Miracle-dz/UniFAR-FTUs huggingface dataset:
The Differential Ability of HLA B*5701+ Long-Term Nonprogressors and Progressors To Restrict Human Immunodeficiency Virus Replication Is Not Caused by Loss of Recognition of Autologous Viral gag Sequences

ABSTRACT Although the HLA B*5701 class I allele is highly overrepresented among human immunodeficiency virus (HIV)-infected long-term nonprogressors (LTNPs), it is also present at the expected frequency (11%) in patients with progressive HIV infection. Whether B57+ progressors lack restriction of viral replication because of escape from recognition of highly immunodominant B57-restricted gag epitopes by CD8+ T cells remains unknown. In this report, we investigate the association between restriction of virus replication and recognition of autologous virus sequences in 27 B*57+ patients (10 LTNPs and 17 progressors). Amplification and direct sequencing of single molecules of viral cDNA or proviral DNA revealed low frequencies of genetic variations in these regions of gag. Furthermore, CD8+ T-cell recognition of autologous viral variants was preserved in most cases. In two patients, responses to autologous viral variants were not demonstrable at one epitope. By using a novel technique to isolate primary CD4+ T cells expressing autologous viral gene products, it was found that 1 to 13% of CD8+ T cells were able to respond to these cells by gamma interferon production. In conclusion, escape-conferring mutations occur infrequently within immunodominant B57-restricted gag epitopes and are not the primary mechanism of virus evasion from immune control in B*5701+ HIV-infected patients. Qualitative features of the virus-specific CD8+ T-cell response not measured by current assays remain the most likely determinants of the differential abilities of HLA B*5701+ LTNPs and progressors to restrict virus replication.
Extending regular expressions with context operators and parse extraction

Regular expressions are used in many applications to specify patterns because any regular expression can be compiled into a very efficient one‐pass pattern matcher called a finite automaton. Finding matches is useful, but even more useful is parse extraction, which describes in detail how a pattern matches some input. After matching an address, for example, parse extraction makes it easy to find out the Zip code part of the address. We present an elegant, efficient algorithm for extracting a parse after matching with a finite automaton. In addition, we extend the regular expression language to include new operators for matching arbitrary left context and single character right context. The extended language can be matched as efficiently as the usual regular expression language, but is more expressive. Finally, we suggest how to apply the matching algorithms to match regular expressions containing arbitrary right context and single character left context. In effect, this allows one to specify patterns that seem to require an unlimited amount of look‐ahead to match.
What Metaphors Mean

Metaphor is the dreamwork of language and, like all dreamwork, its interpretation reflects as much on the interpreter as on the originator. The interpretation of dreams requires collaboration between a dreamer and a waker, even if they be the same person; and the act of interpretation is itself a work of the imagination. So too understanding a metaphor is as much a creative endeavor as making a metaphor, and as little guided by rules.
Akt (Protein Kinase B) Negatively Regulates SEK1 by Means of Protein Phosphorylation*

The protein serine-threonine kinase Akt mediates cell survival signaling initiated by various growth-promoting factors such as insulin. Here we report that SEK1 is a target of Akt in intact cells. Insulin inhibited the anisomycin-induced stimulation of both endogenous SEK1 and its substrate c-Jun N-terminal kinase (JNK), but not that of the upstream kinase MEKK1, in 293T cells. The inhibitory action of insulin on SEK1 or JNK1 activation was prevented by the phosphatidylinositol 3-kinase inhibitor LY294002. Expression of a constitutively active form of Akt also inhibited both SEK1 and JNK1 activation, but not that of MEKK1, in transfected 293T cells. Co-immunoprecipitation analysis revealed that endogenous Akt physically interacted with endogenous SEK1 in cells and that this interaction was promoted by insulin. In vitro and in vivo 32P labeling indicated that Akt phosphorylated SEK1 on serine 78. The SEK1 mutant SEK1(S78A) was resistant to Akt-induced inhibition. Finally, activated Akt inhibited SEK1-mediated apoptosis, and this effect of Akt was prevented by overexpression of SEK(S78A). Taken together, these results suggest that Akt suppresses stress-activated signaling by targeting SEK1.
Discontinuous Space-Vector Modulation for Three-Level PWM Rectifiers

