Miracle-dz/UniFAR-FTUs huggingface dataset:
Immune Response to Mouse Mammary Tumor Virus in Mice Lacking the Alpha/Beta Interferon or the Gamma Interferon Receptor

ABSTRACT Mouse mammary tumor virus (MMTV) is a retrovirus which induces a strong immune response and a dramatic increase in the number of infected cells through the expression of a superantigen (SAg). Many cytokines are likely to be involved in the interaction between MMTV and the immune system. In particular, alpha/beta interferon (IFN-α/β) and gamma interferon (IFN-γ) exert many antiviral and immunomodulatory activities and play a critical role in other viral infections. In this study, we have investigated the importance of interferons during MMTV infection by using mice with a disrupted IFN-α/β or IFN-γ receptor gene. We found that the SAg response to MMTV was not modified in IFN-α/βR0/0 and IFN-γR0/0 mice. This was true both for the early expansion of B and T cells induced by the SAg and for the deletion of SAg-reactive cells at later stages of the infection. In addition, no increase in the amount of proviral DNA was detected in tissues of IFN-α/βR0/0 and IFN-γR0/0 mice, suggesting that interferons are not essential antiviral defense mechanisms during MMTV infection. In contrast, IFN-γR0/0mice had increased amounts of IL-4 mRNA and an altered usage of immunoglobulin isotypes with a reduced frequency of IgG2a- and IgG3-producing cells. This was associated with lower titers of virus-specific antibodies in serum early after infection, although efficient titers were reached later.
LATEST : Lazy Dynamic Test Input Generation

We present lazy expansion, a new algorithm for scalable test input generation using directed concolic execution. Lazy expansion is an instantiation of the counterexample-guided refinement paradigm from static software verification in the context of testing. Our algorithm works in two phases. It first explores, using concolic execution, an abstraction of the function under test by replacing each called function with an unconstrained input. Second, for each (possibly spurious) trace generated by this abstraction, it attempts to expand the trace to a concretely realizable execution by recursively expanding the called functions and finding concrete executions in the called functions that can be stitched together with the original trace to form a complete program execution. Thus, it reduces the burden of symbolic reasoning about interprocedural paths to reasoning about intraprocedural paths (in the exploration phase), together with a localized and constrained search through functions (in the concretization phase). Lazy expansion is particularly effective in testing functions that make more-or-less independent calls to lower level library functions (that have already been unit tested), by only exploring relevant paths in the function under test. We have implemented our algorithm on top of the CUTE concolic execution tool for C and applied it to testing parser code in small compilers. In preliminary experiments, our tool, called LATEST, outperformed CUTE by an order of magnitude in terms of the time taken to generate inputs, and in contrast to CUTE, produced many syntactically valid input strings which exercised interesting paths through the compiler (rather than only the parser error handling code).
Impact of endothelin blockade on acute exercise‐induced changes in blood flow and endothelial function in type 2 diabetes mellitus

What is the central question of this study? Doesendothelin receptor blockade increase exercise‐induced blood flow and post‐exercise endothelial function in men with type 2 diabetes? What is the main finding and its importance? Despite increasing exercise‐induced blood flow, endothelin receptor blockade did not impact post‐exercise endothelial function. The increase in blood flow may have beneficial effects in repeated exercise training.
High Corticosterone Levels in Prenatally Stressed Rats Predict Persistent Paradoxical Sleep Alterations

Prenatal stress predisposes rats to long-lasting disturbances that persist throughout adulthood (e.g., high anxiety, dysfunction of the hypothalamo–pituitary–adrenal axis, and abnormal circadian timing). These disturbances parallel to a large extent those found in depressed patients, in which hypercortisolemia and sleep alterations may be related to stress-inducing events. We studied sleep–wake parameters in control and prenatally stressed adult rats (3–4 months old) and examined possible relationships with their corticosterone levels (determined at 2 months of age). Under baseline conditions, prenatally stressed rats showed increased amounts of paradoxical sleep, positively correlated to plasma corticosterone levels. Other changes include increased sleep fragmentation, total light slow-wave sleep time, and a slight decrease in the percentage of deep slow-wave sleep relative to total sleep time. During recovery sleep from acute restraint stress, all sleep changes persisted and were correlated with stress-induced corticosterone secretion. High corticosterone levels under baseline conditions as well as an acute stress challenge may thus predict long-term sleep–wake alterations in rats. Taken together with other behavioral and hormonal abnormalities in prenatally stressed animals, the pronounced changes in sleep–wake parameters that are similar to those found in depressed patients suggest that prenatal stress may be a useful animal model of depression.
Are implicit self-esteem measures valid for assessing individual and cultural differences?

