gebhart/patrepeval huggingface dataset:
A key leader in homocystinuria research: Jan P. Kraus (1942–2019) (2019)

Homocystinuria (HCU) research recently lost a great leader. Jan Peter Kraus, Professor of Pediatrics at the University of Colorado Anschutz Medical Campus, passed away on July 4 at the age of 77. Jan was born in London during the World War II and the family returned back to Czechoslovakia in 1945. He studied at the Faculty of Sciences of Charles University in Prague, worked at the Academy of Sciences, and emigrated with his family to Switzerland after the occupation of the country by Soviet Union soldiers in 1968. He received a PhD in biochemistry from the University of Basel, subsequently moved to the Yale University School of Medicine, and he finally settled in Denver becoming a faculty member of the University of Colorado in 1989. In the past three and half decades, Jan studied various aspects of several inborn errors of metabolism with a focus on cystathionine beta-synthase deficiency and propionic acidemia. In his work, he combined various approaches including molecular genetics, enzymology, structural biology, and his group also developed cellular and animal models. More recently, his group in Denver developed an enzyme replacement therapy for classical HCU, which is currently being tested in a clinical trial with patients. Jan had many national and international collaborations with academic scientists as well as industry. He published over 170 papers in international journals, 16 book chapters, and held 8 patents. He was invited to deliver lectures at many international conferences and he received numerous awards and grants. Jan was a member of several professional societies. In addition, he actively participated in community outreach programs, increasing awareness about the importance of research on inborn errors of metabolism to develop new therapies. Jan was a Scientific Advisory Board member of the HCU North America and HCU Australia foundations and collaborated with Propionic Acidemia Foundation. He was actively involved in the peer-review system for the scientific literature, serving as an ad hoc reviewer for number of journals and as a dedicated author, reviewer and Communicating Editor for Human Mutation between 2000 and 2018. As an accomplished scientist, he trained and mentored 26 postdoctoral fellows, who typically spent 1–4 years in his laboratory. Not only a brilliant scientist with a meticulous approach to research, Jan was also a joyful person and a good friend to many people. It was always a pleasure to meet him at various occasions, to enjoy his presence and discussions about everything ranging from science to politics. Jan is survived by his wife Eva, two children Alexander and Hana, and five grandchildren.
183 Proposed Classification System of Radiographic Bone Changes After Cervical Disc Replacement (2023)

INTRODUCTION: Cervical Disc Replacement (CDR) is an increasingly utilized procedure to address cervical degenerative conditions, as an alternative to discectomy and fusion, for the purpose of preserving natural segmental motion. METHODS: Using serial radiographs from patients, a panel of experts assembled for the purpose of creating a classification system to aid in reproducibly and consistently identifying boney changes and assessing CDR device radiographic appearance. Subdividing the superior and inferior vertebral bodies into 3 equal sections, observed bone loss such as endplate rounding, cystic erosion adjacent to the endplate, and cystic erosion not adjacent to the endplate, is recorded. Determining if bone loss is progressive and estimating severity of bone loss (measured by the percentage of end plate involved) is recorded. Additional relevant boney changes and device observations include radiolucent lines, heterotopic ossification, loss of core implant height, and presence of device migration, subsidence, and olisthesis. RESULTS: Serial radiographs from 26 patients implanted with a variety of CDR products were assessed by 6 investigators including clinicians and scientists experienced in CDR or appendicular skeleton joint replacement. After several iterations, a classification system emerged that had improved concordance among the participating investigators. Next steps include assessing reliability with a broad group of clinicians, using serial radiographs from a significant number of patients, to confirm the proposed classification scheme. CONCLUSIONS: A standardized nomenclature for boney changes following CDR will facilitate accurate and reproducible scientific communications regarding the clinical outcomes of this procedure. The novel system proposed demonstrated good concordance among experienced investigators in this field and represents an important advancement.
Small‐Angle Neutron Scattering for In Situ Probing of Ion Adsorption Inside Micropores (2013)

