gebhart/patrepeval huggingface dataset:
Comprehensive numerical modeling of vertical-cavity surface-emitting lasers (1996)

We present a comprehensive numerical model for vertical-cavity surface-emitting lasers that includes all major processes affecting cw operation of axisymmetric devices. In particular, our model includes a description of the 2-D transport of electrons and holes through the cladding layers to the quantum well(s), diffusion and recombination of these carriers within the wells, the 2-D transport of heat throughout the device, and a multilateral-mode effective index optical model. The optical gain acquired by photons traversing the quantum wells is computed including the effects of strained band structure and quantum confinement. We employ our model to predict the behavior of higher-order lateral modes in proton-implanted devices and to provide an understanding of index-guiding in devices fabricated using selective oxidation.
Memory B Cells Are Biased Towards Terminal Differentiation: A Strategy That May Prevent Repertoire Freezing (1997)

Isolation of large numbers of surface IgD+CD38- naive and surface IgD-CD38- memory B cells allowed us to study the intrinsic differences between these two populations. Upon in vitro culture with IL-2 and IL-10, human CD40-activated memory B cells undergo terminal differentiation into plasma cells more readily than do naive B cells, as they give rise to five- to eightfold more plasma cells and three- to fourfold more secreted immunoglobulins. By contrast, naive B cells give rise to a larger number of nondifferentiated B blasts. Saturating concentrations of CD40 ligand, which fully inhibit naive B cell differentiation, only partially affect that of memory B cells. The propensity of memory B cells to undergo terminal plasma cell differentiation may explain the extensive extra follicular plasma cell reaction and the limited germinal center reaction observed in vivo after secondary immunizations, which contrast with primary responses in carrier-primed animals. This unique feature of memory B cells may confer two important capacities to the immune system: (a) the rapid generation of a large number of effector cells to efficiently eliminate the pathogens; and (b) the prevention of the overexpansion and chronic accumulation of one particular memory B cell clone that would freeze the available peripheral repertoire.
Photophysics and Photochemistry of Pterins in Aqueous Solution (2006)

Pterins belong to a family of heterocyclic compounds present in a wide range of living systems and participate in relevant biological functions. Interest in the photochemistry and photophysics of this group of compounds has increased since the participation of pterin derivatives in different photobiological processes has been suggested or demonstrated in recent decades. This account describes and connects basic studies on the fluorescence emission, the photooxidation, and the photosensitizing properties of oxidized six-substituted pterins in aqueous solution under UV-A irradiation. The biological implications of these studies are also discussed.
Long-Term Results and Complications of Intracavitary Bacillus Calmette-Guerin Therapy for Bladder Cancer (1984)

Clinical studies on intracavitary bacillus Calmette-Guerin therapy for bladder cancer have been conducted at this institution for more than 10 years. The 82 patients treated for prophylaxis of multiple superficial recurrences, residual tumors or carcinoma in situ have been followed for 2 to 7 years after treatment. The long-term results confirm previous studies showing the effectiveness of bacillus Calmette-Guerin in the prophylaxis and therapy of superficial vesical neoplasms. However, some decrease is observed in the population free of disease with a prolonged followup. Recent modifications in the original protocol have been introduced to enhance the effectiveness of the vaccine. Side effects during or shortly after treatment were minor and self-limiting in the large majority of patients (fever, bladder irritability and hematuria). Mild, transient hepatic dysfunction was noted in 2 patients. Hematological disturbances were insignificant. No patient had permanent structural or functional alterations of the bladder.
Injection of Somatic Cell Cytoplasm into Oocytes Before Intracytoplasmic Sperm Injection Impairs Full-Term Development and Increases Placental Weight in Mice1 (2006)

