gebhart/patrepeval huggingface dataset:
A single-base-pair mutation changes the specificities of both a transcription activation protein and its binding site. (1993)

The C1 protein of bacteriophage P22 binds to a unique site in the -35 region of the PRE promoter and activates transcription of the phage c2 repressor gene. This -35 target has an approximate direct repeat that overlaps the 5' end of the c1 coding region. We have isolated a single-base-pair mutation in this region that changes the PRE -35 target as well as the amino-terminal region of the C1 protein. Although the mutant C1 protein activates the mutant PRE promoter, it fails to activate the wild-type PRE promoter. This suggests that a single-base-pair mutation changes the specificities of both a protein and its target site. These studies also indicate that C1 binding to DNA is influenced by contacts made through residues near the amino terminus.
A Caspase Cascade Regulating Developmental Axon Degeneration (2012)

Axon degeneration initiated by trophic factor withdrawal shares many features with programmed cell death, but many prior studies discounted a role for caspases in this process, particularly Caspase-3. Recently, Caspase-6 was implicated based on pharmacological and knockdown evidence, and we report here that genetic deletion of Caspase-6 indeed provides partial protection from degeneration. However, we find at a biochemical level that Caspase-6 is activated effectively only by Caspase-3 but not other "upstream" caspases, prompting us to revisit the role of Caspase-3. In vitro, we show that genetic deletion of Caspase-3 is fully protective against sensory axon degeneration initiated by trophic factor withdrawal, but not injury-induced Wallerian degeneration, and we define a biochemical cascade from prosurvival Bcl2 family regulators to Caspase-9, then Caspase-3, and then Caspase-6. Only low levels of active Caspase-3 appear to be required, helping explain why its critical role has been obscured in prior studies. In vivo, Caspase-3 and Caspase-6-knockout mice show a delay in developmental pruning of retinocollicular axons, thereby implicating both Caspase-3 and Caspase-6 in axon degeneration that occurs as a part of normal development.
Smokers with active Crohnʼs disease have a clinically relevant dysbiosis of the gastrointestinal microbiota* (2011)

Smokers have luminal microbiota that consist of significantly higher bacteroides. Investigation of whether this is one mechanism through which the negative effects of smoking on CD are mediated is warranted.
High dimensional similarity search with space filling curves (2002)

We present a new approach for approximate nearest neighbor queries for sets of high dimensional points under any L/sub t/-metric, t=1,...,/spl infin/. The proposed algorithm is efficient and simple to implement. The algorithm uses multiple shifted copies of the data points and stores them in up to (d+1) B-trees where d is the dimensionality of the data, sorted according to their position along a space filling curve. This is done in a way that allows us to guarantee that a neighbor within an O(d/sup 1+1/t/) factor of the exact nearest, can be returned with at most (d+1)log, n page accesses, where p is the branching factor of the B-trees. In practice, for real data sets, our approximate technique finds the exact nearest neighbor between 87% and 99% of the time and a point no farther than the third nearest neighbor between 98% and 100% of the time. Our solution is dynamic, allowing insertion or deletion of points in O(d log/sub p/ n) page accesses and generalizes easily to find approximate k-nearest neighbors.
Performance standards in positron emission tomography. (1991)

A standard set of performance measurements is proposed for use with positron emission tomographs. This set of measurements has been developed jointly by the Computer and Instrumentation Council of the Society of Nuclear Medicine and the National Electrical Manufacturers Association. The measurements include tests of spatial resolution, scatter fraction, sensitivity, count rate losses and randoms, uniformity, scatter correction, attenuation correction, and count rate linearity correction.
[Diagnosis of sepsis based on the host response]. (1999)

Sepsis is often a fatal condition, and excessive production of host inflammatory mediators including cytokines, are considered to be responsible for its lethality. We investigated the biology of TNF-alpha, IL-1, IL-6, and IL-10 with particular emphasis on its role in murine gut-derived sepsis due to Pseudomonas aeruginosa and found that these cytokine levels in serum showed significant increases at lethal conditions. Furthermore, we studied the cytokine levels in serum and BALF of mice after pulmonary infection with Klebsiella pneumoniae. The results showed that inflammatory cytokines in BALF demonstrated high levels at the early stage of infection in response to local inflammation of the lung. On the other hand, cytokine levels in serum abruptly increased at the late stage of infection in response to systemic inflammation. These results revealed that it is important to discriminate between systemic inflammation and local inflammation to diagnose sepsis.
Cellular Pharmacology and Protein Binding of Phosphoromonothioate and Phosphorodithioate Oligodeoxynucleotides: A Comparative Study (1994)

