gebhart/patrepeval huggingface dataset:
Differential Expression of Matrix Metalloproteinases and Their Tissue-Derived Inhibitors in Cutaneous Wound Repair (2000)

Wound extracellular matrix is a key regulator of cell adhesion, migration, proliferation, and differentiation during cutaneous repair. The amount and organization of normal wound extracellular matrix are determined by a dynamic balance among overall matrix synthesis, deposition, and degradation. Matrix metalloproteinases (MMPs) are one family of structurally related enzymes that have the collective ability to degrade nearly all extracellular matrix components. The MMPs are broadly categorized into collagenases, gelatinases, stromelysins, and membrane-type MMPs by their substrate specificity. The aim of this study was to characterize the temporal changes in mRNA profiles for rat collagenase [matrix metalloproteinase-1 (MMP-1)], gelatinase A (MMP-2), matrilysin (MMP-7), gelatinase B (MMP-9), and membrane type 1-MMP (MT1-MMP), as well as tissue inhibitor of metalloproteinases-1 (TIMP-1), TIMP-2, and TIMP-3 during the inflammatory, granulation, and early remodeling phases of excisional skin repair. Eight full-thickness skin wounds were made on the backs of each rat (7-mm2 wounds; 16 rats; n = 128 wounds). Two animals at a time were reanesthetized, and all eight wounds on each animal were excised at 12 and 24 hours and at 2, 3, 5, 7, 10, and 14 days after injury. Six wounds from each animal were excised for RNA isolation, whereas two wounds were excised for histology. Controls consisted of nonwounded skin from identical locations in four animals. Total RNA from each time point was isolated and relative mRNA quantitation performed by using reduced-cycle reverse transcription-polymerase chain reaction. Correct polymerase chain reaction product amplification was confirmed by probing the blotted polymerase chain reaction product with a 32P-labeled oligonucleotide specific for a given MMP or TIMP. We demonstrated that the majority of MMP and TIMP mRNA induction and peak expression coincided temporally with the well-characterized inflammatory and granulation stages of repair. In conclusion, there is a distinct pattern of MMP and TIMP expression during normal excisional wound repair.
Antigenic and Genetic Evolution of Swine Influenza A (H3N2) Viruses in Europe (2007)

In the early 1970s, a human influenza A/Port Chalmers/1/73 (H3N2)-like virus colonized the European swine population. Analyses of swine influenza A (H3N2) viruses isolated in The Netherlands and Belgium revealed that in the early 1990s, antigenic drift had occurred, away from A/Port Chalmers/1/73, the strain commonly used in influenza vaccines for pigs. Here we show that Italian swine influenza A (H3N2) viruses displayed antigenic and genetic changes similar to those observed in Northern European viruses in the same period. We used antigenic cartography methods for quantitative analyses of the antigenic evolution of European swine H3N2 viruses and observed a clustered virus evolution as seen for human viruses. Although the antigenic drift of swine and human H3N2 viruses has followed distinct evolutionary paths, potential cluster-differentiating amino acid substitutions in the influenza virus surface protein hemagglutinin (HA) were in part the same. The antigenic evolution of swine viruses occurred at a rate approximately six times slower than the rate in human viruses, even though the rates of genetic evolution of the HA at the nucleotide and amino acid level were similar for human and swine H3N2 viruses. Continuous monitoring of antigenic changes is recommended to give a first indication as to whether vaccine strains may need updating. Our data suggest that humoral immunity in the population plays a smaller role in the evolutionary selection processes of swine H3N2 viruses than in human H3N2 viruses.
Disulfide Bonds Are Generated by Quinone Reduction (2000)

The chemistry of disulfide exchange in biological systems is well studied. However, very little information is available concerning the actual origin of disulfide bonds. Here we show that DsbB, a protein required for disulfide bond formation in vivo, uses the oxidizing power of quinones to generate disulfides de novo. This is a novel catalytic activity, which to our knowledge has not yet been described. This catalytic activity is apparently the major source of disulfides in vivo. We developed a new assay to characterize further this previously undescribed enzymatic activity, and we show that quinones get reduced during the course of the reaction. DsbB contains a single high affinity quinone-binding site. We reconstitute oxidative folding in vitro in the presence of the following components that are necessary in vivo: DsbA, DsbB, and quinone. We show that the oxidative refolding of ribonuclease A is catalyzed by this system in a quinone-dependent manner. The disulfide isomerase DsbC is required to regain ribonuclease activity suggesting that the DsbA-DsbB system introduces at least some non-native disulfide bonds. We show that the oxidative and isomerase systems are kinetically isolated in vitro. This helps explain how the cell avoids oxidative inactivation of the disulfide isomerization pathway.
Antibiotic-Induced Biofilm Formation (2011)

