Miracle-dz/UniFAR-FTUs huggingface dataset:
IN SILICO PREDICTION OF DRUG BINDING TO CYP2D6: IDENTIFICATION OF A NEW METABOLITE OF METOCLOPRAMIDE

Patients with cancer often take many different classes of drugs to treat the effects of their malignancy and the side effects of treatment, as well as their comorbidities. The potential for drug-drug interactions that may affect the efficacy of anticancer treatment is high, and a major source of such interactions is competition for the drug-metabolizing enzymes, cytochromes P450 (P450s). We have examined a series of 20 drugs commonly prescribed to cancer patients to look for potential interactions via CYP2D6. We used a homology model of CYP2D6, together with molecular docking techniques, to perform an in silico screen for binding to CYP2D6. Experimental IC50 values were determined for these compounds and compared with the model predictions to reveal a correlation with a regression coefficient of r2 = 0.61. Importantly, the docked conformation of the commonly prescribed antiemetic metoclopramide predicted a new site of metabolism that was further investigated through in vitro analysis with recombinant CYP2D6. An aromatic N-hydroxy metabolite of metoclopramide, consistent with predictions from our modeling studies, was identified by high-performance liquid chromatography/mass spectrometry. This metabolite was found to represent a major product of metabolism in human liver microsomes, and CYP2D6 was identified as the main P450 isoform responsible for catalyzing its formation. In view of the prevalence of interindividual variation in the CYP2D6 genotype and phenotype, we suggest that those experiencing adverse reactions with metoclopramide, e.g., extrapyramidal syndrome, are likely to have a particular CYP2D6 genotype/phenotype. This warrants further investigation.
Compressive Sampling for Signal Classification

Compressive sampling (CS), also called compressed sensing, entails making observations of an unknown signal by projecting it onto random vectors. Recent theoretical results show that if the signal is sparse (or nearly sparse) in some basis, then with high probability such observations essentially encode the salient information in the signal. Further, the signal can be reconstructed from these "random projections," even when the number of observations is far less than the ambient signal dimension. The provable success of CS for signal reconstruction motivates the study of its potential in other applications. This paper investigates the utility of CS projection observations for signal classification (more specifically, m-ary hypothesis testing). Theoretical error bounds are derived and verified with several simulations.
Outcome after surgery in patients with refractory temporal lobe epilepsy and normal MRI

Our purpose is to determine predictors of outcome in patients with refractory temporal lobe epilepsy and normal high resolution magnetic resonance imaging (MRI) who undergo surgical therapy. We identified 23 patients who underwent temporal lobectomy and had normal pre-operative MRI, including surface coil phased array temporal lobe imaging. All were followed at least 2 years after surgery. We graded outcome as seizure-free, > 75% reduction in seizures, or < 75% reduction in seizures. We examined pre-operative interictal and ictal electroencephalographic (EEG) findings, age of onset, gender, duration of epilepsy, risk factors, family history, physical findings, age at operation, side of operation, and pathology of resected tissue in order to determine if any of these factors were associated with outcome. Overall, 48% (11/23) of patients were seizure-free, 39% (9/23) had > 75% reduction in seizures, while 13% (3/23) had < 75% reduction in seizures. Only the EEG findings were useful in predicting outcome. When ictal onsets arose from basal-temporal regions, 61% (11/18) of patients were seizure-free, while none (0/5) were seizure-free when seizures arose from mid-posterior temporal regions (P = 0.04). Interictally, if all epileptiform patterns were localized exclusively to one basal-temporal region, a finding that invariably correlated with ictal onsets, 78% (7/9) of patients were seizure-free, while only 29% (4/14) were seizure-free if discharges were bilateral or multifocal (P = 0.04). We conclude that surgery may be a reasonable treatment for some patients with intractable temporal lobe seizures and normal MRI. The best outcomes occur when seizure onsets and interictal epileptiform patterns are exclusive to one basal-temporal region. Unfavorable outcomes are most likely to occur when ictal origins are from mid-posterior temporal regions and when interictal discharges are bitemporal or multifocal in distribution.
Signal Representations on Graphs: Tools and Applications