OBJECTIVE Our research utilized two popular theoretical conceptualizations of implicit self-esteem: 1) implicit self-esteem as a global automatic reaction to the self; and 2) implicit self-esteem as a context/domain specific construct. Under this framework, we present an extensive search for implicit self-esteem measure validity among different cultural groups (Study 1) and under several experimental manipulations (Study 2). METHOD In Study 1, Euro-Canadians (N = 107), Asian-Canadians (N = 187), and Japanese (N = 112) completed a battery of implicit self-esteem, explicit self-esteem, and criterion measures. Included implicit self-esteem measures were either popular or provided methodological improvements upon older methods. Criterion measures were sampled from previous research on implicit self-esteem and included self-report and independent ratings. In Study 2, Americans (N = 582) completed a shorter battery of these same types of measures under either a control condition, an explicit prime meant to activate the self-concept in a particular context, or prime meant to activate self-competence related implicit attitudes. RESULTS Across both studies, explicit self-esteem measures far outperformed implicit self-esteem measures in all cultural groups and under all experimental manipulations. CONCLUSION Implicit self-esteem measures are not valid for individual or cross-cultural comparisons. We speculate that individuals may not form implicit associations with the self as an attitudinal object.
Prognostic Value of the Cumulative Cisplatin Dose During Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A Secondary Analysis of a Prospective Phase III Clinical Trial.

BACKGROUND The objective of this study was to evaluate the prognostic value of the cumulative cisplatin dose (CCD) for long-term survival outcomes after concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC). METHODS Patients were included in an open-label phase III multicenter randomized controlled trial performed at seven institutions in China, and the 298 patients receiving CCRT only were assessed. Patient survival between different CCD groups were compared. RESULTS Median CCD for the 298 patients was 240 mg/m2 (range, 40-320 mg/m2); 113 (37.9%) patients received a CCD of <240 (≤200) mg/m2, and 185 (62.1%) received a CCD of ≥240 mg/m2. For CCD of ≥240 mg/m2 vs. <240 mg/m2, the estimated 5-year overall survival, disease-free survival, locoregional relapse-free survival, and distant metastasis-free survival rates were 83.2% vs. 76.2% (p = .403), 73.5% vs. 67.8% (p = .461), 90.4% vs. 86.8% (p = .551), and 82.6% vs. 79.7% (p = .632), respectively. Multivariate analysis demonstrated that CCD (240 mg/m2) was not an independent prognostic factor in either the entire cohort or stage III/IV subgroup. CONCLUSION A CCD of ≥240 mg/m2 was not an independent prognostic factor in patients with locoregionally advanced NPC at high risk of distant metastasis, and 200 mg/m2 cisplatin may be adequate to achieve a survival benefit. IMPLICATIONS FOR PRACTICE The current standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) is cisplatin-based concurrent chemoradiotherapy (CCRT), and the cisplatin is delivered every 3 weeks (100 mg/m2) for three cycles. However, the prognostic value of cumulative cisplatin dose (CCD) delivered during CCRT is controversial. The present study investigated the prognostic value of CCD and demonstrated that a CCD of 200 mg/m2 during CCRT is adequate to achieve satisfactory survival outcomes for patients with locoregionally advanced NPC. This finding is of great importance to clinicians because it could allow patients to avoid excessive treatment and toxicities.
Comprehensive establishment and characterization of orthoxenograft mouse models of malignant peripheral nerve sheath tumors for personalized medicine

