gebhart/patrepeval huggingface dataset:
Equally Potent Inhibition of c-Src and Abl by Compounds that Recognize Inactive Kinase Conformations (2009)

Imatinib is an inhibitor of the Abl tyrosine kinase domain that is effective in the treatment of chronic myelogenic leukemia. Although imatinib binds tightly to the Abl kinase domain, its affinity for the closely related kinase domain of c-Src is at least 2,000-fold lower. Imatinib recognition requires a specific inactive conformation of the kinase domain, in which a conserved Asp-Phe-Gly (DFG) motif is flipped with respect to the active conformation. The inability of c-Src to readily adopt this flipped DFG conformation was thought to underlie the selectivity of imatinib for Abl over c-Src. Here, we present a series of inhibitors (DSA compounds) that are based on the core scaffold of imatinib but which bind with equally high potency to c-Src and Abl. The DSA compounds bind to c-Src in the DFG-flipped conformation, as confirmed by crystal structures and kinetic analysis. The origin of the high affinity of these compounds for c-Src is suggested by the fact that they also inhibit clinically relevant Abl variants bearing mutations in a structural element, the P-loop, that normally interacts with the phosphate groups of ATP but is folded over a substructure of imatinib in Abl. Importantly, several of the DSA compounds block the growth of Ba/F3 cells harboring imatinib-resistant BCR-ABL mutants, including the Thr315Ile "gatekeeper" mutation, but do not suppress the growth of parental Ba/F3 cells.
A role for ubiquitin ligase recruitment in retrovirus release (2000)

Retroviral Gag polyproteins have specific regions, commonly referred to as late assembly (L) domains, which are required for the efficient separation of assembled virions from the host cell. The L domain of HIV-1 is in the C-terminal p6(gag) domain and contains an essential P(T/S)AP core motif that is widely conserved among lentiviruses. In contrast, the L domains of oncoretroviruses such as Rous sarcoma virus (RSV) have a more N-terminal location and a PPxY core motif. In the present study, we used chimeric Gag constructs to probe for L domain activity, and observed that the unrelated L domains of RSV and HIV-1 both induced the appearance of Gag-ubiquitin conjugates in virus-like particles (VLP). Furthermore, a single-amino acid substitution that abolished the activity of the RSV L domain in VLP release also abrogated its ability to induce Gag ubiquitination. Particularly robust Gag ubiquitination and enhancement of VLP release were observed in the presence of the candidate L domain of Ebola virus, which contains overlapping P(T/S)AP and PPxY motifs. The release defect of a minimal Gag construct could also be corrected through the attachment of a peptide that serves as a physiological docking site for the ubiquitin ligase Nedd4. Furthermore, VLP formation by a full-length Gag polyprotein was sensitive to lactacystin, which depletes the levels of free ubiquitin through inhibition of the proteasome. Our findings suggest that the engagement of the ubiquitin conjugation machinery by L domains plays a crucial role in the release of a diverse group of enveloped viruses.
<title>Accurate 3D reconstruction of tortuous coronary vessels using biplane angiography and intravascular ultrasound</title> (1997)

At present, 3D reconstructions of coronary vessels are generated from intravascular ultrasound (IVUS) pullback sequences by stacking up ECG-gated segmented IVUS frames. Since this approach results in straight vessel reconstructions, it clearly fails in tortuous coronary arteries. This shortcoming may be overcome by data fusion with biplane angiography. The 3D course of the vessel is first derived from angiograms and then combined with segmented IVUS images in order to obtain a spatially correct and anatomically complete vessel reconstruction. In this paper, different approaches to two problems associated with the data fusion method are discussed: the definition of the pullback path and the estimation of IVUS catheter twist during pullback. A procedure for image acquisition, segmentation, mapping, and interpolation is proposed that has been designed with respect to its clinical applicability. In vitro validations of our previously reported algorithm for analytic catheter twist quantification is presented along with data fusion results of coronary arteries in cadaveric pig hearts.
Pharmacology of Ursodeoxycholic Acid, an Enterohepatic Drug (1994)