Eingesperrte Ionen: Die hohe Eindringtiefe und Empfindlichkeit der Neutronenstreuung auf Isotopensubstitution wurde genutzt, um Änderungen in der Ionenkonzentration eines porösen Kohlenstoffmaterials als Funktion der angelegten Spannung und der Porengröße zu bestimmen. Abhängig von den Lösungsmitteleigenschaften und den Wechselwirkungen zwischen dem Lösungsmittel und der Porenwand ist die Ionenabsorption verstärkt oder reduziert. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Ask the Experts: Past, Present and Future of the Rule of Five (2013)

Coined in 1997, by Christopher Lipinki et al., the rule of five (Ro5) comprises a set of parameters that determine drug-likeness for oral delivery. The parameters are as follows: no more than five hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms); no more than ten hydrogen bond acceptors (nitrogen or oxygen atoms); a molecular mass less than 500 Da; and an octanol-water partition coefficient log P no greater than 5. Future Medicinal Chemistry invited a selection of leading researchers to express their views on Lipinski's Ro5, which has influenced drug design for over a decade. Their enlightening responses provide an insight into the current and future role of Ro5, and other rules of thumb, in the evolving world of medicinal chemistry.
Protection of calves by a prefusion-stabilized bovine RSV F vaccine (2017)

Bovine respiratory syncytial virus, a major cause of respiratory disease in calves, is closely related to human RSV, a leading cause of respiratory disease in infants. Recently, promising human RSV-vaccine candidates have been engineered that stabilize the metastable fusion (F) glycoprotein in its prefusion state; however, the absence of a relevant animal model for human RSV has complicated assessment of these vaccine candidates. Here, we use a combination of structure-based design, antigenic characterization, and X-ray crystallography to translate human RSV F stabilization into the bovine context. A "DS2" version of bovine respiratory syncytial virus F with subunits covalently fused, fusion peptide removed, and pre-fusion conformation stabilized by cavity-filling mutations and intra- and inter-protomer disulfides was recognized by pre-fusion-specific antibodies, AM14, D25, and MPE8, and elicited bovine respiratory syncytial virus-neutralizing titers in calves >100-fold higher than those elicited by post-fusion F. When challenged with a heterologous bovine respiratory syncytial virus, virus was not detected in nasal secretions nor in respiratory tract samples of DS2-immunized calves; by contrast bovine respiratory syncytial virus was detected in all post-fusion- and placebo-immunized calves. Our results demonstrate proof-of-concept that DS2-stabilized RSV F immunogens can induce highly protective immunity from RSV in a native host with implications for the efficacy of prefusion-stabilized F vaccines in humans and for the prevention of bovine respiratory syncytial virus in calves.
Development of a Recombinant Antigen Vaccine against Infection with the Filarial WormOnchocerca volvulus (2001)

Efforts to control Onchocerca volvulus, the etiologic agent of river blindness, have been limited to vector control and drug treatment to eliminate microfilariae, with no means available to prevent infection. The goal of this study was to develop a vaccine against this infection using recombinant antigens that are expressed in the early larval stages of the parasite. Five recombinant antigens, Ov7, Ov64, OvB8, Ov9M, and Ov73k, were identified by screening adult and larval cDNA libraries with antibodies from immune humans, chimpanzees, or rabbits. When mice were immunized with the five individual recombinant antigens, statistically significant reductions in parasite survival were induced in mice immunized with Ov7, OvB8, or Ov64, when administered in alum but not when injected in Freund's complete adjuvant (FCA). Live larvae recovered from control and immunized mice were analyzed to determine their developmental stages. A decrease in the percentage of larvae molting from the third stage to the fourth stage was observed with mice immunized with Ov7, Ov64, or OvB8 in alum but not with mice immunized with Ov9 and Ov73k or with mice immunized with any of the five antigens in FCA. Mice immunized with a cocktail of the three protective antigens developed protective immunity equal to that seen with mice immunized with individual antigens. This study has identified, for the first time, three recombinant antigens capable of inducing protective immunity to O. volvulus. Furthermore, since the antigens functioned with alum as the adjuvant, this vaccine could potentially be used clinically to prevent river blindness in humans.
Fast Hole Transport in a New Calamitic Liquid Crystal of 2-(4′-Heptyloxyphenyl)-6-Dodecylthiobenzothiazole (1997)

