gebhart/patrepeval huggingface dataset:
Crystal structure of Pseudomonas aeruginosa bacteriophytochrome: Photoconversion and signal transduction (2008)

Phytochromes are red-light photoreceptors that regulate light responses in plants, fungi, and bacteria via reversible photoconversion between red (Pr) and far-red (Pfr) light-absorbing states. Here we report the crystal structure at 2.9 A resolution of a bacteriophytochrome from Pseudomonas aeruginosa with an intact, fully photoactive photosensory core domain in its dark-adapted Pfr state. This structure reveals how unusual interdomain interactions, including a knot and an "arm" structure near the chromophore site, bring together the PAS (Per-ARNT-Sim), GAF (cGMP phosphodiesterase/adenyl cyclase/FhlA), and PHY (phytochrome) domains to achieve Pr/Pfr photoconversion. The PAS, GAF, and PHY domains have topologic elements in common and may have a single evolutionary origin. We identify key interactions that stabilize the chromophore in the Pfr state and provide structural and mutational evidence to support the essential role of the PHY domain in efficient Pr/Pfr photoconversion. We also identify a pair of conserved residues that may undergo concerted conformational changes during photoconversion. Modeling of the full-length bacteriophytochrome structure, including its output histidine kinase domain, suggests how local structural changes originating in the photosensory domain modulate interactions between long, cross-domain signaling helices at the dimer interface and are transmitted to the spatially distant effector domain, thereby regulating its histidine kinase activity.
Efficient gene therapy-based method for the delivery of therapeutics to primate cortex (2009)

Transduction of the primate cortex with adeno-associated virus (AAV)-based gene therapy vectors has been challenging, because of the large size of the cortex. We report that a single infusion of AAV2 vector into thalamus results in widespread expression of transgene in the cortex through transduction of widely dispersed thalamocortical projections. This finding has important implications for the treatment of certain genetic and neurodegenerative diseases.
Short-term cytotoxic effects and long-term instability of RNAi delivered using lentiviral vectors (2004)

Our data demonstrate a rapid cytotoxic effect of shRNAs expressed in human tumor cell lines. There appears to be a cut-off of 21 complementary nucleotides below which there is no interferon response while target gene silencing is maintained. Cytotoxicity or OAS1 induction could be reduced by changing shRNA sequence or vector titre, but stable gene silencing could not be maintained in extended cell culture despite persistent marker gene expression from the RNAi-inducing transgene cassette. These results underscore the necessity of careful controls for immediate and long-term RNAi use in mammalian cell systems.
Identification of an HLA-A*02 restricted immunogenic peptide derived from the cancer testis antigen HOM-MEL-40/SSX2. (2003)

HOM-MEL-40/SSX2 is a SEREX-defined cancer testis antigen with frequent expression in various human neoplasms. To search for HLA-A*0201 restricted peptides that induce HOM-MEL-40/SSX2-specific CD8+ responses in breast cancer patients, we used the SYFPEITHI algorithm to identify three HOM-MEL-40/SSX2-derived nonamers with high binding affinity for HLA-A*0201, which has a prevalence of 40% in the Caucasian population. Of the three peptides, p41-49 and p103-111 but not p167-175 had been shown to be processed by the proteasome. Only stimulation with p103-111 induced HOM-MEL-40-specific CTLs in 5/7 patients with HOM-MEL-40/SSX2 positive breast cancers and in 6/11 healthy controls. HLA-A*0201 restriction of p103-111 was demonstrated by blocking with specific antibodies. The natural processing and presentation of p103-111 was demonstrated by the recognition of the HOM-MEL-40/SSX2 positive cell line SK-MEL-37 and of COS7/A2 cells transfected with HOM-MEL-40/SSX2 by p103-111 specific CD8+ cells. No correlation was found between CD8+ T-cell responses against p103-111 and anti-HOM-MEL-40/SSX2 antibody titers in the serum of patients, suggesting that CD8+ and B-cell responses against HOM-MEL-40/SSX2 are regulated independently. p103-111 holds promise as a broadly applicable peptide vaccine for patients with HOM-MEL-40/SSX2 positive neoplasms.
Turing Award lecture on computational complexity and the nature of computer science (1994)

