Miracle-dz/UniFAR-FTUs huggingface dataset:
Intracellular and Plasma Pharmacokinetics of Saquinavir-Ritonavir, Administered at 1,600/100 Milligrams Once Daily in Human Immunodeficiency Virus-Infected Patients

ABSTRACT Ritonavir-boosted saquinavir (SQV/r) is currently licensed as a twice-daily regimen. Reducing the pill burden with once-daily dosing may improve adherence. Intracellular concentrations of drugs must be related to the clinical efficacy of protease inhibitors. The aims of the study were to determine the cellular and plasma saquinavir and ritonavir concentrations, to determine the half-lives (t1/2s) of the drugs in each compartment, and to examine relationships between drug accumulation and lymphocyte subset P glycoprotein (P-gp) expression. Venous blood samples from 12 human immunodeficiency virus-infected patients receiving a hard-gel formulation of SQV/r (1,600/100 mg once daily) were collected at 2, 6, 12, and 24 h after dosing. Peripheral blood mononuclear cells were separated by density gradient centrifugation, and P-gp expression was measured by dual-color flow cytometry. Plasma and intracellular (cell-associated) drug concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. The ratio of the intracellular drug area under the concentration-time curve from 0 to 24 h (AUC0-24 h) to plasma drug AUC0-24 h was calculated to determine cellular drug accumulation. The median (range) AUC0-24 h of saquinavir in plasma was 16.2 (5.7 to 39.3) mg · h · liter−1, and that in cells was 46.3 (24.7 to 114.6) mg · h · liter−1. Corresponding ritonavir values were 7.5 (1.5 to 14.6) mg · h · liter−1 and 10.4 (3.2 to 13.7) mg · h · liter−1, respectively. The median accumulation ratios of cellular AUC to plasma AUC for saquinavir and ritonavir were 3.31 (range, 1.49 to 6.69) and 1.46 (range, 0.83 to 4.15), respectively. Significant differences between the plasma and intracellular saquinavir t1/2s (4.5 h [range, 2.5 to 9.3 h] and 5.9 h [range, 4.0 to 17.7 h]; P = 0.034) and between the plasma and intracellular ritonavir t1/2s (4.1 h [range, 2.6 to 8.3 h] and 6.2 h [range, 3.9 to 18.6 h]; P = 0.032) were observed. No relationship was observed between the accumulation of saquinavir or ritonavir and lymphocyte subset P-gp expression. The intracellular t1/2s of saquinavir and ritonavir were longer than the plasma t1/2s, indicating that intracellular drug may be available at a time when concentrations in plasma are below the minimum effective concentration.
Analysis of ear , nose and throat injuries reporting to a tertiary care hospital in Sikkim

Aims: This study aims to analyse the pattern of ENT injuries in patient presenting to the institute. Settings and Design: This study was conducted in the department of ENT, Sikkim Manipal Institute of Medical Sciences, Gangtok. Methods and Material: Date was collected from patient record files and post mortem data. Information about the intent, mode, mechanism and examination findings of nasal, maxillofacial, temporal bone and neck injuries was recorded. Results: A total of 505 patients were evaluated in this study (male: female; 4:1. Accidental intent followed by assault was most common. There were 21 cases of suicidal hanging. Injuries by blunt injuries and Road Traffic Accident (RTA) were the commonest. Among maxillofacial injuries, nose was most commonly fractured bone. In temporal bone injuries, post aural injuries were most common. Neck injuries were predominantly due to hanging. Conclusions: Maxillofacial injuries are most common ENT injuries in Sikkim. Maxillofacial injuries to nose are the most common ENT injuries in Sikkim. Suicidal hanging is an unusually common mode of neck injury.
Missing Click History in Sponsored Search : A Generative Modeling Solution

A fundamental problem in sponsored search advertising is the estimation of probability of click for ads displayed in response to search queries. The historical click-through rate (CTR) is one of the most important predictors of the click, and extracted at multiple resolutions of the query-ad hierarchy. However, the new ads do not have any click history, and even the existing ads might miss history at some resolutions due to, for example, tail queries. In addition to a loss in accuracy, the missing features introduce significant complexity in designing conditional probability of click models such as the maximum-entropy model. In this paper, we develop a generative modeling solution to handle missing features in the maximum-entropy and other conditional models. In particular, a mixture of multivariate Gaussian distributions is used to learn a representation of the CTR features. This mixture model then provides information about the missing features to the maximum-entropy model in increasing degrees of sophistication, ranging from the pointwise estimates of the missing features to multi-way interaction terms and to novel posterior features. We show the utility of this approach for sponsored click prediction using the click-view data collected from Yahoo! search engine. We find that the generative modeling approach not only improves click prediction accuracy over a state-of-the-art system, but also results in a significantly less complex system.
Evolution of the mineral fertility of an acidic soil during a period of ten years in the Vosges mountains (France). Impact of humus mineralisation