Surface-attached colonies of bacteria known as biofilms play a major role in the pathogenesis of device-related infections. Biofilm colonies are notorious for their resistance to suprainhibitory concentrations of antibiotics. Numerous studies have shown that subminimal inhibitory concentrations of some antibiotics can act as agonists of bacterial biofilm formation in vitro, a process that may have clinical relevance. This article reviews studies demonstrating that low-dose antibiotics induce bacterial biofilm formation. These studies have provided important information about the regulation of biofilm formation and the signaling pathways involved in global gene regulation in response to cell stressors. It is still unclear whether antibiotic-induced biofilm formation contributes to the inconsistent success of antimicrobial therapy for device infections.
Reusable skinning templates using cage-based deformations (2008)

Character skinning determines how the shape of the surface geometry changes as a function of the pose of the underlying skeleton. In this paper we describe skinning templates, which define common deformation behaviors for common joint types. This abstraction allows skinning solutions to be shared and reused, and they allow a user to quickly explore many possible alternatives for the skinning behavior of a character. The skinning templates are implemented using cage-based deformations, which offer a flexible design space within which to develop reusable skinning behaviors. We demonstrate the interactive use of skinning templates to quickly explore alternate skinning behaviors for 3D models.
122-channel squid instrument for investigating the magnetic signals from the human brain (1993)

A 122-channel d.c. SQUID magnetometer with a helmet-shaped detector array covering the subject's head has been operational in the Low Temperature Laboratory of the Helsinki University of Technology since June 1992. The new system allows simultaneous recording of magnetic activity all over the head. The probe employs 122 planar first-order thin-film gradiometers in dual units with two exactly orthogonal channels at 61 measurement sites. The performance of the device is analyzed and compared with more conventional axial gradiometer arrays by considering signal-to-noise ratios, spatial sampling theory, confidence intervals for the estimated equivalent current dipole positions, and information-theoretical channel capacity. The signal-to-noise ratio and the resolution of the planar and axial arrays with the same number of channels are found practically equal. The number of channels and their spacing in our new Neuromag-122 system are found fully adequate for neuromagnetic measurements. An example of whole cortex recordings of auditory evoked brain activity is presented and analyzed.
The current status of toxicity protectants in cancer therapy. (1992)

Current therapies for the treatment of malignancies are associated with significant toxicity, as chemotherapy and radiation therapy do not discriminate between normal and malignant cells. One approach to ameliorating the toxicity associated with therapy is through the use of chemoprotective agents. This article reviews a variety of agents that have been evaluated as possible protectants, including WR-2721 and the colony-stimulating factors. It is hoped that the understanding of how to optimally use chemoprotective agents will lead to more tolerable treatments for patients, and possibly allow for dose-escalation, which may contribute to improvement in patient survival.
The expression of alpha-haemolysin is required forStaphylococcus aureusphagosomal escape after internalization in CFT-1 cells (2008)

Staphylococcus aureus colonizes the lungs of cystic fibrosis patients and treatment with antibiotics usually results in recurrent and relapsing infections. We have shown that S. aureus can invade and replicate within a cystic fibrosis epithelial cell line (CFT-1), and that these internalized bacteria subsequently escape from the endocytic vesicle. The accessory gene regulator, agr, in S. aureus has been shown to control the expression of a large number of secreted toxins involved in virulence. Here we show that an agr mutant of S. aureus strain RN6390 was unable to escape from the endocytic vesicle after invasion of the CFT-1 cells using markers of vesicular trafficking (LAMP-1 and 2, LysoTracker and Vacuolar-ATPase). Trafficking analysis of live S. aureus which did not express alpha-haemolysin, a specific agr regulated toxin, revealed a defect in vesicular escape that was undistinguishable from the trafficking defect exhibited by the agr mutant. Furthermore, overexpression of alpha-haemolysin under an inducible promoter in an agr mutant of S. aureus partially restored the phagosome-escaping phenotype of an agr mutant. These results demonstrate that the expression of agr is required for vesicular escape, and that biologically active alpha-haemolysin is required for S. aureus escape from the endocytic vesicle into the cytosol of CFT-1 cells.
Brain heating induced by near-infrared lasers during multiphoton microscopy (2016)