This study investigated the effects on fertilized embryo development of somatic cytoplasm after its injection into intact mouse oocytes. Mature oocytes collected from female B6D2F1 mice were injected with cumulus cell cytoplasm of different volumes and from different mouse strains (B6D2F1, ICR, and C57BL/6), or with embryonic cytoplasm. After culture for 1 h, B6D2F1 sperm were injected into those oocytes by intracytoplasmic sperm injection (ICSI). The oocytes were examined for pre- and postimplantation developmental competence. Increases in the volume of the somatic cytoplasm from onefold to fourfold resulted in an impairment of blastocyst development and full-term development (28% and 7%, respectively, vs. 96% and 63%, respectively, in the control group; P < 0.01). An increase in the volume of somatic cytoplasm reduced the expression of POU5F1 (more commonly known as OCT4) in expanded blastocysts. The frequency of embryos that developed to the blastocyst stage did not differ when B6D2F1 or ICR somatic cytoplasm was injected, but injection of C57BL/6 somatic cytoplasm induced a two-cell block in embryo development. Injection of the cytoplasm from fertilized embryos did not reduce the frequency of embryos attaining full-term development. Interestingly, somatic cytoplasm significantly increased the placental weight of ICSI embryos, even the injection of onefold cytoplasm (0.20 +/- 0.02 [n = 32] vs. 0.12 +/- 0.02 in the control group [n = 87]; P < 0.01). These findings indicate that the injection of somatic cytoplasm into oocytes before ICSI causes a decrease in preimplantation development, clearly impairs full-term development, and causes placental overgrowth in fertilized embryos. To our knowledge, placental overgrowth phenotypes are only caused by interspecies hybridization and cloning, and in genetically modified mice. Here, we report for the first time that somatic cytoplasm causes abnormal placentas in fertilized embryos. This study suggests that somatic cell cytoplasmic material is one cause of the low rate of full-term development in cloned mammals.
The solitary pulmonary nodule. Is it malignant or benign? (1996)

Solitary pulmonary nodules are usually identified on routine chest radiographs in asymptomatic patients. Most nodules have a benign cause, but bronchogenic carcinoma, metastases, and other malignant processes are important causes as well and must be excluded in differential diagnosis. Plain chest radiography, computed tomography, and fine-needle aspiration biopsy are useful diagnostic tools. When a malignant cause cannot be ruled out, the patient's age, smoking history, and nodule size must be considered. Observation by serial radiographs may be the appropriate course for patients who are at low risk for malignancy. For moderate- and high-risk patients, an immediate and more invasive workup is indicated.
Intention awareness: improving upon situation awareness in human-centric environments (2013)

Abstract As the gap between human and machine shrinks, it becomes increasingly important to develop computer systems that incorporate or enhance existing Situation Awareness. However, these tend to focus on raw quantitative parameters, such as position and speed of objects. When these situations are governed by human actors, such parameters leave significant margins of uncertainty. In this paper, we discuss the potential of applying the characteristics intrinsic to the human actors that comprise a given situation to Situation Awareness, and the capacity that these concepts have to improve situation-aware systems. We argue that intention-aware based systems offer an advantage over situation-aware based systems in that they reduce the informational burden on humans without limiting effectiveness. We argue that computational analysis and tracking of semantic and affective information associated with human actors' intentions are an effective way to minimize miscommunication and uncertainty, particularly in time-sensitive and information-saturated situations.
Tau Immunotherapy (2015)

In recent years, tau immunotherapy has advanced from proof-of-concept studies [Sigurdsson EM, NIH R01AG020197, 2001; Asuni AA, et al: J Neurosci 2007;27:9115-9129], which have now been confirmed and extended by us and others. Phase I clinical trials on active and passive tau immunizations are being conducted, with several additional passive tau antibody trials likely to be initiated in the near future for Alzheimer's disease and other tauopathies. Because tau pathology correlates better with the degree of dementia than amyloid-β (Aβ) pathology, greater clinical efficacy may be achieved by clearing tau than Aβ aggregates in the later stages of the disease, when cognitive impairments become evident. Substantial insight has now been obtained regarding which epitopes to target, mechanism of action and potential toxicity, but much remains to be clarified. All of these factors likely depend on the model/disease or stage of pathology and the immunogen/antibody. Interestingly, tau antibodies interact with the protein both extra- and intracellularly, but the importance of each site for tau clearance is not well defined. Some antibodies are readily taken up into neurons, whereas others are not. It can be argued that extracellular clearance may be safer but less efficacious than intraneuronal clearance and/or sequestration to prevent secretion and further spread of tau pathology. Development of therapeutic tau antibodies has led to antibody-derived imaging probes, which are more specific than the dye-based compounds that are already in clinical trials. Such specificity may give valuable information on the pathological tau epitope profile, which could then guide the selection of therapeutic antibodies for maximal efficacy and safety. Hopefully, tau immunotherapy will be effective in clinical trials, and further advanced by mechanistic clarification in experimental models with insights from biomarkers and postmortem analyses of clinical subjects.
Identification and Cloning of Human Placental Bikunin, a Novel Serine Protease Inhibitor Containing Two Kunitz Domains (1997)

