Miracle-dz/UniFAR-FTUs huggingface dataset:
Sequential Deletion of the Integrase (Gag-Pol) Carboxyl Terminus Reveals Distinct Phenotypic Classes of Defective HIV-1

ABSTRACT A requisite step in the life cycle of human immunodeficiency virus type 1 (HIV-1) is the insertion of the viral genome into that of the host cell, a process catalyzed by the 288-amino-acid (32-kDa) viral integrase (IN). IN recognizes and cleaves the ends of reverse-transcribed viral DNA and directs its insertion into the chromosomal DNA of the target cell. IN function, however, is not limited to integration, as the protein is required for other aspects of viral replication, including assembly, virion maturation, and reverse transcription. Previous studies demonstrated that IN is comprised of three domains: the N-terminal domain (NTD), catalytic core domain (CCD), and C-terminal domain (CTD). Whereas the CCD is mainly responsible for providing the structural framework for catalysis, the roles of the other two domains remain enigmatic. This study aimed to elucidate the primary and subsidiary roles that the CTD has in protein function. To this end, we generated and tested a nested set of IN C-terminal deletion mutants in measurable assays of virologic function. We discovered that removal of up to 15 residues (IN 273) resulted in incremental diminution of enzymatic function and infectivity and that removal of the next three residues resulted in a loss of infectivity. However, replication competency was surprisingly reestablished with one further truncation, corresponding to IN 269 and coinciding with partial restoration of integration activity, but it was lost permanently for all truncations extending N terminal to this position. Our analyses of these replication-competent and -incompetent truncation mutants suggest potential roles for the IN CTD in precursor protein processing, reverse transcription, integration, and IN multimerization.
Identification of a Genetic Variant Common to Moyamoya Disease and Intracranial Major Artery Stenosis/Occlusion

Background and Purpose— The c.14576G>A variant in ring finger protein 213 (RNF213) was recently identified as a susceptibility gene variant for moyamoya disease (MMD). The occurrence of c.14576G>A variant was evaluated in patients with intracranial major artery stenosis/occlusion (ICASO) without signs of MMD (non-MMD ICASO), as well as in patients with MMD and other cerebrovascular diseases as controls. Methods— This single-hospital–based case-control study was completed in 7 months (from October 2011–April 2012) at Department of Neurosurgery, The University of Tokyo Hospital. The occurrence of c.14576G>A variant was analyzed in 41 patients with non-MMD ICASO, in 48 with MMD, in 21 with cervical disease, in 61 with cerebral aneurysm, and in 25 normal subjects. Results— Nine of 41 patients (21.9%) with non-MMD ICASO and 41 of 48 (85.4%) with MMD had the c.14576G>A variant. One of 61 patients (1.6%) with cerebral aneurysm and no patients with cervical disease or normal subjects had the variant. Comparison of each phenotype group with the normal subjects showed that presence of c.14576G>A variant had significant associations with MMD (odds ratio [OR], 292.8; 95% confidence interval [CI], 15.4–5153.0; P<0.0001) and with non-MMD ICASO (OR, 14.9; 95% CI, 0.82–268.4; P=0.01), but no association with either cerebral aneurysm (OR, 1.2; 95% CI, 0.04–32.0; P=1.00) or cervical disease (OR, 1.1; 95% CI, 0.02–62.3; P=1.00). Conclusions— The present study indicates that a particular subset of Japanese patients with non-MMD ICASO has a genetic variant associated with MMD. Therefore, we propose the existence of a new entity of ICASO caused by the c.14576G>A variant in RNF213.
Increased Lymph Node Yield in Colorectal Cancer Is Not Necessarily Associated with a Greater Number of Lymph Node Positive Cancers

