gebhart/patrepeval huggingface dataset:
Free-energy cost for translocon-assisted insertion of membrane proteins (2011)

Nascent membrane proteins typically insert in a sequential fashion into the membrane via a protein-conducting channel, the Sec translocon. How this process occurs is still unclear, although a thermodynamic partitioning between the channel and the membrane environment has been proposed. Experiment- and simulation-based scales for the insertion free energy of various amino acids are, however, at variance, the former appearing to lie in a narrower range than the latter. Membrane insertion of arginine, for instance, requires 14-17 kcal/mol according to molecular dynamics simulations, but only 2-3 kcal/mol according to experiment. We suggest that this disagreement is resolved by assuming a two-stage insertion process wherein the first step, the insertion into the translocon, is energized by protein synthesis and, therefore, has an effectively zero free-energy cost; the second step, the insertion into the membrane, invokes the translocon as an intermediary between the fully hydrated and the fully inserted locations. Using free-energy perturbation calculations, the effective transfer free energies from the translocon to the membrane have been determined for both arginine and leucine amino acids carried by a background polyleucine helix. Indeed, the insertion penalty for arginine as well as the insertion gain for leucine from the translocon to the membrane is found to be significantly reduced compared to direct insertion from water, resulting in the same compression as observed in the experiment-based scale.
Chemical approaches to the discovery of new drugs. (1991)

The increased understanding of biological phenomena on a molecular level has made it possible to develop powerful approaches to the discovery of new drugs. Once a molecular hypothesis can be derived from the biochemistry, pharmacology, or physiology of the disease, a chemical strategy can be evolved to identify compounds that will serve as leads to new drugs. Several approaches are available and may be used individually or combined to solve a problem. Ideas can be generated from the structures of known biologically active compounds, from mechanistic studies of reactions catalysed by enzymes, or from molecular modelling of intermolecular interactions using advanced computer technology. All of these approaches require substantial inputs from organic (principally synthetic), physical, and theoretical chemists together with the biological contribution in the assay and evaluation of compounds. This article outlines some of the principles involved in the search for new drugs today discovery from the chemical point of view and illustrates the discussion with many examples of commercial drugs and compounds currently under development.
Enhanced transformation by a simian virus 40 recombinant virus containing a Harvey murine sarcoma virus long terminal repeat. (1983)

We have constructed a recombinant simian virus 40 (SV40) DNA containing a copy of the Harvey murine sarcoma virus long terminal repeat (LTR). This recombinant viral DNA was converted into an infectious SV40 virus particle and subsequently infected into NIH 3T3 cells (either uninfected or previously infected with Moloney leukemia virus). We found that this hybrid virus, SVLTR1, transforms cells with 10 to 20 times the efficiency of SV40 wild type. Southern blot analysis of these transformed cell genomic DNAs revealed that simple integration of the viral DNA within the retrovirus LTR cannot account for the enhanced transformation of the recombinant virus. A restriction fragment derived from the SVLTR-1 virus which contains an intact LTR was readily identified in a majority of the transformed cell DNAs. These results suggest that the LTR fragment which contains the attachment sites and flanking sequences for the proviral DNA duplex may be insufficient by itself to facilitate correct retrovirus integration and that some other functional element of the LTR is responsible for the increased transformation potential of this virus. We have found that a complete copy of the Harvey murine sarcoma virus LTR linked to well-defined structural genes lacking their own promoters (SV40 early region, thymidine kinase, and G418 resistance) can be effectively used to promote marker gene expression. To determine which element of the LTR served to enhance the biological activity of the recombinant virus described above, we deleted DNA sequences essential for promoter activity within the LTR. SV40 virus stocks reconstructed with this mutated copy of the Harvey murine sarcoma virus LTR still transform mouse cells at an enhanced frequency. We speculate that when the LTR is placed more than 1.5 kilobases from the SV40 early promoter, the cis-acting enhancer element within the LTR can increase the ability of the SV40 promoter to effectively operate when integrated in a murine chromosome. These data are discussed in terms of the apparent cell specificity of viral enhancer elements.
Light-Induced Modulation of Self-Assembly on Spiropyran-Capped Gold Nanoparticles:  A Potential System for the Controlled Release of Amino Acid Derivatives (2003)