The carrier transport in different phases of a new photoconductive calamitic liquid crystal, 2-(4\ensuremath{'}-heptyloxyphenyl)-6-dodecylthiobenzothiazole was studied by the time-of-flight technique: In the smectic A phase, a fast hole transient photocurrent was obtained in a nondispersive manner, in which the mobility was as high as $5\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}3}\phantom{\rule{0ex}{0ex}}{\mathrm{cm}}^{2}/\mathrm{V}\mathrm{s}$ and independent of applied electric field; in the isotropic phase, however, slower carrier transport was observed, probably due to positive or negative ions, and their mobilities were as low as ${10}^{\ensuremath{-}5}\phantom{\rule{0ex}{0ex}}{\mathrm{cm}}^{2}/\mathrm{V}\mathrm{s}$. These experimental results demonstrate the importance of local molecular alignment in creating the fast electronic conduction in calamitic liquid crystals.
Intramuscular Flunitrazepam Versus Intramuscular Haloperidol in the Emergency Treatment of Aggressive Psychotic Behavior (1999)

OBJECTIVE: The authors examined the efficacy of intramuscular flunitrazepam compared with intramuscular haloperidol for the immediate control of agitated or aggressive behavior in acutely psychotic patients. METHOD: Twenty-eight actively psychotic inpatients, aged 20–60 years, who were under treatment with neuroleptic agents were selected for the study. Each was randomly assigned on a double-blind basis to receive either 5 mg i.m. of haloperidol (N=13) or 1 mg i.m. of flunitrazepam (N=15) during an aggressive event. Verbal and physical aggression was measured over time with the Overt Aggression Scale. Patients were also rated with the Brief Psychiatric Rating Scale and the Clinical Global Impression scale. RESULTS: Both flunitrazepam and haloperidol exhibited acute antiaggressive activity. This beneficial effect, as assessed by the Overt Aggression Scale, was obtained within 30 minutes. CONCLUSIONS: Intramuscular flunitrazepam may serve as a convenient, rapid, safe, and effective adjunct to neuroleptics in reducing aggressive behavior in emergency psychiatric settings.
Treatment of macroprolactinomas with the long-acting and repeatable form of bromocriptine: a report on 29 cases. (1992)

Twenty-nine patients with macroprolactinomas were treated by monthly intramuscular injections of the long-acting and repeatable form of bromocriptine (Parlodel-LAR) in doses ranging from 50-150 mg. They were divided into two groups: group I consisted of 22 patients who received Parlodel LAR before transsphenoidal adenomectomy; group II was composed of 7 patients with earlier neurosurgery and of 2 patients from group I not cured by transsphenoidal adenomectomy. Duration of therapy varied from 1-12 months, and a total of 104 injections was given. At nadir day, serum PRL levels were situated between less than 1% and 43% of pretreatment values. At day 28 after the first injection, serum PRL levels varied between less than 1% to 139% of initial values. No difference could be detected between the two groups regarding the percent of PRL inhibition. Long-term treatment with Parlodel-LAR resulted in a sustained inhibition of PRL secretion, except for 1 case. Resumption of menstrual cycles occurred in 4 out of 15 women and correction of hypogonadism in 4 out of 14 men. Amelioration of disturbed visual fields was recorded in 3 out of 8 patients. Diminution of the adenoma volume was radiologically documented in 14 out of 22 cases. Only few and mild side effects were recorded. One patient with partial adrenal deficiency suffered from a syncope, but this was prevented by hydrocortisone supplementation during the subsequent Parlodel-LAR administration. In conclusion, Parlodel-LAR proved effective in the treatment of macroprolactinomas, achieving rapid inhibition of PRL secretion, and in some patients amelioration of hypopituitarism, reduction in tumor size, and improvement in visual fields, and caused no serious side effects. It is a valuable preparation to surgery and can also be used in long-term medical therapy.
Differential Regional and Subtype-Specific Vulnerability of Enteric Neurons to Mitochondrial Dysfunction (2011)