This paper presents the implementation and experimental verification of two discontinuous pulsewidth modulation (DPWM) methods for three-phase, three-level rectifiers. DPWM's features, such as improved waveform quality, lower switching losses, reduced ac-side passive component size, are investigated and compared to the conventional continuous pulsewidth modulation (CPWM). These features allow higher power density and/or efficiency to be achieved and are important targets for the next generation of power rectifiers. The implementation of the two DPWM strategies is explained by means of space-vectors representation and modulation functions. A detailed analysis of both ac-side and dc-side current waveforms is presented, and there is excellent agreement between the analytical, simulated and experimental results for the mains current ripple amplitude and output center-point current over the practical modulation range. Finally, the control of the center-point voltage is discussed.
Late Cenozoic onset of the latitudinal diversity gradient of North American mammals

Significance The number of species declines from the Earth's equator to the poles—a pattern known as the latitudinal diversity gradient (LDG)—for nearly every group of living organisms in which the LDG has been studied. However, our analyses of fossil occurrences demonstrate that the LDG of terrestrial mammals was substantially weaker than it is today, if not absent entirely, for most of the past 65 My. We also show the strength of the LDG varies with global temperature and is weakest during globally warm periods. We find that the modern LDG became established sometime in only in the last 4 My, most likely as a result of declining global temperatures. The decline of species richness from equator to pole, or latitudinal diversity gradient (LDG), is nearly universal among clades of living organisms, yet whether it was such a pervasive pattern in the geologic past remains uncertain. Here, we calculate the strength of the LDG for terrestrial mammals in North America over the past 65 My, using 27,903 fossil occurrences of Cenozoic terrestrial mammals from western North America downloaded from the Paleobiology Database. Accounting for temporal and spatial variation in sampling, the LDG was substantially weaker than it is today for most of the Cenozoic and the robust modern LDG of North American mammals evolved only over the last 4 My. The strength of the LDG correlates negatively with global temperature, suggesting a role of global climate patterns in the establishment and maintenance of the LDG for North American mammals.
Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67.

The monoclonal antibody Ki-67 detects a nuclear antigen that is present only in proliferating cells. The aim of the present investigation was to clarify whether the Ki-67 nuclear antigen is restricted in its expression to certain phases of the cell cycle. All experiments consistently showed that the Ki-67 nuclear antigen is present in S, G2, and M phase, but is absent in G0. However, the results concerning Ki-67 antigen expression in G1 phase varied: cells passing the early events of mitogen triggered transition from G0 to G1, i.e., G1T and first G1A, lacked the Ki-67 nuclear antigen, whereas G1 cells after mitosis were constantly Ki-67-positive. This result suggests that after mitosis cells might not follow the same metabolic pathways as G0 cells do when entering G1 for the first time. Therefore, we suggest that the early stages of mitogen stimulation represent initial sequences of proliferation and not parts of the cell cycle. Because our data show that the Ki-67 nuclear antigen is present throughout the cell cycle, immunostaining with monoclonal antibody Ki-67 provides a reliable means of rapidly evaluating the growth fraction of normal and neoplastic human cell populations.
Pharmacokinetics and Pharmacodynamics of Cefpirome in Subcutaneous Adipose Tissue of Septic Patients