Un sol tres acide des Basses Vosges (Nord-Est de la France), sous un peuplement d'epicea adulte, a ete analyse en 1986, puis en 1996. La composition chimique des horizons mineraux n'a que peu varie, mais la somme du calcium et du magnesium echangeables des horizons mineraux et totaux des horizons OL, OF et OH a diminue significativement, surtout celle de Mg qui a baisse de 30 kg.ha -1 en dix ans, soit environ 1,7 % par an du magnesium echangeable present en 1986. Cette diminution, preoccupante pour l'avenir, peut s'expliquer par un pic de mineralisation de l'humus pendant les etes chauds combine avec l'incapacite des horizons mineraux, fortement satures en aluminium, a retenir le calcium et le magnesium provenant de la mineralisation des couches d'humus. Ces elements sont donc perdus par drainage au lieu d'etre preleves par les racines. Dans ce sol, pauvre en mineraux alterables, cette perte ne peut pas etre compensee par l'alteration. Une telle situation se produit certainement aussi en fin de revolution, lorsque les horizons humiferes sont exposes a la lumiere et a la chaleur. Ainsi, la degradation de l'humus de mull en dysmoder et, plus tard, sa mineralisation, couplee avec une forte teneur des horizons mineraux en aluminium echangeable, conduit a de fortes pertes de magnesium et, secondairement, de calcium, a differents stades de developpement des peuplements forestiers en sol acide. L'association de ces deux facteurs peut etre consideree comme un des mecanismes-cle de l'acidification des sols et de leur appauvrissement.
Maternal Questions While Reading to Deaf and Hearing Twins: A Case Study

This study examined the frequency and types of questions that a mother used during storybook reading sessions with her 3-year-old twin daughters. One had normal hearing and one was deaf. Results indicated that the mother asked almost twice as many questions of the hearing twin as she did of the deaf twin. The types of questions asked also varied. With the hearing twin, the mother primarily asked conventional test questions. While questions asked the deaf twin appeared to serve the same function as conventional test questions, they were asked in a form not examined in previous research.Differential changes in questions asked the twins across three reading sessions also were noted. Implications for the quality of language during book reading with young deaf children are discussed.
Cell cycle regulation by FasL and Apo2L/TRAIL in human T‐cell blasts. Implications for autoimmune lymphoproliferative syndromes

The Fas‐FasL pathway plays an important role in the homeostasis of mature lymphocytes, with defects causing autoimmune lymphoproliferative syndromes (ALPS). Human T‐cell blasts are not sensitive to FasL or Apo2L/TRAIL‐induced apoptosis unless they get reactivated, but either of those ligands inhibits their growth in the absence of cell death induction due to a cell cycle arrest in S‐G2/M. In the present work, we have studied the mechanism(s) by which FasL or Apo2L/TRAIL regulate T‐cell blast cell cycle in healthy donors and in two types of ALPS patients. Our data indicate that in human CD8+ T‐cell blasts, Fas ligation, and especially Apo2L/TRAIL induce the p53‐dependent decrease in cyclin‐B1 levels. However, the induction of the negative cell cycle regulator p21WAF1 by FasL or Apo2L/TRAIL in either CD4+ or CD8+ T‐cell blasts seems to be the main regulatory mechanism. This mechanism is dependent on caspase activation and on H2O2 generation. The increase in p21 levels by FasL or Apo2L/TRAIL is concomitant with p53 increases only in CD8+ T‐cell blasts, with p21 levels maintained high for longer times than p53 levels. In CD4+ T‐cell blasts p21 levels are controlled through a transient and p53‐independent mechanism. The present results suggest that the etiology of ALP syndromes could be related not only to defects in apoptosis induction, but also in cell cycle regulation.
Global Critical Race Feminism: An International Reader