Phosphorodithioate (PS2) oligodeoxynucleotides (oligos) represent a relatively new class of backbone-modified oligo that have potential use as antisense agents. PS2 oligos are isoelectronic with phosphodiester (PO) and phosphoromonothioate (PS) oligos, and are nuclease resistant. However, unlike their PS congeners, PS2 oligos do not contain chiral centers. Little is known about the manner in which PS2 oligos interact with biological systems. In this study, we compare the cellular pharmacology of PS and PS2 oligos in HL60 cells. Cell surface binding, internalization, and compartmentalization are examined. Furthermore, the ability of PS and PS2 oligos to bind to rsCD4 and bFGF and to inhibit the activity of protein kinase C (PKC) is examined. Although the behavior of PS2 oligos closely parallels that of PS oligos, PS2 oligos appear to interact with some biological systems in a slightly different manner than PS oligos. These results indicate that PS2 oligos may have therapeutic potential other than as antisense agents.
Antidepressants and sexual dysfunction (2006)

Sexual dysfunction may be a preventable or treatable side-effect of antidepressants. Patients need routinely to be asked about sexual function to identify problems early. If sexual dysfunction is ignored it may maintain the depression, compromise treatment outcome and lead to non-compliance.
CXC Chemokine Ligand 4 Induces a Unique Transcriptome in Monocyte-Derived Macrophages (2010)

In atherosclerotic arteries, blood monocytes differentiate to macrophages in the presence of growth factors, such as macrophage colony-stimulation factor (M-CSF), and chemokines, such as platelet factor 4 (CXCL4). To compare the gene expression signature of CXCL4-induced macrophages with M-CSF-induced macrophages or macrophages polarized with IFN-gamma/LPS (M1) or IL-4 (M2), we cultured primary human peripheral blood monocytes for 6 d. mRNA expression was measured by Affymetrix gene chips, and differences were analyzed by local pooled error test, profile of complex functionality, and gene set enrichment analysis. Three hundred seventy-five genes were differentially expressed between M-CSF- and CXCL4-induced macrophages; 206 of them overexpressed in CXCL4 macrophages coding for genes implicated in the inflammatory/immune response, Ag processing and presentation, and lipid metabolism. CXCL4-induced macrophages overexpressed some M1 and M2 genes and the corresponding cytokines at the protein level; however, their transcriptome clustered with neither M1 nor M2 transcriptomes. They almost completely lost the ability to phagocytose zymosan beads. Genes linked to atherosclerosis were not consistently upregulated or downregulated. Scavenger receptors showed lower and cholesterol efflux transporters showed higher expression in CXCL4- than M-CSF-induced macrophages, resulting in lower low-density lipoprotein content. We conclude that CXCL4 induces a unique macrophage transcriptome distinct from known macrophage types, defining a new macrophage differentiation that we propose to call M4.
Dkk2 plays an essential role in the corneal fate of the ocular surface epithelium (2006)

The Dkk family of secreted cysteine-rich proteins regulates Wnt/beta-catenin signaling by interacting with the Wnt co-receptor Lrp5/6. Here, we show that Dkk2-mediated repression of the Wnt/beta-catenin pathway is essential to promote differentiation of the corneal epithelial progenitor cells into a non-keratinizing stratified epithelium. Complete transformation of the corneal epithelium into a stratified epithelium that expresses epidermal-specific differentiation markers and develops appendages such as hair follicles is achieved in the absence of the Dkk2 gene function. We show that Dkk2 is a key regulator of the corneal versus epidermal fate of the ocular surface epithelium.
Identification of a Glycosaminoglycan Binding Surface on Human Interleukin-8 (1998)