ABSTRACT The objective of the present study was to evaluate whether cefpirome, a member of the latest class of broad-spectrum cephalosporins, sufficiently penetrates subcutaneous adipose tissue in septic patients. After the administration of the drug at 2 g, tissue cefpirome concentrations in septic patients (n = 11) and healthy controls (n = 7) were determined over a period of 4 h by means of microdialysis. To assess the antibacterial effect of cefpirome at the target site, the measured pharmacokinetic profiles were simulated in vitro with select strains of Staphylococcus aureus and Pseudomonas aeruginosa. The tissue penetration of cefpirome was significantly impaired in septic patients compared with that in healthy subjects. For subcutaneous adipose tissue, the area under the concentration-versus-time curve values from 0 to 240 min were 13.11 ± 5.20 g · min/liter in healthy subjects and 6.90 ± 2.56 g · min/liter in septic patients (P < 0.05). Effective bacterial growth inhibition was observed in all in vitro simulations. This was attributed to the significantly prolonged half-life in tissue (P < 0.05), which kept the tissue cefpirome levels above the MICs for relevant pathogens for extended periods in the septic group. By consideration of a dosing interval of 8 h, the values for the time above MIC (T > MIC) in tissue were greater than 60% for pathogens for which the MIC was ≤4 mg/liter in all septic patients. The present data indicate that cefpirome is an appropriate agent for the treatment of soft tissue infections in septic patients. However, due to the high interindividual variability of the pharmacokinetics of cefpirome in tissue, dosing intervals of not more than 8 h should be preferred to ensure that susceptible bacterial strains are killed in each patient.
Dietary n-3 Polyunsaturated Fatty Acids in Late Pregnancy and Postpartum Depressive Symptom among Japanese Women

Background The use of n-3 polyunsaturated fatty acids (n-3PUFA) in preventive or therapeutic modalities for postpartum depression, especially long-chain types such as eicosapentaenoic acid (EPA) and a docosahexaenoic acid (DHA), is of considerable interest. High n-3PUFA consumption has been reported among pregnant Japanese women. Therefore, analysis of this group could provide important insights into the relationship between postpartum depression and dietary n-3PUFA consumption. To further examine the relationship between the risk of postpartum depression and n-3PUFA consumption, we conducted a prospective hospital-based birth cohort study in Japan. Design and methods Our prospective birth cohort study was performed at the National Center for Child Health and Development (NCCHD) in suburban Tokyo, Japan. Dietary n-3PUFA intake during late pregnancy was assessed by a semi-quantitative food questionnaire and participants were categorized by quintile distributions of n-3PUFA intake. A Japanese translation of the Edinburgh Postnatal Depression Scale was used to screen women for postpartum depression at 1 month after delivery (967 women) and at 6 months after delivery (710 women). We performed logistic regression analysis to examine the relationship between the risk of postpartum depression and n-3PUFA consumption after adjusting for confounding factors. Results Significant associations between EPA, DHA, and n-3PUFA intakes in late pregnancy and postpartum depression at both 1 and 6 months after delivery were not observed. Conclusion This prospective study indicated that EPA, DHA, and n-3PUFA intake during late pregnancy was not associated with the risk of postpartum depression.
Proanthocyanidin: a natural crosslinking reagent for stabilizing collagen matrices.

While attempting to find a suitable crosslinking reagent for biopolymers, a naturally occurring proanthocyanidin (PA) obtained from grape seeds was selected to fix biological tissues. The cytotoxicity and crosslinking rate, reflected by the in vitro and in vivo degradation of fixed matrices has been studied. The shrinkage temperature of the fixed bovine pericardium increased from 66 to 86 degrees C. A cytotoxicity assay using fibroblast cultures revealed that PA is approximately 120 times less toxic than glutaraldehyde (GA), a currently used tissue stabilizer. In vitro degradation studies showed that fixed tissue was resistant to digestion by bacterial collagenase. Crosslinks between PA and tissues can be stabilized by decreasing the dielectric constant of the solution during storage. After subcutaneous implantation for periods ranging between 3 and 6 weeks, we found no apparent degradation of the GA- or PA-fixed tissues, whereas fresh tissue controls rapidly disintegrated. Beyond 6 weeks PA crosslinks began to degrade. More fibroblasts migrated and proliferated inside the PA-fixed implants compared with GA counterparts. Tissues crosslinked with PA manifested an enhanced collagen expression and deposition and did not calcify after implantation. GA, on the other hand, even after thorough rinsing continued to be cytotoxic, inhibited collagen synthesis and encouraged dystrophic calcification. Collagen matrices crosslinked with PA are expected to be of value in the design of matrices that will encourage cell ingrowth and proliferation, which are temporary in nature, and that are intended to regenerate or replace missing tissues, which can delay the biogradation of collagen. As such they should be of significant value in the emerging field of tissue engineering.
Evaluation of the role of mallard ducks as vectors of porcine reproductive and respiratory syndrome virus

