gebhart/patrepeval huggingface dataset:
Dynamic contrast‐enhanced MRI of experimental spinal cord injury: In vivo serial studies (2001)

The progression of experimental spinal cord injury (SCI) was followed with in vivo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and neurobehavioral studies on postinjury days 0, 2, 4, 7, 10, 14, 17, 21, 28, 35, and 42. Gadopentate dimeglumine (Gd) was administered IV and postcontrast, T(1)-weighted, axial images were acquired repetitively for up to 60 min. Images were analyzed to determine the spatial and temporal evolution of the intensity enhancement. A statistical decision mechanism was developed to objectively detect the enhancement. Strong and rapid enhancement was observed at the epicenter of injury, indicating a significant compromise in blood spinal cord barrier. The enhanced regions in each slice were combined to estimate the area and volume of the lesion. On the day of injury, around 85% of the total cord area at the epicenter showed enhancement within the first 15 min of Gd administration. At the same time, the enhanced volumes attained nearly 40% of the total cord volume and extended axially over 8 mm along the cord. These quantities decreased steadily with time, with a concomitant improvement in the motor functions. The volume of enhancement correlated highly with the neurobehavioral tests (r = -0.87). DCE-MRIs revealed small hyperintense regions distributed inside white matter about two weeks postinjury. Based on histology, these enhancements appear to represent new vessels with "leaky endothelium." Magn Reson Med 45:614-622, 2001.
Querying Shapes of Histories (1995)

We present a shape definition language, called SDL, for retrieving objects based on shapes contained in the histories associated with these objects. It is a small, yet powerful, language that allows a rich variety of queries about the shapes found in historical time sequences. An interesting feature of SDL is its ability to perform blurry matching. A &amp;quot;blurry&amp;quot; match is one where the user cares about the overall shape but does not care about specific details. Another important feature of SDL is its efficient implementability. The SDL operators are designed to be greedy to reduce non-determinism, which in turn substantially reduces the amount of back-tracking in the implementation. We give transformation rules for rewriting an SDL expression into a more efficient form as well as an index structure for speeding up the execution of SDL queries. 1 Introduction Historical time sequences constitute a large portion of data stored in computers. Examples include histories of stock prices, hi...
Physiological Effects of the Synthetic Strigolactone Analog GR24 on Root System Architecture in Arabidopsis: Another Belowground Role for Strigolactones? (2010)

In this study, the role of the recently identified class of phytohormones, strigolactones, in shaping root architecture was addressed. Primary root lengths of strigolactone-deficient and -insensitive Arabidopsis (Arabidopsis thaliana) plants were shorter than those of wild-type plants. This was accompanied by a reduction in meristem cell number, which could be rescued by application of the synthetic strigolactone analog GR24 in all genotypes except in the strigolactone-insensitive mutant. Upon GR24 treatment, cells in the transition zone showed a gradual increase in cell length, resulting in a vague transition point and an increase in transition zone size. PIN1/3/7-green fluorescent protein intensities in provascular tissue of the primary root tip were decreased, whereas PIN3-green fluorescent protein intensity in the columella was not affected. During phosphate-sufficient conditions, GR24 application to the roots suppressed lateral root primordial development and lateral root forming potential, leading to a reduction in lateral root density. Moreover, auxin levels in leaf tissue were reduced. When auxin levels were increased by exogenous application of naphthylacetic acid, GR24 application had a stimulatory effect on lateral root development instead. Similarly, under phosphate-limiting conditions, endogenous strigolactones present in wild-type plants stimulated a more rapid outgrowth of lateral root primordia when compared with strigolactone-deficient mutants. These results suggest that strigolactones are able to modulate local auxin levels and that the net result of strigolactone action is dependent on the auxin status of the plant. We postulate that the tightly balanced auxin-strigolactone interaction is the basis for the mechanism of the regulation of the plants' root-to-shoot ratio.
Pathogenesis of foreign body infection. Evidence for a local granulocyte defect. (1984)