The activation of leukocytes by chemokines is believed to be mediated via binding of chemokines to glycosaminoglycan chains of the extracellular matrix. The binding site on the chemokine interleukin-8 (IL-8) for the glycosaminoglycan heparin has been characterized using a systematic series of site-directed mutants of IL-8 in which the basic residues of the protein have been replaced by alanine. Mutation of K64 and R68 caused the largest decrease in affinity for a heparin Sepharose matrix, with smaller effects seen with mutations of K20, R60, and K67. Heparin-derived disaccharides that could disrupt the IL-8-heparin Sepharose interaction were identified by a competitive binding assay. Heteronuclear NMR spectroscopic titration of 15N-labeled IL-8 with a trisulfated disaccharide revealed a cluster of residues on IL-8 which were perturbed by disaccharide binding. These data identify a heparin-binding surface on IL-8 that includes the C-terminal alpha-helix and the proximal loop around residues 18-23. The heparin-binding site is spatially distinct from the residues involved in receptor binding.
Long‐term Consequences of Repetitive Brain Trauma: Chronic Traumatic Encephalopathy (2011)

Chronic traumatic encephalopathy (CTE) has been linked to participation in contact sports such as boxing and American football. CTE results in a progressive decline of memory and cognition, as well as depression, suicidal behavior, poor impulse control, aggressiveness, parkinsonism, and, eventually, dementia. In some individuals, it is associated with motor neuron disease, referred to as chronic traumatic encephalomyelopathy, which appears clinically similar to amyotrophic lateral sclerosis. Results of neuropathologic research has shown that CTE may be more common in former contact sports athletes than previously believed. It is believed that repetitive brain trauma, with or possibly without symptomatic concussion, is responsible for neurodegenerative changes highlighted by accumulations of hyperphosphorylated tau and TDP-43 proteins. Given the millions of youth, high school, collegiate, and professional athletes participating in contact sports that involve repetitive brain trauma, as well as military personnel exposed to repeated brain trauma from blast and other injuries in the military, CTE represents an important public health issue. Focused and intensive study of the risk factors and in vivo diagnosis of CTE will potentially allow for methods to prevent and treat these diseases. Research also will provide policy makers with the scientific knowledge to make appropriate guidelines regarding the prevention and treatment of brain trauma in all levels of athletic involvement as well as the military theater.
Role of Spatiotemporal Oriented Energy Features for Robust Visual Tracking in Video Surveillance (2012)

We propose an effective approach to take advantage of the rich description provided by Spatiotemporal Oriented Energy features for the purpose of robust tracking. There are two core components in our system. The first one is a compound measure of 'Coherent Motion' and 'Identity Motion Signature' which is introduced based on motion dynamics of the targets. This measure is used for robust optimisation in occluded situations as well as an adaptive template updating scheme. The second component is a state machine which detects various states of the targets based on statistical analysis of their 'Motion Signature'. Empirical evaluations demonstrate improvement in performance of the tracking system along with the role of each component.
Hyperplasia of myocyte nuclei in long-term cardiac hypertrophy in rats. (1987)

In contrast to observations made in the human heart, hyperplasia of myocyte nuclei has never been demonstrated in experimental cardiac hypertrophy. To test the hypothesis that the duration of the mechanical load more than the magnitude of ventricular hypertrophy may be the inciting stimulus for myocyte nuclei hyperplasia, constriction of the pulmonary artery was produced in rats and the hearts were examined 6 mo later. A 76% increase in right ventricular weight was measured. This hypertrophic response was accompanied by a 41% increase in the total number of myocyte nuclei in the ventricle. Furthermore, average myocyte cell volume per nucleus increased by 28%. No changes in weight, myocyte size, and nuclear number were observed in the left ventricle. In conclusion, myocyte nuclear hyperplasia and cellular hypertrophy both participate to the adaptive response of the right ventricular myocardium in long-standing pressure overload cardiac hypertrophy.
EGF mutant receptor vIII as a molecular target in cancer therapy. (2001)