A photoswitchable double-shell structure on Au nanoparticles, consisting of photochromic spiropyran as the first shell, which regulates the assembly and release of an outer shell of amino acid derivatives upon irradiation, is being reported for the first time. The light-regulated changes in the topographic properties of spiropyran-capped Au nanoparticles (i.e., interconversion between the zwitterionic and neutral forms) are exploited for the assembly and release of amino acid-based therapeutic agents such as l-DOPA.
Human Osteoclasts and Osteoclast-Like Cells Synthesize and Release High Basal and Inflammatory Stimulated Levels of the Potent Chemokine Interleukin-8 (1998)

Chemokines, including interleukin-8 (IL-8), function as key mediators in diverse inflammatory disorders via promoting the recruitment, proliferation, and activation of vascular and immune cells. IL-8 levels are elevated in inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, osteomyelitis, and periodontal disease, that also exhibit progressive bone loss. Therefore, it is possible that IL-8 contributes to the osteopenia associated with these pathological conditions. Although macrophages, neutrophils, and endothelial cells are considered the primary sources of inflammation-induced IL-8 increases, we report here for the first time that human bone marrow-derived osteoclast-like cells (hOCL) as well as authentic bone-resorbing human osteoclasts (hOC) isolated from osteoporotic femoral heads express messenger RNA (mRNA) for IL-8 and secrete high levels of IL-8 during culture. Basal IL-8 release by cultured hOC or hOCL was orders of magnitude greater than the release of the proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor-α. At a cellular level, in situ hybridization analysis revealed that IL-8 mRNA was expressed in resorbing hOC of rheumatoid arthritic pannus and was substantially greater than that expressed in hOC of noninflammatory giant cell tumor of bone tissue. Therefore, the potential inflammation-mediated induction of IL-8 was directly assessed using cultured hOCL. IL-8 release was stimulated by proinflammatory signals (IL-1α, tumor necrosis factor-α, lipopolysaccharide, or phorbol 12-myristate 13-acetate), unaffected by various other osteotropic modulators (transforming growth factor-β1 and -β3, IL-6, 17β-estradiol, or calcitonin) and was decreased by interferon-γ, vitamin D3, and the antiinflammatory glucocorticoid dexamethasone. Changes in IL-8 secretion were paralleled by corresponding changes in IL-8 mRNA steady state levels. We conclude that hOC and hOCL synthesize and secrete high constitutive and inflammation-stimulated levels of the chemokine IL-8. Consequently, hOC-derived IL-8 could act as an important regulatory signal for bone, vascular, and immune cell recruitment and activation during normal and pathological bone remodeling.
Nucleic acid dendrimers: novel biopolymer structures (1993)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNucleic acid dendrimers: novel biopolymer structuresRobert H. E. Hudson and Masad J. DamhaCite this: J. Am. Chem. Soc. 1993, 115, 6, 2119–2124Publication Date (Print):March 1, 1993Publication History Published online1 May 2002Published inissue 1 March 1993https://pubs.acs.org/doi/10.1021/ja00059a004https://doi.org/10.1021/ja00059a004research-articleACS PublicationsRequest reuse permissionsArticle Views560Altmetric-Citations126LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts
PureMD: a Computerized Patient Record software for direct data entry by physicians using a keyboard-free pen-based portable computer. (1992)

This paper describes the data acquisition features of the PureMD Computerized Patient Record (CPR) software designed specifically for physicians. The physician uses a stylus to point, draw and handwrite on a Dynamic Dialog Interface that provides the same flexibility as the paper record and numerous other advantages. The clinical data thus entered is highly organized, easily legible and retrievable in many ways. The underlying Medical Knowledge Base (MKB) was optimized for rapid, intuitive and consistent data entry and automatic coding with minimum handwriting.
30-fs pulses tunable across the visible with a 100-kHz Ti:sapphire regenerative amplifier (1995)

