Miracle-dz/UniFAR-FTUs huggingface dataset:
Selective Intracellular Activation of a Novel Prodrug of the Human Immunodeficiency Virus Reverse Transcriptase Inhibitor Tenofovir Leads to Preferential Distribution and Accumulation in Lymphatic Tissue

ABSTRACT An isopropylalaninyl monoamidate phenyl monoester prodrug of tenofovir (GS 7340) was prepared, and its in vitro antiviral activity, metabolism, and pharmacokinetics in dogs were determined. The 50% effective concentration (EC50) of GS 7340 against human immunodeficiency virus type 1 in MT-2 cells was 0.005 μM compared to an EC50 of 5 μM for the parent drug, tenofovir. The (L)-alaninyl analog (GS 7340) was >1,000-fold more active than the (D)-alaninyl analog. GS 7340 has a half-life of 90 min in human plasma at 37°C and a half-life of 28.3 min in an MT-2 cell extract at 37°C. The antiviral activity (>10× the EC50) and the metabolic stability in MT-2 cell extracts (>35×) and plasma (>2.5×) were also sensitive to the stereochemistry at the phosphorus. After a single oral dose of GS 7340 (10 mg-eq/kg tenofovir) to male beagle dogs, the plasma bioavailability of tenofovir compared to an intravenous dose of tenofovir was 17%. The total intracellular concentration of all tenofovir species in isolated peripheral blood mononuclear cells at 24 h was 63 μg-eq/ml compared to 0.2 μg-eq/ml in plasma. A radiolabeled distribution study with dogs resulted in an increased distribution of tenofovir to tissues of lymphatic origin compared to the commercially available prodrug tenofovir DF (Viread).
Dynamiques multi-échelles de l'ADN-B

L'etude de la dynamique intrinseque de l'ADN-B permet de caracteriser l'espace conformationnel explore par cette macromolecule. Cette dynamique, qui depend de la sequence, est un facteur cle dans les mecanismes d'interaction avec les proteines, l'ADN etant plus ou moins predispose a s'adapter a son partenaire. Lors de cette these, nous avons sonde la dynamique de l'ADN a deux echelles de temps, en nous basant sur l'etude de quatre dodecameres par Resonance Magnetique Nucleaire (RMN). Nous nous sommes d'abord interesses a la dynamique des groupements phosphates, qui correspondent a des mouvements rapides (picoseconde-nanoseconde). Nous avons ainsi confirme l'effet de la sequence dinucleotidique sur cette dynamique, qui peut etre predit et quantifie. Nous avons egalement mis en lumiere pour la premiere fois l'etroite inter-dependance qui existe entre deplacements chimiques du phosphore, distances internucleotides et constantes de couplage dipolaire residuel. L'interpretation de ces observables RMN en termes de conformations des phosphates, de parametres helicoidaux et de taille des sillons, montre qu'en fait ces couplages refletent la mecanique intrinseque de l'ADN en solution. En interfacant ces resultats avec l'effet de sequence observe sur la dynamique des phosphates, il est aussi possible de saisir de quelle facon la conformation moyenne de la double helice et l'espace conformationnel associe sont modules par la sequence au niveau dinucleotidique. Enfin, des dynamiques moleculaires realisees avec les tres recents champs de force CHARMM36 et Parmbsc0ezOLI, confrontees aux donnees experimentales, ont permis d'apprecier le realisme croissant des ADN simules et ont aide a preciser des elements de la dynamique qui echappent a l'experience. Le deuxieme volet de cette these a porte sur les mouvements de l'ADN se produisant a l'echelle de la milliseconde, encore tres peu etudies. Nous avons mis au point des experiences de dispersion-relaxation qui ont apporte la preuve de l’existence d’un echange conformationnel d'un type totalement nouveau. Cet echange ne semble apparaitre que sur un type particulier de sequence, riche en A:T. Certaines regions de l’ADN, probablement specifiques, peuvent ainsi localement evoluer vers une forme tres faiblement peuplee, dont la structure detaillee reste a caracteriser. L'ensemble de ces resultats offre un panorama des capacites dynamiques de l'ADN, dependantes de la sequence, et ouvre ainsi de nombreuses perspectives vers une meilleure comprehension des mecanismes qui guident la formation des complexes ADN-proteines.
Changes Implemented During a Workplace Psychosocial Intervention and Their Consistency With Intervention Priorities

