gebhart/patrepeval huggingface dataset:
Current status and perspectives on the development of therapeutic agents for Alzheimer's disease (2004)

Acetylcholinesterase inhibitors have beneficial effects to improve the cognitive impairment in patients with mild to moderate Alzheimer's disease (AD). In addition, a channel blocker of N-methyl-D-aspartate receptor, memantine hydrochloride, was approved as a therapeutic agent for patients with moderate to severe AD in both EU countries in 2002 and USA in 2003, while the clinical development is still ongoing in Japan. In contrast, the pharmacotherapy for a prime cure against AD is not available in the market, although there has been a worldwide search for novel compounds. The most plausible mechanism for the treatment of AD is the reduction of the amyloid beta-peptide (Abeta) plaques, one of the pathological markers of AD, in the brain. For this purpose, the inhibitors of beta-secretase and gamma-secretase, which cleave amyloid precursor protein (APP) to release Abeta, has been developed to interfere with APP processing. The beta-sheet breaker and metal chelators for the breakdown of aggregated Abeta have also been synthesized as well as the immunotherapeutic approach using Abeta vaccine. On the other hand, some nonsteroidal anti-inflammatory drugs, such as ibuprofen and sulindac, noncompetitively inhibited Abeta production but not Notch cleavage. The development of Abeta-lowering drugs is highly expected for the treatment of AD.
Performance Validation of Network-Intensive Workloads on a Full-System Simulator (2005)

Performance accuracy is a critical but often ne-glected aspect of architectural performance simula-tors. One approach to evaluating performance accu-racy is to attempt to reproduce observed performance results from a real machine. In this paper, we at-tempt to model the performance of a Compaq Alpha XP1000 workstation using the M5 full-system simula-tor. There are two novel aspects to this work. First, we simulate complex TCP/IP networking workloads and use network bandwidth as our primary perfor-mance metric. Unlike conventional CPU-intensive applications, these workloads spend most of their time in the operating system kernel and include sig-nificant interactions with platform hardware such as the interrupt controller and network interface device. Second, we attempt to achieve performance accuracy without extremely precise modeling of the reference hardware. Instead, we use simple generic component models and tune them to achieve appropriate band-widths and latencies. Overall, we were able to achieve reasonable accu-racy even with our relatively imprecise model, match-ing the bandwidth of the real system within 15 % in most cases. We also used profiling to break CPU time down into categories, and found that the simulation results correlated well with the real machine. 1
Effect of nitric oxide synthase inhibition on haemodynamics and outcome of patients with persistent cardiogenic shock complicating acute myocardial infarction: a phase II dose-ranging study (2007)

l-NMMA resulted in modest increases in MAP at 15 min compared with placebo but there were no differences at 2 h.
Practical Radical Cyclizations with Arylboronic Acids and Trifluoroborates (2011)

Practical radical cyclizations using organoboronic acids and trifluoroborates take place in water, open to air, and in a scalable fashion employing catalytic silver nitrate and stoichiometric potassium persulfate. Both Pschorr-type cyclizations and tandem radical cyclization/trap cascades are described, illustrating the utility of these mild conditions for the generation of polycyclic scaffolds.
Crystal structures of matrilysin-inhibitor complexes (1995)

Matrix metalloproteases are a family of enzymes that play critical roles in the physiological and pathological degradation of the extracellular matrix. These enzymes may be important therapeutic targets for the treatment of various diseases where tissue degradation is part of the pathology, such as cancer and arthritis. Matrilysin is the smallest member of this family of enzymes, all of which require zinc for catalytic activity. The first X-ray crystal structures of human matrilysin are presented. Inhibitors of metalloproteases are often characterized by the chemical group that interacts with the active site zinc of the protein. The structures of matrilysin complexed with hydroxamate (maximum resolution 1.9 A), carboxylate (maximum resolution 2.4 A), and sulfodiimine (maximum resolution 2.3 A) inhibitors are presented here and provide detailed information about how each functional group interacts with the catalytic zinc. Only the zinc-coordination group is variable in this series of inhibitors. Examination of these inhibitor-matrilysin complexes emphasizes the dominant role the zinc-coordinating group plays in determining the relative potencies of the inhibitors. The structures of these matrilysin-inhibitor complexes also provide a basis for comparing the catalytic mechanism of MMPs and other metalloproteins.
Tumor necrosis factor α blockade reduces the synovial cell infiltrate early after initiation of treatment, but apparently not by induction of apoptosis in synovial tissue (2003)

Infliximab therapy may reduce the number of inflammatory cells in rheumatoid synovial tissue as soon as 48 hours after initiation of treatment, but apparently not by induction of apoptosis. Conceivably, decreased cell infiltration primarily results from early inhibition of cell migration.
Efficient Phantom Source Widening and Diffuseness in Ambisonics (2014)