Implanted foreign bodies are highly susceptible to pyogenic infections and represent a major problem in modern medicine. In an effort to understand the pathogenesis of these infections, we studied the phagocytic function in the vicinity of a foreign body by using a recently developed guinea pig model of Teflon tissue cages subcutaneously implanted (Zimmerli, W., F.A. Waldvogel, P. Vaudaux, and U.E. Nydegger, 1982, J. Infect. Dis., 146:487-497). Polymorphonuclear leukocytes (PMN) purified from tissue cage fluid had poor bactericidal activity against a catalase-positive microorganism. When compared with blood or exudate PMN, they exhibited a significant reduction in their ability to generate superoxide in response to a particulate or a soluble stimulus (72 and 57%, respectively, P less than 0.001). Not only their total contents in myeloperoxidase, beta-glucuronidase, lysozyme, and B12 binding protein were significantly reduced (by 62, 21, 47, and 63%, respectively, P less than 0.01), but also their capability for further secretion of residual B12 binding protein upon stimulation. Ingestion rates of endotoxin-coated opsonized oil particles were reduced by 25% (P less than 0.05). In an effort to reproduce these abnormalities in vitro, fresh peritoneal exudate PMN were incubated with Teflon fibers in the presence of plasma. Interaction of PMN with the fibers led to significant increases in hexose monophosphate shunt activity and exocytosis of secondary granules (P less than 0.01). PMN eluted after such interaction showed defective bactericidal activity, oxidative metabolism, and granular enzyme content similar to those observed in tissue cage PMN. The local injection of fresh blood PMN into tissue cages at the time of, or 3 h after, inoculation with 100 microorganisms (Staphylococcus aureus Wood 46) reduced the infection rate from 50 to 56 cages to 1 of 21 (P less than 0.001) and 3 of 8 cages (P less than 0.001), respectively. These results suggest that the in vivo as well as in vitro interaction of PMN with a nonphagocytosable foreign body induces a complex PMN defect, which may be partly responsible for the high susceptibility to infection of foreign bodies.
Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone (2011)

Metastatic disease is the major cause of cancer deaths, and recurrent tumors at distant organs are a critical issue. However, how metastatic tumor cells become dormant and how and why tumors recur in target organs are not well understood. In this study, we demonstrate that BMP7 (bone morphogenetic protein 7) secreted from bone stromal cells induces senescence in prostate cancer stem-like cells (CSCs) by activating p38 mitogen-activated protein kinase and increasing expression of the cell cycle inhibitor, p21, and the metastasis suppressor gene, NDRG1 (N-myc downstream-regulated gene 1). This effect of BMP7 depended on BMPR2 (BMP receptor 2), and BMPR2 expression inversely correlated with recurrence and bone metastasis in prostate cancer patients. Importantly, this BMP7-induced senescence in CSCs was reversible upon withdrawal of BMP7. Furthermore, treatment of mice with BMP7 significantly suppressed the growth of CSCs in bone, whereas the withdrawal of BMP7 restarted growth of these cells. These results suggest that the BMP7-BMPR2-p38-NDRG1 axis plays a critical role in dormancy and recurrence of prostate CSCs in bone and suggest a potential therapeutic utility of BMP7 for recurrent metastatic disease.
Exploration of a New Type of Antimalarial Compounds Based on Febrifugine (2006)

Febrifugine (1), a quinazoline alkaloid, isolated from Dichroa febrifuga roots, shows powerful antimalarial activity against Plasmodium falciparum. The use of 1 as an antimalarial drug has been precluded because of side effects, such as diarrhea, vomiting, and liver toxicity. However, the potent antimalarial activity of 1 has stimulated medicinal chemists to pursue compounds derived from 1, which may be valuable leads for novel drugs. In this study, we synthesized a new series of febrifugine derivatives formed by structural modifications at (i) the quinazoline ring, (ii) the linker, or (iii) the piperidine ring. Then, we evaluated their antimalarial activities. Thienopyrimidine analogue 15 exhibited a potent antimalarial activity and a high therapeutic selectivity both in vitro and in vivo, suggesting that 15 is a good antimalarial candidate.
Acne and rosacea (1992)

