivity. Dextro-propranolol, a compound with nonspecific antiarrhythmic action equal to that of propranolol but with virtually no beta-blocking effect, abolished shock sensitivity, whereas ICI50,172, a pure beta-blocking agent, did not. Beta-blocking doses of propranolol given to dogs bordering on digitalis toxicity but in normal sinus rhythm caused recurrence of sustained ventricular tachycardia. Reappearance of toxicity appeared to be related to a propranolol-induced decrease in heart rate, since it was averted during continuous electrical pacing of the atrium and reversed by isoproterenol administration.
Automatic Extraction of the Passing Strategies of Soccer Teams

Technology offers new ways to measure the locations of the players and of the ball in sports. This translates to the trajectories the ball takes on the field as a result of the tactics the team applies. The challenge professionals in soccer are facing is to take the reverse path: given the trajectories of the ball is it possible to infer the underlying strategy/tactic of a team? We propose a method based on Dynamic Time Warping to reveal the tactics of a team through the analysis of repeating series of events. Based on the analysis of an entire season, we derive insights such as passing strategies for maintaining ball possession or counter attacks, and passing styles with a focus on the team or on the capabilities of the individual players.
Nonlinear plasmonic nanohybrids as probes for multimodal cell imaging and potential phototherapeutic agents

Silicon carbide (SiC) nanoparticles were coated with gold nanorods to prepare nonlinear plasmonic nanohybrids. Their structural properties were evaluated by Transmission Electron Microscopy. Nonlinear optical properties of the two components (second harmonic generation for SiC nanoparticles, two-photon luminescence for gold nanorods) were simultaneously found into nanohybrids and spatially colocalized. Photothermal effect was observed for nanohybrids. The cytotoxicity of nanoparticles, nanorods and nanohybrids towards healthy and cancer cell lines was then evaluated. SiC nanoparticles and nanohybrids showed no cytotoxicity for healthy cells while gold nanorods were found to exhibit an increasing toxicity with increasing concentrations, which was related to the presence of CTAB surfactant on their surface. Finally, nanohybrids exhibit toxicity for cancer cells and this effect was increased under laser irradiation at 808 nm, which matches the plasmon resonance of gold nanorods.
Gastroretentive microballoons of metformin: Formulation development and characterization

The present study involves preparation and evaluation of floating microballoons with metformin as model drug for prolongation of gastric residence time. The microballoons were prepared by the solvent evaporation method using polymers hydroxypropylmethyl cellulose and ethyl cellulose. The shape and surface morphology of prepared microballoons were characterized by optical and scanning electron microscopy, respectively. In vitro drug release studies were performed and drug release kinetics was evaluated using the linear regression method. Effects of stirring rate during preparation, polymer concentration, solvent composition and dissolution medium on the size of microballoons, and drug release were also observed. The prepared microballoons exhibited prolonged drug release (8 hours) and remained buoyant for >10 hours. The mean particle size increased and the drug release rate decreased at higher polymer concentration. No significant effect of the stirring rate during preparation on drug release was observed. In vitro studies demonstrated diffusion-controlled drug release from the microballoons.
Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

Graft‐versus‐host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) despite current prophylaxis. Methotrexate (MTX) with a calcineurin inhibitor (CNI) is the current standard, however, has several toxicities. Mycophenolate mofetil (MMF) is frequently used in reduced‐intensity HCT, but data in myeloablative transplants is limited. We thus retrospectively identified 241 patients who underwent myeloablative HCT from an HLA‐identical sibling donor; 174 patients received cyclosporine (CSA) + MMF and 67 received CSA+MTX. Patients receiving MMF + CSA had rapid neutrophil (median 11 vs. 19 days with MTX+CSA), and platelet recovery (median 19 vs. 25 days), lower incidence of severe mucositis by OMAS (19% vs. 53%), and shorter length of hospital stay (median 25 vs. 36 days) (P < 0.001 for all comparisons). There were no significant differences in incidence of grade 2–4 (MMF+CSA 37% vs. MTX+CSA 39%) or 3–4 acute GVHD (17% vs. 12%), chronic GVHD (46% vs. 56%), relapse (28% vs. 27%), non‐relapse mortality (20% vs. 27%), or overall survival (47% vs. 44%) (P = NS for all). However, in multivariable analysis, the use of MMF+CSA was associated with an increased risk of severe grade 3–4 acute GVHD (HR 2.92, 95% CI 1.2–7.15, P = 0.019). There were no differences between the two regimens in multivariable analyses for other survival outcomes. This analysis demonstrates that the use of MMF in myeloablative sibling donor transplantation is well tolerated. However, there may be an increased risk of severe GVHD with MMF+CSA compared to MTX+CSA. Further studies evaluating optimal dosing strategies are needed. Am. J. Hematol. 90:144–148, 2015. © 2014 Wiley Periodicals, Inc.
Early language development.