| n scientific work, the recognition by o n e ' s peers is one of the greatest rewards. In particular, an official recognition by the scientific community, as Richard Stearns a n d I are h o n o r e d by the 1993 ACM T u r i n g Award, is very satisfying a n d deeply appreciated. ~ Science is a great intellectual adventure a n d o n e o f h u m a n k i n d ' s greatest achievements. F u r t h e r m o r e , a research career can be an exciting, r e w a r d i n g a n d e n n o b l i n g activity, particularly so if o n e is f o r t u n a t e to participate in the c r e a t i o n o f a c o m p l e t e l y new a n d very i m p o r t a n t science, as m a n y scientists are. My r o a d to c o m p u t e r science was n o t a d i r e c t one. Actually it looks m o r e like a r a
Synthesis and Antitumor Cytotoxicity Evaluation of Novel Thiazole‐Containing Glycosylated Polyamides (2003)

Abstract Certain thiazole‐containing water‐soluble glycosylated polyamides were synthesized and preliminary anti‐cancer evaluation carried out by NCI against three types of cancer‐cells. Glycosyl moieties were introduced onto the polyamide backbone in order to increase the water‐solubility of the longer polymers. This necessitated the development of novel synthetic methods. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2003)
TRIPS Application Binary Interface (ABI) Manual (2005)

This document specifies the TRIPS Application Binary Interface (ABI) Manual for the TRIPS architecture, a novel, scalable, and low power architecture for future technologies.
Leukocyte adhesion molecule-1 (LAM-1, L-selectin) interacts with an inducible endothelial cell ligand to support leukocyte adhesion (1991)

The human lymphocyte homing receptor, LAM-1, mediates the adhesion of lymphocytes to specialized high endothelial venules (HEV) of peripheral lymph nodes. We now report that LAM-1 is also a major mediator of leukocyte attachment to activated human endothelium. In a novel adhesion assay, LAM-1 was shown to mediate approximately 50% of the adhesion of both lymphocytes and neutrophils to TNF-activated human umbilical vein endothelial cells at 4 degrees C. The contribution of LAM-1 to leukocyte adhesion was only detectable when the assays were carried out under rotating (nonstatic) conditions, suggesting that LAM-1 is involved in the initial attachment of leukocytes to endothelium. In this assay at 37 degrees C, essentially all lymphocyte attachment to endothelium was mediated by LAM-1, VLA-4/VCAM-1, and the CD11/CD18 complex, whereas neutrophil attachment was mediated by LAM-1, endothelial-leukocyte adhesion molecule-1, and CD11/CD18. Thus, multiple receptors are necessary to promote optimal leukocyte adhesion to endothelium. LAM-1 also appeared to be involved in optimal neutrophil transendothelial migration using a videomicroscopic in vitro transmigration model system. LAM-1-dependent leukocyte adhesion required the induction and surface expression of a neuraminidase-sensitive molecule that was expressed for at least 24 h on activated endothelium. Expression of the LAM-1 ligand by endothelium was optimally induced by LPS and the proinflammatory cytokines TNF-alpha and IL-1 beta, whereas IFN-gamma and IL-4 induced lower levels of expression. The LAM-1 ligand on HEV and cytokine treated endothelium may be similar carbohydrate-containing molecules, because phosphomannan monoester core complex from yeast Hansenula hostii cell wall blocked binding of lymphocytes to both cell types, and identical epitopes on LAM-1-mediated lymphocyte attachment to HEV and activated endothelium. Thus, LAM-1 and its inducible endothelial ligand constitute a new pair of adhesion molecules that may regulate initial leukocyte/endothelial interactions at sites of inflammation.
The Fate of Intravenously Administered bFGF and the Effect of Heparin (1989)

