gebhart/patrepeval huggingface dataset:
A sensitive genetic assay for the detection of cytosine deamination: determination of rate constants and the activation energy (1990)

Previously it has not been possible to determine the rate of deamination of cytosine in DNA at 37 degrees C because this reaction occurs so slowly. We describe here a sensitive genetic assay to measure the rate of cytosine deamination in DNA at a single cytosine residue. The assay is based on reversion of a mutant in the lacZ alpha gene coding sequence of bacteriophage M13mp2 and employs ung- bacterial strains lacking the enzyme uracil glycosylase. The assay is sufficiently sensitive to allow us to detect, at a given site, a single deamination event occurring with a background frequency as low as 1 in 200,000. With this assay, we determined cytosine deamination rate constants in single-stranded DNA at temperatures ranging from 30 to 90 degrees C and then calculated that the activation energy for cytosine deamination in single-stranded DNA is 28 +/- 1 kcal/mol. At 80 degrees C, deamination rate constants at six sites varied by less than a factor of 3. At 37 degrees C, the cytosine deamination rate constants for single- and double-stranded DNA at pH 7.4 are 1 x 10(-10) and about 7 x 10(-13) per second, respectively. (In other words, the measured half-life for cytosine in single-stranded DNA at 37 degrees C is ca. 200 years, while in double-stranded DNA it is on the order of 30,000 years.) Thus, cytosine is deaminated approximately 140-fold more slowly when present in the double helix. These and other data indicate that the rate of deamination is strongly dependent upon DNA structure and the degree of protonation of the cytosine. The data suggest that agents which perturb DNA structure or facilitate direct protonation of cytosine may induce deamination at biologically significant rates. The assay provides a means to directly test the hypothesis.
adegenet: a R package for the multivariate analysis of genetic markers (2008)

Stable version is available from CRAN: http://cran.r-project.org/mirrors.html. Development version is available from adegenet website: http://adegenet.r-forge.r-project.org/. Both versions can be installed directly from R. adegenet is distributed under the GNU General Public Licence (v.2).
Automatic control design for a dynamic knee-brace system (1999)

A self-contained electronically controlled dynamic knee-brace system (DKBS) has been designed and tested which allows knee flexion during swing phase, but restricts flexion during the stance phase of gait. Cardiovascular energy measurements indicate that DKBS use allowed a more energy efficient gait.
Amino Acid and Insulin Signaling via the mTOR/p70 S6 Kinase Pathway (2001)

Amino acids have emerged as potent modulators of the mTOR/p70 S6 kinase pathway. The involvement of this pathway in the regulation of insulin-stimulated glucose transport was investigated in the present study. Acute exposure (1 h) to a balanced mixture of amino acids reduced insulin-stimulated glucose transport by as much as 55% in L6 muscle cells. The effect of amino acids was fully prevented by the specific mTOR inhibitor rapamycin. Time course analysis of insulin receptor substrate 1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity revealed that incubation with amino acids speeds up its time-dependent deactivation, leading to a dramatic suppression (-70%) of its activity after 30 min of insulin stimulation as compared with its maximal activation (5 min of stimulation). This accelerated deactivation of PI 3-kinase activity in amino acid-treated cells was associated with a concomitant and sustained increase in the phosphorylation of p70 S6 kinase. In marked contrast, inhibition of mTOR by rapamycin maintained PI 3-kinase maximally activated for up to 30 min. The marked inhibition of insulin-mediated PI 3-kinase activity by amino acids was linked to a rapamycin-sensitive increase in serine/threonine phosphorylation of IRS-1 and a decreased binding of the p85 subunit of PI 3-kinase to IRS-1. Furthermore, amino acids were required for the degradation of IRS-1 during long term insulin treatment. These results identify the mTOR/p70 S6 kinase signaling pathway as a novel modulator of insulin-stimulated glucose transport in skeletal muscle cells.
Renal Plasma Membranes: Isolation, General Properties, and Biochemical Components (1992)