The language proficiency of preschoolers born in Newark1 is far below national norms. At three years of age they scored 10 points lower than children in other large cities on a standardized test of English vocabulary (Peabody Picture Vocabulary TestRevised, PPVT-R2). After controlling for demographics known to be related to language development (mothers’ education, poverty and ethnicity3, and child’s gender), their scores were still well below those of other cities. Strikingly, 88 percent of these children scored below average and 62 percent received scores below the 15th percentile.
Solar energetic particle event and radio bursts associated with the 1996 July 9 flare and coronal mass ejection

Using spaceborne particle and gamma-ray detection and radio diagnostics we study solar energetic particle (SEP) production in the 1996 July 9 event. This event is associated with an impulsive soft X-ray flare (9:10 UT) and a coronal mass ejection (CME). In a global classification the event is considered as mixed-impulsive. A sequence of acceleration processes is identified, starting early in the flare impulsive phase and continuing throughout the period when the CME propagated up to several R above the photosphere: (1) Gamma-ray, hard X-ray and cm-wave emitting particles seen during the flare impulsive phase in the low corona had no counterpart at the Solar and Heliospheric Observatory (SoHO) spacecraft. (2) Electrons accelerated at a coronal shock wave were revealed by decimetricto-metric type II radio emission and by simultaneous radio signatures of beams traveling to 1 AU. (3) Mildly relativistic (≥250 keV) electrons detected by SoHO did not correspond to these shock-accelerated populations, but to later mainly impulsive injection which was associated with radio brightenings over a large range of coronal altitudes. (4) Energetic protons detected by SoHO were accelerated during about 100 min after the flare impulsive phase with a gradually evolving production profile that bore some similarity with the time profile of broadband metric (type IV) emission. (5) While all other particle signatures decayed, a second period of interplanetary proton production took place ≥2 hours after flare onset. The first, 100 min period of SEP acceleration, post-impulsive phase coronal acceleration, is definitely dominant in mildly relativistic electrons. Two acceleration periods nearly equally contribute to the production of ∼ 20 MeV protons. However, the second period is more productive in low energy, ∼ 1 MeV, protons. The timing of the SEP injections indicates that neither the impulsive flare acceleration in the low corona nor the interplanetary CME at ≥ 10R are the main sources of the high-energy particles observed onboard SoHO. We suggest that various acceleration processes related to the reconfiguration of the corona in the course of the flare and CME lift-off contribute to the inSend offprint requests to: L. Kocharov (leon.kocharov@srl.utu.fi) teracting and escaping particle populations, with different signatures at different energies and in different species.
Gene expression of normal human epidermal keratinocytes modulated by trivalent arsenicals

Chronic exposure to inorganic arsenic (iAs) is associated with the development of benign and malignant human skin lesions including nonmelanoma skin cancers. The precise arsenical form(s) responsible for this carcinogenic effect are unknown, although trivalent inorganic arsenic (iAsIII) and two of its toxic metabolites, monomethylarsonous acid (MMAIII) and methylarsinous acid (DMAIII), are attractive candidates. In an effort to better understand and compare their toxic effects in the skin, we compared the global gene expression profiles of normal human epidermal keratinocytes (NHEKs) exposed to varying noncytotoxic/slightly cytotoxic concentrations of iAsIII, MMAIII, and DMAIII for 24 h. Exposure to each arsenical treatment group exhibited a dose effect in the number of altered genes and the magnitude of expression change in NHEKs. The most significant gene expression changes associated with iAsIII and MMAIII exposure were consistent with several key events believed to be important to As‐driven skin carcinogenesis, namely induction of oxidative stress, increased transcript levels of keratinocyte growth factors, and modulation of MAPK and NF‐κB pathways. At both comparable arsenical concentrations and comparable NHEK toxicity, greater potential carcinogenic effects were observed in MMAIII‐exposed NHEKs than those exposed to iAsIII, including involvement of more proinflammatory signals and increased transcript levels of more growth factor genes. In contrast, none of these above‐mentioned transcriptional trends were among the most significantly altered functions in the DMAIII treatment group. This study suggests the relative capacity of each of the tested arsenicals to drive suspected key events in As‐mediated skin carcinogenesis is MMAIII > iAsIII with little contribution from DMAIII. © 2010 Wiley‐Liss, Inc.
Automated termination analysis for logic programs with cut*

