gebhart/patrepeval huggingface dataset:
Monomeric Insulins and Their Experimental and Clinical Implications (1990)

Due to the inherent pharmacokinetic properties of available insulins, normoglycemia is rarely, if ever, achieved in insulin-dependent diabetic patients without compromising their quality of life. Subcutaneous insulin absorption is influenced by many factors, among which the associated state of insulin (hexameric) in pharmaceutical formulation may be of importance. This review describes the development of a series of human insulin analogues with reduced tendency to self-association that, because of more rapid absorption, are better suited to meal-related therapy. DNA technology has made it possible to prepare insulins that remain dimeric or even monomeric at high concentration by introducing one or a few amino acid substitutions into human insulin. These analogues were characterized and used for elucidating the mechanisms involved in subcutaneous absorption and were investigated in preliminary clinical studies. Their relative receptor binding and in vitro potency (free-fat cell assay), ranging from 0.05 to 600% relative to human insulin, were strongly correlated (r = 0.97). In vivo, most of the analogues exhibited approximately 100% activity, explainable by a dominating receptor-mediated clearance. This was confirmed by clamp studies in which correlation between receptor binding and clearance was observed. Thus, an analogue with reduced binding and clearance gives higher circulating concentrations, counterbalancing the reduced potency at the cellular level. Absorption studies in pigs revealed a strong inverse correlation (r = 0.96) between the rate of subcutaneous absorption and the mean association state of the insulin analogues. These studies also demonstrated that monomeric insulins were absorbed three times faster than human insulin. In healthy subjects, rates of disappearance from subcutis were two to three times faster for dimeric and monomeric analogues than for human insulin. Concomitantly, a more rapid rise in plasma insulin concentration and an earlier hypoglycemic response with the analogues were observed. The monomeric insulin had no lag phase and followed a monoexponential course throughout the absorption process. In contrast, two phases in rate of absorption were identified for the dimer and three for the normal hexameric human insulin. The initial lag phase and the subsequent accelerated absorption of soluble insulin can now be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process. In the light of these results, the effects of insulin concentration, injected volume, temperature, and massage on the absorption process are now also understood.(ABSTRACT TRUNCATED AT 400 WORDS)
Monitoring and response for real-time voice messages transmitted using wi-fi within net-centric enterprise systems (2010)

Real-time voice communications capabilities over wireless medium, using the Wi-Fi standard IEEE 802.11, have become a potential bottleneck in emerging net-centric enterprise systems used by the DoD and Federal Government agencies. Depending on the priority and precedence of a particular message, mission success may depend on achieving optimal performance with respect to transmission, reception, and interpretation of the message. This paper explores successful interpretation of Wi-Fi messages from the end user perspective as defined through the metric Quality of Experience (QoE). QoE represents the perception of quality experienced by end users of a real-time system. The specific challenge examined herein is that of communicating real-time events using Wi-Fi running within net-centric enterprise systems. In this setting, time-sensitive events may require immediate problem determination and resolution. The paper also introduces a new approach for aggregating Wi-Fi messages across the enterprise, thereby enabling timely and effective interpretation and response to real-time events. Results for a disaster response scenario are presented that combine analysis and simulation measurements from a simulation running on the UK national supercomputing service, HECToR. The paper concludes by highlighting key benefits to the service provider's business from using this approach, such as supporting real-time information sharing over Wi-Fi within net-centric enterprise systems. This paper also provides recommendations for configuration of Wi-Fi QoS mechanisms to support priority and precedence in order to ensure timely response and mission critical communications from local to global operation centers.
Adaptive optics with pupil tracking for high resolution retinal imaging (2012)