A 100-kHz mode-locked Ti:sapphire-seeded regenerative amplifier pumping an optical parametric amplifier generates femtosecond pulses tunable from 470 to 710 nm. This output was compressed with a pair of prisms to bandwidth-limited pulses of 80- to 40-fs duration and more than 150 nJ of energy. These tunable pulses were then bandwidth expanded through self-phase modulation in bulk material and further compressed to less than 30-fs duration.
Steel factor induces serine phosphorylation of Stat3 in human growth factor-dependent myeloid cell lines (1996)

Steel factor (SLF) acts synergistically with various hematopoietic growth factors that use the Jak-Stat pathways in vivo and in vitro, although the contribution by SLF to this pathway is unknown. We show here that SLF induces time- and dose-dependent phosphorylation of Stat3 in the human growth factor-dependent cell lines MO7e and TF-1. This phosphorylation occurs exclusively on serine residues. Simultaneous stimulation with SLF plus other cytokines that induce tyrosine phosphorylation of Stat3, such as interleukin-9 (IL-9) in MO7e cells or IL-6 in TF-1 cells, resulted in tyrosine phosphorylation and enhanced serine phosphorylation of Stat3. Serine phosphorylation alone did not promote nuclear translocation or DNA binding activity to the sis-inducible element of Stat3. However, costimulation with SLF plus IL-9 in MO7e cells resulted in the nuclear translocation of serine-hyperphosphorylated Stat3. Serine phosphorylation of Stat3 was also observed by the stimulation of cells with granulocyte-macrophage colony-stimulating factor and IL-3, which do not induce tyrosine phosphorylation of Stat3. These results suggest that SLF might modulate the Jak-Stat3 pathway by serine phosphorylation and that the Jak-Stat pathway may be differentially regulated by the combinational stimulation of two or more cytokines.
The re-growth of growth hormone in fertility treatment: a critical review (2012)

Several clinical studies have recently been published documenting the possible role of adjuvant growth hormone treatment in in vitro fertilization. These studies have been performed on different groups of patients including poor ovarian responders, patients with polycystic ovary syndrome and with hypogonadotrophic-hypogonadism. The aim of this review is to examine relevant studies in the last 25 years, on the use of growth hormone in assisted conception and trace the train of events that has lead to the resurgence of interest in this subject.
Mouse Tumor Vasculature Expresses NKG2D Ligands and Can Be Targeted by Chimeric NKG2D-Modified T Cells (2013)

Tumor angiogenesis plays an important role in the development of solid tumors, and targeting the tumor vasculature has emerged as a strategy to prevent growth and progression of solid tumors. In this study, we show that murine tumor vasculature expresses Rae1, a ligand for a stimulatory NK receptor NKG2D. By genetic modification of T cells with an NKG2D-based chimeric Ag receptor, referred to as chNKG2D in which the NKG2D receptor is fused to the signaling domain of CD3ζ-chain, T cells were capable of targeting tumor vasculature leading to reduced tumor angiogenesis and tumor growth. This occurred even in tumors where the tumor cells themselves did not express NKG2D ligands. H5V, an endothelial cell line, expresses Rae1 and was lysed by chNKG2D-bearing T cells in a perforin-dependent manner. In vitro capillary tube formation was inhibited by chNKG2D T cells through IFN-γ and cell-cell contact mechanisms. The in vivo antiangiogenesis effects mediated by chNKG2D-bearing T cells at the tumor site were dependent on IFN-γ and perforin. These results provide a novel mechanism for NKG2D-based targeting of solid tumors.
Temporal Changes in Myeloid Cells in the Cervix during Pregnancy and Parturition (2009)

