gebhart/patrepeval huggingface dataset:
Structure-Based Generation of a New Class of Potent Cdk4 Inhibitors:  Newde NovoDesign Strategy and Library Design (2001)

As a first step in structure-based design of highly selective and potent Cdk4 inhibitors, we performed structure-based generation of a novel series of Cdk4 inhibitors. A Cdk4 homology model was constructed according to X-ray analysis of an activated form of Cdk2. Using this model, we applied a new de novo design strategy which combined the de novo design program LEGEND with our in-house structure selection supporting system SEEDS to generate new scaffold candidates. In this way, four classes of scaffold candidates including diarylurea were identified. By constructing diarylurea informer libraries based on the structural requirements of Cdk inhibitors in the ATP binding pocket of the Cdk4 model, we were able to identify a potent Cdk4 inhibitor N-(9-oxo-9H-fluoren-4-yl)-N'-pyridin-2-ylurea 15 (IC(50) = 0.10 microM), together with preliminary SAR. We performed a docking study between 15 and the Cdk4 model and selected a reasonable binding mode which is consistent with the SAR. Further modification based on the proposed binding mode provided a more potent compound, N-[(9bR)-5-oxo-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindol-9-yl]-N'-pyridin-2-ylurea 26a (IC(50) = 0.042 microM), X-ray analysis of which was accomplished by the soaking method. The predicted binding mode of 15 in Cdk4 was validated by X-ray analysis of the Cdk2-26a complex.
Staphylococcus aureus Bacteremia in Patients With Permanent Pacemakers or Implantable Cardioverter-Defibrillators (2001)

The incidence of CDI among patients with SAB and cardiac devices is high. Neither physical examination nor echocardiography can exclude the possibility of CDI. In patients with early SAB, the device is usually involved, and approximately 40% of these patients have obvious clinical signs of cardiac device involvement. Conversely, in patients with late SAB, the cardiac device is rarely the initial source of bacteremia, and there is a paucity of local signs of device involvement. The cardiac device is involved, however, in >/=28% of these patients.
Optimizing multiple-input single-output (miso) communication systems with general gaussian channels: nontrivial covariance and nonzero mean (2003)

We consider a narrow-band point-to-point communication system with many (input) transmitters and a single (output) receiver (i.e., a multiple-input single output (MISO) system). We assume the receiver has perfect knowledge of the channel but the transmitter only knows the channel distribution. We focus on two canonical classes of Gaussian channel models: (a) the channel has zero mean with a fixed covariance matrix and (b) the channel has nonzero mean with covariance matrix proportional to the identity. In both cases, we are able to derive simple analytic expressions for the ergodic average and the cumulative distribution function (c.d.f.) of the mutual information for arbitrary input (transmission) signal covariance. With minimal numerical effort, we then determine the ergodic and outage capacities and the corresponding capacity-achieving input signal covariances. Interestingly, we find that the optimal signal covariances for the ergodic and outage cases have very different behavior. In particular, under certain conditions, the outage capacity optimal covariance is a discontinuous function of the parameters describing the channel (such as strength of the correlations or the nonzero mean of the channel).
Kinetic modeling on drug release from controlled drug delivery systems. (2010)

In this paper we review the mathematical models used to determine the kinetics of drug release from drug delivery systems. The quantitative analysis of the values obtained in dissolution/release rates is easier when mathematical formulae are used to describe the process. The mathematical modeling can ultimately help to optimize the design of a therapeutic device to yield information on the efficacy of various release models.
Vision-based vehicle guidance (2003)

The book Vision-based Vehicle Guidance (Springer-Verlag), edited by the author, is outlined. The book consists of 15 papers, each of which represents a different research project in the field of vision-based vehicle guidance. The author describes some examples of vision algorithms, such as focus of attention, stereo vision, and neural-network-based visual processing. High-speed vision processors, including function-oriented custom chips, are also discussed. Temporal-spatial modeling and fuzzy logic are described as examples of control algorithms. Examples of applications include road following and traffic sign recognition.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
In vitro characterization of micropatterned PLGA‐PHBV8 blend films as temporary scaffolds for photoreceptor cells (2007)