We present a framework for representing and modeling data on graphs. Based on this framework, we study three typical classes of graph signals: smooth graph signals, piecewise-constant graph signals, and piecewise-smooth graph signals. For each class, we provide an explicit definition of the graph signals and construct a corresponding graph dictionary with desirable properties. We then study how such graph dictionary works in two standard tasks: approximation and sampling followed with recovery, both from theoretical as well as algorithmic perspectives. Finally, for each class, we present a case study of a real-world problem by using the proposed methodology.
Early Holocenic and Historic mtDNA African Signatures in the Iberian Peninsula: The Andalusian Region as a Paradigm

Determining the timing, identity and direction of migrations in the Mediterranean Basin, the role of “migratory routes” in and among regions of Africa, Europe and Asia, and the effects of sex-specific behaviors of population movements have important implications for our understanding of the present human genetic diversity. A crucial component of the Mediterranean world is its westernmost region. Clear features of transcontinental ancient contacts between North African and Iberian populations surrounding the maritime region of Gibraltar Strait have been identified from archeological data. The attempt to discern origin and dates of migration between close geographically related regions has been a challenge in the field of uniparental-based population genetics. Mitochondrial DNA (mtDNA) studies have been focused on surveying the H1, H3 and V lineages when trying to ascertain north-south migrations, and U6 and L in the opposite direction, assuming that those lineages are good proxies for the ancestry of each side of the Mediterranean. To this end, in the present work we have screened entire mtDNA sequences belonging to U6, M1 and L haplogroups in Andalusians—from Huelva and Granada provinces—and Moroccan Berbers. We present here pioneer data and interpretations on the role of NW Africa and the Iberian Peninsula regarding the time of origin, number of founders and expansion directions of these specific markers. The estimated entrance of the North African U6 lineages into Iberia at 10 ky correlates well with other L African clades, indicating that U6 and some L lineages moved together from Africa to Iberia in the Early Holocene. Still, founder analysis highlights that the high sharing of lineages between North Africa and Iberia results from a complex process continued through time, impairing simplistic interpretations. In particular, our work supports the existence of an ancient, frequently denied, bridge connecting the Maghreb and Andalusia.
Event-related brain potentials related to attention and to response emission. Possible markers for healthy aging and mild cognitive impairment

El envejecimiento de la poblacion es un problema que afecta a todo el mundo, por lo que su estudio ha ganado importancia en los ultimos anos, tanto para mejorar la calidad de vida de los mayores, como para reducir el alto coste que conllevan las enfermedades relacionadas con la edad (en especial aquellas relacionadas con la demencia), dado que los mayores de 85 anos muestran un ratio de demencia de alrededor del 50%. Se ha propuesto que existe un continuo entre el envejecimiento sano y las demencias, pero la mayor parte de los investigadores opinan que si esperamos a que emerja el deterioro funcional (asociado ya a etapas iniciales de la demencia) podria ser demasiado tarde para tratar la enfermedad subyacente. Por esto, se ha puesto gran interes en estas fases pre-demencia con el objetivo de identificar sintomas clinicos de la enfermedad antes de que el deterioro sea evidente. El concepto de deterioro cognitivo ligero (DCL) pretende identificar este estado intermedio que a menudo es una fase de transicion del envejecimiento normal a la demencia. Para establecer un diagnostico de DCL se requiere que las actividades de la vida diaria se encuentren preservadas, que no exista demencia, y que uno o mas dominios cognitivos se encuentren afectados (subtipos unidominio y multidominio, respectivamente). Asi, si la memoria es un dominio afectado, se pueden identificar dos subtipos de DCL amnesico (DCLa): DCLa unidominio (DCLau) y DCLa multidominio (DCLam). Si la memoria no es un dominio afectado, pueden ser identificados otros dos subtipos de DCL no amnesico (DCLna): DCLna unidominio (DCLnau) y DCLna multidominio (DCLnam). Se ha observado que los subtipos no amnesicos del DCL experimentan un riesgo mayor de desarrollar demencias distintas de la Enfermedad de Alzheimer (EA), mientras que los subtipos amnesicos sufren un mayor riesgo de desarrollar EA. Diversos estudios han sugerido ademas que los pacientes con DCL multidominio muestran un riesgo mayor de progresar a demencia que aquellos con DCL unidominio. La EA es la forma mas comun de demencia, y se asocia a un estado de dependencia de alto coste no solo social, sino tambien economico y psicologico, siendo por lo tanto un problema social y sanitario de primer orden. Por esto, la identificacion de personas con DCL posibilitaria enfrentar la enfermedad incluso desde estadios prodromicos.
Understanding the Transnational Diffusion of Social Movements