To assess the transmission of porcine reproductive and respiratory syndrome virus (PRRSV) from pigs to mallard ducks, 10 adult (one-year-old) female mallard ducks were housed with pigs infected experimentally with PRRSV, and allowed to be in close contact with them for 21 days. To evaluate the transmission of PRRSV from mallard ducks to pigs, two adult ducks were inoculated orally with PRRSV (total dose 106.0 TCID50) and allowed to drink PRRsv-infected water; 24 hours later, two four-week-old PRRSv-naive sentinel pigs were housed in pens below the cages housing the ducks for 14 days. In both experiments, cloacal and faecal samples were collected three times a week from the ducks and tested by PcR, virus isolation and a pig bioassay. Blood samples from the pigs were tested by ELISA, PCR and virus isolation. Sera from the ducks were tested by serum neutralisation. The ducks were examined postmortem and selected tissues were tested by PcR, virus isolation, histopathology and pig bioassay. In both experiments all the cloacal swabs, faecal samples, tissues and sera from the ducks were negative by all the tests. The sera from the pigs in the first experiment were PCR positive at three, seven, 14 and 21 days after infection and ELISA positive at 14 and 21 days. Sera from the pigs in the second experiment were negative by all the tests. The virus was isolated from the oral inoculum and the drinking water provided for the ducks in the second experiment. Under the conditions of this study, it was not possible to demonstrate the transmission of PRRSV either from the pigs to the ducks or from the ducks to the pigs.
Device Exchange in HeartMate II Recipients: Long-Term Outcomes and Risk of Thrombosis Recurrence

Successful long-term use of the HeartMate II (HM II) left ventricular assist device has become commonplace but may be complicated by mechanical failure, infection, or thrombosis necessitating device exchange (DE). A subcostal approach to device exchange with motor exchange only is less traumatic, but long-term outcomes have not been reported. A retrospective chart review of all patients who required HM II to HM II device exchange at our institution was conducted. Of the 232 HM II patients implanted between January 2008 and July 2013, 28 required 36 device exchanges during a follow-up of 33.72 ± 17.25 months. The Kaplan–Meier 1 year survival was 63% for sternotomy exchanges and 100% for subcostal exchanges. Twenty-one exchanges were performed for initial or recurring device thrombosis. Although there was no difference in the risk of subsequent thrombosis after subcostal versus sternotomy exchange, the overall risk of recurring device thrombosis after device exchange for the same was high (31%). HM II device exchange via the subcostal approach has excellent short- and long-term outcomes. Device exchange performed for thrombosis is associated with a high recurrence risk irrespective of surgical approach
Sphingosine-1-phosphate and sphingosine kinase are critical for transforming growth factor-beta-stimulated collagen production by cardiac fibroblasts.

AIMS Following injury, fibroblasts transform into myofibroblasts and produce extracellular matrix (ECM). Excess production of ECM associated with cardiac fibrosis severely inhibits cardiac function. Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, regulates the function of numerous cell types. In this study, we determined the role of S1P in promoting pro-fibrotic actions of cardiac fibroblasts (CFs). METHODS AND RESULTS S1P-mediated effects on myofibroblast transformation, collagen production, and cross-talk with transforming growth factor-beta (TGF-beta) using mouse CF were examined. S1P increased alpha-smooth muscle actin (a myofibroblast marker) and collagen expression in a S1P2 receptor- and Rho kinase-dependent manner. TGF-beta increased sphingosine kinase 1 (SphK1; the enzyme responsible for S1P production) expression and activity. TGF-beta-stimulated collagen production was inhibited by SphK1 or S1P2 siRNA, a SphK inhibitor, and an anti-S1P monoclonal antibody. CONCLUSION These findings suggest that TGF-beta-stimulated collagen production in CF involves 'inside-out' S1P signalling whereby S1P produced intracellularly by SphK1 can be released and act in an autocrine/paracrine fashion to activate S1P2 and increase collagen production.
Chronic Activation of Protein Kinase C in Soleus Muscles and Other Tissues of Insulin-Resistant Type II diabetic Goto-Kakizaki (GK), Obese/Aged, and Obese/Zucker Rats: A Mechanism For Inhibiting Glycogen Synthesis