In developed countries the aging population faces increasing risks of blinding retinal diseases, for which there are few effective treatments available. Photoreceptor transplantation represents one approach, but generally results have been disappointing. We hypothesize that micropatterned biodegradable poly(L-lactic acid-co-glycolic acid)/poly(hydroxybutyrate-co-hydroxyvaleric acid) (PLGA-PHBV8) blend films could deliver photoreceptor cells in a more organized manner than bolus injections. Blending of PLGA and PHBV8 was used to optimize the degradation rate of the temporary template. At the end of 8 weeks, for both thin and thick films of PLGA-PHBV8 a 50% decrease of their initial weight with increasing water uptake was observed. When photoreceptor cells were seeded onto micropatterned PLGA-PHBV8 films with parallel grooves (21- and 42-microm-wide grooves and 20 microm ridge width and depth), the cells preferred laminin-deposited grooves to ridges and expressed rod- and cone-specific markers such as rhodopsin and arrestin. A loss in photoreceptor viability of 50% was observed after 7 days in culture. The effects of either retinal pigment epithelium (RPE)-derived or Muller glial cell-derived conditioned media or bFGF on the survival of photoreceptor cells seeded on PLGA-PHBV8 films were investigated. Addition of either RPE- and Muller-conditioned media increased statistically (p < 0.01) the viability of photoreceptor cells after 7 days of incubation. Our results suggest that such biodegradable micropatterned PLGA-PHBV8 blend films have a potential to deliver photoreceptor cells to the subretinal space and ensure laminar organization and maintenance of differentiation, and that incorporation of intrinsic factors within the scaffold would enhance the survival rate of transplanted cells.
A clock net routing algorithm for high performance VLSI (2003)

Presents a new algorithm, called FSTM ('feasible segment tree method'), for the clock net routing of high performance VLSI designs. To avoid the clock skew, FSTM constructs a binary tree such that for each internal vertex of the tree, the cardinality of its sub-trees are balanced and the distances to its children are equal. The authors evaluate their results in terms of wire length and delay time (by the SPICE simulator). Experiments show that the clock net trees routed by FSTM achieve 13% in wire length, 3% in maximum delay and 36% in clock skew improvement over previously published results.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
A novel sense amplifier for flexible voltage operation NAND flash memories (2002)

This paper proposes a new bit-by-bit verify circuit for application in NAND flash memories. The Sense Amplifier (S/A) employed confers two benefits: flexible power supply voltage (ex. 3 V or 5 V) operation with a high noise immunity and an intelligent page copy function. The benefits are very useful to the flash memory card or system and accelerate the replacement of magnetic memories by flash memories. The S/A has been successfully implemented in the commercial version of the 32 Mbit NAND-EEPROM, in which the S/A is newly introduced in comparison with the prototype version.
A gene cluster for macrolide antibiotic biosynthesis in Streptomyces venezuelae : Architecture of metabolic diversity (1998)

In a survey of microbial systems capable of generating unusual metabolite structural variability, Streptomyces venezuelae ATCC 15439 is notable in its ability to produce two distinct groups of macrolide antibiotics. Methymycin and neomethymycin are derived from the 12-membered ring macrolactone 10-deoxymethynolide, whereas narbomycin and pikromycin are derived from the 14-membered ring macrolactone, narbonolide. This report describes the cloning and characterization of the biosynthetic gene cluster for these antibiotics. Central to the cluster is a polyketide synthase locus (pikA) that encodes a six-module system comprised of four multifunctional proteins, in addition to a type II thioesterase (TEII). Immediately downstream is a set of genes for desosamine biosynthesis (des) and macrolide ring hydroxylation. The study suggests that Pik TEII plays a role in forming a metabolic branch through which polyketides of different chain length are generated, and the glycosyl transferase (encoded by desVII) has the ability to catalyze glycosylation of both the 12- and 14-membered ring macrolactones. Moreover, the pikC-encoded P450 hydroxylase provides yet another layer of structural variability by introducing regiochemical diversity into the macrolide ring systems. The data support the notion that the architecture of the pik gene cluster as well as the unusual substrate specificity of particular enzymes contributes to its ability to generate four macrolide antibiotics.
Generation and rescue of a murine model of platelet dysfunction: The Bernard-Soulier syndrome (2000)