Global Critical Race Feminism is the first anthology to focus explicitly on the legal rights of women of color around the world. Containing nearly thirty essays, the book addresses such topical themes as responses to white feminism; the flashpoint issue of female genital mutilation; the intersections of international law with U.S. law; "Third World" women in the "First World;" violence against women; and the global workplace. Broadly representative, the reader addresses the role and status-legal and otherwise-of women in such countries as Cuba, New Zealand, France, Serbia, Nicaragua, Colombia, South Africa, Japan, China, Australia, Ghana, and many others. Authors include: Aziza al-Hibri, Penelope Andrews, Taimie Bryant, Devon Carbado, Mai Chen, Brenda Cossman, Lisa Crooms, Mary Dudziak, Isabelle Gunning, Anna Han, Berta Hernandez, Laura Ho, Sharon Hom, Rosemary King, Kiyoko Knapp, Hope Lewis, Martha Morgan, Zorica Mrsevic, Vasuki Nesiah, Leslye Obiora, Gaby Ore-Aguilar, Catherine Powell, Jenny Rivera, Celina Romany, Judy Scales-Trent, Antoinette Sedillo Lopez, J. Clay Smith, and Leti Volpp.
Up-regulation of ATP Binding Cassette Transporter A1 Expression by Very Low Density Lipoprotein Receptor and Apolipoprotein E Receptor 2*

Background: VLDLR and apoER2 are receptors for reelin and apoE. Results: Reelin or apoE3 induced macrophage ABCA1 expression and increased cholesterol efflux. Down-regulation of VLDLR, apoER2, or inhibition of Dab1, PI3K, PKCζ and Sp1 attenuated reelin- or apoE3-induced ABCA1 expression. Conclusion: Activation of VLDLR- and apoER2-mediated signaling up-regulates ABCA1 expression. Significance: Up-regulation of ABCA1 expression is a novel function of VLDLR and apoER2. Activation of very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (apoER2) results in either pro- or anti-atherogenic effects depending on the ligand. Using reelin and apoE as ligands, we studied the impact of VLDLR- and apoER2-mediated signaling on the expression of ATP binding cassette transporter A1 (ABCA1) and cholesterol efflux using RAW264.7 cells. Treatment of these mouse macrophages with reelin or human apoE3 significantly increased ABCA1 mRNA and protein levels, and apoAI-mediated cholesterol efflux. In addition, both reelin and apoE3 significantly increased phosphorylated disabled-1 (Dab1), phosphatidylinositol 3-kinase (PI3K), protein kinase Cζ (PKCζ), and specificity protein 1 (Sp1). This reelin- or apoER2-mediated up-regulation of ABCA1 expression was suppressed by 1) knockdown of Dab1, VLDLR, and apoER2 with small interfering RNAs (siRNAs), 2) inhibition of PI3K and PKC with kinase inhibitors, 3) overexpression of kinase-dead PKCζ, and 4) inhibition of Sp1 DNA binding with mithramycin A. Activation of the Dab1-PI3K signaling pathway has been implicated in VLDLR- and apoER2-mediated cellular functions, whereas the PI3K-PKCζ-Sp1 signaling cascade has been implicated in the regulation of ABCA1 expression induced by apoE/apoB-carrying lipoproteins. Taken together, these data support a model in which activation of VLDLR and apoER2 by reelin and apoE induces ABCA1 expression and cholesterol efflux via a Dab1-PI3K-PKCζ-Sp1 signaling cascade.
Reseña de un sitio arqueológico en la Mesa de los Santos (Santander)

En Abril de 1988, se tuvo la oportunidad de visitar con un grupo de estudiantes de la Universidad Industrial de Santander, un sitio arqueologico, localizado en el municipio de los Santos, vereda la Pumia. El lugar corresponde a dos abrigos rocosos que fueron utilizados por los indigenas como lugar funerario. Estos se encontraban en gran estado de alteracion por efectos de la guaqueria. A pesar de esta situacion se logro hacer una recoleccion de elementos utiles asociados al abrigo principal y obtener una muestra osea humana de los dos. El material permite, mediante su analisis y estudio, aportar informacion de gran utilidad para el conocimiento cultural del grupo indigena que habito en la region y utilizo las grutas y cuevas localizadas en las comisas, como sitios de entierro y ofrenda. La tradicion de estas cuevas como lugares de entierro y resguardo, se remonta a varios siglos antes de la llegada de los espanoles. Como se vera mas adelante, uno de los entierros (No.l), que tenia una momia, restos oseos, textiles, etc., por asociacion, podria ubicarse cronologicamente hacia el siglo XII d.C.
Set-shifting ability across the spectrum of eating disorders and in overweight and obesity: a systematic review and meta-analysis