We examined the possibility that protein kinase C (PKC) is chronically activated and may contribute to impaired glycogen synthesis and insulin resistance in soleus muscles of hyperinsulinemic type II diabetic Goto-Kakizaki (GK) rats. Relative to nondiabetic controls, PKC enzyme activity and levels of immunoreactive PKC-α, β, є, and delta were increased in membrane fractions and decreased cytosolic fractions of GK soleus muscles. In addition, PKC-θ levels were decreased in both membrane and cytosol fractios, whereas PKC-ζ levels were not changed in either fraction in GK soleus muscles. These increases in membrane PKC (α, β, є, and δ) could not be accounted for by alterations in PKC mRNA or total PKC levels but were associated with increases in membrane diacylglycerol (DAG) and therefore appeared to reflect translocative activation of PKC. In evaluation of potential causes for persistent PKC activation, membrane PKC levels were decreased in soleus muscles of hyperglycemic streptozotocin (STZ)-induced diabetic rats; thus, a role for simple hyperglycemia as a cause of PKC activation in GK rats was not evident in the STZ model. In support of the possibility that hyperinsulinemia contributed to PKC activation in GK soleus muscles, we found that DAG levels were increased, and PKC was translocated, in soleus muscles of both (1) normoglycemic hyperinsulinemic obese/aged rats and (2) mildly hyperglycemic hyperinsulinemic obese/Zucker rats. In keeping with the possibility that PKC activation may contribute to impaired glycogen synthase activation in GK muscles, phorbol esters inhibited, and a PKC inhibitor, RO 31-8220, increased insulin effects on glycogen synthesis in soleus muscles incubated in vitro. Our findings suggested that: (1) hyperinsulinemia, as observed in type II diabetic GK rats and certain genetic and nongenetic forms of obesity in rats, is associated with persistent translocation and activation of PKC in soleus muscles, and (2) this persistent PKC activation may contribute to impaired glycogen synthesis and insulin resistance.
The Course of Etoposide-induced Apoptosis from Damage to DNA and p53 Activation to Mitochondrial Release of Cytochromec *

Treatment of L929 fibroblasts by the topoisomerase II inhibitor etoposide killed 50% of the cells within 72 h. The cell killing was preceded by the release of cytochromec from the mitochondria. Simultaneous treatment of the cells with wortmannin, cycloheximide, furosemide, cyclosporin A, or decylubiquinone prevented the release of cytochrome c and significantly reduced the loss of viability. Etoposide caused the phosphorylation of p53 within 6 h, an effect prevented by wortmannin, an inhibitor of DNA-dependent protein kinase (DNA-PK). The activation of p53 by etoposide resulted in the up-regulation of the pro-apoptotic protein Bax, a result that was prevented by the protein synthesis inhibitor cycloheximide. The increase in the content of Bax was followed by the translocation of this protein from the cytosol to the mitochondria, an event that was inhibited by furosemide, a chloride channel inhibitor. Stably transfected L929 fibroblasts that overexpress Akt were resistant to etoposide and did not translocate Bax to the mitochondria or release cytochrome c. Bax levels in these transfected cells were comparable with the wild-type cells. The release of cytochromec upon translocation of Bax has been attributed to induction of the mitochondrial permeability transition (MPT). Cyclosporin A and decylubiquinone, inhibitors of MPT, prevented the release of cytochrome c without affecting Bax translocation. These data define a sequence of biochemical events that mediates the apoptosis induced by etoposide. This cascade proceeds by coupling DNA damage to p53 phosphorylation through the action of DNA-PK. The activation of p53 increases Bax synthesis. The translocation of Bax to the mitochondria induces the MPT, the event that releases cytochrome c and culminates in the death of the cells.