This enlarged and revised edition covers all aspects of acne, acne-like disorders and rosacea. It is designed for those physicians - general practitioners, paediatricians, gynaecologists, pharmacologists, surgeons and dermatologists - who must identify and treat the many different forms of these diseases. It not only covers the physiology, pathology, bacteriology and endocrinology of these disorders, but also places special emphasis on their histopathologic examination. The text is supplemented by selected references and an illustrated portfolio of gross and histopathological pictures. The latest therapeutic strategies as well as conventional options are covered. The spectrum of pharmacological and physical methods of controlling acne, acne-like diseases and rosacea are critically examined.
Human bactericidal/permeability-increasing protein and a recombinant NH2-terminal fragment cause killing of serum-resistant gram-negative bacteria in whole blood and inhibit tumor necrosis factor release induced by the bacteria. (1992)

The bactericidal/permeability-increasing protein (BPI) of neutrophils and BPI fragments neutralize the effects of isolated Gram-negative bacterial lipopolysaccharides both in vitro and in vivo. Since endotoxin most commonly enters the host as constituents of invading Gram-negative bacteria, we raised the question: Can BPI and its bioactive fragments also protect against whole bacteria? To determine whether the bactericidal and endotoxin-neutralizing activities of BPI/fragments are expressed when Gram-negative bacteria are introduced to the complex environment of whole blood we examined the effects of added BPI and proteolytically prepared and recombinant NH2-terminal fragments on: (a) the fate of serum-resistant encapsulated Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa that survive the antibacterial actions of whole blood and (b) the ability of these bacteria to trigger cytokine release. Added BPI in nanomolar concentrations killed each of three encapsulated strains of E. coli and in closely parallel fashion inhibited tumor necrosis factor (TNF) release. Holo-BPI and its NH2-terminal fragment were equipotent toward a rough LPS chemotype K1-encapsulated strain, but the fragment was substantially more potent than holo-BPI toward two encapsulated smooth LPS chemotype strains. TNF release induced by K. pneumoniae and P. aeruginosa was also inhibited by both holo-BPI and fragment but, at the protein concentrations tested, P. aeruginosa was killed only by the fragment and K. pneumoniae was not killed by either protein. The bactericidal action of BPI/fragment toward E. coli is inhibited by C7-depleted serum, but accelerated by normal serum, indicating that BPI, acting in synergy with late complement components, enhances extracellular killing of serum-resistant bacteria. Thus, BPI and an even more potent NH2-terminal fragment may protect against Gram-negative bacteria in the host by blocking bacterial proliferation as well as endotoxin-mediated effects, not only as components of the intracellular antibacterial arsenal of the neutrophil, but also as potentially therapeutic extracellular agents.
Expression of nicotinic acetylcholine receptor subunits in the cerebral cortex in Alzheimer’s disease: histotopographical correlation with amyloid plaques and hyperphosphorylated‐tau protein (1999)

Abstract Impairment of cholinergic transmission and decreased numbers of nicotinic binding sites are well‐known features accompanying the cognitive dysfunction seen in Alzheimer’s disease (AD). In order to elucidate the underlying cause of this cholinoceptive dysfunction, the expression of two pharmacologically different nicotinic acetylcholine receptor (nAChR) subunits (α4, α7) was studied in the cerebral cortex of Alzheimer patients as compared to controls. Patch‐clamp recordings of 14 dissociated neurons of control cortices showed responses suggesting the existence of α4‐ and α7‐containing functional nAChRs in the human cortex. In cortices of Alzheimer patients and controls, the pattern of distribution and the number of α4 and α7 mRNA‐expressing neurons were similar, whereas at the protein level a decrease in the density of α4‐ and α7‐expressing neurons of ≈ 30% was observed in Alzheimer patients. The histotopographical correlation of nAChR expression with accompanying pathological changes, e.g. accumulation of hyperphosphorylated‐tau (HP‐tau) protein and β‐amyloid showed that neurons in the vicinity of β‐amyloid plaques bore both nAChR transcripts. Neurons heavily labelled for HP‐tau, however, expressed little or no α4 and α7 mRNA. These results point to an impaired synthesis of nAChRs on the protein level as a possible cause of the cholinoceptive deficit in AD. Further investigations need to elucidate whether interactions of HP‐tau with nAChR mRNA, or alterations in the quality of α4 and α7 transcripts give rise to decreased protein expression at the level of individual neurons.
Clinical Gene Therapy Research Utilizing Ribozymes: Application to the Treatment of HIV/AIDS (2004)