Adaptive optics, when integrated into retinal imaging systems, compensates for rapidly changing ocular aberrations in real time and results in improved high resolution images that reveal the photoreceptor mosaic. Imaging the retina at high resolution has numerous potential medical applications, and yet for the development of commercial products that can be used in the clinic, the complexity and high cost of the present research systems have to be addressed. We present a new method to control the deformable mirror in real time based on pupil tracking measurements which uses the default camera for the alignment of the eye in the retinal imaging system and requires no extra cost or hardware. We also present the first experiments done with a compact adaptive optics flood illumination fundus camera where it was possible to compensate for the higher order aberrations of a moving model eye and in vivo in real time based on pupil tracking measurements, without the real time contribution of a wavefront sensor. As an outcome of this research, we showed that pupil tracking can be effectively used as a low cost and practical adaptive optics tool for high resolution retinal imaging because eye movements constitute an important part of the ocular wavefront dynamics.
Reddish, scaly, and itchy: how proteases and their inhibitors contribute to inflammatory skin diseases (2009)

The skin protects us from water loss and mechanical damage. The surface-exposed epidermis, a self-renewing stratified squamous epithelium composed of several layers of keratinocytes, is most important in the barrier defense against these challenges. Endogenous and exogenous proteases such as kallikreins, matriptase, caspases, cathepsins, and proteases derived from microorganisms are important in the desquamation process of the stratum corneum and are able to activate and inactivate defense molecules in human epidermis. Protease inhibitors such as like LEKTI, elafin, SLPI, SERPINs, and cystatins regulate their proteolytic activity and contribute to the integrity and protective barrier function of the skin. Changes in the proteolytic balance of the skin can result in inflammation, which leads to the typical clinical signs of redness, scaling, and itching. This review summarizes the current knowledge of how proteases, their inhibitors, and their target proteins, including filaggrin, protease-activated receptors, and corneodesmosin, contribute to the pathophysiology of inflammation of the skin and highlight their role in common inflammatory skin diseases such as atopic dermatitis, rosacea, and psoriasis.
Dipole−Dipole Interactions in Nanoparticle Superlattices (2007)

Nanoparticles often self-assemble into hexagonal-close-packed (hcp) structures although it is predicted to be less stable than face-centered-cubic (fcc) packing in hard-sphere models. In addition to close-packed fcc and hcp superlattices, we observe formation of nonclose-packed simple-hexagonal (sh) superlattices of nearly spherical PbS, PbSe, and gamma-Fe2O3 nanocrystals. This surprisingly rich phase diagram of monodisperse semiconducting nanoparticles is explained by considering the interactions between nonlocal dipoles of individual nanoparticles. By calculating the total electrostatic and dispersive energies, we explain stability of the hcp and sh nanoparticle superlattices, introduce the superlattice phase diagram, and predict antiferroelectric ordering in dipolar nanoparticle superlattices.
Effects of interfacial microstructure on uniformity and thermal stability of AuNiGe ohmic contact to n-type GaAs (1987)

As part of the investigation of the use of AuNiGe as the ohmic contact to n-type GaAs at a high integration level, cross-sectional transmission electron microscopy was used to explore the uniformity at the metal/GaAs interface and the thermal stability of the AuNiGe contact after the ohmic contact formation. A close relation between spread of the contact resistance and nonuniformity of the interfacial microstructure of the contact was found. Deposition of 5-nm-thick Ni as the first layer of the AuNiGe ohmic contact significantly reduced the spread of the contact resistance and led to the formation of a uniform interface without large protrusions. The improvement in uniformity of compound distribution and the reduction of interface roughness are believed to be due to a change in the sequence of alloying reactions, compared to those in the contact without a Ni first layer. This suggests an ideal interface structure for a low resistance AuNiGe ohmic contact after alloying to be a uniform two layer structure: a high density of the NiAs(Ge) grains contacting the GaAs substrate, and a homogeneous β-AuGa phase close to the top surface. However, due to the existence of β-AuGa phases with a low melting point of around 375 °C, the thermal stability of the contact at 400 °C is of serious concern. Segregation of the NiAs(Ge) grains was observed after annealing at 400 °C for 10 h, which reduced the contact areas between the NiAs(Ge) grains and GaAs. During subsequent annealing at this temperature for up to 90 h, liquidlike flow of the β-AuGa phase was observed which deteriorated the interface uniformity, causing an increase in contact resistance. A typical contact edge slide distance after contact alloying at 440 °C for 2 min was measured to be 0.2 μm and the longest distance among specimens examined was 0.47 μm. This edge deterioration could limit the use of the AuNiGe contact in GaAs submicron devices.
The affinity and stoichiometry of binding of human factor VIII to von Willebrand factor (1995)