Preterm birth occurs at a rate of 12.7% in the U.S. and is the primary cause of fetal morbidity in the first year of life as well as the cause of later health problems. Elucidation of mechanisms controlling cervical remodeling is critical for development of therapies to reduce the incidence of prematurity. The cervical extracellular matrix must be disorganized during labor to allow birth, followed by a rapid repair postpartum. Leukocytes infiltrate the cervix before and after birth and are proposed to regulate matrix remodeling during cervical ripening via release of proteolytic enzymes. In the current study, flow cytometry and cell sorting were used to determine the role of immune cells in cervical matrix remodeling before, during, and after parturition. Markers of myeloid cell differentiation and activation were assessed to define phenotype and function. Tissue monocytes and eosinophils increased in the cervix before birth in a progesterone-regulated fashion, whereas macrophage numbers were unchanged. Neutrophils increased in the postpartum period. Increased mRNA expression of Csfr1 and markers of alternatively activated M2 macrophages during labor or shortly postpartum suggest a function of M2 macrophages in postpartum tissue repair. Changes in cervical myeloid cell numbers are not reflected in the peripheral blood. These data along with our previous studies suggest that myeloid-derived cells do not orchestrate processes required for initiation of cervical ripening before birth. Additionally, macrophages with diverse phenotypes (M1 and M2) are present in the cervix and are most likely involved in the postpartum repair of tissue.
Performance of optical flow techniques (2003)

The performance of six optical flow techniques is compared, emphasizing measurement accuracy. The most accurate methods are found to be the local differential approaches, where nu is computed explicitly in terms of a locally constant or linear model. Techniques using global smoothness constraints appear to produce visually attractive flow fields, but in general seem to be accurate enough for qualitative use only and insufficient as precursors to the computations of egomotion and 3D structures. It is found that some form of confidence measure/threshold is crucial for all techniques in order to separate the inaccurate from the accurate. Drawbacks of the six techniques are discussed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Respiratory Syncytial Virus Infection in Adults (2000)

Respiratory syncytial virus (RSV) is now recognized as a significant problem in certain adult populations. These include the elderly, persons with cardiopulmonary diseases, and immunocompromised hosts. Epidemiological evidence indicates that the impact of RSV in older adults may be similar to that of nonpandemic influenza. In addition, RSV has been found to cause 2 to 5% of adult community-acquired pneumonias. Attack rates in nursing homes are approximately 5 to 10% per year, with significant rates of pneumonia (10 to 20%) and death (2 to 5%). Clinical features may be difficult to distinguish from those of influenza but include nasal congestion, cough, wheezing, and low-grade fever. Bone marrow transplant patients prior to marrow engraftment are at highest risk for pneumonia and death. Diagnosis of RSV infection in adults is difficult because viral culture and antigen detection are insensitive, presumably due to low viral titers in nasal secretions, but early bronchoscopy is valuable in immunosuppressed patients. Treatment of RSV in the elderly is largely supportive, whereas early therapy with ribavirin and intravenous gamma globulin is associated with improved survival in immunocompromised persons. An effective RSV vaccine has not yet been developed, and thus prevention of RSV infection is limited to standard infection control practices such as hand washing and the use of gowns and gloves.
Precise Orbit Determination of Low Earth Orbiters with GPS Point Positioning (2001)

Precise orbit determination (POD) of low earth orbiters (LEOs) with GPS is becoming a standard practice in the space science community. The need for such information has been growing rapidly due to such scientific applications as radio occultation and ever increasing demands from engineering applications such as space based earth sensor positioning. The conventional GPS based POD strategies rely on data from a network of terrestrial GPS receivers as well as the spaceborne receiver. A complex, lengthy estimation procedure is carried out integrating the GPS data with h igh-fidelity dynamic models for the LEO. These strategies rely greatly on the GPS measurement strength, especially for low altitude spacecraft. A completely geometric approach based on a kinematic, sequential least-squares filter/smoother has been devised
Specific inhibition of ADP‐induced platelet aggregation by clopidogrel in vitro (1999)