Antiretroviral drug therapy can effectively reduce the viral load, and is associated with a degree of immune reconstitution in human immunodeficiency virus (HIV)-infected patients. However, the presence of a latent viral reservoir, the development of drug resistance, drug toxicity, and compliance problems are obstacles that impede full eradication of HIV through drug therapy. The cellular introduction of genetic elements that are capable of inhibiting HIV replication is conceptually appealing as a potential new treatment paradigm for acquired immunodeficiency syndrome (AIDS). In theory, this approach can lead to the development of regenerated hematopoiesis with cells that inhibit viral replication and are protected from the pathogenic effects of HIV. Ribozymes are catalytic RNA molecules that can efficiently and selectively cleave target RNA. By ex vivo retroviral transduction, we have introduced a HIV-1 tat gene-targeted ribozyme (RRz2) and a control construct (LNL6) into granulocyte-colony-stimulating factor (G-CSF) mobilized CD34+ hematopoietic progenitor cells (HPC). Transduced autologous CD34+ cells (an approximately equal mix of RRz2 and LNL6) were infused in 10 patients in this Phase I study. After a median follow-up of 2.5 yr, gene presence and expression were detected by a sensitive polymerase chain reaction (PCR) assay in a transduced-CD34+ cell dose-dependent manner. In this chapter, we describe general considerations related to HIV hematopoietic progenitor-cell gene therapy trial design, implementation, and safety, with an emphasis on the critical steps of this process, namely vector production and characterization, target-cell selection, transduction, final product release testing, and evaluation of vector presence.
Polypeptides of Bovine Rotavirus (1979)

Polyacrylamide gel electrophoresis of bovine rotavirus or neonatal calf diarrhoea virus (NCDV) grown in cell culture resolved eight species of polypeptide. The inner shell particles contained five polypeptides and the outer shell three polypeptides. A major polypeptide of the outer shell was glycosylated. The infectivity of NCDV was enhanced by treatment with trypsin in vitro. All eight polypeptides were affected by trypsin treatment as judged by diminished intensity of polypeptide bands by radiography and several new bands appeared. The intracellular synthesis of NCDV polypeptides was studied by pulse and pulse-chase experiments. Infected cells contained all eight virus capsid proteins and, in addition, three presumably virus-specific polypeptides which were non-capsid polypeptides (NCVP). There was no evidence that any of these polypeptides was processed after synthesis. It is suggested, therefore, that all these polypeptides are primary gene products.
Third-generation feed stocks for the clean and sustainable biotechnological production of bulk chemicals: synthesis of 2-hydroxyisobutyric acid (2012)

Abstract Background The synthesis of 2-hydroxyisobutyric acid (2-HIB), a promising building block for, e.g., Plexiglas® production, is described as an example for a clean and sustainable bioproduction. Methods A derivative strain of Cupriavidus necator H16, impaired in the poly- ß -hydroxybutyrate synthesis pathway and equipped with xenogenic 2-hydroxyisobutyryl-coenzyme A mutase from Aquincola tertiaricarbonis L108, was applied. Batch cultivation was performed in the presence of vitamin B12 by supplying a gas mixture comprising hydrogen, oxygen, and carbon dioxide. Results Exploiting the chemo-litho-autotrophic potential of this so-called knallgas bacterium, 2-HIB was synthesized and excreted into the cultivation broth under aerobic conditions when inorganic nitrogen-limited conditions allowed an overflow metabolism of carbon metabolites. 2-HIB synthesis proceeded at a rate of 8.58 mg/[(g bacterial dry mass)·h]. Approximately 400 mg/L in total was obtained. The results were subsequently compared to calculated model data to evaluate the efficiency of the conversion of the substrates into the product. To achieve overall yield data regarding the substrate conversion, the model describes an integral process which includes both 2-HIB synthesis and biomass formation. Conclusions This study has confirmed the feasibility of the microbial synthesis of the bulk chemical 2-HIB from hydrogen and carbon dioxide by exploiting the chemo-litho-autotrophic metabolism of C. necator H16 PHB − 4, additionally expressing the foreign 2-HIB-coenzyme A mutase. The product synthesis was satisfying as a proof of principle but does not yet approach the maximum value as derived from the model data. Furthermore, the biosynthesis potential of an optimized process is discussed in view of its technical application.
In vitro Screening of Putative Compounds Inducing Fetal Porcine Pancreatic β-cell Differentiation: Implications for Cell Transplantation in Insulin-dependent Diabetes Mellitus (1993)