To study the interaction between factor VIII and von Willebrand factor (vWF), binding experiments were performed using immobilized plasma vWF. Plasma was obtained from healthy donors and from patients with severe hemophilia A. For normal and hemophilic vWF, the dissociation constants (kd) for binding of factor VIII to vWF were 0.21 +/- 0.04 and 0.22 +/- 0.05 nmol/L, respectively. At saturation, the stoichiometry was one factor VIII molecule per 50 vWF monomers. In gel-filtration experiments, vWF was saturated by 23 times more factor VIII. However, when this FVIII-vWF complex was immobilized on microtiter plates, the ratio of factor VIII/vWF decreased to the same ratio as in the solid-phase binding assay. To exclude any effect of antibody binding, colloidal gold particles with a diameter of 15 nm were coupled to purified vWF. This vWF-gold complex remained immunoreactive toward polyclonal and monoclonal antibodies, and was able to bind factor VIII, specifically, saturably, and reversibly. After incubation of vWF-gold with factor VIII, unbound and bound factor VIII were separated by centrifugation. Binding isotherms of these fluid-phase binding experiments indicated a kd of 0.32 +/- 0.09 nmol/L and a stoichiometry of approximately 0.5 factor VIII molecule per vWF monomer. We conclude that vWF-binding to a surface, with or without an antibody, may induce a conformational change causing a dissociation of bound factor VIII from vWF.
Architectural and material contributions to fracture of the spine and proximal femur. (1998)

One of the most significant musculoskeletal diseases affecting society in terms of social, physical, and economic costs is osteoporosis. Although osteoporosis is defined clinically by a fracture resulting from excessive cancellous bone loss with aging, the quantity of bone alone is not adequate to predict who will sustain a fracture. To further our understanding of the mechanisms underlying osteoporotic fracture, the influences of architecture and material quality on mechanical behavior of cancellous bone must be examined. Four specific factors hypothesized to contribute to age-related bone fragility were examined. First, the collagen fibril diameter distribution in human vertebral bone as a function of age was characterized. Fibril diameter distributions changed during growth and development, but not after early adulthood, suggesting that fibril distribution profiles may affect bone mechanics of younger persons but do not appear to contribute to age-related vertebral fragility. Next, human vertebral bone was examined histologically for the presence, numerical density, and morphology of in vivo microscopic cracking. Associations of the amount and type of microdamage with race, gender, age, and bone mass were evaluated. Microcracks were consistently present in vertebral bone at very low levels. No gender or age effects were found, but whites had higher microcrack density than blacks. Microcracks were more prevalent among persons with low bone mass. The third factor examined was fatigue properties of vertebral tissue. Fatigue life increased with aging, which we hypothesize may be a consequence of age-related changes in bone microstructure at the trabecular level. The age-related increase in fatigue life may reflect a qualitative improvement in tissue properties that prolongs structural integrity of the vertebral body despite bone loss. Finally, the microstructure and mechanical properties of cancellous bone from the proximal femur of female hip fracture patients and controls were characterized and compared. Fracture specimens had a significantly more anisotropic structure than controls, even when matched for bone volume. Assuming that bone adapts to its mechanical environment, this suggests that fracture patients either experience altered mechanical loading about the hip or that their mechanotransduction and/or bone adaptation systems are different.
Pimelic Diphenylamide 106 Is a Slow, Tight-binding Inhibitor of Class I Histone Deacetylases (2008)