Mitochondrial dysfunction is a central mediator of disease progression in diverse neurodegenerative diseases that often present with prominent gastrointestinal abnormalities. Gastrointestinal dysfunction in these disorders is related, at least in part, to defects in the enteric nervous system (ENS). The role of mitochondrial deficits in ENS neurodegeneration and their relative contribution to gastrointestinal dysfunction, however, are unclear. To better understand how mitochondrial abnormalities in the ENS influence enteric neurodegeneration and affect intestinal function, we generated mice (Tfam-ENSKOs) with impaired mitochondrial metabolism in enteric neurons and glia through the targeted deletion of the mitochondrial transcription factor A gene (Tfam). Tfam-ENSKO mice were initially viable but, at an early age, they developed severe gastrointestinal motility problems characterized by intestinal pseudo-obstruction resulting in premature death. This gastrointestinal dysfunction was caused by extensive, progressive neurodegeneration of the ENS involving both neurons and glia. Interestingly, mitochondrial defects differentially affected specific subpopulations of enteric neurons and regions of the gastrointestinal tract. Mitochondrial deficiency-related neuronal and glial loss was most prominent in the proximal small intestine, but the first affected neurons, nitrergic inhibitory neurons, had the greatest losses in the distal small intestine. This regional and subtype-specific variability in susceptibility to mitochondrial defects resulted in an imbalance of inhibitory and excitatory neurons that likely accounts for the observed phenotype in Tfam-ENSKO mice. Mitochondrial dysfunction, therefore, is likely to be an important driving force of neurodegeneration in the ENS and contribute to gastrointestinal symptoms in people with neurodegenerative disorders.
The nature of HT V/sub t/ shift in NROM memory transistors (2006)

Physical mechanisms of V/sub t/ shift in NROM (micro FLASH) memory transistors microFLASH memory is the trademark of Tower Semiconductor Ltd. microFLASH is based on the NROM technology. NROM is the trademark of Saifun Semiconductor Ltd. after cycling are considered. Computer simulation is combined with analytical description of kinetics of "fast" V/sub t/ shift after cycling. The distinguishing feature of the developed model is its consistency with the positions of trapped charges obtained from charge pumping measurements and account for Coulomb correlation effects in the dynamics of injected charges in ONO. Accumulation of residual electrons and holes in the injection region and electrons trapped far from the drain is accounted in the model. Two main processes during the cycling determine the further HT V/sub t/ shift: the first one is caused by Coulomb repulsion of injected electrons, and another one is linked to the trapping and re-trapping of electrons. The dependence of "fast" V/sub t/ shift on the number of cycles is obtained and verified by experimental data. The approach can be used to predict the behavior of V/sub t/ during the long-term exploitation of memory devices that experienced up to 10 k program/erase cycles.
Confidence in the National Immunization Program among parents in Sweden 2016 – A cross-sectional survey (2020)

The study demonstrates that parents in Sweden have confidence in and are positive towards vaccinations given within the NIP. One in five parents question vaccines, particularly regarding the HPV vaccine, but still concur to the NIP. Information on vaccines online and at vaccination appointments, including vaccine safety, is important for maintaining confidence in vaccination. Conducting recurring studies is valuable for monitoring vaccine confidence and changes in attitudes towards vaccination.
1P1-C07 Simulation of Radiotherapy for Metastatic Cervical Lymph nodes (2010)

The importance of accurate prediction of the radiotherapeutic effect has increased recently with developing the irradiation techniques. The authors have proposed a novel computational method to simulate changes in tumor volume during the treatment. In this work, the method was applied to six clinical cases of metastatic cervical lymph nodes to examine the feasibility of clinical application of this method. The volume change in tumor shrinkage during treatment was formulated mathematically using analogical equations of an elastic deformation in solid mechanics. The values of simulation parameters were determined for each case so that calculated tumor volume change could be obeyed actual tumor volume change through the treatment. The average difference between the calculated and measured volumes for the six cases was 9.9%. The simulation method was able to represent various patterns of decreases in tumor volume in the cases of metastatic cervical lymph nodes.
Compartmented microfluidic bioreactor system using magnetic enzyme immobilisates for fast small‐scale biotransformation studies (2015)