Malignant peripheral nerve sheath tumors (MPNSTs) are soft‐tissue sarcomas that can arise either sporadically or in association with neurofibromatosis type 1 (NF1). These aggressive malignancies confer poor survival, with no effective therapy available. We present the generation and characterization of five distinct MPNST orthoxenograft models for preclinical testing and personalized medicine. Four of the models are patient‐derived tumor xenografts (PDTX), two independent MPNSTs from the same NF1 patient and two from different sporadic patients. The fifth model is an orthoxenograft derived from an NF1‐related MPNST cell line. All MPNST orthoxenografts were generated by tumor implantation, or cell line injection, next to the sciatic nerve of nude mice, and were perpetuated by 7–10 mouse‐to‐mouse passages. The models reliably recapitulate the histopathological properties of their parental primary tumors. They also mimic distal dissemination properties in mice. Human stroma was rapidly lost after MPNST engraftment and replaced by murine stroma, which facilitated genomic tumor characterization. Compatible with an origin in a catastrophic event and subsequent genome stabilization, MPNST contained highly altered genomes that remained remarkably stable in orthoxenograft establishment and along passages. Mutational frequency and type of somatic point mutations were highly variable among the different MPNSTs modeled, but very consistent when comparing primary tumors with matched orthoxenografts generated. Unsupervised cluster analysis and principal component analysis (PCA) using an MPNST expression signature of ~1,000 genes grouped together all primary tumor–orthoxenograft pairs. Our work points to differences in the engraftment process of primary tumors compared with the engraftment of established cell lines. Following standardization and extensive characterization and validation, the orthoxenograft models were used for initial preclinical drug testing. Sorafenib (a BRAF inhibitor), in combination with doxorubicin or rapamycin, was found to be the most effective treatment for reducing MPNST growth. The development of genomically well‐characterized preclinical models for MPNST allowed the evaluation of novel therapeutic strategies for personalized medicine.
Preoperative Serum Caveolin-1 as a Prognostic Marker for Recurrence in a Radical Prostatectomy Cohort

Purpose: Up-regulation of caveolin-1 (cav-1) is associated with virulent prostate cancer, and serum cav-1 levels are elevated in prostate cancer patients but not in benign prostatic hyperplasia. In this study, we evaluated the potential of high preoperative serum cav-1 levels to predict biochemical progression of prostate cancer. The value of the combined preoperative markers, prostate-specific antigen (PSA), biopsy Gleason score, and serum cav-1 for predicting biochemical recurrence was also investigated. Experimental Design: Serum samples taken from 419 prostate cancer patients before radical prostatectomy were selected from our Specialized Programs of Research Excellence prostate cancer serum and tissue bank. Serum samples were obtained 0 to 180 days before surgery and all patients had complete data on age, sex, race, stage at enrollment, and follow-up for biochemical recurrence. Serum cav-1 levels were measured according to our previously reported ELISA protocol. Results: Cav-1 levels were measured in the sera of 419 prostate cancer patients; the mean serum level was 4.52 ng/mL (median 1.01 ng/mL). Patients with high serum cav-1 levels had a 2.7-fold (P = 0.0493) greater risk of developing biochemical recurrence compared with those with low serum cav-1 levels. Importantly, patients with serum PSA ≥ 10 ng/mL and elevated levels of serum cav-1 had 2.44 times higher risk (P = 0.0256) of developing biochemical recurrence compared with patients with low levels of cav-1. In addition, high serum cav-1 levels combined with increasing biopsy Gleason score predicted much shorter recurrence-free survival in the group of patients with PSA ≥ 10 ng/mL (P = 0.0353). Cav-1 was also able to distinguish between high- and low- risk patients with biopsy Gleason score of seven, after adjusting, for patients PSA levels (P = 0.0429). Conclusions: Overall, elevated preoperative levels of serum cav-1 predict decreased time to cancer recurrence. In the subset of patients with serum PSA of ≥10 ng/mL, the combination of serum cav-1 and biopsy Gleason score has the capacity to predict time to biochemical recurrence.
Non‐Monoamine Oxidase Inhibitor Antidepressants and Epilepsy: A Review