Interrogation of the public expressed sequence tag (EST) data base with the sequence of preproaprotinin identified ESTs encoding two potential new members of the Kunitz family of serine protease inhibitors. Through reiterative interrogation, an EST contig was obtained, the consensus sequence from which encoded both of the novel Kunitz domains in a single open reading frame. This consensus sequence was used to direct the isolation of a full-length cDNA clone from a placental library. The resulting cDNA sequence predicted a 252-residue protein containing a putative NH2-terminal signal peptide followed sequentially by each of the two Kunitz domains within a 170-residue ectodomain, a putative transmembrane domain, and a 31-residue hydrophilic COOH terminus. The gene for this putative novel protein was mapped by use of a radiation hybrid panel to chromosome 19q13, and Northern analysis showed that the corresponding mRNA was expressed at high levels in human placenta and pancreas and at lower levels in brain, lung, and kidney. An endogenous soluble form of this protein, which was designated as placental bikunin, was highly purified from human placenta by sequential kallikrein-Sepharose affinity, gel filtration, and C18 reverse-phase chromatography. The natural protein exhibited the same NH2 terminus as predicted from the cloned cDNA and inhibited trypsin, plasma kallikrein, and plasmin with IC50 values in the nanomolar range.
Chain Length Dependence of the Frictional Properties of Alkylsilane Molecules Self-Assembled on Mica Studied by Atomic Force Microscopy (1996)

We show that the frictional properties of alkylsilane monolayers self-assembled on mica in contact with Si3N4 tips depend strongly on the length of the alkyl chains. Friction is particularly high with short chains of less than eight carbons. We attribute this to the large number of dissipative modes in the less ordered short chains. Longer chains, stabilized by van der Waals attractions form more compact and rigid layers and act as much better lubricants. This lubricating action is lost at a certain threshold load, where wear of the molecular layer occurs, leading to much higher friction force values. The results presented here clearly indicate that the chemical identity of the exposed end groups is not sufficient to determine the frictional properties of monolayer films. The increased number of energy dissipation modes facilitated by the presence of molecular disorder (e.g., rotations about a C−C axis), in fact dominates the frictional behavior of monolayers with short chains.
The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells (2002)

Monocytes and macrophages express cytokines and procoagulant molecules in various inflammatory diseases. In sepsis, lipopolysaccharide (LPS) from Gram-negative bacteria induces tumor necrosis factor-alpha (TNF-alpha) and tissue factor (TF) in monocytic cells via the activation of the transcription factors Egr-1, AP-1, and nuclear factor-kappa B. However, the signaling pathways that negatively regulate LPS-induced TNF-alpha and TF expression in monocytic cells are currently unknown. We report that inhibition of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway enhances LPS-induced activation of the mitogen-activated protein kinase pathways (ERK1/2, p38, and JNK) and the downstream targets AP-1 and Egr-1. In addition, inhibition of PI3K-Akt enhanced LPS-induced nuclear translocation of nuclear factor-kappa B and prevented Akt-dependent inactivation of glycogen synthase kinase-beta, which increased the transactivational activity of p65. We propose that the activation of the PI3K-Akt pathway in human monocytes limits the LPS induction of TNF-alpha and TF expression. Our study provides new insight into the inhibitory mechanism by which the PI3K-Akt pathway ensures transient expression of these potent inflammatory mediators.
Regulation of the protein tyrosine kinase pp72syk by platelet agonists and the integrin alpha IIb beta 3. (1994)