Objectives: To describe the changes implemented as part of a workplace psychosocial intervention. Methods: The intervention was conducted in a public organization employing 1630 white-collar workers. The intervention was defined as all changes implemented to reduce adverse psychosocial work factors. A logbook was held to describe the changes implemented in the intervention group and in a comparable control group (N = 1282). Results: Social support and reward were the psychosocial factors most targeted (41% to 83%). In comparison with the control group, the intervention group implemented four times more major changes and implemented changes, improving the employees' workload. Conclusions: Changes mainly targeted social support and reward. The intervention group implemented four times more major changes than the control group. The intervention group implemented changes targeting the workload, whereas no such changes were implemented in the control group.
The Diagnostic Value of Sinus Radiography in the Evaluation of Sinusitis

Acute or chronic sinusitis is a common illness among adults and children. Sinus radiography is the primary imaging study that most otolar-yngologists utilize when diagnosing sinusitis. In this study, we recruited 42 patients (26 males and 16 females) with age ranging from 5 to 83 years (average: 52.3 years) without a history of trauma or neoplasm, between January 2008 and July 2009. Upon receiving a diagnosis of sinusitis, the patients received sinus radiography followed by computed tomography (CT) within two weeks. Images of both sinus radiography and CT were reviewed retrospectively and compared with each other. The results showed that CT confirmed sinus fluid accumulation in all 42 patients, 39 of them were identified with sinus fluid accumulation or opacification by sinus radiography alone, the sensitivity of 92.9%. For individual paranasal sinus, the sensitivities of sinus radiography for discerning fluid accumulation or opacification in maxillary, frontal, ethmoid, and sphenoid sinuses were 88.6%, 88.9%, 57%, and 28.6%, respectively. Our study confirmed that sinus radiography had a higher sensitivity in detecting fluid accumulation or opacification in the maxillary and frontal sinuses, sinus radiography remains a useful imaging modality in assessing sinusitis in clinical settings.
Lenalidomide in combination with gemcitabine in patients with untreated metastatic carcinoma of the pancreas: A Sarah Cannon Research Institute phase II trial.

e14640 Background: Lenalidomide is an oral Imid immunomodulatory compound with both anti-angiogenic and immunomodulatory properties. The objectives of this phase II study were to assess the safety, tolerability, and anti-tumor activity, including response rate, progression-free (PFS), and overall survivals (OS), of lenalidomide combined with gemcitabine in patients (pts) with untreated metastatic pancreas cancer. METHODS Eligibility included: previously untreated metastatic adenocarcinoma of the pancreas (locally advanced disease excluded); ECOG PS 0-2; adequate organ function. Prophylactic anticoagulation was required (ASA, LMWH, or warfarin). Pts received lenalidomide 25mg PO days 1-21 and gemcitabine 1,000 mg/m2 IV days 1, 8, and 15 of 28-day cycles. RESULTS Between 5/2009 - 4/2010, 72 patients (median age 64 years; 49 [68%] male; 30 [42%] ECOG PS 0; 41 [57%] ECOG PS 1) began combination therapy at 9 sites, and received median of 2 cycles (range: 0-17+). Grade 3/4 hematologic toxicity included thrombocytopenia (15 pts, 21%) and neutropenia (12 pts, 17%), with no febrile neutropenia. Common non-hematologic toxicities were fatigue (49%), nausea (33%), anorexia (21%), constipation (19%), and rash (19%). Hematologic toxicity resulted in dose reduction of gemcitabine and lenalidomide in 33 pts (46%) and 27 pts (38%), respectively; an additional 17 and 32 patients required dosing interruption. Despite prophylactic anticoagulation (79% ASA, 13% LMWH, 5% warfarin), 13 pts (18%) developed grade 3/4 venous thromboembolic events. Three patients remain on treatment. Fifty pts (69%) have ended treatment for disease progression or death due to disease; other reasons for treatment discontinuation included: symptomatic deterioration (6), intercurrent illness (6), patient choice (6), and toxicity (1). Eight patients (11%) achieved partial response. PFS and OS were 2.5 (95% CI 1.9-3.5) and 4.73 (95% CI 3.4-6) months, respectively. Six-month OS was 38% (95% CI 27-50%). CONCLUSIONS Compared to expected results with gemcitabine alone, the addition of lenalidomide did not improve the survival of patients with untreated metastatic pancreatic cancer.
The age of an allele in a finite population.

