gebhart/patrepeval huggingface dataset:
Synthesis and Structure−Activity Relationships of Phenylenebis(methylene)- Linked Bis-azamacrocycles That Inhibit HIV-1 and HIV-2 Replication by Antagonism of the Chemokine Receptor CXCR4 (1999)

Bis-tetraazamacrocycles such as the bicyclam AMD3100 are a class of potent and selective anti-HIV-1 and HIV-2 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the co-receptor for entry of X4 viruses. With the aim of optimizing the anti-HIV-1 and HIV-2 activity of bis-azamacrocycles, a series of analogues were synthesized which contain neutral heteroatom (oxygen, sulfur) or heteroaromatic (of lower pK(a) than a secondary amine) replacements for the amino groups of AMD3100. The introduction of one or more heteroatoms such as oxygen or sulfur into the macrocyclic ring of p-phenylenebis(methylene)-linked dimers (to give N(3)X or N(2)X(2) bis-macrocycles) gave analogues with substantially reduced anti-HIV-1 (III(B)) and anti-HIV-2 (ROD) potency. In addition, the bis-sulfur analogue was also markedly more cytotoxic to MT-4 cells. However, bis-tetraazamacrocycles featuring a single pyridine group incorporated within the macrocyclic framework exhibited anti-HIV-1 and HIV-2 potency comparable to that of their saturated, aliphatic counterparts. The p-phenylenebis(methylene)-linked dimer of the py[14]aneN(4) macrocycle inhibited HIV-1 replication at a 50% effective concentration (EC(50)) of 0.5 microM while remaining nontoxic to MT-4 cells at concentrations approaching 200 microM. A series of analogues containing macrocyclic heteroaromatic groups of varying pK(a) were also synthesized, and their ability to inhibit HIV replication was evaluated. Replacing the pyridine moiety of the py[14]aneN(4) macrocyclic ring with pyrazine or pyridine groups substituted in the 4-position (with electron-withdrawing or -donating groups) either reduced antiviral potency or increased cytotoxicity to MT-4 cells. Finally, we synthesized a series of analogues in which the ring size of the bis-pyridyl macrocycles was varied between 12 and 16 members per ring including the py[iso-14]aneN(4) ring system, an isomer of the py[14]aneN(4) macrocycle. The p-phenylenebis(methylene)-linked dimer of the py[iso-14]aneN(4) (AMD3329) displayed the highest antiviral activity of the bis-azamacrocyclic analogues reported to date, exhibiting EC(50)'s against the cytopathic effects of HIV-1 and HIV-2 replication of 0.8 and 1.6 nM, respectively, that is, about 3-5-fold lower than the EC(50) of AMD3100. AMD3329 also inhibited the binding of a specific CXCR4 mAb and the Ca(2+) flux induced by SDF-1alpha, the natural ligand for CXCR4, more potently than AMD3100. Furthermore, AMD3329 also interfered with virus-induced syncytium formation at an EC(50) of 12 nM.
Pulmonary gas exchange during exercise in highly trained cyclists with arterial hypoxemia (1999)

The causes of exercise-induced hypoxemia (EIH) remain unclear. We studied the mechanisms of EIH in highly trained cyclists. Five subjects had no significant change from resting arterial PO(2) (Pa(O(2)); 92.1 +/- 2.6 Torr) during maximal exercise (C), and seven subjects (E) had a >10-Torr reduction in Pa(O(2)) (81.7 +/- 4.5 Torr). Later, they were studied at rest and during various exercise intensities by using the multiple inert gas elimination technique in normoxia and hypoxia (13.2% O(2)). During normoxia at 90% peak O(2) consumption, Pa(O(2)) was lower in E compared with C (87 +/- 4 vs. 97 +/- 6 Torr, P < 0.001) and alveolar-to-arterial O(2) tension difference (A-aDO(2)) was greater (33 +/- 4 vs. 23 +/- 1 Torr, P < 0. 001). Diffusion limitation accounted for 23 (E) and 13 Torr (C) of the A-aDO(2) (P < 0.01). There were no significant differences between groups in arterial PCO(2) (Pa(CO(2))) or ventilation-perfusion (VA/Q) inequality as measured by the log SD of the perfusion distribution (logSD(Q)). Stepwise multiple linear regression revealed that lung O(2) diffusing capacity (DL(O(2))), logSD(Q), and Pa(CO(2)) each accounted for approximately 30% of the variance in Pa(O(2)) (r = 0.95, P < 0.001). These data suggest that EIH has a multifactorial etiology related to DL(O(2)), VA/Q inequality, and ventilation.
Consideration of a millisecond pulsed glow discharge time-of-flight mass spectrometer for concurrent elemental and molecular analysis (1999)