1. The thienopyridine clopidogrel is a specific inhibitor of ADP-induced platelet aggregation ex vivo. No direct effects of clopidogrel (< or = 100 microM) on platelet aggregation in vitro have been described so far. 2. Possible in vitro antiaggregatory effects (turbidimetry) of clopidogrel were studied in human platelet-rich plasma and in washed platelets. 3. Incubation of platelet-rich plasma with clopidogrel (< or = 100 microM) for up to 8 h did not result in any inhibition of ADP (6 microM)-induced platelet aggregation. 4. Incubation of washed platelets with clopidogrel resulted in a time- (maximum effects after 30 min) and concentration-dependent (IC50 1.9+/-0.3 microM) inhibition of ADP (6 microM)-induced platelet aggregation. Clopidogrel (30 microM) did not inhibit collagen (2.5 microg ml(-1))-, U46619 (1 microM)- or thrombin (0.1 u ml(-1))-induced platelet aggregation. The inhibition of ADP-induced aggregation by clopidogrel (30 microM) was insurmountable indicating a non-equilibrium antagonism of ADP actions. The R enantiomer SR 25989 C (30 microM) was significantly less active than clopidogrel (30 microM) in inhibiting platelet aggregation (32+/-5% vs 70+/-1% inhibition, P < 0.05, n = 5). 5. In washed platelets, clopidogrel (< or = 30 microM) did not significantly reverse the inhibition of prostaglandin E1 (1 microM)-induced platelet cyclic AMP formation by ADP (6 microM). 6. The antiaggregatory effects of clopidogrel were unchanged when the compound was removed from the platelet suspension. However, platelet inhibition by clopidogrel was completely abolished when albumin (350 mg ml(-1)) was present in the test buffer. 7. It is concluded that clopidogrel specifically inhibits ADP-induced aggregation of washed platelets in vitro without hepatic bioactivation. Inhibition of ADP-induced platelet aggregation by clopidogrel in vitro occurs in the absence of measurable effects on the reversal of PGE1-stimulated cyclic AMP by ADP.
Modeling of Hydraulic Fracture Network Propagation in a Naturally Fractured Formation (2011)

Abstract Hydraulic fracturing in shale gas reservoirs has often resulted in complex fracture network growth, as evidenced by microseismic monitoring. The nature and degree of fracture complexity must be clearly understood to optimize stimulation design and completion strategy. Unfortunately, the existing single planar fracture models used in the industry today are not able to simulate complex fracture networks. A new hydraulic fracture model is developed to simulate complex fracture network propagation in a formation with preexisting natural fractures. The model solves a system of equations governing fracture deformation, height growth, fluid flow, and proppant transport in a complex fracture network with multiple propagating fracture tips. The interaction between a hydraulic fracture and pre-existing natural fractures is taken into account by using an analytical crossing model and is validated against experimental data. The model is able to predict whether a hydraulic fracture front crosses or is arrested by a natural fracture it encounters, which leads to complexity. It also considers the mechanical interaction among the adjacent fractures (i.e., the "stress shadow" effect). An efficient numerical scheme is used in the model so it can simulate the complex problem in a relatively short computation time to allow for day-to-day engineering design use. Simulation results from the new complex fracture model show that stress anisotropy, natural fractures, and interfacial friction play critical roles in creating fracture network complexity. Decreasing stress anisotropy or interfacial friction can change the induced fracture geometry from a bi-wing fracture to a complex fracture network for the same initial natural fractures. The results presented illustrate the importance of rock fabrics and stresses on fracture complexity in unconventional reservoirs. They have major implications on matching microseismic observations and improving fracture stimulation design.
Stochastic Detection of Enantiomers (2006)

The rapid quantification of the enantiomers of small chiral molecules is very important, notably in pharmacology. Here, we show that the enantiomers of drug molecules can be distinguished by stochastic sensing, a single-molecule detection technique. The sensing element is an engineered alpha-hemolysin protein pore, fitted with a beta-cyclodextrin adapter. By using the approach, the enantiomeric composition of samples of ibuprofen and thalidomide can be determined in less than 1 s.