The presence of lymph node metastasis is a key prognostic factor in colorectal cancer and lymph node yield is an important parameter in assessing the quality of histopathology reporting of colorectal cancer excision specimens. This study assesses the trend in lymph node evaluation over time in a single institution and the relationship with the identification of lymph node positive tumours. It compares the lymph node yield of a contemporary dataset compiled from the histopathology reports of 2178 patients who underwent surgery for primary colorectal cancer between 2005 and 2012 with that of a historic dataset compiled from the histopathology reports of 1038 patients who underwent surgery for colorectal cancer at 5 yearly intervals from 1975 to 2000. The mean lymph node yield was 14.91 in 2005 rising to 21.38 in 2012. In 2012 92.9% of all cases had at least 12 lymph nodes examined. Comparison of the mean lymph node yield and proportion of Dukes C cases shows a significant increase (Pearson correlation = 0.927, p = 0.001) in lymph node yield while there is no corresponding significant trend in the proportion of Dukes C cases (Pearson correlation = −0.138, p = 0.745). This study shows that there is increasing yield of lymph nodes from colorectal cancer excision specimens. However, this is not necessarily associated with an increase number of lymph node positive cancers. Further risk stratifying of colorectal cancer requires consideration of other pathological parameters especially the presence of extramural venous invasion and relevant biomarkers.
Uncovering the Neural Mechanisms Underlying Learning from Tests

People learn better when re-study opportunities are replaced with tests. While researchers have begun to speculate on why testing is superior to study, few studies have directly examined the neural underpinnings of this effect. In this fMRI study, participants engaged in a study phase to learn arbitrary word pairs, followed by a cued recall test (recall second half of pair when cued with first word of pair), re-study of each pair, and finally another cycle of cued recall tests. Brain activation patterns during the first test (recall) of the studied pairs predicts performance on the second test. Importantly, while subsequent memory analyses of encoding trials also predict later accuracy, the brain regions involved in predicting later memory success are more extensive for activity during retrieval (testing) than during encoding (study). Those additional regions that predict subsequent memory based on their activation at test but not at encoding may be key to understanding the basis of the testing effect.
An Efficient Approach for Differentiating Alzheimer's Disease from Normal Elderly Based on Multicenter MRI Using Gray-Level Invariant Features

Machine learning techniques, along with imaging markers extracted from structural magnetic resonance images, have been shown to increase the accuracy to differentiate patients with Alzheimer's disease (AD) from normal elderly controls. Several forms of anatomical features, such as cortical volume, shape, and thickness, have demonstrated discriminative capability. These approaches rely on accurate non-linear image transformation, which could invite several nuisance factors, such as dependency on transformation parameters and the degree of anatomical abnormality, and an unpredictable influence of residual registration errors. In this study, we tested a simple method to extract disease-related anatomical features, which is suitable for initial stratification of the heterogeneous patient populations often encountered in clinical data. The method employed gray-level invariant features, which were extracted from linearly transformed images, to characterize AD-specific anatomical features. The intensity information from a disease-specific spatial masking, which was linearly registered to each patient, was used to capture the anatomical features. We implemented a two-step feature selection for anatomic recognition. First, a statistic-based feature selection was implemented to extract AD-related anatomical features while excluding non-significant features. Then, seven knowledge-based ROIs were used to capture the local discriminative powers of selected voxels within areas that were sensitive to AD or mild cognitive impairment (MCI). The discriminative capability of the proposed feature was measured by its performance in differentiating AD or MCI from normal elderly controls (NC) using a support vector machine. The statistic-based feature selection, together with the knowledge-based masks, provided a promising solution for capturing anatomical features of the brain efficiently. For the analysis of clinical populations, which are inherently heterogeneous, this approach could stratify the large amount of data rapidly and could be combined with more detailed subsequent analyses based on non-linear transformation.
Latex Sensitization: A Special Risk for the Obstetric Population?