Agonist stimulation of platelets induces multiple waves of tyrosine phosphorylation, several of which are dependent on the integrin alpha IIb beta 3. At least two classes of protein tyrosine kinases are activated during various stages of platelet activation, 1) Src family tyrosine kinases are activated during an early phase of platelet activation by an integrin-independent mechanism and 2) pp125FAK is activated during a late stage of platelet activation, and it is dependent on platelet aggregation mediated by fibrinogen binding to alpha IIb beta 3. In this report, we examined the mechanism of agonist-induced phosphorylation and activation of the tyrosine kinase pp72syk, which is known to couple with immune response receptors in B cells and mast cells. pp72syk was found to be regulated by both agonist and integrin receptors in a pattern distinct from that of pp60src and pp125FAK. Specifically, thrombin induced the tyrosine phosphorylation and activation of pp72syk independent of platelet aggregation. However, full activation of pp72syk required integrin engagement since treatment with antibodies that block fibrinogen binding to alpha IIb beta 3 reduced pp72syk phosphorylation by 40%. Furthermore, fibrinogen binding to alpha IIb beta 3 stimulated directly with an anti-beta 3 antibody activated pp72syk 3-fold and stimulated its tyrosine phosphorylation. Thus, pp72syk is the only platelet tyrosine kinase identified to date that can be directly activated through integrin ligation. In addition, we found that the activation of pp72syk is dependent upon the state of actin polymerization and that pp72syk redistributes to actin-rich cytoskeletal complexes in an aggregation-dependent manner. These results suggest a role for pp72syk in both early, integrin-independent tyrosine phosphorylation events as well as those dependent upon subsequent integrin engagement.
Induction of Pulmonary Allergic Responses by Antigen-Specific Th2 Cells (1998)

The development of pulmonary allergic responses was examined in mice following pulmonary transfer of Ag (conalbumin)-specific Th2 cells. The levels of serum-specific IgE, cellular infiltrates, airway mucus goblet cells, and airway responsiveness were analyzed and compared with those in Ag-sensitized and -challenged mice. Pulmonary transfer of the conalbumin-specific Th2 clone (D10) induced, in an Ag-specific manner, high levels of the Th2 cytokines IL-4 and IL-5 in the bronchoalveolar lavage fluids and mucosal eosinophils, concomitant with an increase in airway responsiveness. The D10 cell-induced responses were seen in the absence of serum specific IgE. In the presence of Ag, the transferred D10 cells not only remained in the lungs, but also increased in number 72 h post-cell transfer. Although significantly higher levels of IL-4 and IL-5 in the bronchoalveolar lavage fluids were found in D10-transferred mice, the levels of pulmonary eosinophilia, mucus goblet cells, and airway responsiveness were significantly lower than those in Ag-sensitized and -challenged mice. These results demonstrate that although Ag-specific activation of Th2 cells at mucosal sites is able to mediate the recruitment of eosinophils and the subsequent induction of airway hyper-responsiveness, the more severe pulmonary allergic responses were observed only in mice sensitized and challenged with Ag.
Shortcomings of the first-generation proton pump inhibitors. (2001)

Proton pump inhibitors (PPIs) are widely prescribed for the treatment of gastro-oesophageal reflux disease (GORD) as well as gastric and duodenal ulcers, and these agents are now considered the drugs of choice for managing such acid-related disorders. Despite their well-documented efficacy and safety, first-generation PPIs (omeprazole, pantoprazole and lansoprazole) have notable limitations. These drugs exhibit substantial interpatient variability in pharmacokinetics and may have significant interactions with other drugs. The time of dosing and ingestion of meals may also influence the pharmacokinetics of these agents as well as their ability to suppress gastric acid secretion. First-generation PPIs also have a relatively slow onset of pharmacological action and may require several doses to achieve maximum acid suppression and symptom relief, possibly limiting their usefulness in on-demand GORD therapy. First-generation PPIs may also fail to provide 24-h suppression of gastric acid, and noctural acid breakthrough can occur even with twice-daily dosing. Both first- and second-generation PPIs may be associated with adverse events consequent to gastric acid suppression, but newer PPIs have the potential to overcome some critical pharmacokinetic, pharmacodynamic, and clinical limitations of the first-generation drugs.
Real-Time Measurement of Multiple Intramolecular Distances during Protein Folding Reactions:  A Multisite Stopped-Flow Fluorescence Energy-Transfer Study of Yeast Phosphoglycerate Kinase (1997)