Object-based spatial audio considers virtual sound sources having a width/diffuseness parameter. This parameter aims at controlling the perceived width or diffuseness of the auditory object, or phantom source, created by the renderer. Width/diffuseness provides an important salience parameter that is independent of perceived direction and timbre. A highly efficient sparse filter structure for two-channel stereophony was described and tested recently, but it becomes ineffective for most parts of a large audience. This paper presents phantom source width/diffuseness control for Ambisonics. The new approach is a remarkably elegant application of the previously described stereo phantom source widening on Ambisonics. Compared with former experimental data, our experiments show a greater freedom of increasing the width and widening that works for a larger listening area.
Impact of three-dimensional transistor on the pattern area reduction for ULSI (2003)

The impact of three-dimensional transistors, double-gate transistor, trench-isolated transistor (TIS) (using sidewall gate)/FinFET, and surrounding gate transistor (SGT) on the pattern area reduction for ultra-large-scale integration (ULSI) has been described. The pattern area of the gate logic, such as NAND or NOR, with the double-gate transistor, TIS/FinFET or SGT can be reduced to 58, 47, 48%, respectively, compared with the conventional planar case using the same feature size, F. The pattern area of the tapered buffer circuit with the double-gate transistor, TIS/FinFET or SGT can be reduced to 58, 20, 48%, respectively. These three-dimensional transistors can be adapted to ULSI such as application specific integrated circuit (ASIC), microprocessor (MPU), dynamic random access memory (DRAM), and embedded DRAM. The smallest pattern area may be realized with TIS/FinFET or SGT of 47-48% for ASIC, with TIS/FinFET of 42% for MPU, with SGT of 65% for DRAM and with TIS/FinFET or SGT for embedded DRAM. For designing the circuit with TIS/FinFET the design of the trench depth (2F for gate logic, 12F for tapered buffer) is the key issue. The design of the cell library for SGT is a task for the future.
The Female Prostate Revisited: Perineal Ultrasound and Biochemical Studies of Female Ejaculate (2007)

Data of the two women presented further underline the concept of the female prostate both as an organ itself and as the source of female ejaculation.
Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects (2011)

Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL(-1) . They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. http://dx.doi.org/10.1111/bph.2011.163.issue-7.
[Antitumor activities of 4 derivatives of artemisic acid and artemisinin B in vitro]. (1992)

The cytotoxicities of 2 derivatives of artemisinin B and 2 derivatives of artemisic acid (designated as Compound A, B, C, and D) were investigated, using trypan blue dye exclusion test and colony-forming units assay. At the concentration of 5 micrograms.ml-1, the inhibition rates of these 4 compounds against murine leukemia cell line P388 were > 85%. When tested against human hepatoma cell line SMMC-7721 at 25 micrograms.ml-1, the inhibition rates of Compound A, B, C, and D were found to be 92.3%, 96.9%, 84%, and 82.1%, respectively, and 27%, 8%, 37.8%, 1.7% against normal human embryonic lung cell line WI-38, respectively. These 4 compounds all showed an inhibition rate of 100% against human gastric cancer cell line SGC-7901 at 50 micrograms.ml-1.
Role of M protein in adherence of group A streptococci (1991)

The role of the M protein in adherence of group A streptococci to human epithelial cells was directly tested by using an isogenic pair of M+ and M- strains. There was no difference between these strains in the number of streptococcal units that adhered to buccal or tonsillar epithelial cells, indicating the following: (i) that adhesins that are not dependent upon M protein expression are present on the surface of group A streptococci and (ii) that the M protein is not the primary streptococcal adherence ligand. However, the M+ strain adhered to tonsillar epithelial cells as aggregates. This aggregation was dependent on the presence of the M protein, since the isogenic M- strain did not clump. The coaggregation of streptococci suggests that the M protein plays an important role in promoting the formation of microcolonies after initial attachment. Binding to fibronectin, a potential epithelial cell receptor for group A streptococci, was also the same for the isogenic M+ and M- strains as well as for an isogenic strain with a regulatory mutation that decreases the expression of M protein. In summary, the M protein is not the primary streptococcal adhesin, nor is it required to orient the streptococcal adhesin and/or fibronectin receptor.
Lanthanide β-diketonate glyme complexes exhibiting unusual co-ordination modes (1993)