The literature dealing with the convul‐sant effects of the antidepressant drugs of the non‐monoamine oxidase inhibitor variety is reviewed. It is concluded that most of these drugs do lower the seizure threshold and may precipitate seizures even at normal therapeutic doses. The pathophysiology of antidepressant‐induced seizures is discussed, and attention is drawn to biochemical differences in those antidepressants that have the least epileptogenic potential or may even be anticonvulsant. The clinical difficulties regarding administration of antidepressant drugs to epileptic patients are mentioned, and some practical advice is offered.
Evolutionary variants of the human immunodeficiency virus type 1 V3 region characterized by using a heteroduplex tracking assay

Syncytium-inducing (SI) variants of human immunodeficiency virus type 1 (HIV-1) are evolutionary variants that are associated with rapid CD4+ cell loss and rapid disease progression. The heteroduplex tracking assay (HTA) was used to detect evolutionary V3 variants by amplifying the V3 sequences from viral RNA derived from 50 samples of patient plasma. For this V3-specific HTA (V3-HTA), heteroduplexes were formed between the patient V3 sequences and a probe with the subtype B consensus V3 sequence. Evolution was then measured by divergence from the consensus. The presence of evolutionary variants was correlated with SI detection data on the same samples from the MT-2 cell culture assay. Evolutionary variants were correlated with the SI phenotype in 88% of the samples, and 96% of the SI samples contained evolutionary variants. In most cases the evolutionary V3 variants represented discrete clonal outgrowths of virus. Sequence analysis of the six discordant samples that did not show this correlation indicated that three non-syncytium-inducing (NSI) samples had V3 sequences that had evolved away from the consensus sequence but not toward an SI genotype. A fourth sample showed little evolution away from the consensus but was SI, which indicates that not all SI variants require basic substitutions in V3. The other two samples had SI-like genotypes and NSI phenotypes, suggesting that V3-HTA was able to detect SI emergence in these samples in the absence of their detection in vitro. V3-HTA was also used to confirm SI variant selection in MT-2 cells and to examine the possibility of variant selection during virus culture in peripheral blood cells.
Use-Dependent Decline of Paired-Pulse Facilitation atAplysia Sensory Neuron Synapses Suggests a Distinct Vesicle Pool or Release Mechanism

We have characterized paired-pulse facilitation atAplysia sensory neuron-to-motoneuron synapses. This simple form of very short-term synaptic plasticity displayed an unusual feature: it decreased dramatically with repeated testing. Synaptic depression at these synapses and this use-dependent decrease in paired-pulse facilitation occurred independently of each other. Paired-pulse facilitation was inversely correlated with the size of the initial synaptic connection and was absent at stronger synapses. The use-dependent decrease in paired-pulse facilitation occurred at the same rate at large synapses as at small synapses, although the initial paired-pulse facilitation at large synapses was substantially smaller. Rates of synaptic depression were also independent of initial synaptic strength. Paired-pulse facilitation was blocked by presynaptic EGTA injection, but not by postsynaptic EGTA or BAPTA injection. These results indicate that presynaptic Ca2+ influx plays a critical role in paired-pulse facilitation. However, the persistence of the decrease in paired-pulse facilitation for longer than 15 min suggests that Ca2+ from the first paired action potential produces facilitation via a modulatory mechanism rather than by summating with Ca2+ influx during the second paired action potential in activating the Ca2+binding sites that initiate exocytosis. This modulatory mechanism may not involve protein phosphorylation because paired-pulse facilitation was unaffected by the protein kinase inhibitors H7 and KN-62. These findings further suggest that release by the second paired action potential occurs at sites distinct from those that mediate release by the first action potential.
Basic Study on Presenting Distance Information to the Blind for Navigation

Most electronic travel aids for the visually impaired and blind persons use voice instruction to inform the device users of the distance to the destination. However, presentation method of voice instruction have not been designed by taking into account the specific characteristics of human cognition, and so users sometimes would be confused. Then, in this paper, we would like to investigate optimal presentation method. From the results, we proposed a new distance-presentation method by voice instruction and revealed its efficacy.
Coenzyme B12-dependent ribonucleotide reductase: evidence for the participation of five cysteine residues in ribonucleotide reduction.