In the year 2000, an estimated 1220 100 new cases of invasive cancer will be diagnosed in the United States, and about 552 200 people are expected to die of it (Greenlee et al. 2000). Treatment of cancer has conventionally consisted of surgery, radiation and chemotherapy. Despite improved cancer therapy involving early detection, the surgical removal of solid tumor masses, and the use of radiotherapy, cytotoxic agents, or both, truly effective therapeutic approaches are still lacking and thus urgently needed. Extensive analyses have defined tumor-associated and, less frequently, tumor-specific, surface antigens displayed on the malignant cell surface. Targeting cells selectively through these surface antigens by molecular probes is inherently different from surgery, radiation, and chemotherapy and has been considered as a favored modality for cancer therapy. A considerable effort has been made over the past decade to develop new immunotherapeutic strategies against cancer; recently, such strategies have shown promise (Waksal 1999, Yang et al. 1999, Kreitman et al. 2000). Targeted therapy can be accomplished by using tumor-specific monoclonal antibodies (Mabs) alone or Mabs armed with radionuclides, prodrugs, or toxins, which selectively kill tumor cells while not destroying normal cells. Many growth factors and their receptors play important roles in modulating cell division, proliferation and differentiation, and the possibility of disrupting these processes has led to the development of novel therapeutic agents for cancer treatment. Therefore, growth factor receptors are attractive candidates for targeted therapy, as they are often overexpressed on the surface of cancer cells. Among these, the type I epidermal growth factor (EGF)-related family of tyrosine kinase growth factor receptors are expressed in a broad spectrum of tumor types, which classifies them as one of the most frequently implicated cell-surface markers for human cancers. This family consists of four members: EGF receptor (EGFR), ErbB-2, ErbB-3 and ErbB-4 (Gullick 1998). EGFR was the first cell-surface glycoprotein identified to be amplified and rearranged in glioblastoma multiforme (GBM) and to act
Accessibility of Nucleic Acid-complexed Biomolecules to Hydroxyl Radicals Correlates with their Conformation: A Fluorescence Polarization Spectroscopy Study (1994)

A fluorescence methodology has been developed to examine the relationship between the conformational state of specific biomolecules in simple chromatin models and their accessibility to hydroxyl radicals (OH). Polylysine and histone H1 were labelled with SECCA, the succinimidyl ester of coumarin-3-carboxylic acid, which generates the fluorescent derivative 7-OH-SECCA following its interaction with radiation-induced OH in aqueous solution. The fluorescence induced per unit gamma-ray dose reflecting the accessibility of OH to such SECCA-conjugated biomolecules was recorded. The biomolecules were also labelled with the fluorescent derivative 7-OH-SECCA in trace amounts to study their conformation under identical conditions via fluorescence polarization spectroscopy. When these biomolecules were complexed with a polynucleotide or DNA, a major increase in polarization anisotropy was recorded. Upon salt-induced dissociation of these biomolecules from the nucleic acids, the increase in anisotropy was reversed. The histone H1-DNA complexes also exhibited an initial increase in anisotropy with increasing NaCl concentration (maximum at 100 mmol dm-3) indicating the possible formation of a more compact conformation. The fluctuations in anisotropy were inversely proportional to the recorded fluorescence/Gy. The data indicate a direct correlation between the accessibility of OH to polylysine or histone H1 complexed with nucleic acids and the conformation of these biomolecules.
Suppressive effects of insulin and insulin-like growth factor-1 (IGF1) on immune responses. (1986)

This paper describes conditions wherein the serum peptides insulin and IGF1, which are typically associated with growth-promoting functions, can suppress in vitro immune responses. IL 2-induced proliferation of lymphocytes as well as in vitro antibody-producing cultures are suppressed by physiologic concentrations of IGF1 or by superphysiologic concentrations of insulin. Suppression of IL 2-induced proliferation is not overcome by increasing the IL 2 concentration and is mediated only during the first 24 to 48 hr of the 110-hr incubation period required to measure the proliferative response to IL 2. By analogy to other biologic systems, these effects of insulin and of IGF1 are probably mediated by occupancy of the IGF1-receptor, which is cross-occupied by insulin at superphysiologic concentrations. These data support the possibility of a novel function for these endocrine and endocrine-like peptides and also expands their range of biologic activities to within the immune system.
Murine anti–third-party central-memory CD8+ T cells promote hematopoietic chimerism under mild conditioning: lymph-node sequestration and deletion of anti-donor T cells (2012)