Abstract The sections in this article are: Studies on Isolated Plasma Membranes: Conceptual Framework Isolation of Plasma Membranes of the Proximal Tubule Definition of Membranes Membrane Marker Starting Material Isolation of Microvillous Membranes Isolation of Basal‐lateral Membranes Simultaneous Isolation of Microvillous and Basal‐lateral Membranes Isolation of Endosomes and Reserve Vesicles Purity and General Properties of Plasma Membranes Isolated from the Proximal Tubule Microvillous Membranes Basal‐lateral Membranes Endosomes and Reserve Vesicles Isolation of Plasma Membranes of the Thick Ascending limb of Henle's Loop Definition of Membranes Membrane Marker Starting Material Methods for Membrane Isolation Purity and General Properties of Plasma Membranes Isolated from the Thick Ascending Limb Purity of Membrane Fractions General Properties Isolation of Plasma Membranes of the Collecting Duct Definition of Membranes Membrane Marker Starting Material Methods for Membrane Isolation Purity and General Properties of Membranes Isolated from the Collecting Duct Biochemical Components of Isolated Renal Plasma Membranes Membrane Lipids Lipid Composition of Isolated Membranes of the Proximal Tubule Lipid Composition of Plasma Membranes Isolated from Kidney Medulla Identification of Membrane Proteins Enzymes in Renal Membranes Antigens in Renal Membranes Transport Proteins in Renal Membranes Protein Fingerprints of Renal Membranes Concluding Remarks
Alvimopan pharmacokinetics (PK) & pharmacodynamics (PD) in patients with chronic constipation (CC) (2005)

Background To characterize the PK/PD of alvimopan and its active metabolite (ADL 08–0011) in CC patients. Method Twenty females/three males with CC received placebo or 3 mg alvimopan (a peripherally-acting μ-opioid antagonist) BID for 7 days in a double-blind, randomized, crossover study. The PK of alvimopan & metabolite were characterized. Whole bowel transit (WBT) & mean colonic transit time (MCTT) were determined. Total bowel movements (BM) & spontaneous complete BM (SCBM) were recorded. Safety was monitored. PD assessments were reported previously.a Results The geometric mean steady-state (SS) AUCτ, Cmax, & Cmin of alvimopan were 10.7 ng*hr/mL, 2.1 ng/mL, & 0.3 ng/mL, respectively. Metabolite concentrations were variable. Metabolite concentrations were at steady-state (SS) in ~50% of subjects on day 6 and were higher in patients that were at SS than those not at SS (AUC12= 98 and 48 hr*ng/mL, respectively). The relationship between concentrations of alvimopan or metabolite and response (WBT, MCTT, BM or SCBM) was explored. Simulations were used to predict doses to be used in further clinical trials. Conclusion Alvimopan PK in CC patients was similar to healthy volunteers, although Cmin was higher in CC patients. Metabolite concentrations were variable, but were in the range of those predicted. The relative contribution of plasma concentrations of parent and metabolite to activity remains unclear in CC. Clinical Pharmacology & Therapeutics (2005) 77, P49–P49; doi: 10.1016/j.clpt.2004.12.080
ABCD1 deletion‐induced mitochondrial dysfunction is corrected by SAHA: implication for adrenoleukodystrophy (2014)