The pharmacokinetics, metabolism, as well as the pharmacodynamic actions of ursodeoxycholic acid are reviewed and related to its physicochemical properties. Ursodeoxycholic acid is absorbed incompletely because of its low aqueous solubility. After absorption, it is conjugated with glycine or taurine and circulates with the endogenous bile acids. At usual doses (8-10 mg/kg/day), the pool of ursodeoxycholyl conjugates constitutes 30-60% of circulating bile acids. Ursodeoxycholic acid is metabolized by intestinal bacteriae to lithocholic acid which does not accumulate in the circulating bile acids because of efficient hepatic sulfation. Administration of ursodeoxycholic acid causes decreased cholesterol absorption, increased bile acid biosynthesis, and decreased biliary cholesterol secretion. Ursodeoxycholic acid is a choleretic agent, as all bile acids, but differs from other dihydroxy-bile acids in being non-cytotoxic because it has less affinity for membranes, and when present at micellar concentrations does not solubilize membranes. Chronic administration of ursodeoxycholic acid appears to increase canalicular transport.
Effect of tension induced by Shouldice repair on postoperative course and long-term outcome (2002)

Postoperative pain and recurrences depend on many factors, but induced intraoperative tension can be excluded. The reported advantages of tension-free procedures are not based on the avoidance of tension. The Shouldice repair can therefore continued to be used as a routine technique in uncomplicated primary inguinal hernia repair.
Cardiopoietic programming of embryonic stem cells for tumor-free heart repair (2007)

Embryonic stem cells have the distinct potential for tissue regeneration, including cardiac repair. Their propensity for multilineage differentiation carries, however, the liability of neoplastic growth, impeding therapeutic application. Here, the tumorigenic threat associated with embryonic stem cell transplantation was suppressed by cardiac-restricted transgenic expression of the reprogramming cytokine TNF-alpha, enhancing the cardiogenic competence of recipient heart. The in vivo aptitude of TNF-alpha to promote cardiac differentiation was recapitulated in embryoid bodies in vitro. The procardiogenic action required an intact endoderm and was mediated by secreted cardio-inductive signals. Resolved TNF-alpha-induced endoderm-derived factors, combined in a cocktail, secured guided differentiation of embryonic stem cells in monolayers produce cardiac progenitors termed cardiopoietic cells. Characterized by a down-regulation of oncogenic markers, up-regulation, and nuclear translocation of cardiac transcription factors, this predetermined population yielded functional cardiomyocyte progeny. Recruited cardiopoietic cells delivered in infarcted hearts generated cardiomyocytes that proliferated into scar tissue, integrating with host myocardium for tumor-free repair. Thus, cardiopoietic programming establishes a strategy to hone stem cell pluripotency, offering a tumor-resistant approach for regeneration.
Practical Partial Synthesis of Myriceric Acid A, an Endothelin Receptor Antagonist, from Oleanolic Acid (1997)

Myriceric acid A (1) is an oleanane triterpene that is a potent and specific endothelin A receptor antagonist. A practical procedure for large-scale synthesis of myriceric acid A (1) has been developed starting from oleanolic acid 4. The conversion of oleanolic acid 4 to the key intermediate myricerone 3 was achieved in an efficient manner employing a photochemical reaction (the Barton reaction) of nitrite 7. Our synthetic procedure alleviated several difficulties of the original Barton's procedure with regard to yields and large-scale operation. Myricerone 3 afforded Horner−Wadsworth−Emmons (HWE) type phosphonate 2 which has proved to be a versatile precursor of 1. The preparation of phosphonate 2 on a scale of several hundred grams is described. The synthesis was completed by condensation of 2 with 3,4-bis[(diphenylmethyl)oxy]benzaldehyde (21), giving α,β-unsaturated ester 22, which was deprotected to afford 1. The whole synthetic sequence is efficient (14 steps, 31% yield) and requires no chromatographic purification except to obtain the final product 1.
Redesign of Glycopeptide Antibiotics: Back to the Future (2012)