The glow discharge ionization source operated in the pulsed (or modulated) power mode offers unique characteristics not available from its steady state counterpart. It has been well established that higher instantaneous power densities are obtainable without compromising the sample integrity when pulsed plasmas are implemented. This operating parameter affords higher sputter yields and lower limits of detection relative to the steady state plasmas. Of special interest are the discrete temporal regions associated with the modulated plasma. The presence of these time regimes offers temporal selectivity, allowing the collection of analytical data in a region where the contribution from background and contaminant species is minimized. These regions are characterized by strikingly different ionization mechanisms. Acquisition of data during each of these temporal regimes provides both molecular and elemental information. In this work the potential use of the pulsed glow discharge for collecting concurrent molecular and elemental information was explored. This task was accomplished using time-of-flight mass spectrometry (TOFMS). TOFMS has a significantly high throughput and duty cycle, making it ideally suited for rapid acquisition of spectra. This characteristic allows data acquisition during each of these temporal regions for each discharge pulse power cycle, affording concurrent elemental and molecular detection. p-Xylene was used as a test molecule for these studies.
Environmental characterization of the marine boundary layer for electromagnetic wave propagation (2003)

Radar and infrared propagation drastically depend on the meteorological and oceanographic conditions. Concerning a joint sea trial of German research institutes at the Baltic Sea 2001, FWG was responsible for the environmental characterization of the marine boundary layer. In-situ measurements included recordings of atmospheric properties and sea surface parameters. They were studied by two multi-sensor buoys, on board a vessel and with radiosondes. Pressure, air temperature and humidity were measured from the sea surface to 1 km altitude. The free drifting buoys which have been constructed at FWG offer the opportunity to gain unperturbed, time resolved information about environmental parameters up to 5 m above sea level. Based on the in-situ measurements refractivity profiles can be calculated. With the help of the vertical refractivity gradient and the air sea temperature difference, conditions for radar and infrared propagation are determined. Further experimental results include wind speed and direction, wave height, rain rate and other important parameters. Taking advantage of the parabolic equation model radar propagation is calculated numerically. In conclusion, the experimental results and calculations underline the importance of the environmental characterization of the marine boundary layer with high temporal and spatial resolution.
An Assessment of Name Matching Algorithms (1996)

CaMKII activation has been reported to be involved in HIF-1alpha stabilization, but incubation with SMP-114, a specific CaMKII inhibitor, had no effect on HIF-1-induced VEGF production by rheumatoid synovial fibroblasts.
Whole-body hypoxic preconditioning protects mice against acute hypoxia by improving lung function (2004)

Survival in severe hypoxia such as occurs in high altitude requires previous acclimatization, which is acquired over a period of days to weeks. It was unknown whether intrinsic mechanisms existed that could be rapidly induced and could exert immediate protection on unacclimatized individuals against acute hypoxia. We found that mice pretreated with whole-body hypoxic preconditioning (WHPC, 6 cycles of 10-min hypoxia-10-min normoxia) survived significantly longer than control animals when exposed to lethal hypoxia (5% O2, survival time of 33.2 +/- 6.1 min vs. controls at 13.8 +/- 1.2 min, n = 10, P < 0.005). This protective mechanism became operative shortly after WHPC and remained effective for at least 8 h. Accordingly, mice subjected to WHPC demonstrated improved gas exchange when exposed to sublethal hypoxia (7% O2, arterial blood Po2 of 49.9 +/- 4.2 vs. controls at 39.7 +/- 3.6 Torr, n = 6, P < 0.05), reduced formation of pulmonary edema (increase in lung water of 0.491 +/- 0.111 vs. controls at 0.894 +/- 0.113 mg/mg dry tissue, n = 10, P < 0.02), and decreased pulmonary vascular permeability (lung lavage albumin of 7.63 +/- 0.63 vs. controls at 18.24 +/- 3.39 mg/dl, n = 6-10, P < 0.025). In addition, the severity of cerebral edema caused by exposure to sublethal hypoxia was also reduced after WHPC (increase in brain water of 0.254 +/- 0.052 vs. controls at 0.491 +/- 0.034 mg/mg dry tissue, n = 10, P < 0.01). Thus WHPC protects unacclimatized mice against acute and otherwise lethal hypoxia, and this protection involves preservation of vital organ functions.
Transient Poly(ADP-ribosyl)ation of Nuclear Proteins and Role of Poly(ADP-ribose) Polymerase in the Early Stages of Apoptosis (1998)