Two-photon imaging and optogenetic stimulation rely on high illumination powers, particularly for state-of-the-art applications that target deeper structures, achieve faster measurements, or probe larger brain areas. However, little information is available on heating and resulting damage induced by high-power illumination in the brain. In the current study we used thermocouple probes and quantum dot nanothermometers to measure temperature changes induced by two-photon microscopy in the neocortex of awake and anaesthetized mice. We characterized heating as a function of wavelength, exposure time, and distance from the center of illumination. Although total power is highest near the surface of the brain, heating was most severe hundreds of micrometers below the focal plane, due to heat dissipation through the cranial window. Continuous illumination of a 1-mm 2 area produced a peak temperature increase of ∼1.8°C/100 mW. Continuous illumination with powers above 250 mW induced lasting damage, detected with immunohistochemistry against Iba1, glial fibrillary acidic protein, heat shock proteins, and activated caspase-3. Higher powers were usable in experiments with limited duty ratios, suggesting an approach to mitigate damage in high-power microscopy experiments.
Visual interface for retrieval of electronic-formed books (2002)

The authors address visual interface and virtual manipulation for full text management. Their objective is to investigate the retrieval/reference mechanism of computer-readable full texts as if paper-form books were being manipulated directly in the real world. This mechanism is derived basically from the object-linking facility of hypersystems. Of course, the facility must be applicable to the manipulation of a great deal of electronic-formed books, like the traditional information retrieval systems, through hypersystems are suitable to only private filing applications.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Thyromimetic effects of 3,5,3'-triiodothyronine sulfate in hypothyroid rats. (1993)

Several parameters of the effects of thyroid hormone were examined in hypothyroid thyroidectomized (Tx) rats treated with T3 sulfate (T3S) or T3 [0.46 (low dose) or 2.3 (high dose) nmol/day for 10 days, ip]. Tx rats showed a marked degree of growth retardation, which improved significantly after treatment with both doses of T3S and T3. The mean serum GH level was markedly reduced in Tx rats, and it improved significantly to similar levels after treatment with the high dose of T3S and the low dose of T3. Type I monodeiodinase (MD) activity was markedly reduced in liver and kidney tissues of Tx rats. It increased significantly in Tx rats treated with the high dose of T3S; the latter values were similar to those observed in Tx rats treated with the low dose of T3. Hepatic and renal type I MD activities increased to supranormal levels in Tx rats treated with the high dose of T3. Cardiac outer ring (5') monodeiodination of 3',5'-diiodothyronine to 3'-monoiodothyronine was also significantly reduced in Tx rats, but it improved significantly only after treatment with the high dose of T3. Type III 5-MD activity was significantly reduced in the cerebral cortex of Tx rats. It was restored to normal in Tx rats treated with the high dose of T3S and both doses of T3. Serum TSH, markedly elevated in Tx rats, was appreciably reduced only in rats treated with the high dose of T3. In another study, significant suppression of serum TSH was observed when Tx rats were treated with T3S (11.5 nmol/day) or T3 (2.3 nmol/day) for 3 days. We conclude that administration of T3S to hypothyroid rats produces thyromimetic effects, with a potency approximately one fifth that of T3.
SENSORY ACTION POTENTIALS AND BIOPSY OF THE SURAL NERVE IN NEUROPATHY (1978)