Background. In this meta-analysis we review the findings from neuropsychological studies on set-shifting in people with eating disorders (EDs) or overweight/obesity. Method. Four databases (PubMed, PsycINFO, PSYNDEX and Web of Science) were searched for eligible studies. Effect sizes (ESs) were pooled using random-effects models. Moderator analyses were conducted for ED and overweight/obese subgroups, adult/adolescent samples and measures of set-shifting. Results. Sixty-four studies with a total of 1825 ED patients [1394 anorexia nervosa (AN), 376 bulimia nervosa (BN) and 55 binge eating disorder (BED)] and 10 studies with a total of 449 overweight/obese individuals were included. The meta-analysis revealed a small to medium ES for inefficient set-shifting across all three ED diagnoses (Hedges’ g = –0.45). Subgroup analyses yielded small to medium ESs for each ED subtype (g = –0.44 for AN, –0.53 for BED, –0.50 for BN), which did not differ significantly. There was a medium ES for restricting type AN (ANR; g = –0.51) but no significant ES for binge/purge type AN (AN/BP; g = –0.18). A medium ES was found across obesity studies (g = –0.61). The ES across overweight studies was not significant (g = –0.07). Adult samples did not differ from adolescent samples in either ED or overweight/obesity studies. The different set-shifting measures were associated with largely varying ESs. Conclusions. The meta-analysis provides strong support that inefficient set-shifting is a salient neuropsychological phenomenon across ED subtypes and obesity, but is less prominent in AN/BP and overweight. Compulsivity seems to be a common underlying factor supporting a dimensional and transdiagnostic conceptualization of EDs and obesity.
Reduction in Transforming Growth Factor β Receptor I Expression and Transcription Factor CBFa1 on Bone Cells by Glucocorticoid*

Glucocorticoid in excess suppresses bone formation in vivo and disrupts bone matrix protein synthesis by osteoblasts in vitro. In contrast, transforming growth factor β (TGF-β) potently enhances bone matrix apposition. The rat TGF-β type I receptor gene promoter contains cis-acting elements for transcription factor CBFa1, which increases in parallel with osteoblast differentiation. Here we present molecular data linking these events. We show that previously unexplained effects of glucocorticoid on bone loss may be mediated in part by suppression of CBFa1, with a resultant decrease in the expression and activity of the TGF-β type I receptor on matrix-producing bone cells.
Dynamic redundancy resolution of redundant manipulators with local optimization of a kinematic criterion

To consider the dynamic effects of redundancy resolution in redundant manipulators, the inverse kinematics of the redundant manipulator must be resolved at the acceleration level, focussing mainly on using selective dynamic criteria to resolve the redundancy. These local dynamic redundancy resolution techniques reveal some instability problems due to the high joint velocities. The buildup of high joint velocities is due to the lack of a kinematic criterion in the local optimization process to reflect the changes of joint velocities. In order to avoid instability due to high joint velocities, this paper proposes dynamic redundancy resolution techniques (SMV and SMTV) which locally optimize the performance function, including a kinematic criterion as the norm of joint velocities to reflect the changes of joint velocities. These prevent the occurrence of high joint velocities and guarantee that joint velocities at end of motion are near zero. In addition, the redundancy is resolved at the joint acceleration level to consider the manipulator dynamics and the effect of kinematic criterion on the manipulator joint torques. Computer simulations were performed on a three-link planar rotary manipulator to verify the performance of the proposed dynamic redundancy resolution techniques and to compare its performance with existing local dynamic redundancy resolution techniques.
Hemodynamics of Phenylephrine Infusion Versus Lower Extremity Compression During Spinal Anesthesia for Cesarean Delivery: A Randomized, Double-Blind, Placebo-Controlled Study