The age of an allele segregating in a finite population may be defined in two ways. They are (1) the age of a mutant gene that has never reached fixation in the population, and (2) the age including any fixation period in the past. Theoretical expressions for these are derived on the assumption that every mutant is unique.
Subjective cognitive impairment of older adults: a comparison between the US and China

Subjective assessment may be incomparable across countries due to differences in reporting styles. Based on two nationally representative surveys from the US and China, this study used data from three anchoring vignettes to estimate to what extent the US and Chinese older adults aged 50 and above differed in their reporting styles of subjective cognitive impairment. Cross country differences of subjective cognitive impairment were then estimated, both before and after adjusting for reporting heterogeneity. Directly assessed word recall test scores were analyzed to evaluate whether findings based on subjective cognitive impairment was consistent with objective performance. The results revealed a discrepancy between self‐reported subjective cognitive impairment and directly assessed memory function among older adults: while Chinese respondents reported lower severity levels of subjective cognitive impairment, the US respondents demonstrated better performance in immediate word recall tests. By accounting for differences in reporting styles using anchoring vignettes data, Chinese older adults showed higher levels of subjective cognitive impairment than the US older adults, which was consistent with results from direct assessment of memory function. Non‐negligible differences are present in reporting styles of subjective cognitive impairment. Cross country comparison needs to take into account such reporting heterogeneity. Copyright © 2016 John Wiley & Sons, Ltd.
Stopping a trial early – and then what?

Background This article addresses a problem arising when a trial shows such strong evidence of benefit of the tested intervention that it stops early with an observed effect size for the experimental treatment that is statistically significantly better than the control. Within the classical frequentist framework of group sequential trials, the observed estimated effect size, the associated naïve confidence interval, and the p-value are all biased estimates of the true values. The bias is in the direction of the overestimation of the treatment effect, creation of narrower confidence intervals than appropriate, and a p-value that is too small. Purpose To discuss methods for correcting the bias in observed effect sizes, confidence intervals, and p-values for trials stopped early and to show the extent to which such correction would have modified the conclusions of the Randomized Aldactone Evaluation Study (RALES). Results In RALES, the effect of not correcting for bias is negligible. Limitations This article does not show general results; it only explores a few examples that use conservative methods for early stopping. It does not consider sequential methods that allow a relatively high probability of stopping early. Conclusions This article points out that there is no unique solution to the correction of the p-value, but it recommends stagewise ordering, which states that earlier stopping of a trial is ipso facto stronger evidence of effect than later stopping so long as the stopping is governed by a monitoring boundary that preserves the Type I error rate. Associated with stagewise ordering is a method for calculating the estimated effect size and its confidence interval. In the RALES trial, which stopped at 50% information time, the corrections to the estimated values are small.
Mycoflora associated with Hyoscyamus muticus growing under an extremely arid desert environment (Aswan region, Egypt)