Histone deacetylase (HDAC) inhibitors, including various benzamides and hydroxamates, are currently in clinical development for a broad range of human diseases, including cancer and neurodegenerative diseases. We recently reported the identification of a family of benzamide-type HDAC inhibitors that are relatively non-toxic compared with the hydroxamates. Members of this class of compounds have shown efficacy in cell-based and mouse models for the neurodegenerative diseases Friedreich ataxia and Huntington disease. Considerable differences in IC(50) values for the various HDAC enzymes have been reported for many of the HDAC inhibitors, leading to confusion as to the HDAC isotype specificities of these compounds. Here we show that a benzamide HDAC inhibitor, a pimelic diphenylamide (106), is a class I HDAC inhibitor, demonstrating no activity against class II HDACs. 106 is a slow, tight-binding inhibitor of HDACs 1, 2, and 3, although inhibition for these enzymes occurs through different mechanisms. Inhibitor 106 also has preference toward HDAC3 with K(i) of approximately 14 nm, 15 times lower than the K(i) for HDAC1. In comparison, the hydroxamate suberoylanilide hydroxamic acid does not discriminate between these enzymes and exhibits a fast-on/fast-off inhibitory mechanism. These observations may explain a paradox involving the relative activities of pimelic diphenylamides versus hydroxamates as gene activators.
A new iron–sulphide cluster containing the ‘prismane’[Fe6(µ-S)6]3+core. Synthesis, structure, and properties of [Et4N]3[Fe6S6Cl6] (1984)

M. G. Kanatzidis, W. R. Dunham, W. R. Hagen and D. Coucouvanis, J. Chem. Soc., Chem. Commun., 1984, 356 DOI: 10.1039/C39840000356
Automated lung nodule segmentation using dynamic programming and EM-based classification (2002)

In this paper we present a robust and automated algorithm to segment lung nodules in three dimensional (3D) Computed Tomography (CT) volume dataset. The nodule is segmented out in slice-per-slice basis, that is, we first process each CT slice separately to extract two dimensional (2D) contours of the nodule which can then be stacked together to get the whole 3D surface. The extracted 2D contours are optimal as we utilize dynamic programming based optimization algorithm. To extract each 2D contour, we utilize a shape based constraint. Given a physician specified point on the nodule, we blow a circle which gives us rough initialization of the nodule from where our dynamic programming based algorithm estimates the optimal contour. As a nodule can be calcified, we pre-process a small region-of-interest (ROI), around the physician selected point on the nodule boundary, using the Expectation Maximization (EM) based algorithm to classify and remove calcification. Our proposed approach can be consistently and robustly used to segment not only the solitary nodules but also the nodules attached to lung walls and vessels.
Expression of variant‐specific antigen genes in African trypanosomes (1988)

Among the large collection of antigen genes present in the Trypanosoma brucei genome, only one is usually transcribed at a time when the parasites develop in the mammalian bloodstream. The antigen gene is transcribed in a telomeric expression site, together with other genes whose function is unknown. The nature of the RNA polymerase and transcription promoter, as well as the overall organization of the transcription unit, suggests that transcription of the antigen gene is of the ribosomal type. This transcription rapidly stops when the temperature of the parasite medium is lowered, probably accounting for the gene inactivation in the procyclic form of the insect midgut. Antigen gene expression resumes in 2 steps: first, induction of specific metacyclic variants occurs in the fly salivary glands, then injection into the blood reactivates the expression site silenced at the procyclic stage. Several telomeres can act as alternative expression sites, but the mechanism for expression-site switching is unknown. In a given expression site, the specificity of the antigen gene can change following gene conversion, telomeric reciprocal recombination, or point mutation. The alternate use of these mechanisms leads to the successive appearance of a very high number of antigenic variants, as well as to rapid evolution of the antigen gene repertoire. The relative extent of homology between nontelomeric antigen genes and the expression site may condition the programming of antigenic variation late in chronic infection, as well as the generation of chimaeric antigen genes.
Activation of Mammalian Toll-like Receptors by Endogenous Agonists (2003)