X-linked Adrenoleukodystrophy (X-ALD), an inherited peroxisomal metabolic neurodegenerative disorder, is caused by mutations/deletions in the ATP-binding cassette transporter (ABCD1) gene encoding peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). Metabolic dysfunction in X-ALD is characterized by the accumulation of very long chain fatty acids ≥ C22:0) in the tissues and plasma of patients. Here, we investigated the mitochondrial status following deletion of ABCD1 in B12 oligodendrocytes and U87 astrocytes. This study provides evidence that silencing of peroxisomal protein ABCD1 produces structural and functional perturbations in mitochondria. Activities of electron transport chain-related enzymes and of citric acid cycle (TCA cycle) were reduced; mitochondrial redox status was dysregulated and the mitochondrial membrane potential was disrupted following ABCD1 silencing. A greater reduction in ATP levels and citrate synthase activities was observed in oligodendrocytes as compared to astrocytes. Furthermore, most of the mitochondrial perturbations induced by ABCD1 silencing were corrected by treating cells with suberoylanilide hydroxamic acid, an Histone deacetylase inhibitor. These observations indicate a novel relationship between peroxisomes and mitochondria in cellular homeostasis and the importance of intact peroxisomes in relation to mitochondrial integrity and function in the cell types that participate in the pathobiology of X-ALD. These observations suggest suberoylanilide hydroxamic acid as a potential therapy for X-ALD. Schematic description of the effects of loss of peroxisomal ATP-binding cassette transporter D1 (ABCD1) gene on cellular Redox and mitochondrial activities and their correction by suberoylanilide hydroxamic acid (SAHA) treatment. Pathogenomic accumulation of very long chain fatty acids (VLCFA) as a result of loss of ABCD1 leads to dysfunctions of mitochondrial biogenesis and its activities. Treatment with SAHA corrects mitochondrial dysfunctions. These studies describe unique cooperation between mitochondria and peroxisome for cellular activities.
Enantioselective Radiosynthesis of Positron Emission Tomography (PET) Tracers Containing [18F]Fluorohydrins (2014)

Herein, we describe an operationally straightforward radiosynthesis of a chiral transition metal fluoride catalyst, [(18)F](salen)CoF, and its use for late-stage enantioselective aliphatic radiofluorination. We demonstrate the utility of the method by preparing single enantiomer experimental and clinically validated PET tracers that contain base-sensitive functional groups, epimerizable stereocenters, and nitrogen-rich motifs. Unlike the conventional radiosyntheses of these targets with [(18)F]KF, labeling with (salen)CoF is possible in the last step and under exceptionally mild conditions. These results constitute a rare example of a nucleophilic radiofluorination using a transition metal fluoride and highlight the potential of such reagents to enhance traditional methods for labeling aliphatic hydrocarbons.
Monocyte-derived inhibitor of interleukin 1 induced by human cytomegalovirus (1985)

It has previously been shown that human cytomegalovirus (HCMV) can exert immunosuppressive effects, and it has been suggested that these may be mediated by monocytes, although the mechanism is unclear. We showed that infection of human monocytes with the AD169 strain of HCMV abrogates their production of interleukin 1 (IL-1) activity. This was associated with the release from infected monocytes of an inhibitor of IL-1 activity which was also released after HCMV infection of the U937 macrophage-like cell line. The inhibitor of IL-1 activity is a protein with an apparent molecular weight of ca. 95,000. This action of HCMV strain AD169 was virus specific and required infectious virus but occurred without virus replication or detectable expression of viral proteins. This effect may account, at least in part, for the previously observed immunosuppressive properties of HCMV.
Alcohol Use Disorders in Female Survivors of Childhood Sexual Abuse (2000)

Abstract This article reviews some of the recent research concerning factors that contribute to the development of alcohol use disorders in females who were sexually abused as children. Issues pertaining to a possible history of childhood sexual abuse are often overlooked in treating adult females who have alcohol use disorders. Implications for assessment and treatment are discussed. It is recommended that mental health and substance abuse counselors become aware of strategies to detect the interactive effects of these two disorders so that a more integrated and effective treatment approach can be implemented.
Blocking the CD28-B7 T cell costimulation pathway induces long term cardiac allograft acceptance in the absence of IL-4 (1997)

Abstract Blocking the CD28-B7 T lymphocyte costimulatory pathway with the recombinant protein CTLA4Ig induces long term allograft survival in rodents. It has been suggested that this results from selective activation of the Th2 immune pathway. To test this hypothesis, we compared vascularized cardiac allograft survival in wild-type (IL-4 +/+) and homozygous IL-4 gene-knockout (IL-4 -/-) mice. We report in this study that long term survival (&amp;gt;100 days) of fully allogeneic grafts can be induced readily in IL-4 -/- recipients treated with a short course of CTLA4Ig. We also demonstrate that IL-4 -/- mice are deficient in Th2-type cytokine expression following in vitro or in vivo allostimulation. These results suggest that IL-4 production and subsequent generation of a Th2-type immune response are not obligatory for CTLA4Ig-induced long term acceptance of vascularized allografts.
Mutant Influenza Viruses with a Defective NS1 Protein Cannot Block the Activation of PKR in Infected Cells (1999)