A transient burst of poly(ADP-ribosyl)ation of nuclear proteins occurs early, prior to commitment to death, in human osteosarcoma cells undergoing apoptosis, followed by caspase-3-mediated cleavage of poly(ADP-ribose) polymerase (PARP). The generality of this early burst of poly(ADP-ribosyl)ation has now been investigated with human HL-60 cells, mouse 3T3-L1, and immortalized fibroblasts derived from wild-type mice. The effects of eliminating this early transient modification of nuclear proteins by depletion of PARP protein either by antisense RNA expression or by gene disruption on various morphological and biochemical markers of apoptosis were then examined. Marked caspase-3-like PARP cleavage activity, proteolytic processing of CPP32 to its active form, internucleosomal DNA fragmentation, and nuclear morphological changes associated with apoptosis were induced in control 3T3-L1 cells treated for 24 h with anti-Fas and cycloheximide but not in PARP-depleted 3T3-L1 antisense cells exposed to these inducers. Similar results were obtained with control and PARP-depleted human Jurkat T cells. Whereas immortalized PARP +/+ fibroblasts showed the early burst of poly(ADP-ribosyl)ation and a rapid apoptotic response when exposed to anti-Fas and cycloheximide, PARP -/- fibroblasts exhibited neither the early poly (ADP-ribosyl)ation nor any of the biochemical or morphological changes characteristic of apoptosis when similarly treated. Stable transfection of PARP -/- fibroblasts with wild-type PARP rendered the cells sensitive to Fas-mediated apoptosis. These results suggest that PARP and poly(ADP-ribosyl)ation may trigger key steps in the apoptotic program. Subsequent degradation of PARP by caspase-3-like proteases may prevent depletion of NAD and ATP or release certain nuclear proteins from poly(ADP-ribosyl)ation-induced inhibition, both of which might be required for late stages of apoptosis.
Acute Cigarette Smoke–Induced Connective Tissue Breakdown Requires both Neutrophils and Macrophage Metalloelastase in Mice (2002)

The cells/proteases responsible for the development of smoke-induced emphysema is an area of intense investigation. Mice with knockout of macrophage metalloelastase genes (MME(-/-)) do not develop emphysema after smoke exposure, but we also observed that neutrophils (PMN) in lavage appeared to be a requirement for acute connective tissue breakdown. In this study we exposed mice to cigarette smoke and examined lavage PMN, macrophages (MAC), desmosine (DES, a measure of elastin breakdown) and hydroxyproline (HP, a measure of collagen breakdown) 24 h afterwards. MME(+/+) mice exposed to smoke showed elevations in PMN, DES, and HP, but no elevations were seen in MME-deficient mice. Both PMN influx and increased levels of DES/HP could be restored by administering MAC from MME(+/+) mice to MME-deficient mice and then exposing them to smoke. RS113456, a metalloprotease inhibitor, also prevented PMN influx and connective tissue breakdown. Western blots against mouse alpha(1)-antitrypsin (alpha(1)AT) showed that alpha(1)AT was not protected in MME-deficient mice, nor by administration of RS113456. We conclude that, in mice, acute smoke-induced connective tissue breakdown, the precursor to emphysema, requires both PMN and MME, that PMN influx appears to be secondary to MAC activation, and that this process initially does not involve protection of alpha(1)AT from metalloprotease attack.
Directed Evolution as a Method To Create Enantioselective Cyclohexanone Monooxygenases for Catalysis in Baeyer–Villiger Reactions (2004)

The direction and degree of enantioselectivity in the cyclohexanone monooxygenase catalyzed air-mediated Baeyer–Villiger reactions, such as the desymmetrization of 1, can be controlled by directed evolution.
Design of a bright polarized head-mounted projection display (2007)