Background:Previous studies have reported a greater frequency of sensitization to latex in the female population and a higher incidence of anaphylactic reactions to latex during cesarean section. In this study, the authors investigated the prevalence of latex sensitization in obstetric patients compared with nonpregnant subjects. Methods:Two hundred ninety-four healthy pregnant women who were at term with a singleton fetus and scheduled for caesarean section (group A) were compared with 294 healthy nulliparous women with childbirth potential undergoing gynecologic surgery (group B). Before surgery, patients completed a questionnaire, and venous blood samples were collected to measure specific immunoglobulin E serum concentrations with a fluorescent enzyme immunoassay test. Skin-prick tests were performed if adverse reactions occurred during surgery. Latex allergy was diagnosed on the basis of immunoglobulin E results and/or positive skin-prick tests. Results:The prevalence of latex sensitization was higher in group A than in group B (15/294, 5.1% vs. 5/294, 1.7%; P < 0.05). A significant difference in specific immunoglobulin E serum concentration was noted between pregnant and nonpregnant patients who had a positive fluorescent enzyme immunoassay test (median serum concentration: 1.93 kilounits/l; interquartile range = 2.28 vs. 0.78 kilounits/l; interquartile range = 1.07; P less than 0.05). Two patients in group A experienced an anaphylactic reaction to latex. Statistical analysis disclosed no association between latex sensitization and accepted risk factor for latex allergy. Conclusions:The authors report a higher prevalence of latex sensitization in the obstetric population than in nonpregnant subjects undergoing gynecologic surgery.
Validity of the Test of Infant Motor Performance for prediction of 6‐, 9‐ and 12‐month scores on the Alberta Infant Motor Scale

The Test of Infant Motor Performance (TIMP) is a test of functional movement in infants from 32 weeks’post‐conceptional age to 4 months postterm. The purpose of this study was to assess in 96 infants (44 females, 52 males) with varying risk, the relation between measures on the TIMP at 7, 30,60, and 90 days after term age and percentile ranks (PR) on the Alberta Infant Motor Scale (AIMS). Correlation between scores on the TIMP and the AIMS was highest for TIMP tests at 90 days and AIMS testing at 6 months (r=0.67,p=0.0001), but all comparisons were statistically significant except those between the TIMP at 7 days and AIMS PR at 9 months. In a multiple regression analysis combining a perinatal risk score and 7‐day TIMP measures to predict 12‐month AIMS PR, risk, but not TIMP, predicted outcome (21% of variance explained). At older ages TIMP measures made increasing contributions to prediction of 12‐month AIMS PR (30% of variance explained by 90‐day TIMP). The best TIMP score to maximize specificity and correctly identify 84% of the infants above versus below the 10th PR at 6 months was a cut‐off point of 1 SD below the mean. The same cut‐off point correctly identified 88% of the infants at 12 months. A cut‐off of‐0.5 SD, however, maximized sensitivity at 92%. A negative test result, i.e. score above ‐0.5 SD at 3 months, carried only a 2% probability of a poor 12‐month outcome. We conclude that TIMP scores significantly predict AIMS PR 6 to 12 months later, but the TIMP at 3 months of age has the greatest degree of validity for predicting motor performance on the AIMS at 12 months and can be used clinically to identify infants likely to benefit from intervention.
Control of Palmar Hyperhidrosis with a New “Dry‐Type” Iontophoretic Device

BACKGROUND Palmar hyperhidrosis is characterized by excessive sweating on the palm, and among the various treatment modalities, tap water iontophoresis has been widely used. OBJECTIVE The objective of this study was to assess the effect of a new “dry-type” iontophoretic device that was locally manufactured and did not use tap water to control sweating. METHODS Ten subjects with palmar hyperhidrosis were enrolled in this study. To be treated the patients were instructed that they only have to grasp the device. Only one palm was treated for 2 weeks, and then the treatment was discontinued the following next 2 weeks. The other palm was not treated as a control. At the end of second week, biopsy specimens were obtained from untreated and treated palm, respectively, and examined histologically. RESULTS Nine of 10 patients were satisfied with this therapy reducing their sweat outputs from 33% to 51% of baseline at the end of 2 weeks' treatment, and after 2 weeks of discontinuation of treatment sweat productions returned to near baseline. The pathologic examinations showed some occlusions and destruction of intraepithelial eccrine ducts only in the treated palm. CONCLUSION We suggest that dry-type iontophoresis could reduce palmar sweating more conveniently than other conventional methods.
Differential logging: a commutative and associative logging scheme for highly parallel main memory database