Hyoscyamus muticus L. (Egyptian henbane) is one of the desert medicinal plants of family Solanaceae. The plant produces pharmaceutically important compounds (tropane alkaloids) as secondary metabolites. In the present study, we describe mycoflora of H. muticus grown in four different locations in Egyptian southern desert (Aswan region): Aswan university campus, Wadi Allaqi down stream part, Aswan airport road, and Sahari city. Eighty‐one species and two varieties belonging to 31 genera were isolated from soils surrounding H. muticus plants, the surface of the plants, and inside the plants as endophytic fungi. Aspergillus was the most common genus in all study areas. The highest number of genera and species of fungi were recorded in Aswan university campus followed by Aswan airport road. Fungal diversity analysis revealed that these two locations have higher fungal diversity compared to other two locations. A higher number of fungal species were isolated from rhizosphere soil and rhizoplane than from non‐rhizosphere and other plant organs. Endophytic fungi were isolated from all plant parts of H. muticus. Communications between H. muticus plants and fungi under desert conditions both in rhizosphere and inside the plant are deduced. (© 2008 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Dam Methyltransferase from Escherichia coli: Kinetic Studies Using Modified DNA Oligomers: Nonmethylated Substrates

Steady-state kinetics of the N6-adenine Dam methyltransferase have been measured using as substrates non-self-complementary tetradecanucleotide duplexes that contain the GATC target sequence. Modifications in the GATC target sequence of one or both of the strands included substitution of guanine by hypoxanthine, thymine by uracil or 5-ethyl-uracil and adenine by diamino-purine (2-amino-adenine). Thermodynamic parameters for the 14-mer duplexes were also determined. DNA methylation of duplexes containing single dl for dG substitution of the Dam recognition site was little perturbed compared with the canonical substrate. Replacement of dG residues by dl in both strands resulted in a decrease of the specificity constant. Substitution in both strands appears to be cumulative. Substitution of the methyl-accepting adenine residues by 2-amino-adenine resulted in surprisingly little perturbation. Dam methyltransferase is rather tolerant to different substitutions. The results show much less spread than those for the analogous hemimethylated substrates studied previously (Marzabal et al., 1995). The absence of the methylation marker appears to be deleterious to the specificity of the transition state of the active complex, while the binding of the DNA substrate to the enzyme appears to be mostly determined by the thermodynamic stability of the DNA duplex.
Rapid Communication: Subclinical bovine respiratory disease – loci and pathogens associated with lung lesions in feedlot cattle1

ABSTRACT Bovine respiratory disease (BRD) is an economically important disease of feedlot cattle that is caused by viral and bacterial pathogen members of the BRD complex. Many cases of subclinical BRD go untreated and are not detected until slaughter, when lung lesions are identified. The objectives of this study were to identify which BRD pathogens were associated with the presence of lung lesions at harvest and to identify genomic loci that were associated with susceptibility to lung lesions as defined by consolidation of the lung and/or the presence of fibrin tissue. Steers from a Colorado feedlot (n = 920) were tested for the presence of viral and bacterial pathogens using deep pharyngeal and mid-nasal swabs collected on entry into the study. Pathogen profiles were compared between cattle with or without lung consolidation (LC), fibrin tissue in the lung (FT), a combination of LC and FT in the same lung (lung lesions [LL]), and hyperinflated lungs (HIF) at harvest. Genotyping was conducted using the Illumina BovineHD BeadChip. Genomewide association analyses (GWAA) were conducted using EMMAX (efficient mixed-model association eXpedited), and pseudoheritabilities were estimated. The pathogen profile comparisons revealed that LC (P = 0.01, odds ratio [OR] = 3.37) and LL cattle (P = 0.04, OR = 4.58) were more likely to be infected with bovine herpes virus-1 and that HIF cattle were more likely to be infected with Mycoplasma spp. (P = 0.04, OR = 4.33). Pseudoheritability estimates were 0.25 for LC, 0.00 for FT, 0.28 for LL, and 0.13 for HIF. Because pseudoheritability for FT was estimated to be 0, GWAA results for FT were not reported. There were 4 QTL that were moderately associated (P < 1 × 10−5) with only LC, 2 that were associated with only LL, and 1 that was associated with LC and LL. Loci associated with HIF included 12 that were moderately associated and 3 that were strongly associated (uncorrected P < 5 × 10−7). A 24-kb region surrounding significant lead SNP was investigated to identify positional candidate genes. Many positional candidate genes underlying or flanking the detected QTL have been associated with signal transduction, cell adhesion, or gap junctions, which have functional relevance to the maintenance of lung health. The identification of pathogens and QTL associated with the presence of lung abnormalities in cattle exhibiting subclinical BRD allows the identification of loci that may not be detected through manifestation of clinical disease alone.
Hip Adductor Injury in Competitive Swimmers