The human Bernard-Soulier syndrome is an autosomal recessive disorder of platelet dysfunction presenting with mild thrombocytopenia, circulating "giant" platelets and a bleeding phenotype. The bleeding in patients with the Bernard-Soulier syndrome is disproportionately more severe than suggested by the reduced platelet count and is explained by a defect in primary hemostasis owing to the absence of the platelet glycoprotein (GP) Ib-IX-V membrane receptor. However, the molecular basis for the giant platelet phenotype and thrombocytopenia have remained unresolved but assumed to be linked to an absent receptor complex. We have disrupted the gene encoding the alpha-subunit of mouse GP Ib-IX-V (GP Ibalpha) and describe a murine model recapitulating the hallmark characteristics of the human Bernard-Soulier syndrome. The results demonstrate a direct link between expression of a GP Ib-IX-V complex and normal megakaryocytopoiesis and platelet morphogenesis. Moreover, using transgenic technology the murine Bernard-Soulier phenotype was rescued by expression of a human GP Ibalpha subunit on the surface of circulating mouse platelets. Thus, an in vivo model is defined for analysis of the human GP Ib-IX-V receptor and its role in the processes performed exclusively by megakaryocytes and platelets.
The Malaria Parasite's Chloroquine Resistance Transporter is a Member of the Drug/Metabolite Transporter Superfamily (2004)

The malaria parasite's chloroquine resistance transporter (CRT) is an integral membrane protein localized to the parasite's acidic digestive vacuole. The function of CRT is not known and the protein was originally described as a transporter simply because it possesses 10 transmembrane domains. In wild-type (chloroquine-sensitive) parasites, chloroquine accumulates to high concentrations within the digestive vacuole and it is through interactions in this compartment that it exerts its antimalarial effect. Mutations in CRT can cause a decreased intravacuolar concentration of chloroquine and thereby confer chloroquine resistance. However, the mechanism by which they do so is not understood. In this paper we present the results of a detailed bioinformatic analysis that reveals that CRT is a member of a previously undefined family of proteins, falling within the drug/metabolite transporter superfamily. Comparisons between CRT and other members of the superfamily provide insight into the possible role of the protein and into the significance of the mutations associated with the chloroquine resistance phenotype. The protein is predicted to function as a dimer and to be oriented with its termini in the parasite cytosol. The key chloroquine-resistance-conferring mutation (K76T) is localized in a region of the protein implicated in substrate selectivity. The mutation is predicted to alter the selectivity of the protein such that it is able to transport the cationic (protonated) form of chloroquine down its steep concentration gradient, out of the acidic vacuole, and therefore away from its site of action.
Regulation of B cell apoptosis by Bcl-2 and Bcl-XL and its role in the development of autoimmune diseases (Review). (1998)

Cell death is a common event during B cell development. The demise of developing B cells is a regulated process that serves to select cell populations bearing functional receptors and to remove cells that are no longer needed or potentially autoreactive. Bcl-2 and Bcl-XL, two members of the bcl-2 gene family of programmed cell death regulators with anti-apoptotic activity, are expressed in a highly regulated pattern during B cell maturation. Overexpression of Bcl-2 in developing B cells of transgenic mice, in the presence of T cell dependent costimulatory signals, results in the generation of a modified B cell repertoire and in the production of pathogenic autoantibodies. While disregulation of programmed cell death in B cells may cause autoimmune manifestations in mice, the involvement of such alterations in the pathogenesis of autoimmune diseases in humans merits further investigation.
Orbital and Charge-Resolved Polaron States in CdSe Dots and Rods Probed by Scanning Tunneling Spectroscopy (2009)