Ribonucleoside triphosphate reductase (RTPR) from Lactobacillus leichmannii catalyzes the conversion of ribonucleotides to 2'-deoxyribonucleotides and requires adenosylcobalamin (AdoCbl) as a cofactor. Recent cloning, sequencing, and expression of this protein [Booker, S. , & Stubbe, J. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 8352-8356] have now allowed its characterization by site-directed mutagenesis. The present study focuses on the role of five cysteines postulated to be required for catalysis. The choice of which of the ten cysteines of RTPR were to be mutated was based on extensive studies on the Escherichia coli ribonucleoside diphosphate reductase. Despite the differences between these two reductases in primary sequence, quaternary structure, and cofactor requirements, their mechanisms are strikingly similar. The mutagenesis studies reported herein further suggest that the complex role of the five cysteines is also very similar. A variety of single and double mutants of RTPR were prepared (C731S, C736S, C731 and 736S, C119S, C419S, C408S, and C305S), and their interaction with the normal substrate (CTP) was characterized under several sets of conditions. Mutants C731S, C736S, and C731 and 736S all catalyzed the formation of dCTP at rates similar to those of the wild-type (wt) enzyme in the presence of the artificial reductant DTT. In the presence of the in vivo reducing system (thioredoxin, thioredoxin reductase, and NADPH), however, each of these mutants catalyzed the formation of only 0.6-0.8 dCTPs per mole of enzyme. The inability of these mutants to catalyze multiple turnovers with respect to the in vivo reducing system suggests that their function might be to transfer reducing equivalents from thioredoxin into the active site disulfide of the reductase. Mutants C119S and C419S were targeted as being the active site cysteines, the ones which directly reduce the ribonucleotide substrate. As expected, neither of these mutants catalyzed the formation of dCTP. However, they did catalyze a time-dependent formation of cytosine, destruction of the cofactor, and the appearance of a chromophore associated with the protein--all phenotypes previously observed for the corresponding active site cysteines of the E. coli reductase. Mutant C408S was unable to catalyze dNTP production or cytosine release. Moreover, it was ineffective in catalyzing two additional reactions which are unique to this enzyme: the exchange of tritium from the 5' hydrogens of AdoCbl with H2O and the destruction of AdoCbl under anaerobic conditions to give 5'-deoxyadenosine and cob(II)alamin. These results are consistent with the role of this cysteine as the protein radical responsible for initiating catalysis.
Genetic variations in E-selectin and ICAM-1: Relation to atherosclerosis

Summary Background This study aimed to investigate the association of both intercellular adhesion molecule-1 (ICAM-1) and endothelial cell adhesion molecule (E-selectin) polymorphisms using PCR technique and their role in the pathogenesis of atherosclerosis. Material/Methods The study enrolled 285 individuals, classified into 4 groups: 63 cerebrovascular atherosclerotic patients, 75 cardiovascular patients, 72 peripheral atherosclerotic patients and 75 normal healthy individuals. Results The frequency of the mutant AC genotype of E-selectin in peripheral, cerebral and cardiovascular atherosclerotic patients was significantly higher than in control subjects (29.17%, 28.53% and 28% vs. 8%, respectively). However, no significant difference was observed in the frequency of mutant CC allele between all atherosclerotic patients and control groups. The frequency of the mutant EE homozygotes of ICAM-1 in peripheral, cerebral and cardiovascular atherosclerotic patients was significantly higher compared to controls (45.8%, 42.9% and 36% vs. 12%, respectively). The frequency of EK of ICAM-1 showed no significant difference between atherosclerotic patients and the control group. The frequency of the mutant E allele of ICAM-1 was significantly higher in peripheral, cerebral and cardiovascular patients compared to controls (58.3%, 54.8% and 54% vs. 26%, respectively). Conclusions Ser 128Arg of E-selectin and the K469E of ICAM-1 polymorphisms may be involved in predisposition to atherosclerosis.