Successful transplantation of fetal pancreatic beta-cells to diabetic recipients requires that differentiation of the immature beta-cells is achieved. Animal experiments have shown that this can occur in vivo, but it would be desirable to induce beta-cell maturation in vitro prior to transplantation. For that purpose the effect of several putative inducers of beta-cell differentiation and/or replication in explant cultures of fetal porcine pancreatic islet-like cell clusters (ICC) were investigated. Initial screening experiments indicated that dexamethasone (DEX; 200 ng/ml) and sodium butyrate (BUT; 2 mM) might promote beta-cell differentiation as evidenced by increased insulin/DNA contents in the ICC. In subsequent experiments these two substances, and also nicotinamide (NIC; 10 mM) which previously has been found to promote fetal beta-cell differentiation, were added alone or in combinations to the basal control medium consisting of RPMI 1640 + 1% human serum. All three test agents alone or in combinations increased the insulin content/DNA of the ICC compared with that of the control group. The combination of NIC+DEX increased the insulin mRNA levels of the ICC. No significant stimulation of insulin release was observed in any test group after short-term incubation with high glucose alone. Addition of 5 mM theophylline to high glucose stimulation, however, increased the insulin secretion in most groups of ICC. Finally, ICC in groups of about 600, which had developed in the presence of NIC or NIC+DEX, were transplanted under the kidney capsule of alloxan-diabetic nude mice. However, neither the time for reversal of diabetes (4 weeks) nor the amount of insulin secretion during perfusion from the grafted ICC were further affected by adding DEX to the NIC supplemented medium. The marked increase of the insulin content of the ICC cultured with DEX supplementation, appeared transient and was not manifested after transplantation. In conclusion, the present study demonstrated that some compounds can stimulate porcine fetal beta-cells in an in vitro system, but in order to attain terminal differentiation of the beta-cells including glucose-sensitive insulin secretion, longer observation periods might be required than used herein. Alternatively, an in vivo environment like that after transplantation is mandatory for this process.
Sacral nerve stimulation for faecal incontinence: response rate, satisfaction and the value of preoperative investigation in patient selection (2009)

The findings suggest that investigation for FI does not facilitate patient selection for SNS and cannot be used to predict outcome.
A Universal Approach to Optimize the Folding and Stability of Prefusion-Closed HIV-1 Envelope Trimers (2018)

The heavily glycosylated native-like envelope (Env) trimer of HIV-1 is expected to have low immunogenicity, whereas misfolded forms are often highly immunogenic. High-quality correctly folded Envs may therefore be critical for developing a vaccine that induces broadly neutralizing antibodies. Moreover, the high variability of Env may require immunizations with multiple Envs. Here, we report a universal strategy that provides for correctly folded Env trimers of high quality and yield through a repair-and-stabilize approach. In the repair stage, we utilized a consensus strategy that substituted rare strain-specific residues with more prevalent ones. The stabilization stage involved structure-based design and experimental assessment confirmed by crystallographic feedback. Regions important for the refolding of Env were targeted for stabilization. Notably, the α9-helix and an intersubunit β sheet proved to be critical for trimer stability. Our approach provides a means to produce prefusion-closed Env trimers from diverse HIV-1 strains, a substantial advance for vaccine development.