Conduction electrons interact with lattice vibrations, leading to coupled electron-phonon states. This effect is of fundamental importance in understanding electron transport and energy relaxation in nanoscale systems. We report quantitative results on the electron-phonon coupling strength in CdSe quantum dots (QDs) and rods, obtained by low-temperature scanning tunneling microscopy. We resolve the polaron eigenstates arising from coupling of the electrons to longitudinal optical phonons. The electron-phonon coupling strength is dependent on the electron orbital symmetry, the number of added electrons, and the size and dielectric environment of the QD.
Uric Acid Is a Mediator of the Plasmodium falciparum-Induced Inflammatory Response (2009)

Uric acid is a major contributor of the inflammatory response triggered by P. falciparum in human peripheral blood mononuclear cells. Since the inflammatory reaction induced by P. falciparum is considered a major cause of malaria pathogenesis, identifying the mechanisms used by the parasite to induce the host inflammatory response is essential to develop urgently needed therapies against this disease.
Host adaptive immunity deficiency in severe pandemic influenza (2010)

Our findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome.
A simple approximate mathematical model to predict the number of severe acute respiratory syndrome cases and deaths (2003)

Using the proposed mathematical model, it was estimated that about 1.5 to 2 new infectious cases were produced per infectious case every five days. Also, about 20% to 30% of the cases die within 14 days. The case-fatality may therefore be considerably higher than initially thought. The model indicates that SARS can spread very fast when there are no interventions.
Power conservation and quality of surveillance in target tracking sensor networks (2004)

Target tracking is an important application of wireless sensor networks. In this application, the sensor nodes collectively monitor and track the movement of an event or target object. The network operations have two states: the surveillance state during the absence of any event of interest, and the tracking state which is in response to any moving targets. Thus, the power saving operations, which is of critical importance for extending network lifetime, should be operative in two different modes as well. In this paper, we study the power saving operations in both states of network operations. During surveillance state, a set of novel metrics for quality of surveillance is proposed specifically for detecting moving objects. In the tracking state, we propose a collaborative messaging scheme that wakes up and shuts down the sensor nodes with spatial and temporal preciseness. This study, which is a combination of theoretical analysis and simulated evaluations, quantifies the trade-off between power conservation and quality of surveillance while presenting guidelines for efficient deployment of sensor nodes for target tracking application.
Discriminating functional and non‐functional p53 in human tumours by p53 and MDM2 immunohistochemistry (2005)

Mutation and/or loss of the TP53 tumour suppressor gene is the single most common genetic abnormality in human cancer. The majority of TP53 mutations lead to stabilization of the protein, so that immunohistochemical staining for p53 can suggest mutation status in many cases. However, various false-positive and false-negative situations mean that simple immunostaining for p53 is not informative in a substantial number of tumours. In the present study, a series of 119 human cancers were immunostained using a highly sensitive technique that detects the low levels of wild-type protein expressed in normal cells, such that homozygous gene deletion or non-sense TP53 mutation can be identified by an absence of staining. TP53 gene status was also assessed using FASAY as a genetic/functional screen and in selected cases by direct sequencing. A quantitative scoring system was employed to assess p53 levels, and p53 post-translational modification was evaluated using antibodies that detect specific phosphorylation sites. Phosphorylated p53 correlated with total p53 levels and did not improve the prediction of TP53 mutation status. The transcriptional activity of TP53 was determined by staining for two downstream target genes, p21(WAF1) and MDM2, and statistical correlations between MDM2/p21(WAF1) and p53 were found in tumours with wild-type, but not mutant TP53. Measurement of staining for p53 and MDM2 accurately identifies the TP53 status of tumours. This simple and cost-effective method, applicable to automated staining and quantitation methods, improves the identification of TP53 status over standard methods for p53 immunostaining and provides information about tumour p53 phenotype that is complementary to genotyping data.
Determination of Picomolar Concentrations of Metal Ions Using Fluorescence Anisotropy:  Biosensing with a “Reagentless” Enzyme Transducer (1998)