A short model genome RNA and also the genome RNA of influenza A virus bearing both 5'- and 3'-terminal common sequences activated the interferon-induced double-stranded-RNA-dependent protein kinase, PKR, by stimulating autophosphorylation in vitro. The activated PKR catalyzed phosphorylation of the alpha subunit of eucaryotic translation initiation factor 2 (eIF2alpha). The NS1 protein efficiently eliminated the PKR-activating activity of these RNAs by binding to them. Two mutant NS1 proteins, each harboring a single amino acid substitution at different regions, exhibited temperature sensitivity in their RNA binding activity in the mutant virus-infected cell lysates as well as when they were prepared as fusion proteins expressed in bacteria. The virus strains carrying these mutant NS1 proteins exhibited temperature sensitivity in virus protein synthesis at the translational level, as reported previously, and could not repress the autophosphorylation of PKR developing during the virus growth, which is normally suppressed by a viral function(s). As a result, the level of eIF2alpha phosphorylation was elevated 2.5- to 3-fold. The defect in virus protein synthesis was well correlated with the level of phosphorylation of PKR and eIF2alpha.
IncHI2 Plasmids Are the Key Vectors Responsible for oqxAB Transmission among Salmonella Species (2016)

This study reported and analyzed the complete sequences of two oqxAB-bearing IncHI2 plasmids harbored by a clinical Salmonella enterica serovar Typhimurium strain and an S Indiana strain of animal origin, respectively. In particular, pA3T recovered from S Indiana comprised the resistance determinants oqxAB, aac(6')Ib-cr, fosA3, and bla<sub>CTX-M-14</sub> Further genetic screening of 63 oqxAB-positive Salmonella isolates revealed that the majority carried IncHI2 plasmids, confirming that such plasmids play a pivotal role in dissemination of oqxAB in Salmonella spp.
VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia (2003)

Vascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it is not known how these are coordinately regulated to result in more complex morphogenetic events, such as tubular sprouting, fusion, and network formation. We show here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts. The tip cells respond to VEGF-A only by guided migration; the proliferative response to VEGF-A occurs in the sprout stalks. These two cellular responses are both mediated by agonistic activity of VEGF-A on VEGF receptor 2. Whereas tip cell migration depends on a gradient of VEGF-A, proliferation is regulated by its concentration. Thus, vessel patterning during retinal angiogenesis depends on the balance between two different qualities of the extracellular VEGF-A distribution, which regulate distinct cellular responses in defined populations of endothelial cells.
Open-Label Topiramate as Primary or Adjunctive Therapy in Chronic Civilian Posttraumatic Stress Disorder (2002)

Topiramate appeared effective as add-on or monotherapy for chronic PTSD. It demonstrated a rapid onset of action and minimally serious, dose-related side effects without the development of tolerance. Double-blind studies are indicated.
The immediate postoperative kinematic state after anterior cruciate ligament reconstruction with increasing peroperative tension (1998)

The last steps in anterior cruciate ligament (ACL) reconstruction are tensioning and fixation of the ligament. However, how much tension should be applied to the ligament in general or in each individual and in which position the ligament should be fixed remain unanswered questions. The purpose of this study was to investigate the effect of increasing ligament tension on the immediate postoperative kinematic state of the ACL-reconstructed knee. Nine cadaver knees were mounted in a mechanical measuring device based on a redesign of the Genucom knee testing system, so that the femur was fixed to a force plate and the moving tibia to a goniometer arm for registration of movement. The ligament was attached on the tibial side to a Kistler load cell and a turn-buckle for adjustment of ligament tension. The ligament was tensioned at 30 degrees of flexion with 5, 33, 66, 99 and 132 N. The cadaver knees were tested with an intact ACL, after sacrifice of the ACL and after reconstruction of the ACL with an ABC ligament. Results showed that there was a significant decrease in knee motion when the tension was higher than 33 N. This resulted in an overconstrained knee with less anteroposterior translation, internal-external rotation and varus-valgus movement compared with the uninjured knee.
Mining from Time Series Human Movement Data (2006)