Methods The authors conducted a survey of 296 competitive swimmers to assess the incidence and importance of interfering groin pain in breaststroke swimmers. Results Breaststroke swimmers were more likely to have current groin pain (6.92%) than individual medley swimmers who did not compete in pure breaststroke events (0, P= 0.015). Breaststroke swimmers (42.7%) were also more likely than individual medley swimmers (21.5%, P= 0.000622) or nonbreaststroke, nonindividual medley swimmers (5.8%, P= 0.00000311) to have been unable to train breaststroke in practice during the past year due to groin injury. Conclusion Results indicate that breaststroke swimmers are at significant risk of groin injury, groin injury is positively correlated with increased magnitude of breaststroke training, and groin injury may prevent participation in practices and competitions.
Electronic Supplementary Information for: Photophysical Deactivation Pathways in Adenine Oligonucleotides

In this document we present additional data supporting the current work. Initially we provide some monomer adenine calculations to better understand the local minima obtained. ADC(2) and NEVPT2 energies and properties not shown in the main paper are shown in sections 2 and 3. Also presented are linear least motion (LLM) pathways calculated with ADC(2) between the various minima obtained to demonstrate the proposed progression of species is barrierless. Helical conformations of the initial geometries are also presented in order to illustrate decay progression is strongly correlated to the environment. IR spectra at the minima are shown in section 6. The geometrical measurements of the six model minima is also presented along with their xyz coordinates.
Israeli Psychiatric Inpatients Go to the Polls

In 1996, mobile polls were introduced in Israel, enabling physically and emotionally ill inpatients to vote. We surveyed the rate of participation of inpatients at Lev-Hasharon Mental Health Center in parliamentary elections, their feelings regarding voting, and the nature of their vote, compared with the general population. One hundred eighteen of 306 (38.6%) patients voted compared with 63.8% of the general population. Forty-nine more patients (16%) wanted to vote but were unable to for technical reasons. More patients voted in the open than the closed wards (&khgr;2 = 14.5; df = 1; p = .001). Most patients reported positive subjective feelings, a sense of responsibility (39%), belonging to the general community (28%), and pride (22%) after voting. Psychiatric inpatients voted similarly to the general population, though their percentage of voters was significantly lower. This discrepancy can be accounted for by lack of concern and ineligibility due to lack of identification documents that may reflect fundamental illness-related problems.
Highly efficient lentiviral transduction of phenotypically and genotypically characterized endothelial progenitor cells from adult peripheral blood

Postnatal vasculogenesis has been implicated as an important mechanism for neovascularization via bone marrow-derived endothelial progenitor cells (EPCs) circulating in peripheral blood. In preparation of the utilization of EPCs in clinical protocols, we have generated blood-derived EPCs according to two established protocols by culturing either nonadherent mononuclear cells on fibronectin or adherent mononuclear cells on collagen. To explore the feasibility of these EPCs for their potential clinical use as target cells for genetic transduction to enhance their thromboresistance, newly designed retroviral and lentiviral gene ontology expression vectors were tested. Whereas cell clusters derived from the nonadherent cells demonstrated an only limited proliferative potential, cell colonies derived from collagen-adherent cells expanded more than a million-fold. Characterization of the exponentially growing cells by surface antigen and gene expression profiling revealed a consistently strong expression of characteristic endothelial markers, whereas expression of leukocyte markers was gradually lost. Using a single-step transduction protocol, we were able to achieve gene transfer efficiency of up to 99%. Our results suggest that the generated blood-derived EPC population might be attractive target cells for tissue engineering and gene therapy protocols due to their well defined phenotype, extensive proliferative potential, and efficient genetic transducibility, three important qualities that need to be defined prior to any clinical use.