The fate and effects of intravascular bFGF are unknown. We have investigated the fate of bFGF administered intravenously to rats in the presence and absence of heparin, and evaluated the effect of a 3-day IV infusion of bFGF on proliferation of endothelial and vascular smooth muscle cells in situ. [125I]bFGF, administered as an IV bolus, was rapidly cleared from the circulation (t1/2 = 1.5 min) by the liver. Nevertheless, it was maintained at a constant, predictable concentration in the blood (9.7 +/- 4% of the amount infused) by continuous IV infusion. Heparin consistently altered the pattern: slowing the rate of clearance (t1/2 = 4.5 min), increasing the plateau concentration in the blood during continuous infusion (32.5 +/- 14.3% of the amount infused), and allowing intact (as determined by gel analysis) bFGF to cross from the circulation into the urine. A 3-day infusion of bFGF alone (2.5 ng/kg/min) and with adenosine (11.6 microM/kg/hr) did not increase [3H]thymidine incorporation in either endothelial cells or vascular smooth muscle cells, suggesting that they are refractory to this factor when it is administered intravascularly.
Fibrinogen degradation product fragment D induces endothelial cell detachment by activation of cell-mediated fibrinolysis. (1992)

We studied the effects of fibrinogen degradation product (FDP) fragment D on endothelial monolayer integrity and the mechanisms of fragment D-induced endothelial cell detachment from the substratum. Incubation of bovine pulmonary artery endothelial cells (BPAEC) with fragment D caused concentration- and time-dependent cell detachment from the substratum. The optimal response occurred at fragment D concentrations of 2 microM and required an incubation time of 24 h. BPAEC challenged with fragment D increased the concentration and activity of urokinase-type plasminogen activator (uPA) in the conditioned medium within 2 to 4 h of incubation. Fragment D also induced the release of tissue-type plasminogen activator, but to a lesser extent than uPA. Fragment D concurrently increased plasminogen activator (PA) activity in a concentration-dependent manner. Increased PA activity was followed by augmentation of cell-associated plasmin activity and subsequent increase in the degradation of 125I-fibrinogen and 125I-vitronectin precoated in the subendothelial matrix. Pretreatment of BPAEC with anti-uPA antibody, and inhibitors of uPA (dansyl-GGACK) and plasmin (aprotinin) prevented approximately 60% of the fragment D-induced endothelial cell detachment. We conclude that FDP fragment D increases secretion of endothelial PAs and enhances the generation of plasmin, thereby contributing to proteolysis of extracellular matrix and endothelial cell detachment. Fragment D may be a critical mediator linking activation of fibrinolysis to vascular endothelial injury in inflammatory disorders.
A Single Center Experience of GBT440 Treatment of Severe Anemia in Sickle Cell Disease (SCD) (2017)