Because of their high affinity and selectivity, metalloproteins can be used as transducers in novel sensors, i.e., biosensors, for the determination of trace levels of metal ions in solution. Here, we exploit carbonic anhydrase to determine picomolar to nanomolar concentrations of free transition metal ions by fluorescence anisotropy (polarization) in a reagentless format. Carbonic anhydrase variants engineered with a cysteine replacing a residue chosen near the active site (F131C and H64C) were covalently labeled with derivatives of benzoxadiazole sulfonamide. These labeled variants exhibited changes in anisotropy up to 0.07 upon binding free Cu(II), Co(II), and Zn(II) with apparent Kd's close to the values observed with wild-type apocarbonic anhydrase. The covalent attachment of the label has significant advantages over noncovalent labels we have described previously. Furthermore, the metal ion-dependent anisotropy changes were predictable using simple theory. The results demonstrate that free transition metal ions can be determined at trace levels in aqueous solution using inexpensive instruments.
Coinjection with CpG-Containing Immunostimulatory Oligodeoxynucleotides Reduces the Pathogenicity of a Live Vaccine against Cutaneous Leishmaniasis but Maintains Its Potency and Durability (2003)

The inoculation of live, nonattenuated Leishmania major to produce a lesion in a selected site that heals, referred to as leishmanization, is to date the only vaccine against leishmaniasis that has proven to be effective in humans. Its use has been restricted or abandoned entirely, however, due to safety concerns. In an attempt to develop a leishmanization protocol that minimizes pathology while maintaining long-term protection, live parasites were coinjected with CpG-containing immunostimulatory oligodeoxynucleotides (CpG ODNs) alone or in combination with whole-cell lysates of heat-killed L. major promastigotes bound to alum (ALM). C57BL/6 mice infected intradermally by using L. major plus CpG ODN with or without ALM developed few or no dermal lesions and showed an early containment of parasite growth, while mice infected with L. major with or without ALM developed sizable dermal lesions that required up to 10 weeks to heal. The CpG ODNs provoked a transient inflammation that included an early recruitment and accumulation of gamma interferon-producing CD4(+) lymphocytes in the site. Attenuation of the live vaccine did not compromise its ability to confer long-term immunity, as mice receiving L. major and CpG ODN plus ALM were totally protected against reinfection with L. major for up to 6 months. By comparison, the immunity elicited by two efficient nonlive vaccines began to wane by 6 months. Our results suggest that immune modulation using CpG ODNs might be a practical approach to improving the safety of a highly effective live vaccine that has already been widely applied.
A VISUALIZATION AND DESIGN TOOL (AVID) FOR DATA MINING WITH THE SELF-ORGANIZING FEATURE MAP (2000)

This paper presents a software tool called AVID (A VIsualization and Design) which is particularly useful for data mining with an artificial neural network known as the self-organising feature map (SOM). AVID supports network training in both the i) selection of network inputs and ii) visualisation of the trained SOM. Both these features are novel aids to SOM network training and are particularly important when consideration is given to using the SOM for data mining. Once trained the SOM produces a 2-dimensional topological ordering of the input training data and it is particularly useful for representing the relationships within multi-dimensional data. The main classes within the data can be identified from the output map. AVID is an important software tool which enables data mining with the SOM by the selection of network inputs and the subsequent visualisation of the classes within these input vectors.