In 167 consecutive patients with various types of neuropathy, the amplitude of the sensory potential and the maximum conduction velocity along the sural nerve were compared with conduction in other sensory nerves, and were related to structural changes revealed by nerve biopsy. Electrophysiological findings in the sural nerve were similar to those in the superficial peroneal and the median nerve, though the distal segment of the median nerve was normal in 20 per cent of the patients when it was abnormal in the sural nerve. Quantitation of histological findings was a more sensitive method than the electrophysiological study in that two-thirds of 33 patients with normal electrophysiology in the sural nerve showed mild loss of fibres or signs of remyelination in teased fibres. The amplitude of the sensory potential was grossly related to the number of large myelinated fibres (more than 7 micrometer in diameter). Considering the 95 nerves from which teased fibres were obtained, maximum conduction velocity was abnormal in half. In 18 of these nerves, slowing in conduction was due to axonal degeneration: the velocity was as to be expected from the diameter of the largest fibres in the biopsy ("proportionate slowing"). In 9 nerves slowing was severe and more marked than to be expected from loss of the largest fibres ("disproportionate slowing"); these nerves showed paranodal or segmental demyelination in more than 30 per cent of the fibres. In 16 nerves from patients with neuropathy of different aetiology neither loss of fibres nor demyelination could explain the moderate slowing. The cause of slowing in these nerves is unknown; other conditions are referred to in which slowing in conduction cannot be attributed to morphological changes. Finally, electrophysiological and histological findings are reported in some patients with neuropathy associated with malignant neoplasm, with rheumatoid arthritis, with polyarteritis nodosa, with acute intermittent porphyria and with cirrhosis of the liver.
Safety, PK/PD, and anti-tumor activity of RO6874281, an engineered variant of interleukin-2 (IL-2v) targeted to tumor-associated fibroblasts via binding to fibroblast activation protein (FAP). (2018)

e15155 Background: High-dose (HD) IL-2 is approved for patients with melanoma and renal cell carcinoma but is associated with significant toxicity, given only in an inpatient setting. RO6874281 is a novel, monomeric, bispecific IL-2v immunocytokine that completely lacks binding to IL-2Rα, retains IL-2Rβγ binding, and shows pM binding affinity to FAP on tumor-associated fibroblasts. While the IL-2v domain activates IL-2R expressing immune effector CD8 T and NK cells independent of FAP-binding, targeting via FAP results in retention of IL-2v within tumors in order to selectively promote immune responses within the tumor microenvironment. Methods: Study BP29842 investigated safety, PK/PD and anti-tumor activity of RO6874281. Multiple ascending doses ranging from 5mg to 35mg were given weekly i.v. in an outpatient setting to 35 patients with metastatic solid tumors. Results: Most frequent adverse events ( > 30%) were pyrexia, infusion related reactions, fatigue/asthenia, nausea, diarrhea, decreased appetite and elevated aspartate and/or alanine transaminase. The majority of events were mild or moderate (Grade 1/2). The maximum tolerated dose was declared at 20mg, using one-step intra-patient escalation (15mg followed by 20mg). Preliminary PK analysis indicated a non-linear elimination profile typical of target mediated drug disposition. Single safe doses of RO6874281 yielded > 6 fold higher exposures than those achieved with a full cycle of conventional HD IL-2. As expected from abolished IL-2Rα binding, RO6874281 rapidly expands effector T and NK cells but not Tregs, both in peripheral blood and tumors. Objective long-lasting ( > 6 months) responses were observed in one patient each with head and neck cancer, penile squamous cell carcinoma and checkpoint inhibitor resistant malignant melanoma across the tested dose range. Conclusions: RO6874281 is the first targeted IL-2 variant with acceptable outpatient safety to display monotherapy activity including in tumor types not previously reported to respond to IL-2. Ph1b/Ph2 studies in combination with atezolizumab and other agents are currently underway. Clinical trial information: NCT02627274.
Biofunctionalization of Silica-Coated CdTe and Gold Nanocrystals (2002)

This contribution reports the synthesis of water-soluble silica-coated CdTe nanocrystals that possess an ideally designed ligand shell with respect to colloidal properties and surface coupling reactions. We describe conjugation strategies for the modification of the fluorescent biocompatible nanocrystals with biomolecules that provide a molecular recognition potential like the biotin/avidin couple and DNA.
Cooperativity in the dissociation of nitric oxide from hemoglobin. (1976)