This article focuses on the transnational diffusion of social movement ideas. How do social movements in one country or region of the world diffuse to another country or region? How do social movement participants learn about other movements and ideas in faraway countries and mobilize around these same ideas? What are the channels and mechanisms of diffusion? These are the research questions the article addresses. I draw on the theoretical literature on social movements and recent research on diffusion to explore these questions. The discussion is applied to two recent cases of diffusion: The diffusion of the Transition movement from the United Kingdom to the United States and the diffusion of the solidarity economy movement from Latin America, France, and Canada to the United States. I argue that a combination of relational, nonrelational, and mediated diffusion explain the spread of the transition and solidarity economy movements. The article contributes to the literature on social movements in two ways. First, it contributes to the recent efforts to better understand the process of diffusion of social movements and their ideas. Second, it provides an account of two very recent social movements that have not been fully studied and documented yet.
LARGE DEVIATION PRINCIPLES FOR MARKOV PRO- CESSES VIA Φ-SOBOLEV INEQUALITIES

LIMING WU Department of Math., Wuhan University, 430072 Hubei, China Université Blaise Pascal, 24 Avenue des Landais 63117 Aubière email: Li-Ming.Wu@math.univ-bpclermont.fr NIAN YAO Department of Math., Wuhan University, 430072 Hubei, China email: laduoduo@msn.com Submitted February 28, 2007, accepted in final form October 19, 2007 AMS 2000 Subject classification: 60F15
Molecular Mechanisms of Basic Fibroblast Growth Factor Effect on Healing of Ulcerative Colitis in Rats

We demonstrated previously that basic fibroblast growth factor (bFGF) accelerated the healing of experimental duodenal ulcers, and we now hypothesize that bFGF might also accelerate the healing of experimental ulcerative colitis (UC). We also explored the potential molecular mechanisms involved in the accelerated healing of UC in rats treated with bFGF. The results demonstrated that colonic lesions were significantly reduced by bFGF treatment, whereas neutralization of bFGF aggravated iodoacetamide-induced UC. Protein expression of bFGF was increased during the healing stage of UC. Tumor necrosis factor-α levels and myeloperoxidase activity were significantly decreased in UC rats treated with bFGF, whereas they increased in rats treated with anti-bFGF antibody. Real-time polymerase chain reaction and immunohistochemistry showed decreased levels of p27 in the UC rats compared with the healthy controls, which was reversed by bFGF treatment in a dose-dependent manner. By immunohistochemistry and double labeling of Ki-67 and CD34, prominent positive staining of Ki-67 and CD34 was seen after bFGF treatment, indicating the enhanced proliferation of fibroblasts and epithelial and endothelial cells, i.e., angiogenesis. We conclude that bFGF plays a beneficial role in the healing of UC in rats. The molecular mechanisms of bFGF in UC healing not only involve the expected increased cell proliferation, especially angiogenesis, but also encompass the reduction of inflammatory cytokines and infiltration of inflammatory cells. Thus, bFGF enema may be a new therapeutic option for UC.
Immunostimulatory Effects of Polysaccharides Isolated from Makgeolli (Traditional Korean Rice Wine)