In the last decade, microfluidic bioreactor systems became increasingly important due to their high suitability for lab‐on‐a‐chip applications and resource‐saving experiments with small sample volumes. Here, a prototype of a microfluidic device for fast small‐scale investigations of enzymatic and biochemical reactions is introduced. Single or consecutive enzyme‐catalyzed reactions can be implemented within compartmented reaction environments separated by immiscible fluidic plugs. By immobilizing one of the reactants onto magnetic microcarriers, a fast and easy separation of the reaction products is possible allowing the realization of a sequence of different reaction steps with different enzymes and varying chemical environments. Besides permanent magnetic fields for separation processes, alternating electromagnetic fields can be applied to resuspend the carriers. This leads to an intense mixing as well as even microcarrier distribution within the compartment. In a proof of concept, kinetic studies of HRP immobilized onto polyvinyl alcohol‐magnetite composite microcarriers are presented. The results showed a specific enzyme activity of approximately 89 units per gram immobilized biocatalyst under the applied reaction conditions. In addition, results of recycling experiments point out the importance of the magnetically induced resuspension. While ten times reuse with immobilisate resuspension resulted in substrate conversion yields between 95 and 65%, the same experiment without the magnetically induced resuspension showed conversion yields below 10% over all cycles.
Sequence-dependent effects in drug-DNA interaction: the crystal structure of Hoechst 33258 bound to the d(CGCAAATTTGCG)2duplex (1994)

The bis-benzimidazole drug Hoechst 33258 has been co-crystallized with the dodecanucleotide sequence d(CGCAAATTTGCG)2. The structure has been solved by molecular replacement and refined to an R factor of 18.5% for 2125 reflections collected on a Xentronics area detector. The drug is bound in the minor groove, at the five base-pair site 5'-ATTTG and is in a unique orientation. This is displaced by one base pair in the 5' direction compared to previously-determined structures of this drug with the sequence d(CGCGAATTCGCG)2. Reasons for this difference in behaviour are discussed in terms of several sequence-dependent structural features of the DNA, with particular reference to differences in propeller twist and minor-groove width.
Genetically modified natural killer cells specifically recognizing the tumor-associated antigens ErbB2/HER2 and EpCAM (2004)

The continuously growing natural killer (NK) cell line NK-92 is highly cytotoxic against malignant cells of various origin without affecting normal human cells. Based on this selectivity, the potential of NK-92 cells for adoptive therapy is currently being investigated in phase I clinical studies. To further enhance the antitumoral activity of NK-92 cells and expand the range of tumor entities suitable for NK-92-based therapies, here by transduction with retroviral vectors we have generated genetically modified NK-92 cells expressing chimeric antigen receptors specific either for the tumor-associated ErbB2 (HER2/neu) antigen or the human Epithelial Cell Adhesion Molecule (Ep-CAM). Both antigens are overexpressed by many tumors of epithelial origin. The chimeric antigen receptors consist of either the ErbB2 specific scFv(FRP5) antibody fragment or the Ep-CAM specific scFv(MOC31), a flexible hinge region derived from CD8, and transmembrane and intracellular regions of the CD3 zeta chain. Transduced NK-92-scFv(FRP5)-zeta or NK-92-scFv(MOC31)-zeta cells express high levels of the fusion proteins on the cell surface as determined by FACS analysis. In europium release assays no difference in cytotoxic activity of NK-92 and transduced NK-92 cells towards ErbB2 or Ep-CAM negative targets was found. However, even at low effector to target ratios transduced NK-92 cells specifically and efficiently lysed established ErbB2 or Ep-CAM expressing tumor cells that were completely resistant to cytolytic activity of parental NK-92 cells. Similarly, ErbB2-positive primary breast cancer cells isolated from pleural effusions of patients with recurrent disease were selectively killed by NK-92-scFv(FRP5)-zeta. In an in vivo model in immunodeficient mice treatment with retargeted NK-92-scFv(FRP5)-zeta, but not parental NK-92 cells resulted in markedly delayed growth of ErbB2 transformed cancer cells. These results demonstrate that efficient retargeting of NK-92 cytotoxicity can be achieved, and might allow the generation of potent cell-based therapeutics for the treatment of ErbB2 and Ep-CAM expressing malignancies. This therapeutic approach might be applicable for a large variety of different cancers where suitable cell surface antigens have been identified.