Toll-like receptors activate innate and adaptive immune systems in mammals. This ancient family of receptors has been evolving since before the taxonomic split between the plant and animal kingdoms. The discovery of the mammalian Toll-like receptors was heralded as confirmation of a predicted biological system explicitly designed to detect exogenous molecules from micro-organisms. However, there is accumulating evidence that Toll-like receptors also detect endogenous agonists, such as the degradation products of macromolecules, products of proteolytic cascades, intracellular components of ruptured cells, and products of genes that are activated by inflammation. Here we review endogenous models of Toll-like receptor activation, a subject of extensive debate. Endogenous activation of mammalian Toll-like receptors may provide key insights for the treatment of multiple conditions, from atherosclerosis to transplant rejection.
Immunotherapy of Malignant Disease Using Chimeric Antigen Receptor Engrafted T Cells (2012)

Chimeric antigen receptor- (CAR-) based immunotherapy has been under development for almost 25 years, over which period it has progressed from a new but cumbersome technology to an emerging therapeutic modality for malignant disease. The approach involves the genetic engineering of fusion receptors (CARs) that couple the HLA-independent binding of cell surface target molecules to the delivery of a tailored activating signal to host immune cells. Engineered CARs are delivered most commonly to peripheral blood T cells using a range of vector systems, most commonly integrating viral vectors. Preclinical refinement of this approach has proceeded over several years to the point that clinical testing is now being undertaken at several centres, using increasingly sophisticated and therapeutically successful genetic payloads. This paper considers several aspects of the pre-clinical and clinical development of CAR-based immunotherapy and how this technology is acquiring an increasing niche in the treatment of both solid and haematological malignancies.
Functional Proteomic Analysis for Regulatory T Cell Surveillance of the HIV-1-Infected Macrophage (2010)

Regulatory T cells (Treg) induce robust neuroprotection in murine models of neuroAIDS, in part, through eliciting anti-inflammatory responses for HIV-1-infected brain mononuclear phagocytes (MP; macrophage and microglia). Herein, using both murine and human primary cell cultures in proteomic and cell biologic tests, we report that Treg promotes such neuroprotection by an even broader range of mechanisms than previously seen including inhibition of virus release, killing infected MP, and inducing phenotypic cell switches. Changes in individual Treg-induced macrophage proteins were quantified by iTRAQ labeling followed by mass spectrometry identifications. Reduction in virus release paralleled the upregulation of interferon-stimulated gene 15, an ubiquitin-like protein involved in interferon-mediated antiviral immunity. Treg killed virus-infected macrophages through caspase-3 and granzyme and perforin pathways. Independently, Treg transformed virus-infected macrophages from an M1 to an M2 phenotype by down- and up- regulation of inducible nitric oxide synthase and arginase 1, respectively. Taken together, Treg affects a range of virus-infected MP functions. The observations made serve to challenge the dogma of solitary Treg immune suppressor functions and provides novel insights into how Treg affects adaptive immunosurveillance for control of end organ diseases, notably neurocognitive disorders associated with advanced viral infection.
Vitamins B6, B12, and Folate: Association with Plasma Total Homocysteine and Risk of Coronary Atherosclerosis (1998)

The presently accepted view that vitamin B6 mainly affects tHcy after methionine loading, and not fasting tHcy, is contradicted by our findings in referents. Low vitamin B12 concentrations were associated with an increased risk of coronary atherosclerosis, partly independently of tHcy. Although low folate status was a strong determinant of elevated tHcy concentrations, it was not associated with increased risk of coronary atherosclerosis.
Comparing de novo assemblers for 454 transcriptome data (2010)

Transcriptome assemblies are smaller than genome assemblies and thus should be more computationally tractable, but are often harder because individual contigs can have highly variable read coverage. Comparing single assemblers, Newbler 2.5 performed best on our trial data set, but other assemblers were closely comparable. Combining differently optimal assemblies from different programs however gave a more credible final product, and this strategy is recommended.
Ultrasound Perfusion Imaging in Acute Middle Cerebral Artery Infarction Predicts Outcome (2004)

In the early phase of acute ischemic stroke, BHI after SonoVue bolus injection is a useful ultrasound tool for analyzing cerebral perfusion deficits at the patient's bedside. BHI data correlate with the definite area of infarction and outcome after 4 months.