With a GByte of memory priced at less than $2000, main-memory DBMSs (MMDBMSs) are emerging as an economically viable alternative to disk-resident DBMSs (DRDBMSs) in many problem domains. The MMDBMS can show significantly higher performance than the DRDBMS by reducing disk accesses to the sequential form of log writing and occasional checkpointing. Upon a system crash, the recovery process begins by accessing the disk-resident log and checkpoint data to restore a consistent state. With increasing CPU speed, however, such disk access is still the dominant bottleneck in MMDBMSs. To overcome this bottleneck, this paper explores alternatives of parallel logging and recovery. The major contribution of this paper is the so-called differential logging scheme that permits unrestricted parallelism in logging and recovery. Using the bit-wise XOR operation both to compute the differential log between the before and after images and to recover the consistent database state, this scheme offers the room for significant performance improvement in the MMDBMS. First, with logging done on the difference, the log volume is reduced to almost half compared with the conventional physical logging. Second, the commutativity and associativity of XOR enables processing of log records in an arbitrary order. This means that we can freely distribute log records to multiple disks to improve the logging performance. During the recovery time, we can do a parallel restart independently for each log disk. This paper shows the superior performance of the differential logging compared to the physical logging in a shared-memory multiprocessor environment.
Differential distribution of angiotensin AT2 receptors in the normal and failing human heart.

Cardiac expression of angiotensin II (Ang II) AT1 and AT2 receptor subtypes is species dependent, and changes in their relative proportion may influence myocardial hypertrophy and fibrosis. Regional differences in the distribution of Ang II receptors in the normal and failing human heart were assessed using 125I-(Sar1,Ile8)Ang II binding and quantitative autoradiography. Receptor subtypes were distinguished by their affinity for selective nonpeptide antagonists (losartan and PD123319) and sensitivity to dithiothreitol. Ventricular and atrial tissues displayed a heterogeneous distribution of ligand binding sites. AT2 receptors predominated, representing 70% to 77% of the sites in normal and noninfarcted myocardium. Endocardial, interstitial, perivascular and infarcted regions in the ventricles of patients with end-stage ischemic heart disease or dilated cardiomyopathy exhibited a significantly greater density (P < .001) of high affinity AT2 binding sites (Kd = 0.57 nmol/liter) compared with adjacent noninfarcted myocardium. Regions displaying the relative increase in AT2 binding sites corresponded to areas of fibroblast proliferation and collagen deposition, shown by picrosirius red staining. AT1 binding sites were localized to nerves, occurred at relatively low density in coronary vessels and represented only 23% to 29% of myocardial 125I-(Sar1,Ile8)Ang II binding sites. The border zone between infarcted and noninfarcted myocardium characteristically contained numerous microvessels, exhibiting perivascular AT2 receptors and endothelial angiotensin converting enzyme activity, as demonstrated by binding of 125I-351A. Specific myocardial AT2 receptor mRNA transcripts (approximately 3 kb) were identified and exhibited alternative splicing of untranslated 5' exons. The differential distribution of cardiac Ang II receptor subtypes and selective increase in binding to AT2 sites in the diseased heart suggest that cells bearing the AT2 receptor represent a significant target for Ang II, possibly contributing to its growth-related actions.
Thematic review series: Brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal Published, JLR Papers in Press, May 16, 2004. DOI 10.1194/jlr.R400004-JLR200

Unesterified cholesterol is an essential structural component of the plasma membrane of every cell. During evolution, this membrane came to play an additional, highly specialized role in the central nervous system (CNS) as the major architectural component of compact myelin. As a consequence, in the human the mean concentration of unesterified cholesterol in the CNS is higher than in any other tissue (∼23 mg/g). Furthermore, even though the CNS accounts for only 2.1% of body weight, it contains 23% of the sterol present in the whole body pool. In all animals, most growth and differentiation of the CNS occurs in the first few weeks or years after birth, and the cholesterol required for this growth apparently comes exclusively from de novo synthesis. Currently, there is no evidence for the net transfer of sterol from the blood into the brain or spinal cord. In adults, the rate of synthesis exceeds the need for new structural sterol, so that net movement of cholesterol out of the CNS must take place. At least two pathways are used for this excretory process, one of which involves the formation of 24(S)-hydroxycholesterol. Whether or not changes in the plasma cholesterol concentration alter sterol metabolism in the CNS or whether such changes affect cognitive function in the brain or the incidence of dementia remain uncertain at this time.
Innovation in Health Care: A Primer

