gebhart/patrepeval huggingface dataset:
Nuclear Magnetic Resonance Structure of a Prototype Lin12-Notch Repeat Module from Human Notch1 (2003)

Notch1 is a member of a conserved family of large modular heterodimeric type 1 transmembrane receptors that control differentiation in multicellular animals. Receptor maturation is accompanied by a furin-dependent cleavage that converts the Notch1 precursor polypeptide into a heterodimer consisting of an extracellular ligand-binding subunit (NEC) and a transmembrane signaling subunit (NTM). Binding of a physiologic ligand to NEC induces signaling by triggering additional proteolytic cleavages in NTM, which allow its intracellular region to translocate to the nucleus where it participates in a transcriptional activation complex. In the absence of ligand, the three conserved LNR modules of the NEC subunit participate in maintaining the receptor in its resting conformation. Here, we report the solution structure of the first LNR module (LNR_A) of human Notch1, and identify residues of LNR_A perturbed by the presence of the adjacent module LNR_B. LNR_A is held together by a unique arrangement of three disulfide bonds and a single bound Ca(2+) ion, and adopts a novel fold that falls in the general class of irregular disulfide-bonded structures. Residues perturbed by the presence of the adjacent LNR_B module are predominantly hydrophobic, and lie on one face of the module. These studies represent an initial step toward understanding the structural interrelationships among the three contiguous LNR modules required for proper regulation of Notch signaling.
Intratumoral Approaches for the Treatment of Melanoma (2017)

There have been significant advances in the immunotherapy of melanoma over the last decade. The tumor microenvironment is now known to promote an immune-suppressive milieu that can block effective immune-mediated tumor rejection. Several novel strategies designed to overcome local immunosuppression hold promise for treatment of melanoma and other cancers. These approaches include oncolytic viruses, plasmid DNA delivery, Toll-like receptor agonists, inflammatory dyes, cytokines, checkpoint inhibitors, immunomodulatory agents, and host and pathogenic cell-based vectors. In addition, there are several novel methods for local drug delivery, including direct injection, image-guided, electroporation, and nanodelivery techniques under study. The approval of talimogene laherparepvec (Imlygic), an attenuated, recombinant oncolytic herpesvirus, for melanoma treatment is the first intratumoral agent to receive regulatory approval for the treatment of patients with melanoma. This review will focus on the rationale for intratumoral treatment in melanoma, describe the clinical and safety data for some of the agents in clinical development, and provide a perspective for future clinical investigation with intratumoral approaches. Melanoma has been a paradigm tumor for progress in targeted therapy and immunotherapy and will likely also be the tumor to establish the therapeutic role of intratumoral treatment for cancer.
Surface Plasmon Resonance Biosensor for Rapid Label-Free Detection of Microribonucleic Acid at Subfemtomole Level (2010)

Microribonucleic acids (miRNAs) have been linked with various regulatory functions and disorders, such as cancers and heart diseases. They, therefore, present an important target for detection technologies for future medical diagnostics. We report here a novel method for rapid and sensitive miRNA detection and quantitation using surface plasmon resonance (SPR) sensor technology and a DNA*RNA antibody-based assay. The approach takes advantage of a novel high-performance portable SPR sensor instrument for spectroscopy of surface plasmons based on a special diffraction grating called a surface plasmon coupler and disperser (SPRCD). The surface of the grating is functionalized with thiolated DNA oligonucleotides which specifically capture miRNA from a liquid sample without amplification. Subsequently, an antibody that recognizes DNA*RNA hybrids is introduced to bind to the DNA*RNA complex and enhance sensor response to the captured miRNA. This approach allows detection of miRNA in less than 30 min at concentrations down to 2 pM with an absolute amount at high attomoles. The methodology is evaluated for analysis of miRNA from mouse liver tissues and is found to yield results which agree well with those provided by the quantitative polymerase chain reaction (qPCR).
Hyperlipidemia in Concert With Hyperglycemia Stimulates the Proliferation of Macrophages in Atherosclerotic Lesions (2004)