A single center experience of GBT440 treatment of severe anemia in sickle cell disease (SCD) Authors Gershwin Blyden, Kenneth Bridges, Josh Lehrer, Lanetta Bronte. Academic Centers/ Institutions Foundation for Sickle Cell Disease Research, Hollywood FL Background GBT440 is an oral, once-daily therapy that modulates hemoglobin9s affinity for oxygen, thereby inhibiting HbS polymerization. Clinical trials assessing efficacy and safety in SCD are underway including a randomized Phase 3 study. Patients with SCD and severe anemia, i.e. Hb Methods Once-daily GBT440 began at 900 mg. Initial assessments at 2 and 4 weeks were followed by routine evaluations at least monthly. Table 2 shows the key tests. Baseline echocardiograms were performed. PHQ-9 assessment at each visit gauged depression and was accompanied by a simple 1-10 pain score index. All transfusions and hospitalizations were captured. Results Tables 1 and 2 summarize the patient clinical characteristics and laboratory data. In 5/7 patients, baseline Hb was 2 sat ≤ 90% (A, C, E) values rose to 98-99% and two (A,E) ceased chronic supplemental O 2 . Pts A and B have received GBT440 for more than 15 months. All patients experienced striking improvement in overall well-being and reduced fatigue, most often within 2 to 3 weeks of starting GBT440. In most, mood improved and depression lessened as assessed by PHQ-9. GBT440 was well-tolerated with no dose reductions or discontinuations at 900 mg. An increase to 1500 mg in Pt A caused grade 2 diarrhea which resolved with a return to 900 mg. No GBT440-related SAE occurred. Pt C died in the setting of ACS, unrelated to GBT440. Conclusion In these 7 SCD patients with severe anemia who were not eligible for the Phase 3 clinical program, GBT440 administered via the EAP substantially improved a variety of clinical, laboratory and PRO parameters. Controlled clinical trials will be needed to confirm the benefit of GBT440 in patients with severe anemia. Disclosures Bridges: Global Blood Therapeutics: Employment.
Exploring the Biology of Lipid Peroxidation-Derived Protein Carbonylation (2011)

The sustained overproduction of reactive oxygen and nitrogen species results in an imbalance of cellular prooxidant-antioxidant systems and is implicated in numerous disease states, including alcoholic liver disease, cancer, neurological disorders, inflammation, and cardiovascular disease. The accumulation of reactive aldehydes resulting from sustained oxidative stress and lipid peroxidation is an underlying factor in the development of these pathologies. Determining the biochemical factors that elicit cellular responses resulting from protein carbonylation remains a key element to developing therapeutic approaches and ameliorating disease pathologies. This review details our current understanding of the generation of reactive aldehydes via lipid peroxidation resulting in protein carbonylation, focusing on pathophysiologic factors associated with 4-hydroxynonenal-protein modification. Additionally, an overview of in vitro and in vivo model systems used to study the physiologic impact of protein carbonylation is presented. Finally, an update of the methods commonly used in characterizing protein modification by reactive aldehydes provides an overview of isolation techniques, mass spectrometry, and computational biology. It is apparent that research in this area employing state-of-the-art proteomics, mass spectrometry, and computational biology is rapidly evolving, yielding foundational knowledge concerning the molecular mechanisms of protein carbonylation and its relation to a spectrum of diseases associated with oxidative stress.
Expression and Functional Characterization of an Abnormal Platelet Membrane Glycoprotein Ibα (Met239 → Val) Reported in Patients With Platelet-Type von Willebrand Disease (1997)

Platelet-type von Willebrand disease (vWD) is a congenital bleeding disorder characterized by heightened ristocetin-induced platelet aggregation caused by abnormally high affinity between the platelet membrane glycoprotein (GP) Ib/IX complex and von Willebrand factor (vWF ). Two distinct point mutations, Gly233 to Val and Met239 to Val, have been reported in GPIbα. We have constructed a recombinant GPIbα fragment containing the latter mutation, Met239 to Val (M239V) and characterized the mutant molecule using two methods, ie, interaction between soluble vWF and immobilized M239V and inhibition of platelet aggregation by purified soluble M239V. Spontaneous binding (ie, binding without any inducers) was observed between 125I-vWF and immobilized M239V but not between 125I-vWF and immobilized wild-type (WT) GPIbα. The addition of low concentrations of ristocetin (0.2 mg/mL) induced specific 125I-vWF binding to immobilized M239V, but not to WT GPIbα. At high concentrations of ristocetin (1.2 mg/mL), both WT GPIbα and M239V specifically bound to 125I-vWF. Thus, M239V reproduced the unique functional abnormality of the GPIb/IX complex in platelet-type vWD. Moreover, the purified soluble M239V inhibited platelet aggregation induced by low concentration of ristocetin (0.3 mg/mL) in platelet-rich plasma from a patient having Met239 to Val mutation, whereas purified WT did not. These results provide direct evidences that the reported point mutation is the responsible molecular basis of this disorder.
Biological and biochemical characterization of Fusobacterium necrophorum leukotoxin (1994)