BACKGROUND:Phenylephrine infusion is the current first-line choice for prevention of spinal hypotension during cesarean delivery. The optimal dosage regimen is still undetermined. A mechanical alternative, lower limb wrapping, has been examined in a few small studies showing moderate success. In this trial, we compared the effect of leg wrapping with low-dose phenylephrine infusion and with placebo treatment on systolic arterial blood pressure during spinal anesthesia for cesarean delivery. METHODS:In this randomized, double-blinded, placebo-controlled study, healthy women received either phenylephrine (n = 38; initial bolus of 0.25 &mgr;g kg−1 and infusion of 0.25 &mgr;g kg−1 min−1), leg wrapping (n = 38), or no treatment (control; n = 36) during spinal anesthesia for elective cesarean delivery. LiDCOplus was used for continuous minimally invasive hemodynamic monitoring. The extent of decrease in systolic arterial blood pressure (for 13 minutes after spinal induction) was the primary outcome. Cardiac output, systemic vascular resistance, stroke volume, heart rate, neonatal acid–base status, and Apgar score were secondary outcome variables. Mixed model analysis of continuous hemodynamic trends during the first 13 minutes after induction of spinal anesthesia was performed. RESULTS:In the phenylephrine group, the decrease in systolic arterial blood pressure was significantly less (difference in rate of change, 0.09 mm Hg 5 s−1; 95% confidence interval, 0.02–0.16; P = 0.013); systemic vascular resistance (P < 0.001) was significantly higher; stroke volume (P = 0.41) was similar; and heart rate (P = 0.002) and cardiac output (P < 0.001) were significantly lower compared with the leg wrapping group. Compared with control, the leg wrapping group had a significantly smaller decrease in systolic arterial blood pressure (0.39 mm Hg 5 s−1; 95% confidence interval, 0.32–0.46; P < 0.001), higher stroke volume (P < 0.001), and higher cardiac output (P = 0.001). CONCLUSIONS:An initial bolus of phenylephrine followed by a low-dose phenylephrine infusion was superior to leg wrapping and no intervention for the prevention of hypotension during spinal anesthesia for cesarean delivery. Phenylephrine prevented hypotension primarily by restoring systemic vascular resistance and did not cause hypertension or a clinically relevant reduction in cardiac output. Leg wrapping prevented hypotension compared with no intervention by limiting modest early spinal anesthesia-mediated venodilation.
Relating Structure to Mechanism in Creatine Kinase

Abstract Found in all vertebrates, creatine kinase catalyzes the reversible reaction of creatine and ATP forming phosphocreatine and ADP. Phosphocreatine may be viewed as a reservoir of “high-energy phosphate” which is able to supply ATP, the primary energy source in bioenergetics, on demand. Consequently, creatine kinase plays a significant role in energy homeostasis of cells with intermittently high energy requirements. The enzyme is of clinical importance and its levels are routinely used as an indicator of myocardial and skeletal muscle disorders and for the diagnosis of acute myocardial infarction. First identified in 1928, the enzyme has undergone intensive investigation for over 75 years. There are four major isozymes, two cytosolic and two mitochondrial, which form dimers and octamers, respectively. Depending on the pH, the enzyme operates by a random or an ordered bimolecular mechanism, with the equilibrium lying towards phosphocreatine production. Evidence suggests that conversion of creatine to phosphocreatine occurs via the in-line transfer of a phosphoryl group from ATP. A recent X-ray structure of creatine kinase bound to a transition state analog complex confirmed many of the predictions based on kinetic, spectroscopic, and mutagenesis studies. This review summarizes and correlates the more significant mechanistic and structural studies on creatine kinase.
ABCE1: A special factor that orchestrates translation at the crossroad between recycling and initiation

ABSTRACT For many years initiation and termination of mRNA translation have been studied separately. However, a direct link between these 2 isolated stages has been suggested by the fact that some initiation factors also control termination and can even promote ribosome recycling; i.e. the last stage where post-terminating 80S ribosomes are split to start a new round of initiation. Notably, it is now firmly established that, among other factors, ribosomal recycling critically requires the NTPase ABCE1. However, several earlier reports have proposed that ABCE1 also somehow participates in the initiation complex assembly. Based on an extended analysis of our recently published late-stage 48S initiation complex from rabbit, here we provide new mechanistic insights into this putative role of ABCE1 in initiation. This point of view represents the first structural evidence in which the regulatory role of the recycling factor ABCE1 in initiation is discussed and establishes a corner stone for elucidating the interplay between ABCE1 and several initiation factors during the transit from ribosomal recycling to formation of the elongation competent 80S initiation complex.