Hyperglycemia and hyperlipidemia are important risk factors for diabetes-accelerated atherosclerosis. Macrophage proliferation has been implicated in the progression of atherosclerosis. We therefore investigated the effects of hyperglycemia and hyperlipidemia on macrophage proliferation in murine atherosclerotic lesions and isolated primary macrophages. Hyperglycemic LDL receptor-deficient mice that were fed a cholesterol-free diet for 12 weeks did not have elevated cholesterol levels compared with nondiabetic mice, and there was no evidence of increased macrophage proliferation in atherosclerotic lesions. Moreover, elevated glucose levels did not increase proliferation of isolated mouse peritoneal macrophages. In contrast, hyperglycemic LDL receptor-deficient mice that were fed a cholesterol-rich diet showed increased cholesterol levels concomitant with macrophage proliferation in atherosclerotic lesions. Glucose promoted lipid and protein oxidation of LDL in vitro. Glucose-oxidized LDL resulted in phosphorylation of extracellular signal-regulated kinase and protein kinase B/Akt and stimulated proliferation of isolated macrophages. The mitogenic effect of glucose-oxidized LDL was mediated by CD36 and by extracellular signal-regulated kinase activation induced by protein kinase C-dependent and phosphatidylinositol 3-kinase-dependent pathways. Thus, hyperglycemia is not sufficient to stimulate macrophage proliferation in lesions of atherosclerosis or in isolated macrophages. A combination of hyperglycemia and hyperlipidemia, however, stimulates macrophage proliferation by a pathway that may involve the glucose-dependent oxidation of LDL.
The Regulation of Isoleucine‐Valine Biosynthesis in Saccharomyces cerevisiae (1968)

Acetohydroxyacid synthetase activity has been characterized, independently of the acetoin‐forming system in Saccharomyces cerevisiae by a differential colorimetric assay. Maximum pH and K m values have been established for both enzymes with pyruvate as the substrate. Acetolactate formation by acetohydroxyacid synthetase has been shown directly by the separation of dinitrophenylosazones by thin‐layer chromatography. Evidence for the biosynthetic role of the activity measured resides in its presence in wild‐type strains, in its absence in the is 2 class of mutants (isoleucine‐valine auxotrophs) and in its reappearance in prototrophic revertants of these mutants.
Nucleocytoplasmic shuttling of phospholipase C‐δ1: A link to Ca2+ (2005)

Phosphoinositides (PIs) and proteins involved in the PI signaling pathway are distributed in the nucleus as well as at the plasma membrane and in the cytoplasm, although their nuclear localization mechanisms have not been clarified in detail. Generally, proteins that shuttle between the cytoplasm and nucleus contain nuclear localization signal (NLS) and nuclear export signal (NES) sequences for nuclear import and export, respectively. They bind to specific carrier proteins of the importin/exportin family and are transported to and from the nucleus. Thus there is a steady state shuttling of the cargo molecules to and from the nucleus, and the shift in equilibrium determines their nuclear or cytoplasmic localization. Our previous studies have shown that phospholipase C (PLC)-delta1, regarded as having cytoplasmic- or plasma membrane-bound localization, accumulates in the nucleus when its NES sequence is disrupted. In addition, a cluster of positively charged residues on the surface of the catalytic barrel is important for nuclear import. In quiescent cells, the shuttling equilibrium seems to be shifted to the nuclear export of PLCdelta1. In this review, recent findings regarding the molecular machineries and mechanisms of the nucleocytoplasmic shuttling of PLCdelta1 will be discussed. It is important to know when and how they are regulated. A shift in the equilibrium in a certain stage of the cell cycle or by external stimuli is possible and resulting changes in the intra-nuclear environments (or architectures) may alter proliferation and differentiation patterns. Evidences support the idea that an increase in the levels of intracellular Ca2+ shifts the equilibrium to the nuclear import of PLCdelta1. A myriad of external stimuli have also been reported to change the nuclear PI metabolism following accelerated accumulation in the nucleus of other phospholipases such as phospholipase A2 and phospholipase D in addition to PLC isoforms such as PLCbeta1 and PLCgamma1. The consequence of the nuclear accumulation of PLC is also discussed.
Tilings of the time-frequency plane: construction of arbitrary orthogonal bases and fast tiling algorithms (1993)