Biological and biochemical characteristics of the leukotoxin of Fusobacterium necrophorum were determined. Culture supernatant of F necrophorum was toxic to polymorphonuclear neutrophilic leukocytes from cattle and sheep, but not to those from pigs and rabbits. Culture supernatant and sonicated bacterial cell fractions had low hemolytic activity and did not cause dermonecrosis in a guinea pig. Supernatant-derived leukotoxin was inactivated at 56 C for 5 minutes and became unstable at pH > 7.8 or < 6.6. Chemical treatment with 0.1% sodium dodecyl sulfate, 0.25% sodium deoxycholate, 5.2% sodium sulfide, or 0.25 mM titanium (III) citrate markedly decreased leukotoxicity. Enzymatic treatment with protease, trypsin, and chymotrypsin inactivated the toxin completely, whereas amylase had no effect. Use of protease inhibitors failed to prevent loss of leukotoxin activity. Using membrane partition chromatography and gel filtration, the estimated molecular weight of the toxin was > 300,000. On reduction and denaturation, the toxin dissociated into several components by use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
A diagnostic test for heparin-induced thrombocytopenia (1986)

Heparin-induced thrombocytopenia can be a serious and difficult-to-diagnose complication of heparin therapy. Serum from patients with heparin-induced thrombocytopenia can cause heparin-dependent platelet aggregation, but the low sensitivity and specificity of this test limit its clinical usefulness. In this report we describe an assay for heparin-induced thrombocytopenia that is both sensitive and specific. The improvement in the assay was accomplished by measuring platelet release instead of aggregation and by measuring platelet release at two heparin concentrations. The rationale for the use of two heparin concentrations was that sera from patients with heparin-induced thrombocytopenia caused release at therapeutic but not at high concentrations of heparin. Twenty-eight sera samples from patients suspected of having heparin-induced thrombocytopenia and 573 controls were coded and tested in the assay. The patients with possible heparin-induced thrombocytopenia were ranked according to the likelihood of having this disorder by using prospectively defined criteria. The test had a high specificity (99%); only one of 573 controls showed a positive result. The test was also very sensitive, and the likelihood of a positive test result was directly correlated with the clinical likelihood of the patient having heparin-induced thrombocytopenia. Six of six patients with definitive heparin-induced thrombocytopenia had positive test results, whereas zero of four patients in whom the diagnosis was unlikely had positive test results. The two-point test for heparin-induced thrombocytopenia represents a sensitive and specific test for this disorder. This test may be useful not only in confirming the diagnosis of this disorder but also may provide information about its pathogenesis.
Cellular Heterogeneity and Molecular Evolution in Cancer (2012)

Intratumor heterogeneity represents a major obstacle to effective cancer treatment and personalized medicine. However, investigators are now elucidating intratumor heterogeneity at the single-cell level due to improvements in technologies. Better understanding of the composition of tumors, and monitoring changes in cell populations during disease progression and treatment, will improve cancer diagnosis and therapeutic design. Measurements of intratumor heterogeneity may also be used as biomarkers to predict the risk of progression and therapeutic resistance. We summarize important considerations related to intratumor heterogeneity during tumor evolution. We also discuss experimental approaches that are commonly used to infer intratumor heterogeneity and describe how these methodologies can be translated into clinical practice.
Multicenter Study Assessing Effects of Heat and Moisture Exchanger Use on Respiratory Symptoms and Voice Quality in Laryngectomized Individuals (2003)

The observed decrease in pulmonary symptoms and improvement in voice quality confirm earlier reports from the Netherlands, United Kingdom, and Spain indicating improvement in postlaryngectomy quality of life.
Effect of Molecule−Molecule Interaction on the Electronic Properties of Molecularly Modified Si/SiOxSurfaces (2003)