The dissociation of nitric oxide from hemoglobin, from isolated subunits of hemoglobin, and from myoglobin has been studied using dithionite to remove free nitric oxide. The reduction of nitric oxide by dithionite has a rate of 1.4 X 10(3) M-1 S-1 at 20 degrees in 0.05 M phosphate, pH 7.0, which is small compared with the rate of recombination of hemoglobin with nitric oxide (25 X 10(6) M-1 S-1 (Cassoly, R., and Gibson, Q. H. (1975) J. Mol. Biol. 91, 301-313). The rate of NO combination with chains and myoglobin was found to be 24 X 10(6) M-1 S-1 and 17 X 10(6) M-1 S-1, respectively. Hence, the observed progress curve of the dissociation of nitric oxide is dependent upon the dithionite concentration and the total heme concentration. Addition of excess carbon monoxide to the dissociation mixture reduces the free heme yielding a single exponential process for chains and for myoglobin which is dithionite and heme concentration independent over a wide range of concentrations. The rates of dissociation of nitric oxide from alpha chains, from beta chains, and from myoglobin are 4.6 X 10(-5) S-1, 2.2 X 10(-5) S-1, and 1.2 X 10(4) S-1, respectively, both in the presence and in the absence of carbon monoxide at 20 degrees in 0.05 M phosphate, pH 7.0. Analogous heme and dithionite concentration dependence is found for the dissociation of nitric oxide from tetrameric hemoglobin. The reaction is cooperative, the intrinsic rate constants for the dissociation of the 1st and 4th molecules of NO differing about 100-fold. With hemoglobin, replacement of NO by CO at neutral pH is biphasic in phosphate buffers. The rate of the slow phase is 1 X 10(-5) S-1 and is independent of pH. The amplitude of the fast phase increases with lowering of pH. By analogy with the treatment of the HbCO + NO reaction given by Salhany et al. (Salhany, J.M., Ogawa, S., and Shulman, R.G. (1975) Biochemistry 14, 2180-2190), the fast phase is attributed to the dissociation of NO from T state molecules and the slow phase to dissociation from R state molecules. Analysis of the data gives a pH-independent value of 0.01 for the allosteric constant c (c = Kr/Kt where Kr and Kt are the dissociation constants for NO from the R and T states, respectively) and pH-dependent values of L (2.5 X 10(7) at pH 7 in 0.05 M phosphate buffer). The value of c is considerably greater than that for O2 and CO. Studies of the difference spectrum induced in the Soret region by inositol hexaphosphate are also reported. This spectrum does not arise directly from the change of conformation between R and T states. The results show that if the equilibrium binding curve for NO could be determined experimentally, it would show cooperativity with Hill's n at 50% saturation of about 1.6.
Glucose Transporter of Escherichia coli:  NMR Characterization of the Phosphocysteine Form of the IIBGlc Domain and Its Binding Interface with the IIAGlc Subunit (1997)

The transmembrane subunit of the glucose transporter, IICB(Glc), mediates vectorial transport with concomitant phosphorylation of glucose. Glucose phosphorylation proceeds through a cystein phosphate intermediate of the cytosolic IIB domain of IIC(Glc), which is phosphorylated by the IIA(Glc) subunit of the glucose transporter. Two- and three-dimensional NMR experiments were used to characterize the phosphorylation of the 10 kDa subclonal IIB domain and the complementary binding interfaces of [15N]IIB and [15N]IIA(Glc). The largest chemical shift perturbations and the only NOE differences accompanying IIB phosphorylation are confined to the active site residue Cys35, as well as Ile36, Thr37, Arg38, Leu39, and Arg40, which are all located in the turn between strands beta1 and beta2 and on beta2 itself. The significant increase of the amide cross-peak intensities of Ile36, Thr37, and Arg38 upon phosphorylation suggests that the conformational freedom of these groups becomes restrained, possibly due to hydrogen bonding to the oxygens of the bound phosphate and to interactions between the guanidinium group of Arg38 and the phosphoryl group. The residues of IIB which experience chemical shift perturbations upon binding of IIA are located on a protruding surface formed by residues of strands beta1, beta2, and beta4, the beta4/alpha3 loop, and residues from the first two turns of alpha3. The corresponding binding surface of the IIA(Glc) domain is comprised of residues on five adjacent beta-strands and two short helices surrounding the active site His90. The binding surface of IIA(Glc) for IIB coincides with the binding surface for HPr, the phosphoryl carrier protein by which IIA(Glc) is phosphorylated [Chen, Y., Reizer, J., Saier, M. H., Fairbrother, W. J., & Wright, P. E. (1993) Biochemistry 32, 32-37].