The authors consider expansions which give arbitrary orthonormal tilings of the time-frequency plane. These differ from the short-time Fourier transform, wavelet transform, and wavelet packets tilings in that they change over time. They show how this can be achieved using time-varying orthogonal tree structures, which preserve orthogonality, even across transitions. The method is based on the construction of boundary and transition filters; these allow us to construct essentially arbitrary tilings. Time-varying modulated lapped transforms are a special case, where both boundary and overlapping solutions are possible with filters obtained by modulation. They present a double-tree algorithm which for a given signal decides on the best binary segmentation in both time and frequency. That is, it is a joint optimization of time and frequency splitting. The algorithm is optimal for additive cost functions (e.g., rate-distortion), and results in time-varying best bases, the main application of which is for compression of nonstationary signals. Experiments on test signals are presented.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Mac Arthur y la transición de Japón a la democracia (1997)

Los historiadores han sostenido que la ocupacion aliada de Japon, entre 1945 y 1952, es uno de los capitulos mas notables en la historia del mundo. El tono y el estilo de la ocupacion fueron establecidos por el general Douglas Mac Arthur, Comandante Supremo de las Potencias Aliadas, quien por el esclarecido liderazgo de su propio personal y de toda la nacion japonesa dio el sello de su personalidad a toda la empresa. Ante la postracion moral del pueblo, planteo la necesidad de una mistica y de un renacimiento moral para poner de nuevo en pie a la nacion. Su obra mas duradera fue la reforma de la constitucion que establecio un sistema parlamentario de gobierno y en la cual la posicion del Emperador fue cambiada, quedando solo como el Simbolo del Estado y de la unidad del pueblo. Sus reformas fueron vastas y profundas y modernizaron la sociedad japonesa: la reforma agraria, la legislacion anti -trust, la legislacion laboral y la reforma educacional. El ex embajador de Estados Unidos en Japon, Edwin Reischaner, escribio que Mac Arthur ha sido una de las grandes figuras del mundo de post-guerra y realizo mas en Japon que ningun otro hombre.
First-line liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) in pancreatic ductal adenocarcinoma: A phase I/II study (2021)

This open-label, phase I/II study evaluated safety and efficacy for first-line liposomal irinotecan + oxaliplatin + 5-fluorouracil + leucovorin (NALIRIFOX).Patients (aged ≥18 years) had locally advanced/metastatic pancreatic ductal adenocarcinoma (mPDAC), with an Eastern Cooperative Oncology Group performance status score of 0/1 and adequate organ function. Primary objectives were to determine the maximum tolerated dose (MTD) and to evaluate safety and tolerability. Treatment-emergent adverse events (TEAEs) were graded using National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Efficacy end-points included progression-free survival (PFS) and overall survival (OS); disease assessments used Response Evaluation Criteria in Solid Tumors 1.1.The MTD (liposomal irinotecan 50 mg/m2 [free-base equivalent], oxaliplatin 60 mg/m2, 5-fluorouracil 2400 mg/m2, leucovorin 400 mg/m2 every 2 weeks) was based on dose-limiting toxicities and cumulative safety data in four dose-exploration cohorts. The MTD was received by 32 of 56 patients, seven during dose exploration and 25 during dose expansion (median age 58.0 years [range, 39-76], 28 [87.5%] with metastatic disease at diagnosis [29 at study entry], and one receiving study treatment at data cutoff [26 February 2020]). Of these patients, 22 of 32 had grade ≥3 treatment-related TEAEs, most commonly neutropenia (31.3%), febrile neutropenia (12.5%) and hypokalaemia (12.5%); ten had serious treatment-related TEAEs; and three died from TEAEs considered unrelated to treatment. Median PFS and OS were 9.2 (95% CI: 7.69-11.96) and 12.6 (8.74-18.69) months, respectively.First-line NALIRIFOX for patients with locally advanced/mPDAC was generally manageable and tolerable. A randomised, controlled phase III study is underway.
[Inhibition of HSP70-2 expression by RNA interference induces apoptosis of human hepatocellular carcinoma cells]. (2008)

Our results indicated that HSP70-2 down-regulation induces apoptosis of HCC cells through the mitochondrial apoptotic pathway, highlighting the importance of HSP70-2 in survival of HCC cells and maintenance of liver function.
Enzymes in organic media (2004)