We use the adsorption of systematically substituted silanes with either simple alkyl or alkyl phenyl ether chains onto oxidized Si to study the electronic effects of such molecular monolayers on Si. While there is no significant effect of distance of the substituents from the surface, a strong effect of what we interpret as depolarization is found for layers made up of molecules with high (>5 D) free molecule dipole moment. This is also apparent from differences in UV−visible and Fourier transform infrared (FTIR) spectral features, suggesting changes in molecular conformation, and, especially, from the measured contact potential differences. These reflect the modified surface's electron affinity and, thus, the effective dipole moment of the monolayer. The effect is ascribed to the system's response to the energetic price of dipole−dipole repulsion.
특집 : 남북관계와 비대칭적 분단국체제론 (2009)

이 논문의 목적은 남북기본합의서에서 ``잠정적 특수관계``로 정의된 바 있는 남북관계에 대한 새로운 개념화를 시도하는 것이다. 기본합의서 체결 당시의 특수성론은 탈냉전기 민족공동체와 국가공동체의 불일치를 일정하게 수용하는 현실논리에 바탕을 두고 있다. 하지만 1990년 이래 진행된 한반도 안팎의 변화를 고려할 때 사회적 차원의 변화를 주목할 필요가 있다. 다시 말해 남북관계의 특수성은 민족/국가의 2원 모델로는 현 남북관계의 특수성을 제대로 포착하기 어렵고 민족/국가/사회의 3원 모델로 이해되어야 한다. 남북관계를 구성하는 주체는 민족적 차원과 정치적 차원, 그리고 사회적 차원을 함께 고려해야 한다. 민간부문 내지 시민사회로 지칭되는 영역의 중요성을 정부간 관계와 함께 설명할 필요가 커지고 있다. 남북관계의 성격도 정치적 적대성과 민족적 포용성 못지않게 사회적 다양성과 비대칭성을 포괄적으로 고려해야 제대로 설명가능하다. 남북관계의 시간성에 대해서도 잠정성과 영속성 못지 않게 구성되고 형성되는 자발적 관계성을 주목할 필요가 있다. 이런 측면들을 적절히 반영하기 위해서는 비대칭적 분단국체제라는 개념이 유용하다는 것이 이 논문의 주장이다. 남북한은 서로 통일을 지향하면서도 60년간 지속된 각각의 국가성을 보유한 채 유엔에 별개로 속해있는 독특한 주체라는 점, 정전협정에 의해 규율되는 일정한 체제적 속성을 지녔다는 점, 그리고 무엇보다도 사회경제적 차원에서 매우 큰 비대칭성을 지닌 관계라는 점을 보여줄 수 있는 개념이기 때문이다.
Antigenic Diversity of GranulocyticEhrlichiaIsolates from Humans in Wisconsin and New York and a Horse in California (1997)

The agent of human granulocytic ehrlichiosis (HGE), Ehrlichia phagocytophila, and Ehrlichia equi are very similar. HGE is of variable severity. Genetic and antigenic differences among 3 human isolates (Webster, Spooner, and NY-8) and 1 horse isolate (MRK) were evaluated. The 16S rRNA gene sequences were identical in all human isolates. By use of 5 homologous antisera from these 3 humans and 1 horse and an additional 5 antisera in heterologous reactions, the immunodominant antigens of each isolate were noted to differ in molecular size: 43 kDa in the Webster (Wisconsin) isolate, 46 kDa in the Spooner (Wisconsin) isolate, 42 and 45 kDa in the NY-8 (New York State) isolate, and a 42 kDa doublet in the E. equi MRK isolate from California. Two sera from a Wisconsin patient reacted weakly or not at all with the NY-8 isolate. Antigenic structural diversity exists among otherwise indistinguishable granulocytic ehrlichial isolates.