Understanding the set of rules which dictate how the primary amino acid sequence determines tertiary structure is an unsolved problem in biophysics. If it were possible to simultaneously measure all of the intramolecular distances in a protein (in real time) during a folding reaction, the "second" genetic code problem would be solved. Regrettably, no such technique currently exists. As a first step toward this goal, an optical distance assay system has been developed for a two-domain protein, yeast phosphoglycerate kinase (PGK), using Förster resonance energy transfer [Lillo, M. P., et al. (1997) Biochemistry 36, 11261-11272]. In this study, real-time stopped-flow distance changes are measured using six unique pairs of donor/acceptor fluorescent labels strategically placed throughout the tertiary structure of PGK. These multiple donor/acceptor sites were genetically engineered into PGK by cysteine substitution mutagenesis followed by extrinsic labeling with fluorescent probes, 5-[[[(2-iodoacetyl)amino]ethyl]amino]naphthalenesulfonic acid (as a donor) and 5-iodoacetamidofluorescein (acceptor). The unfolding of PGK is found to be a sequential multistep process (native --> I1 --> I2 --> unfolded) with rate constants of 0.30, 0.16, and 0.052 s-1, respectively (from native to unfolded). Unique to this unfolding study, six intramolecular distance vectors have been resolved for both the I1 and I2 states. With this distance information, it is shown that the transition from the native to I1 state can be modeled as a large hinge-bending motion, in which both domains "swing away" from each other by about 15 A. As the domains move apart, the carboxyl-terminal domain rotates almost 90 degrees about the hinge region connecting the two domains. It is also shown that the amino-terminal domain remains intact during the native --> I1 transition, consistent with our previous site-specific tryptophan fluorescence anisotropy stopped-flow study [Beechem, J. M., et al. (1995) Biochemistry 34, 13943-13948]. Future experiments are proposed which will attempt to resolve in detail the unfolding/refolding transitions in this protein with a resolution of approximately 5-10 A.
Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. (1997)

Advanced glycation end products (AGEs) include a variety of protein adducts whose accumulation alters the structure and function of tissue proteins and stimulates cellular responses. They have been implicated in tissue damage associated with diabetic complications. To assess the possible link between AGE accumulation and the development of diabetic nephropathy (DN), we have examined the immunohistochemical localization of various AGE structures postulated to date, i.e., pentosidine, Nepsilon-(carboxymethyl)lysine (CML), and pyrraline, in diabetic and control kidneys. CML and pentosidine accumulate in the expanded mesangial matrix and thickened glomerular capillary walls of early DN and in nodular lesions and arterial walls of advanced DN, but were absent in control kidneys. By contrast, pyrraline was not found within diabetic glomeruli but was detected in the interstitial connective tissue of both normal and diabetic kidneys. Although the distribution of pyrraline was topographically identical to type III collagen, distribution of pentosidine and CML was not specific for collagen type, suggesting that difference in matrix protein composition per se could not explain heterogeneous AGE localization. Since oxidation is linked closely to the formation of pentosidine and CML, we also immunostained malondialdehyde (MDA), a lipid peroxidation product whose formation is accelerated by oxidative stress, assuming that local oxidative stress may serve as a mechanism of pentosidine and CML accumulation. Consistent with our assumption, diabetic nodular lesions were stained positive for MDA. These findings show that AGE localization in DN varies according to AGE structure, and suggest that the colocalization of markers of glycoxidation (pentosidine and CML) with a marker of lipid peroxidation reflects a local oxidative stress in association with the pathogenesis of diabetic glomerular lesions. Thus, glycoxidation markers may serve as useful biomarkers of oxidative damage in DN.