Enzyme catalysis in low water containing organic solvents is finding an increasing number of applications in diverse areas. This review focuses on some aspects which have not been reviewed elsewhere. Different strategies for obtaining higher activity and stability in such media are described. In this context, the damaging role of lyophilization and the means of overcoming such effects are discussed. Ultrasonication and microwave assistance are two emerging approaches for enhancing reaction rates in low water media. Control of water activity and medium engineering are two crucial approaches in optimization of catalytic behaviour in nonaqueous enzymology. Organometallics and synthesis/modification of polymers are two areas where nonaqueous enzymology can play a greater role in the coming years. The greater understanding of enzyme behaviour in nonaqueous media is expected to lead to larger and even more diverse kinds of applications.
Long‐range mate location and close‐range courtship behaviour of the Green Stink Bug, Nezara viridula and its mediation by sex pheromones (1987)

Abstract Temporal and sequential aspects of the courtship of the green stink bug, Nezara viridula are reported. The sequence of courtship behaviour can be divided into two phases: long‐range mate location and short‐range courtship. Long‐range behaviour includes those components of the behaviour that lead to the arrival of females in the vicinity of males. Short‐range behaviour includes those components that coordinate the interaction of both sexes once they are in close proximity. The individual components of both the long and short range behaviour were found to occur in stereotyped sequences, each step having a high probability of transition to the next. When the odour stimuli of live males were replaced by chemical extracts from males, obtained by aeration collection, only the long range sequences of female behaviour were elicited. The lack of close‐range behavioural sequences may indicate that visual and acoustic stimuli have some role in the later stages of sexual communication. The pheromonal extract from males, which was elucidated by GC—MS analysis, contained n‐dodecane, n‐tridecane, sesquiterpene (hydrocarbon), sesquiterpene (mono‐oxygenated) and n‐nonadecane. Résumé Localisation à grande distance du conjoint et pariade à courte distance chez Nezara viridula, intervention des phéromones sexuelles Ce travail concerne les aspects séquentiels et temporels du comportement précopulatoire de N. viridula . Ce dernier peut être divisé en deux périodes: le repérage à grande distance du conjoint et le comportement de pariade à faible distance. Le comportement à grande distance comprend les éléments du comportement qui conduisent les femelles à proximité des mâles. Le comportement à faible distance comprend les éléments qui coordonnent les interactions des deux sexes jusqu'à ce qu'ils soient à proximité immédiate. Les éléments particuliers à chacun des comportements à faible et grande distances se produisent dans des séquences stéréotypées, chaque étape ayant une forte probabilité de passage vers la suivante. Quand les stimuli odorants de mâles vivants ont été remplacés par des extraits chimiques de ces derniers, récoltés par barbotage d'air sur colonne absorbante, seules les séquences du comportement à grande distance des femelles ont été induites. L'absence des séquences à faible distance peut indiquer une influence des stimuli visuels et acoustiques dans les stades ultérieurs de la communication sexuelle. L'extrait phéromonal des mâles, qui a été mis en évidence par GC—MS, contenait du n‐dodécane, du n‐tridécane, des sesquiterpènes (hydrocarbures), des sesquiterpènes (mono‐oxygénés) et du n‐nonadécane.
Fine Particulate Air Pollution is Associated with Higher Vulnerability to Atrial Fibrillation—the Apacr Study (2011)

The acute effects and the time course of fine particulate pollution (PM₂.₅) on atrial fibrillation/flutter (AF) predictors, including P-wave duration, PR interval duration, and P-wave complexity, were investigated in a community-dwelling sample of 106 nonsmokers. Individual-level 24-h beat-to-beat electrocardiogram (ECG) data were visually examined. After identifying and removing artifacts and arrhythmic beats, the 30-min averages of the AF predictors were calculated. A personal PM₂.₅ monitor was used to measure individual-level, real-time PM₂.₅ exposures during the same 24-h period, and corresponding 30-min average PM₂.₅ concentration were calculated. Under a linear mixed-effects modeling framework, distributed lag models were used to estimate regression coefficients (βs) associating PM₂.₅ with AF predictors. Most of the adverse effects on AF predictors occurred within 1.5-2 h after PM₂.₅ exposure. The multivariable adjusted βs per 10-μg/m³ rise in PM₂.₅ at lag 1 and lag 2 were significantly associated with P-wave complexity. PM₂.₅ exposure was also significantly associated with prolonged PR duration at lag 3 and lag 4. Higher PM₂.₅ was found to be associated with increases in P-wave complexity and PR duration. Maximal effects were observed within 2 h. These findings suggest that PM₂.₅ adversely affects AF predictors; thus, PM₂.₅ may be indicative of greater susceptibility to AF.
Kinetics of Tertiary Reaction of HF on Alumino-Silicates (1996)