Human motion not only contains a wealth of information about actions and intentions, but also about identity and personal attributes of the moving person. Research also indicates that there are positive relationships between the health of a person and their pattern of motion. In this research we utilize human walking data collected from volunteers to identify age categories and to detect possible changes in the individual's health condition. The approach is based on transforming biological motion data into a representation that subsequently allows for analysis using artificial intelligence techniques. Using wireless accelerometer sensors we were able to collect and transform the data into a numeric representation. We then applied the numeric data to various artificial intelligence algorithms to form classification models and use it for our analysis.
Studies on antidiabetic agents. 11. Novel thiazolidinedione derivatives as potent hypoglycemic and hypolipidemic agents (1992)

In the course of further chemical modification of the novel antidiabetic pioglitazone (AD-4833, U-72,107), a series of 5-[4-(2- or 4-azolylalkoxy)benzyl- or -benzylidene]-2,4-thiazolidinediones was prepared and evaluated for hypoglycemic and hypolipidemic activities in insulin-resistant, genetically obese, and diabetic KKA(y) mice. Replacement of the 2-pyridyl moiety of pioglitazone by a 2- or 4-oxazolyl or a 2- or 4-thiazolyl moiety greatly enhanced in vivo potency. The corresponding 5-benzylidene-type compounds, in which a methine was used as a linker between the benzene ring and the thiazolidinedione ring, also had potent biological activity. Among the compounds synthesized, 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-2,4- thiazolidinedione (18) exhibited the most potent activity, more than 100 times that of pioglitazone. The synthesis and structure-activity relationships for this novel series of derivatives are detailed.
Basic principles of thermal dosimetry and thermal thresholds for tissue damage from hyperthermia (2003)

This paper is one of several in this Special Issue of the International Journal of Hyperthermia that discusses the current state of knowledge about the human health risks of hyperthermia. This special issue emanated from a workshop sponsored by the World Health Organization in the Spring of 2002 on this topic. It is anticipated that these papers will help to establish guidelines for human exposure to conditions leading to hyperthermia. This comprehensive review of the literature makes it clear that much more work needs to be done to clarify what the thresholds for thermal damage are in humans. This review summarizes the basic principles that govern the relationships between thermal exposure (temperature and time of exposure) and thermal damage, with an emphasis on normal tissue effects. Methods for converting one time-temperature combination to a time at a standardized temperature are provided as well as a detailed discussion about the underlying assumptions that go into these calculations. There are few in vivo papers examining the type and extent of damage that occurs in the lower temperature range for hyperthermic exposures (e.g. 39-42 degrees C). Therefore, it is clear that estimation of thermal dose to effect at these thermal exposures is less precise in that temperature range. In addition, there are virtually no data that directly relate to the thermal sensitivity of human tissues. Thus, establishment of guidelines for human exposure based on the data provided must be done with significant caution. There is detailed review and presentation of thermal thresholds for tissue damage (based on what is detectable in vivo). The data are normalized using thermal dosimetric concepts. Tables are included in an Appendix Database which compile published data for thresholds of thermal damage in a variety of tissues and species. This database is available by request (contact MWD or PJH), but not included in this manuscript for brevity. All of the studies reported are for single acute thermal exposures. Except for brain function and physiology (as detailed in this issue by Sharma et al) one notes the critical lack of publications examining effects of chronic thermal exposures as might be encountered in occupational hazards. This review also does not include information on the embryo, which is covered in detail elsewhere in this volume (see article by Edwards et al.) as well as in a recent review on this subject, which focuses on thermal dose.
Kaposiʼs sarcoma-associated herpesvirus infection prior to onset of Kaposiʼs sarcoma (1996)

AIDS-KS patients are significantly more likely to show evidence of KSHV infection in PBMC prior to KS onset than control HIV-infected patients. Because identical PBMC samples from cases and controls were examined blindly, these results are not caused by a bias in tissue sampling. Homo-/bisexual and hemophiliac AIDS patients who do not develop KS appear to have a low prevalence of infection. These findings indicate that KSHV infection is specifically associated with the subsequent development of KS in AIDS patients.