Makgeolli is a traditional Korean rice wine, reported to have various biological functions. In this study, the immunostimulatory activity of a polysaccharide from makgeolli (PSM) was investigated. The polysaccharide fraction was isolated from makgeolli by hot water extraction, ethanol precipitation, dialysis, and lyophilization. The major constituents in PSM were neutral sugars (87.3%). PSM was composed of five different sugars, glucose, mannose, galactose, xylose, and arabinose. In normal mice, PSM treatment increased the spleen index (p < 0.05) as well as splenocyte proliferation (p < 0.05) in combination with concanavalin A or lipopolysaccharide. The immunostimulatory activities of PSM were also examined in cyclophosphamide (CY)-induced immunosuppressed mice. Mice treated with PSM exhibited increased splenocyte proliferation (p < 0.05), natural killer cell activity, and white blood cell counts (p < 0.01) compared with immunosuppressed mice. These results indicate that PSM can enhance immune function in normal mice and CY-induced immunosuppressed mice.
Interactive Proof-of-stake

The paper examines decentralized cryptocurrency protocols that are based on the use of internal tokens as identity tools. An analysis of security problems with popular Proof-of-stake consensus protocols is provided. A new protocol, Interactive Proof-of-stake, is proposed. The main ideas of the protocol are to reduce a number of variables a miner can iterate over to a minimum and also to bring a communication into block generation. The protocol is checked against known attacks. It is shown that Interactive Proof-of-stake is more secure than current pure Proof-of-stake protocols.
Mass cultured human fibroblasts overexpressing hTERT encounter a growth crisis following an extended period of proliferation.

During the process of immortalization, at least two mortality checkpoints, M1 and M2, must be bypassed. Cells that have bypassed M1 (senescence) have an extended life span, but are not necessarily immortal. Recent studies have shown that ectopic expression of the catalytic subunit of telomerase (hTERT) enables normal human cells to bypass senescence (M1) and oncogene transformed cells to avert crisis (M2) and become immortal. However, it is unclear whether hTERT expression is sufficient for normal human fibroblasts to overcome both M1 and M2 and become immortal. We have investigated the role of telomerase in immortalization by maintaining mass cultures of hTERT-transduced primary human fetal lung fibroblasts (MRC-5 cells) for very long periods of time (more than 2 years). In the present studies, up to 70% of MRC-5 cells were transduced with retroviral vectors that express hTERT. hTERT-transduced cells exhibited high levels of telomerase activity, elongation of telomeres, and proliferation beyond senescence. However, after proliferating for more than 36 population doublings (PDLs) beyond senescence, the overall growth rate of hTERT-expressing cells declined. During theses periods of reduced growth, hTERT-transduced MRC-5 cells exhibited features typical of cells in crisis, including an increased rate of cell death and polyploidy. In some instances, very late passage cells acquired a senescence-like phenotype characterized by arrest in the G1 phase of the cell cycle and greatly reduced DNA synthesis. At the onset of crisis, hTERT-transduced cells expressed high levels of telomerase and had very long telomeres, ranging up to 30 kb. Not all cells succumbed to crisis and, consequently, some cultures have proliferated beyond 240 PDLs, while another culture appears to be permanently arrested at 160 PDLs. Late passage MRC-5 cells, including postcrisis cells, displayed no signs of malignant transformation. Our results are consistent with the model in which telomerase and telomere elongation greatly extends cellular life span without inducing malignant changes. However, these investigations also indicate that hTERT-expressing cells may undergo crisis following an extended life span and that immortality is not the universal outcome of hTERT expression in normal diploid fibroblasts.
Uncomplicated Intraventricular Hemorrhage Is Followed by Reduced Cortical Volume at Near-Term Age