Abstract The standard description of HF acidizing chemistry clearly demonstrates a primary and secondary reaction of HF with alumino-silicates.1 Field experience has taught our industry that possible precipitation during the secondary reaction can adversely affect treatment success.2 This statement has been particularly true in formations with high K-feldspar content or formations having temperatures above 300°F. Recent work has also reported the existence of a third, or tertiary reaction of HF with alumino-silicates.3 This paper reports how the rate law and kinetics for this tertiary reaction are determined on kaolinite and feldspar over a broad temperature range. This document also discusses the discovery of how most clays were thermally unstable to HC1 at temperatures above 250°F. These findings were made possible by recently applied experimental techniques including l9FNMR Spectroscopy,3 fractional pore volume flow experiments,4 and an accurate knowledge of the HF stoichiometry.5 The tertiary reaction of aluminum fluorides, AlFx (where x is the average F/Al ratio), with clay was slow below 200°F and was dominated by HC1 decomposition of the clay above 250°F. The tertiary reaction required the presence and consumption of acid to proceed. Feldspars were very stable in HC1 at all temperatures while every clay tested had a temperature above which it was easily decomposed by HC1. Ion-exchanging clays tended to be the least stable of the clays, while kaolinite was the most stable clay.
Therapeutic potential of immunostimulatory monoclonal antibodies (2006)

The aim of cancer immunotherapy is to employ the specificity of the immune system to provide a more effective, less toxic, treatment compared with conventional therapies. Although many strategies have been used to try to generate effective anticancer immune responses, very few have reached mainstream clinical use. A new approach introduced over the last few years is to use immunostimulatory mAbs (monoclonal antibodies) to boost weak endogenous antitumour immune responses to levels which are therapeutic. Such agonistic or antagonistic mAbs bind to key receptors in the immune system acting to enhance antigen presentation, provide co-stimulation or to counteract immunoregulation. In animal models, this approach has been shown to promote powerful tumour-specific T-cell responses capable of clearing established tumour and leaving the animal with long-term immunity. In addition to this impressive therapy seen in tumour models, these same mAbs also have the potential to be therapeutically useful in autoimmune and infectious diseases. This review discusses the use of these mAbs as therapeutic agents, their advantages and disadvantages and the challenges that need to be overcome to use them clinically.
Adoptive Cell Therapy for Patients with Melanoma, Using Tumor-Infiltrating Lymphocytes Genetically Engineered to Secrete Interleukin-2 (2008)

Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) after lymphodepletion mediates regression in 50% of patients with metastatic melanoma. In vivo persistence and telomere length of the transferred cells correlate with antitumor response. In an attempt to prolong the in vivo survival of the transferred cells, TILs were genetically engineered to produce interleukin (IL)-2. In vitro, these transduced TILs secreted IL-2 while retaining tumor specificity and exhibited prolonged survival after IL-2 withdrawal. In a phase I/II clinical trial, seven evaluable patients received transduced TILs and one patient experienced a partial response associated with in vivo persistence of IL-2-transduced TILs in circulating lymphocytes. An additional five patients received transduced TILs in conjunction with IL-2 administration. Persistence of IL-2-transduced TILs was observed in three patients, including one partial responder. The transgene DNA as well as vector-derived IL2 mRNA could be detected for 4 months in responding patients. The low response rate in this trial was possibly due to a reduction in telomere length in cells as a result of prolonged in vitro culture. In this study, insertion of the IL-2 gene into antitumor TILs increased their ability to survive after IL-2 withdrawal in vitro but did not increase their in vivo persistence or clinical effectiveness.