Abstract Termination is an important and well-studied property for logic programs. However, almost all approaches for automated termination analysis focus on definite logic programs, whereas real-world Prolog programs typically use the cut operator. We introduce a novel pre-processing method which automatically transforms Prolog programs into logic programs without cuts, where termination of the cut-free program implies termination of the original program. Hence after this pre-processing, any technique for proving termination of definite logic programs can be applied. We implemented this pre-processing in our termination prover AProVE and evaluated it successfully with extensive experiments.
The Epidermal Growth Factor Homology Domain of the LDL Receptor Drives Lipoprotein Release through an Allosteric Mechanism Involving H190, H562, and H586*

The low density lipoprotein (LDL) receptor (LDLR) mediates efficient endocytosis of VLDL, VLDL remnants, and LDL. As part of the endocytic process, the LDLR releases lipoproteins in endosomes. The release process correlates with an acid-dependent conformational change in the receptor from an extended, “open” state to a compact, “closed” state. The closed state has an intramolecular contact involving H190, H562, and H586. The current model for lipoprotein release holds that protonation of these histidines drives the conformational change that is associated with release. We tested the roles of H190, H562, and H586 on LDLR conformation and on lipoprotein binding, uptake, and release using variants in which the three histidines were replaced with alanine (AAA variant) or in which the histidines were replaced with charged residues that can form ionic contacts at neutral pH (DRK variant). Contrary to expectation, both the AAA and the DRK variants exhibited normal acid-dependent transitions from open to closed conformations. Despite this similarity, both the AAA and DRK mutations modulated lipoprotein release, indicating that H190, H562, and H586 act subsequent to the conformational transition. These observations also suggest that the intramolecular contact does not drive release through a competitive mechanism. In support of this possibility, mutagenesis experiments showed that β-VLDL binding was inhibited by mutations at D203 and E208, which are exposed in the closed conformation of the LDLR. We propose that H190, H562, and H586 are part of an allosteric mechanism that drives lipoprotein release.
Respiratory Syncytial Virus Disease Is Mediated by Age-Variable IL-33

Respiratory syncytial virus (RSV) is the most common cause of infant hospitalizations and severe RSV infections are a significant risk factor for childhood asthma. The pathogenic mechanisms responsible for RSV induced immunopathophysiology remain elusive. Using an age-appropriate mouse model of RSV, we show that IL-33 plays a critical role in the immunopathogenesis of severe RSV, which is associated with higher group 2 innate lymphoid cells (ILC2s) specifically in neonates. Infection with RSV induced rapid IL-33 expression and an increase in ILC2 numbers in the lungs of neonatal mice; this was not observed in adult mice. Blocking IL-33 with antibodies or using an IL-33 receptor knockout mouse during infection was sufficient to inhibit RSV immunopathogenesis (i.e., airway hyperresponsiveness, Th2 inflammation, eosinophilia, and mucus hyperproduction); whereas administration of IL-33 to adult mice during RSV infection was sufficient to induce RSV disease. Additionally, elevated IL-33 and IL-13 were observed in nasal aspirates from infants hospitalized with RSV; these cytokines declined during convalescence. In summary, IL-33 is necessary, either directly or indirectly, to induce ILC2s and the Th2 biased immunopathophysiology observed following neonatal RSV infection. This study provides a mechanism involving IL-33 and ILC2s in RSV mediated human asthma.
A reduction of proof complexity to computational complexity for AC0[p] Frege systems

We give a general reduction of lengths-of-proofs lower bounds for constant depth Frege systems in DeMorgan language augmented by a connective counting modulo a prime $p$ (the so called $AC^0[p]$ Frege systems) to computational complexity lower bounds for search tasks involving search trees branching upon values of maps on the vector space of low degree polynomials over the finite filed with $p$ elements.