Background. Intraventricular hemorrhage (IVH) is the most common brain injury among premature infants. Neonates with IVH are at greater risk of impaired neurodevelopmental outcomes, compared with those without IVH. IVH causes destruction of the germinal matrix and glial precursor cells, with possible effects on cortical development. Objective. To investigate cortical development after uncomplicated IVH (with no parenchymal involvement and no posthemorrhagic hydrocephalus). We hypothesized that uncomplicated IVH would be followed by reduced cortical volume among premature infants at near-term age. Methods. A prospective cohort study was conducted, with preset selection criteria. Infants with small-for-gestational age birth weight, congenital abnormalities or brain malformations, metabolic disorders, recurrent sepsis, or necrotizing enterocolitis were excluded. Also, infants with posthemorrhagic hydrocephalus, parenchymal involvement of hemorrhage, cystic periventricular leukomalacia, or persistent ventriculomegaly were excluded, on the basis of routine serial ultrasonographic assessments. Three-dimensional images were acquired for 23 infants at near-term age, with 3-T magnetic resonance imaging and a magnetization-prepared rapid gradient echo sequence. Image analysis and segmentation of the cerebrum in different tissue types were based on signal contrast and anatomic localization. The cortical gray matter (CGM), subcortical gray matter, white matter, and intraventricular cerebrospinal fluid volumes of 12 infants with uncomplicated IVH were compared with those of 11 infants without IVH, using multivariate analysis of variance. Results. The multivariate analysis of variance for the regional brain volumes in the 2 groups indicated significance (Wilks' λ = 0.546). The CGM volume was significantly reduced in the IVH group (no-IVH group: 122 ± 12.9 mL; IVH group: 102 ± 14.6 mL; F = 13.218). This finding remained significant after testing for possible confounding factors and adjustment for size differences between the infants (F = 9.415). There was no difference in the volumes of subcortical gray matter, white matter, and cerebrospinal fluid. Conclusions. This is the first study to document impaired cortical development after uncomplicated IVH. The impairment was demonstrated by a 16% reduction in cerebral CGM volume at near-term age. The finding supports concerns regarding possible glial precursor cell loss after germinal matrix IVH, but its clinical significance is still unclear. The alteration in brain development demonstrated in this report supports closer neurodevelopmental follow-up monitoring of preterm infants with uncomplicated IVH.
THE OTTO AUFRANC AWARD: Bone Augmentation around and within Porous Implants by Local Bisphosphonate Elution

The bisphosphonate zoledronic acid chemically and physically was bound to hydroxyapatite-coated porous tantalum implants. The zoledronic acid elution characteristics in saline were determined as a function of time and the in vivo effects of elution were quantified at 12 weeks in a canine ulnar implant model. Intramedullary implants surgically were implanted bilaterally into the ulnae of a control group of five dogs and a zoledronic acid-dosed (0.05 mg zoledronic acid) group of four dogs. Computerized image analysis of undecalcified histologic sections was used to quantify the amount of peri-implant bone within the intramedullary canal, the percentage of available pore space filled with new bone, and the number and size of the individual bone islands within the implant pores. The data were analyzed using a hierarchical analysis of variance with 95% confidence intervals. The peri-implant bone occupied a mean of 13.8% of the canal space in controls and 32.2% of the canal space in zoledronic acid-dosed dogs, a relative difference of 134% (2.34-fold) that was significant. The mean extent of bone ingrowth was 12.5% for the control implants and 19.8% for the zoledronic acid-dosed dogs, a relative difference of 58% that was statistically significant. Individual islands of new bone formation with the implant pores were similar in number in both implant groups but were 71% larger on average in the ZA-dosed group. We are the first authors to show that local elution of a bisphosphonate can cause substantial bone augmentation around and within porous orthopaedic implants. The concept represents a potential tool for restoration of bone stock and enhancement of implant fixation in primary and revision cementless joint arthroplasty surgeries in the face of compromised or deficient bone.