The reaction of the hydrated β-diketonate complexes [Ln(tmhd)3(H2O)] with triglyme (2,5,8,11-tetraoxadodecane, L1) in hexane yielded the eight-coordinate triglyme-bridged dimeric complexes, [{Ln(tmhd)3}2L1](Ln = Eu 1 or Tb 2; tmhd = ButCOCHCOBut). In contrast, the reaction of [La(tmhd)3(H2O)] with tetraglyme, (2,5,8,11,14-pentaoxapentadecane, L2) in hexane yielded the nine-co-ordinate monomeric compound [La(tmhd)3L2]3, though with only three of the five possible oxygen atoms of the glyme utilized in bonding to the lanthanum. All of these complexes are air- and moisture-stable and most importantly have good volatility and thermal stability, as demonstrated by sublimation, differential scanning calorimetry and thermal gravimetic analysis. The structures of all three complexes have been determined by single-crystal X-ray diffraction.
Effects of Film Variety on the Amounts of Carboxylic Acids from Electron Beam Irradiated Polyethylene Film (1984)

The amounts of carboxylic acids released from electron beam irradiated polyethylene film, which can be indicators of the intensity of off-odor, were examined. The conditions for trapping acetic acid, propionic acid, n-butyric acid, and n-valeric acid from two grams of film irradiated with a dose of 20 kGy in air were established as follows; carboxylic acids volatilized at 80°C from irradiated film were concentrated on Tenax GC by passing nitrogen gas at a flow rate of 20 ml/min for 30 minutes. The amounts of carboxylic acids varied considerably depending upon the properties of the resin, the presence of additives, etc. Without additives, the total amounts of the acids from the film which gave the strongest off-odor was three times the total amounts of the acids from the film which gave the weakest off-odor. The addition of butylated hydroxytoluene to film reduced remarkably the formation of carboxylic acids.
Enzyme-catalyzed protein crosslinking (2012)

The process of protein crosslinking comprises the chemical, enzymatic, or chemoenzymatic formation of new covalent bonds between polypeptides. This allows (1) the site-directed coupling of proteins with distinct properties and (2) the de novo assembly of polymeric protein networks. Transferases, hydrolases, and oxidoreductases can be employed as catalysts for the synthesis of crosslinked proteins, thereby complementing chemical crosslinking strategies. Here, we review enzymatic approaches that are used for protein crosslinking at the industrial level or have shown promising potential in investigations on the lab-scale. We illustrate the underlying mechanisms of crosslink formation and point out the roles of the enzymes in their natural environments. Additionally, we discuss advantages and drawbacks of the enzyme-based crosslinking strategies and their potential for different applications.
Structure and Assembly of the Native Collagen Fibril (1982)

Assembly in vitro of the native collagen fibril is a multistep process involving an initial intermediate of unknown structure, linear growth of thin filaments, lateral growth to form the fibril, and stabilization by covalent crosslinks. A model for the structure of the fibril is proposed consisting of a substructure of five-stranded microfibrils laterally compressed to place molecules in cross section on a near-hexagonal lattice.
Interleaving Delaunay refinement and optimization for practical isotropic tetrahedron mesh generation (2009)

We present a practical approach to isotropic tetrahedral meshing of 3D domains bounded by piecewise smooth surfaces. Building upon recent theoretical and practical advances, our algorithm interleaves Delaunay refinement and mesh optimization to generate quality meshes that satisfy a set of user-defined criteria. This interleaving is shown to be more conservative in number of Steiner point insertions than refinement alone, and to produce higher quality meshes than optimization alone. A careful treatment of boundaries and their features is presented, offering a versatile framework for designing smoothly graded tetrahedral meshes.
Embryo morphology or cleavage stage: how to select the best embryos for transfer after in-vitro fertilization (1997)

This retrospective study of 1001 in-vitro fertilization (IVF) cycles included a consecutive series of single transfers (n = 341), dual transfers (n = 410) and triple transfers (n = 250) where all the transferred embryos in each cycle were of identical quality score and identical cleavage stage. In our 2 day culture system, transfer of 4-cell embryos resulted in a significantly higher implantation rate and pregnancy rate (23 and 49%) compared with 2-cell embryos (12 and 22%) and 3-cell embryos (7 and 15%). Furthermore, the transfer of 4-cell embryos resulted in a significantly higher pregnancy rate compared with embryos that had cleaved beyond the 4-cell stage (28%). The implantation rate (21%) and pregnancy rate (43%) after transfer of embryos of score 1.0 were significantly higher than after transfer of embryos of score 2.0 (14 and 32% respectively). Transferring embryos of score 2.1 resulted in significantly higher implantation rates (26%) and similar pregnancy rates compared with score 1.0. Transferring embryos of score 2.2-3.0 resulted in a significantly lower implantation rate (5%) and pregnancy rate (15%). A striking finding was that embryos of quality score 2.0 had a significantly lower implantation rate compared with embryos of quality score 1.0 and 2.1 and a significantly lower pregnancy rate compared to embryos of quality score 1.0. We also found a lower implantation rate and pregnancy rate when transferring 3-cell embryos. These findings may indicate periods of increased sensitivity to damage during the cell cycle. In conclusion, these results substantiate the idea of the superiority of 4-cell embryos and demonstrate that minor amounts of fragments in the embryo may not be of any importance. These findings may call for a shift when weighing the two main morphological components (quality score and cleavage stage) in the sense that reaching a 4-cell cleavage stage even with the presence of a minor amount of fragments should be preferred to a 2-cell embryo with no fragments.
Prolonged duration local anesthesia with minimal toxicity (2009)