As organizations strive for ways to control health care spending, address the growing needs of an aging population, and respond satisfactorily to a more informed and demanding consumer base, the opportunities for innovation have increased exponentially. By means of this article, the authors describe the basic concepts of purposeful innovation, and compare and contrast it to quality improvement. The authors also provide an overview of the terminology and types of innovation, describe the innovation life cycle, and discuss diffusion and commercialization of innovations. This article provides a primer on innovation for quality improvement practitioners and physician leaders who play a key role in creating innovation and environments for innovations to flourish. (Am J Med Qual 2008;23:382-388)
Androgen-mediated sex bias impairs efficiency of leukotriene biosynthesis inhibitors in males

Proinflammatory leukotrienes (LTs) are produced by 5-lipoxygenase (5-LO) aided by 5-LO–activating protein (FLAP). LT biosynthesis inhibitors are currently under clinical investigation as treatments for respiratory and cardiovascular diseases. Here, we have revealed a sex bias in the efficiency of clinically relevant LT biosynthesis inhibitors, showing that their effects are superior in females. We found that androgens cause these sex differences by impeding the LT-biosynthetic 5-LO/FLAP complex assembly. Lower doses of the FLAP inhibitor MK886 were required to reduce LTB4 levels in exudates of female versus male mice and rats. Following platelet-activating factor–induced shock, MK886 increased survival exclusively in female mice, and this effect was abolished by testosterone administration. FLAP inhibitors and the novel-type 5-LO inhibitors licofelone and sulindac sulfide exhibited higher potencies in human blood from females, and bioactive 5-LO/FLAP complexes were formed in female, but not male, human and murine leukocytes. Supplementation of female blood or leukocytes with 5&agr;-dihydrotestosterone abolished the observed sex differences. Our data suggest that females may benefit from anti-LT therapy to a greater extent than males, prompting consideration of sex issues in LT modifier development.
EWS-FLI1 confers exquisite sensitivity to NAMPT inhibition in Ewing sarcoma cells

Ewing sarcoma (EwS) is the second most common bone cancer in children and adolescents with a high metastatic potential. EwS development is driven by a specific chromosomal translocation resulting in the generation of a chimeric EWS-ETS transcription factor, most frequently EWS-FLI1. Nicotinamide adenine dinucleotide (NAD) is a key metabolite of energy metabolism involved in cellular redox reactions, DNA repair, and in the maintenance of genomic stability. This study describes targeting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD synthesis, by FK866 in EwS cells. Here we report that blocking NAMPT leads to exhaustive NAD depletion in EwS cells, followed by a metabolic collapse and cell death. Using conditional EWS-FLI1 knockdown by doxycycline-inducible shRNA revealed that EWS-FLI1 depletion significantly reduces the sensitivity of EwS cells to NAMPT inhibition. Consistent with this finding, a comparison of 7 EwS cell lines of different genotypes with 5 Non-EwS cell lines and mesenchymal stem cells revealed significantly higher FK866 sensitivity of EWS-ETS positive EwS cells, with IC50 values mostly below 1nM. Taken together, our data reveal evidence of an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of EwS cells and suggest NAMPT inhibition as a potential new treatment approach for Ewing sarcoma.
Local Asymmetry and the Inner Radius of Nodal Domains

Let M be a closed Riemannian manifold of dimension n. Let ϕλ be an eigenfunction of the Laplace–Beltrami operator corresponding to an eigenvalue λ. We show that the volume of {ϕλ > 0} ∩ B is ≥C|B|/λ n , where B is any ball centered at a point of the nodal set. We apply this result to prove that each nodal domain contains a ball of radius ≥C/λ n . The results in this paper extend previous results of Nazarov, Polterovich, Sodin and of the author.