The glycopeptide antibiotics are the most important class of drugs used in the treatment of resistant bacterial infections including those caused by methicillin-resistant Staphylococcus aureus (MRSA). After more than 50 years of clinical use, the emergence of glycopeptide-resistant Gram-positive pathogens such as vancomycin-resistant enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA) presents a serious global challenge to public health at a time few new antibiotics are being developed. This has led to renewed interest in the search for additional effective treatments including the development of new derivatives of the glycopeptide antibiotics. General approaches have been explored for modifying glycopeptide antibiotics, typically through the derivatization of the natural products themselves or more recently through chemical total synthesis. In this Perspective, we consider recent efforts to redesign glycopeptide antibiotics for the treatment of resistant microbial infections, including VRE and VRSA, and examine their future potential for providing an even more powerful class of antibiotics that are even less prone to bacterial resistance.
Real-time focus range sensor (1996)

Structures of dynamic scenes can only be recovered using a real-time range sensor. Depth from defocus offers an effective solution to fast and dense range estimation. However, accurate depth estimation requires theoretical and practical solutions to a variety of problems including recovery of textureless surfaces, precise blur estimation, and magnification variations caused by defocusing. Both textured and textureless surfaces are recovered using an illumination pattern that is projected via the same optical path used to acquire images. The illumination pattern is optimized to maximize accuracy and spatial resolution in computed depth. The relative blurring in two images is computed using a narrow-band linear operator that is designed by considering all the optical, sensing, and computational elements of the depth from defocus system. Defocus invariant magnification is achieved by the use of an additional aperture in the imaging optics. A prototype focus range sensor has been developed that has a workspace of 1 cubic foot and produces up to 512/spl times/480 depth estimates at 30 Hz with an average RMS error of 0.2%. Several experimental results are included to demonstrate the performance of the sensor.
Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus (2013)

Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under 5 years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature. Six RSV F crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.
Association of variants of ABCB11 with transient neonatal cholestasis (2013)

Approximately 3% of TNC cases can be attributed to ABCB11 mutations.
Clinical evaluation of live, oral types 1, 2, and 5 adenovirus vaccines. (1974)

Live, oral, enteric-coated, monovalent vaccines containing types 1, 2, and 5 adenoviruses and an identical placebo capsule were administered to 9, 8, 11, and 10 volunteers, respectively. The subjects lacked homologous serum antibody. Administration of the vaccines was not associated with clinical illness or other adverse reactions. One third of the type 1 vaccinees, 38 per cent of the type 2 vaccinees, and 64 per cent of the type 5 vaccinees subsequently excreted homologous virus per rectum. Virus isolates from the rectum predominated between day 5 and day 14 post-vaccination, and ranged from day 3 to day 21. Excretion of the virus by the pharynx was observed in 2 and 5 subjects who received type 2 and type 5 vaccine, respectively. Serum neutralizing antibody developed in 8 subjects (77 per cent) in the type 1 group, 7 (88 per cent) in the type 2 group, and 8 (73 per cent) in the type 5 group. Increased serum titers were detected as early as day 11 and were maximal at day 21. Nasal secretory antibody was ...
Targeting of thylakoid proteins by the ΔpH‐driven twin‐arginine translocation pathway requires a specific signal in the hydrophobic domain in conjunction with the twin‐arginine motif (1998)

Superficially similar cleavable targeting signals specify whether lumenal proteins are transported across the thylakoid membrane by a Sec- or delta pH-dependent pathway. A twin-arginine motif is essential but not sufficient to direct delta pH-dependent targeting; here we show that a second determinant is located in the hydrophobic region. A highly hydrophobic amino acid is found either two or three residues C-terminal to the twin-arginine in all known transfer peptides for the delta pH-dependent system, and substitution of this residue in the 23-kDa (23K) peptide markedly inhibits translocation. Further, whereas the insertion of twin-arginine in a Sec-dependent precursor does not permit efficient delta pH-dependent targeting, the simultaneous presence of a leucine at the +3 position (relative to the RR) enables the peptide to function as efficiently as an authentic transfer peptide. RRNVL, RRAAL and RRALA within a Sec targeting signal all support efficient delta pH-dependent targeting, RRNVA is less effective and RRNAA/RRNAG are totally ineffective. We conclude that the core signal for this pathway is a twin-arginine together with an adjacent hydrophobic determinant.
Imaging of bone tumors using a monoclonal antibody raised against human osteosarcoma (1986)