In optical see-through head-mounted displays, it has been a common challenge that the displayed image lacks brightness and contrast compared with the direct view of a real-world scene. Consequently, such displays are usually used in dimmed lighting conditions, which limits the feasibility of applying such information displays outdoors or in scenarios where well-lit environments, such as in operation rooms, are required. The lack of image brightness is aggravated in the design of a see-through head-mounted projection display (HMPD). For instance, the overall flux transfer efficiency of existing HMPD designs is less than 10%. The design of a polarized head-mounted projection display (p-HMPD) is presented. The images of a p-HMPD system can potentially be three times brighter than those in existing HMPD designs. It is further demonstrated that the p-HMPD design is able to dramatically improve image brightness, contrast, and color vividness with experimental results. Finally, the design of a compact optical system and helmet prototype is described.
Four Years’ Treatment Efficacy of Patients with Severe Hyperlipidemia. Lipid Lowering Drugs versus LDL-Apheresis (1995)

A total of 47 patients suffering from heterozygous hyperlipidemia were treated with LDL-apheresis (24 patients, aged 49.5 +/- 11.5 years), diet and/or lipid-lowering drugs or with diet and lipid-lowering drugs only (23 patients, aged 48.0 +/- 11.9 years). After treatment periods of 44.4 +/- 14.3 (apheresis group) and 33.5 +/- 15.9 (drug group) months, respectively, the ensuing results revealed significant differences (p < 0.0001): total cholesterol decreased from 10.4 to 5.5 vs 9.9 to 8.7 mmol/l, LDL from 7.4 to 3.9 vs 6.6 to 5.2 mmol/l, triglycerides from 5.8 to 3.7 vs 4.8 to 4.1 mmol/l and the LDL/HDL-ratio decreased from 7.1 to 3.4 vs 6.7 to 5.8. In the apheresis group one patient died from myocardial infarction vs one non-fatal myocardial infarction and the manifestation of coronary heart disease in three cases in the drug group. There were no severe side-effects in either group. All patients in the apheresis group experienced an increased clinical performance. On the other hand physological well-being of these patients was lower than that of the drug group (scores 42.3 +/- 8.9 vs 50.2 +/- 9.9, p < 0.002). The present trial suggests that a continuing reduction in serum lipid concentrations may lower in a dose dependent manner the risk of development and progression of coronary heart disease. With respect to clinical and laboratory results, LDL-apheresis seems safe and appears to be the most effective therapy.
Advanced Glycation End Products Increase Collagen-specific Chaperone Protein in Mouse Diabetic Nephropathy (2004)

Advanced glycation end products (AGEs) appear to contribute to the diabetic complications. This study reports the inhibitory effect of OPB-9195 (OPB), an inhibitor of AGEs formation, and the role of a collagen-specific molecular chaperone, a 47-kDa heat shock protein (HSP47) in diabetic nephropathy. Transgenic mice carrying nitric-oxide synthase cDNA fused with insulin promoter (iNOSTg) leads to diabetes mellitus. The iNOSTg mice at 6 months of age represented diffuse glomerulosclerosis, and the expression of HSP47 was markedly increased in the mesangial area in parallel with increased expression of types I and IV collagens. OPB treatment ameliorated glomerulosclerosis in the iNOSTg mice associated with the decreased expression of HSP47 and types I and IV collagens. The expression of transforming growth factor-beta (TGF-beta) was increased in glomeruli of iNOSTg mice and decreased after treatment with OPB. To confirm these mechanisms, cultured mesangial cells were stimulated with AGEs. AGEs significantly increased the expression of HSP47, type IV collagen, and TGF-beta mRNA. Neutralizing antibody for TGF-beta inhibited the overexpression of both HSP47 and type IV collagen in vitro. In conclusion, AGEs increase the expression of HSP47 in association with collagens, both in vivo and in vitro. The processes may be mediated by TGF-beta.
Performance comparison of four exome capture systems for deep sequencing (2014)

We show key differences in performance between the four technologies. Our data should help researchers who are planning exome sequencing to select appropriate exome capture technology for their particular application.
Suppression of Quantum Yield of Photosystem II by Hyperosmotic Stress in <italic>Chlamydomonas reinhardtii</italic> (1995)