Transplantation of T cell-depleted BM (TDBM) under mild conditioning, associated with minimal toxicity and reduced risk of GVHD, offers an attractive therapeutic option for patients with nonmalignant hematologic disorders and can mediate immune tolerance to subsequent organ transplantation. However, overcoming TDBM rejection after reduced conditioning remains a challenge. Here, we address this barrier using donorderived central memory CD8(+) T cells (Tcms), directed against third-party antigens. Our results show that fully allogeneic or (hostXdonor)F1-Tcm, support donor chimerism (> 6 months) in sublethally irradiated (5.5Gy) mice, without GVHD symptoms. Chimerism under yet lower irradiation (4.5Gy) was achieved by combining Tcm with short-term administration of low-dose Rapamycin. Importantly, this chimerism resulted in successful donor skin acceptance, whereas third-party skin was rejected. Tracking of host anti-donor T cells (HADTCs), that mediate TDBMT rejection, in a novel bioluminescence-imaging model revealed that Tcms both induce accumulation and eradicate HADTCs in the LNs,concomitant with their elimination from other organs, including the BM. Further analysis with 2-photon microcopy revealed that Tcms form conjugates with HADTCs, resulting in decelerated and confined movement of HADTCs within the LNs in an antigen-specific manner. Thus, anti-third-party Tcms support TDBMT engraftment under reduced-conditioning through lymph-node sequestration and deletion of HADTCs, offering a novel and potentially safe approach for attaining stable hematopoietic chimerism.
Antagonism of the prostaglandin D 2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans (2006)

Nicotinic acid (NA) is commonly used to treat dyslipidemia, but it elicits an adverse effect, termed flushing, which consists of cutaneous vasodilation with associated discomfort. An animal model of NA-induced flushing has been established in mice. As in humans, NA stimulated vasodilation in a dose-dependent manner, was associated with an increase of the vasodilatory prostaglandin (PG) D2 in plasma and could be blocked by pretreatment with aspirin. Two PGD2 receptors have been identified: PGD2 receptor 1 (DP1, also called DP) and PGD2 receptor 2 (DP2, sometimes termed CRTH2). DP2 does not mediate NA-induced vasodilation; the DP2-specific agonist DK-PGD2 (13,14-dihydro-15-keto-PGD2) did not induce cutaneous vasodilation, and DP2-/- mice had a normal vasodilatory response to NA. By contrast, BW245C, a DP1-selective agonist, induced vasodilation in mice, and MK-0524, a DP1-selective antagonist, blocked both PGD2- and NA-induced vasodilation. NA-induced vasodilation was also studied in DP1+/+, DP1+/-, and DP1-/- mice; although NA-induced vasodilation depended almost completely on DP1 in female mice, it depended only partially on DP1 in male mice. The residual NA-induced vasodilation in male DP-/- mice was aspirin-sensitive. Thus, in the mouse, DP1 appears to be an important component involved in NA-induced vasodilation, but other cyclooxygenase-dependent mechanisms also may be involved. A clinical study in healthy men and women demonstrated that treatment with MK-0524 reduced the symptoms of flushing and the increase in skin perfusion after the administration of NA. These studies suggest that DP1 receptor antagonism may be an effective means to suppress NA-induced flushing in humans.
Automated learning for reducing the configuration of a feedforward neural network (1996)

In this paper, we present two learning mechanisms for artificial neural networks (ANN's) that can be applied to solve classification problems with binary outputs. These mechanisms are used to reduce the number of hidden units of an ANN when trained by the cascade-correlation learning algorithm (CAS). Since CAS adds hidden units incrementally as learning proceeds, it is difficult to predict the number of hidden units required when convergence is reached. Further, learning must be restarted when the number of hidden units is larger than expected. Our key idea in this paper is to provide alternatives in the learning process and to select the best alternative dynamically based on run-time information obtained. Mixed-mode learning (MM), our first algorithm, provides alternative output matrices so that learning is extended to find one of the many one-to-many mappings instead of finding a unique one-to-one mapping. Since the objective of learning is relaxed by this transformation, the number of learning epochs can be reduced. This in turn leads to a smaller number of hidden units required for convergence. Population-based learning for ANN's (PLAN), our second algorithm, maintains alternative network configurations to select at run time promising networks to train based on error information obtained and time remaining. This dynamic scheduling avoids training possibly unpromising ANNs to completion before exploring new ones. We show the performance of these two mechanisms by applying them to solve the two-spiral problem, a two-region classification problem, and the Pima Indian diabetes diagnosis problem.