Injectable local anesthetics that would last for many days could have a marked impact on periprocedural care and pain management. Formulations have often been limited in duration of action, or by systemic toxicity, local tissue toxicity from local anesthetics, and inflammation. To address those issues, we developed liposomal formulations of saxitoxin (STX), a compound with ultrapotent local anesthetic properties but little or no cytotoxicity. In vitro, the release of bupivacaine and STX from liposomes depended on the lipid composition and on whether dexamethasone was incorporated. In cell culture, bupivacaine, but not STX, was myotoxic (to C2C12 cells) and neurotoxic (to PC12 cells) in a concentration- and time-dependent manner. Liposomal formulations containing combinations of the above compounds produced sciatic nerve blockade lasting up to 7.5 days (with STX + dexamethasone liposomes) in male Sprague-Dawley rats. Systemic toxicity only occurred where high loadings of dexamethasone increased the release of liposomal STX. Mild myotoxicity was only seen in formulations containing bupivacaine. There was no nerve injury on Epon-embedded sections, and these liposomes did not up-regulate the expression of 4 genes associated with nerve injury in the dorsal root ganglia. These results suggest that controlled release of STX and similar compounds can provide very prolonged nerve blocks with minimal systemic and local toxicity.
Central Core Domain of Retroviral Integrase Is Responsible for Target Site Selection (1997)

Integration of retroviral DNA can occur into many sites on target DNA with a wide variation in preference. One factor known to affect target site selection is integrase, the viral protein required for the integration reaction. In this study, assays that measure the distribution and frequency of retroviral DNA integration showed that purified integrases of human immunodeficiency virus type 1 (HIV-1) and feline immunodeficiency virus (FIV) had different patterns of target site usage. The integrase domain involved in target site selection was mapped by analyzing the integration pattern of chimeric proteins formed between HIV-1 and FIV integrases and of deletion variants of the two wild-type integrases. The results indicate that the domain responsible for target site selection resides in the central core region of integrase.
The Pathogenesis of Mycosis Fungoides (2004)

The most common cutaneous lymphoma is mycosis fungoides, a non-Hodgkin's, peripheral T-cell lymphoma. Recent advances in the understanding of the molecular and biologic behavior of T cells in this lymphoma — notably, their ability to home to the skin, function in an activated state, and achieve clonal dominance — have had a tremendous influence on current treatment. In this review, the expanding armamentarium of biologic agents, phototherapeutic and irradiation techniques, and combination regimens available to treat mycosis fungoides is discussed.
Oligonucleotides as Anticancer Agents: From the Benchside to the Clinic and Beyond (2005)

Prevention, improved screening, and better treatment regimens have improved cancer incidence and mortality in the last decade. Chemoradiation continues to cause high morbidity in patients undergoing treatment. DNA therapeutics have the potential to modify the genes that cause tumor progression in order to produce a response that is tumor-specific, efficacious and systemic without toxicity to normal cells. The most widely used and most experimentally advanced DNA therapeutic is the antisense oligonucleotide. These oligomers are predominantly used to inhibit mRNA expression. For cancer chemotherapy, the Bcl-2 antisense oligonucleotide is currently in phase III clinical trials. Transcription factor decoys form DNA:protein heteroduplexes and produce cellular responses at the genomic rather than transcriptional level. The use of other transcription factor decoys as oncologic reagents is now being developed. The phenomenon of RNA interference has only recently been discovered to occur in plants as a response to viral infection. Small interfering RNAs cause mRNA inhibition. siRNAs also inhibit expression of mRNA, however the intracellular cascade is quite different. siRNA could prove to be more powerful and longer lasting than antisense. Several DNA therapeutics are currently being studied. This review will focus on antisense oligonucleotides, transcription factor decoys and siRNA with an emphasis on how they can be employed as anticancer agents. Mechanism of action and design strategies will be summarized, as well as therapeutic targets and demonstrated clinical efficacy for each reagent.