The radiolabeled monoclonal antibody 791T/36 raised against a human osteosarcoma was injected into 20 patients with known or suspected bone tumors. Gamma camera images were acquired at 48 or 72 hours after injection, and assessed for antibody localization. Positive images were obtained in all five osteosarcomas and four other primary malignant sarcomas. Two of the four other primary bone tumors gave positive images. Three patients with trauma had negative images as did one patient with Paget's disease. Two patients with suppurative disease gave positive images. The antibody localized in the majority of malignant sarcomas tested. In one tumor where tissue was available, a tumor:non-tumor ratio of 2.8:1 was measured. Repeat imaging was performed in five patients. Immunoscintigraphy using the monoclonal antibody 791T/36 has shown tumor localization in patients with bone and soft tissue sarcomas.
Symmetric adaptive maximum likelihood estimationfor noise cancellation and signal separation (1997)

The symmetric adaptive maximum likelihood estimation (SAMLE) algorithm is proposed. It is shown to be a generalisation of the symmetric adaptive decorrelation (SAD) algorithm for noise cancellation and signal separation. Both the SAD and SAMLE algorithms are applied to the separation of a mixture of natural speech recorded in a realistic acoustic environment. A comparative simulation confirms that the SAMLE algorithm provides superior separation capabilities.
A New Calculus for the Treatment of Optical Systems VII Properties of the N-Matrices (1948)

The preceding papers of this series have examined the properties of an optical calculus which represented each of the separate elements of an optical system by means of a single matrix M. This paper is concerned with the properties of matrices, denoted by N, which refer not to the complete element, but only to a given infinitesimal path length within the element.If M is the matrix of the optical element up to the point z, where z is measured along the light path, then the N-matrix at the point z is defined by (A)N≡(dM/dz)M-1.Thus one may write symbolically, (B)N=dlogM/dz,and (C)M=M0 exp(∫Ndz).A general introduction is contained in Part I. The definition and general properties of the N-matrices are treated in Part II. Part III contains a detailed discussion of the important special case in which the optical medium is homogeneous, so that N is independent of z; Part III contains in Eq. (3.26) the explicit relation which corresponds to the symbolic relation (C). Part IV describes a systematic method, based on the N-matrices, by which the optical properties of the system at each point may be described uniquely and quantitatively as a combination of a certain amount of linear birefringence, a certain amount of circular dichroism, etc.; the method of resolution is indicated in Table I. Part V treats the properties of the inhomogeneous crystal which is obtained by twisting a homogeneous crystal about an axis parallel to the light path.
Review of light parameters and photobiomodulation efficacy: dive into complexity (2018)

Photobiomodulation (PBM) therapy, previously known as low-level laser therapy, was discovered more than 50 years ago, yet there is still no agreement on the parameters and protocols for its clinical application. Some groups have recommended the use of a power density less than 100 mW/cm2 and an energy density of 4 to 10 J/cm2 at the level of the target tissue. Others recommend as much as 50 J/cm2 at the tissue surface. The wide range of parameters that can be applied (wavelength, energy, fluence, power, irradiance, pulse mode, treatment duration, and repetition) in some cases has led to contradictory results. In our review, we attempt to evaluate the range of effective and ineffective parameters in PBM. Studies in vitro with cultured cells or in vivo with different tissues were divided into those with higher numbers of mitochondria (muscle, brain, heart, nerve) or lower numbers of mitochondria (skin, tendon, cartilage). Graphs were plotted of energy density against power density. Although the results showed a high degree of variability, cells/tissues with high numbers of mitochondria tended to respond to lower doses of light than those with lower number of mitochondria. Ineffective studies in cells with high mitochondrial activity appeared to be more often due to over-dosing than to under-dosing.
A mutant herpes simplex virus type 1 unable to express glycoprotein L cannot enter cells, and its particles lack glycoprotein H (1993)