Addition of ethylene glycol (EG) or NaCl to cells of Chlamydomonas reinhardtii induced transient non-photochemical quenching of Chl fluorescence correlated with the inhibition of photosynthetic oxygen evolution. The induction of the quenching and subsequent recovery proceeded not only in the light but also in the dark. The quenching was almost unaffected by the protonophore nigericin, suggesting the involvement of a type of non-photochemical quenching attributable to a state 2 transition. Higher concentrations of EG or NaCl caused a delay of the recovery of the maximum fluorescence yield (Fm′). Dark reduction rate of P700+ after the application of a flash light in the presence of DCMU was enhanced by the hyperosmotic shock, suggesting a stimulated reduction of the intersystem electron carriers. It is proposed that the osmotic stress stimulates electron donation from stromal components via the NAD(P)H dehydrogenase, which results in the reduction of the intersystem chain and triggering of a state 2 transition leading to stimulated cyclic PSI activity.
A Novel Strategy To Reduce the Immunogenicity of Biological Therapies (2010)

Biological therapies, even humanized mAbs, may induce antiglobulin responses that impair efficacy. We tested a novel strategy to induce tolerance to a therapeutic mAb. Twenty patients with relapsing-remitting multiple sclerosis received an initial cycle of alemtuzumab (Campath-1H), up to 120 mg over 5 d, preceded by 500 mg SM3. This Ab differs from alemtuzumab by a single point mutation and is designed not to bind to cells. Twelve months later, they received a second cycle of alemtuzumab, up to 72 mg over 3 d. One month after that, 4 of 19 (21%) patients had detectable serum anti-alemtuzumab Abs compared with 145 of 197 (74%) patients who received two cycles of alemtuzumab without SM3 in the phase 2 CAMMS223 trial (p < 0.001). The efficacy and safety profile of alemtuzumab was unaffected by SM3 pretreatment. Long-lasting "high-zone" tolerance to a biological therapy may be induced by pretreatment with a high i.v. dose of a drug variant, altered to reduce target-binding.
Recent developments in transient receptor potential vanilloid receptor 1 agonist-based therapies (2004)

Capsaicin and other naturally occurring pungent molecules have been used for centuries as topical analgesics and rubefactants to treat a variety of chronically painful conditions. Recently, instillations of high-concentration capsaicin and resiniferatoxin solutions have been found to be useful for the management of persistent bladder pain or overactive bladder. However, only within the last 7 years has it been appreciated that the selective action of these compounds on a subset of sensory nerve fibres is mediated by agonist activity at a ligand-gated ion channel called the transient receptor potential vanilloid receptor 1 (TRPV1). Accordingly, this discovery has fueled intensive research and drug development efforts, mainly in a search for novel analgesic or anti-inflammatory therapies. Two different, but non-mutually exclusive, strategies are being pursued: optimisation of TRPV1 agonist-based therapies, which can functionally inactivate nociceptive nerve fibres, and identification of receptor antagonists, which would prevent nociceptive fibres from being activated by ongoing inflammatory stimuli. Available information on TRPV1 agonists in development and their biological rationale will be summarised in this review.
Atopic dermatitis: a disease of altered skin barrier and immune dysregulation (2011)

Atopic dermatitis (AD) is an important chronic or relapsing inflammatory skin disease that often precedes asthma and allergic disorders. New insights into the genetics and pathophysiology of AD point to an important role of structural abnormalities in the epidermis as well as immune dysregulation not only for this skin disease but also for the development of asthma and allergies. Patients with AD have a unique predisposition to colonization or infection by microbial organisms, most notably Staphylococcus aureus and herpes simplex virus. Measures directed at healing and protecting the skin barrier and addressing the immune dysregulation are essential in the treatment of patients with AD, and early intervention may improve outcomes for both the skin disease as well as other target organs.
High power demonstration at 10 GHz with GaN-AlGaN HEMT hybrid amplifiers (2002)

The GaN/AlGaN-on-SiC HEMT is being pursued as an RF power device on which to base next generation X-band and K-band power amplifiers. Previous demonstrations of extremely high power density and total RF power from GaN/AlGaN HEMTs on SI SiC substrates (Sheppard et al., 1999; Wu et al., 1999) adequately demonstrate their potential for improved performance over GaAs-based devices. Considering the recent advances in III-nitride growth and processing techniques, it is not surprising that GaN/AlGaN HEMTs on SiC substrates are beginning to the reach the extremely high power levels that have been predicted for this material system. To continue this trend, we are pursuing high quality HEMT structures with 15% AlGaN molar fraction (MF) in order to fabricate large area devices and demonstrate high power levels. We report the demonstration of over 40 W from a single GaN/AlGaN transistor at 10 GHz under pulsed mode conditions. This high power demonstration includes the first implementation of SiC substrate vias on a GaN-on-SiC microwave transistor for improved gain at X-band.