Herpes simplex virus type 1 (HSV-1) glycoprotein H (gH) is essential for virus entry into cells and forms a hetero-oligomer with a newly described viral glycoprotein, gL. Normal folding, posttranslational processing, and intracellular transport of both gH and gL depend upon the coexpression of gH and gL in cells infected with vaccinia virus vectors (L. Hutchinson, H. Browne, V. Wargent, N. Davis-Poynter, S. Primorac, K. Goldsmith, A. C. Minson, and D. C. Johnson, J. Virol. 66:2240-2250, 1992). Homologs of gH and gL have been found in herpesviruses of all subgroups, and thus it appears likely that the gH-gL complex serves a highly conserved function during herpesvirus penetration into cells. To examine the role of gL in the infectious cycle of HSV-1, a mutant HSV-1 unable to express gL was constructed by inserting a lacZ gene cassette into the coding sequences of the UL1 (gL) gene. Because gL was found to be essential for virus replication, cell lines capable of expressing gL were constructed to complement the virus mutant. In the absence of gL, virus particles were produced, and these particles reached the cell surface; however, gL-negative particles purified from infected cells were also deficient in gH. Mutant virions lacking gH and gL were able to adsorb onto cells but were unable to enter cells and initiate an infection. Further, the role of gL in fusion of infected cells was reexamined. A mutation in HSV-1 (804) which produces the syncytial phenotype had previously been mapped to a region of the HSV-1 genome which includes the UL1 gene and no other open reading frame. However, in contrast to this previous report, we found that the syncytial mutation in 804 affects the UL53 gene, which encodes gK, a gene commonly mutated in syncytial viruses.
Polarization control of vertical-cavity surface-emitting lasers by a birefringent metal/semiconductor polarizer terminating a distributed Bragg reflector (2002)

We propose a polarization controlled vertical-cavity surface-emitting laser (VCSEL) using a birefringent metal/semiconductor polarizer on a distributed Bragg reflector. Theoretically, we found that the proposed concept can provide an extremely large polarization selectivity at the resonant cavity wavelength by adjusting the phase condition between two polarization states. Experimentally, we have demonstrated a 0.98 /spl mu/m InGaAs/GaAs VCSEL with an Au/GaAs polarizer exhibiting a fairly good polarization control and maintaining low thresholds.
Voltage-sensitive calcium channels in spinal nociceptive processing: blockade of N- and P-type channels inhibits formalin-induced nociception (1994)

The role of spinal voltage-sensitive calcium channels (VSCC) in a behavioral model of prolonged nociception was examined in rats. Blockade of VSCC by the trivalent cations neodymium (NdCl3) and lanthanum (LaCl3) resulted in a dose-dependent suppression of both phases of the response to formalin. omega-Conopeptides, which selectively block N-type VSCC, also produced a dose-dependent inhibition of both the initial behavior [phase 1; ED50 (nmol): SNX-111 (0.003) > SNX-185 (0.010) > SNX-239 (0.16) >> SNX-159 (> 0.26); SNX-199 (> 0.30)] and the facilitated response [phase 2; ED50 (nmol): SNX-111 (0.003) > SNX-185 (0.009) > SNX-239 (0.020) > SNX-159 (0.120) = SNX-199 (0.230)]. In contrast, SNX-231 (0.24 nmol), which is selective for a non-L/non-N site and also the L-type VSCC blockers nifedipine (24 nmol), nimodipine (29 nmol), verapamil (200 nmol), and diltiazem (220 nmol), had minimal effects on either phase of the formalin test at the highest dose examined. The P-type channel blocker omega-agatoxin IVA produced a 40% inhibition of phase 1 at the highest dose and phase 2 was suppressed in a dose-dependent fashion (ED50, 0.001 nmol). The response latency to a high-threshold thermal stimulus (the 52.5 degrees C hot plate) was moderately (20%) increased by NdCl3 (0.30 nmol) and SNX-111 (0.008 nmol), but not verapamil (200 nmol) and omega-agatoxin IVA (0.006 nmol). High doses of the N-type VSCC produced characteristic shaking behavior, serpentine-like tail movements, and impaired coordination. However, at antinociceptive doses there was no significant motor effect, though three of the N-type antagonists produced some tail movements. These studies demonstrate that VSCC of the N- and P-type, but not L-type, are involved in facilitated nociceptive processing at the spinal level.