gebhart/patrepeval huggingface dataset:
Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression. (1994)

Phosphorylation of CREB (cyclic AMP [cAMP]- response element [CRE]-binding protein) by cAMP-dependent protein kinase (PKA) leads to the activation of many promoters containing CREs. In neurons and other cell types, CREB phosphorylation and activation of CRE-containing promoters can occur in response to elevated intracellular Ca2+. In cultured cells that normally lack this Ca2+ responsiveness, we confer Ca(2+)-mediated activation of a CRE-containing promoter by introducing an expression vector for Ca2+/calmodulin-dependent protein kinase type IV (CaMKIV). Activation could also be mediated directly by a constitutively active form of CaMKIV which is Ca2+ independent. The CaMKIV-mediated gene induction requires the activity of CREB/ATF family members but is independent of PKA activity. In contrast, transient expression of either a constitutively active or wild-type Ca2+/calmodulin-dependent protein kinase type II (CaMKII) fails to mediate the transactivation of the same CRE-containing reporter gene. Examination of the subcellular distribution of transiently expressed CaMKIV and CaMKII reveals that only CaMKIV enters the nucleus. Our results demonstrate that CaMKIV, which is expressed in neuronal, reproductive, and lymphoid tissues, may act as a mediator of Ca(2+)-dependent gene induction.
Innovative Therapies in Wound Healing (2003)

Bioengineered skin acts as a "smart" delivery system for growth factors and other stimulatory substances. Not only does it present a novel treatment for chronic and diabetic ulcers, but it could also be considered for application to other types of acute wounds.
Incidence, Seasonality, Age Distribution, and Mortality of Pneumococcal Meningitis in Burkina Faso and Togo (2009)

Streptococcus pneumoniae causes a substantial proportion of meningitis cases in the African meningitis belt; however, few reports exist to quantify its burden and characteristics. We conducted population-based and sentinel hospital surveillance of acute bacterial meningitis among persons of all ages in Burkina Faso and Togo in 2002-2006. S. pneumoniae and other organisms were identified by culture, polymerase chain reaction, or detection of antigen in cerebrospinal fluid (CSF). Information was collected on 2843 patients with suspected acute bacterial meningitis. CSF specimens were collected from 2689 (95%) of the patients; of these 2689, 463 (17%) had S. pneumoniae identified, 234 (9%) had Haemophilus influenzae type b identified, and 400 (15%) had Neisseria meningitidis identified. Of the 463 cases of S. pneumoniae meningitis, 99 (21%) were aged <1 year, 71 (15%) were aged 1-4 years, 95 (21%) were aged 5-14 years, and 189 (41%) were aged >or=15 years (age was unknown for 9 [2%]). In Burkina Faso, the annual incidence rate of pneumococcal meningitis was 14 cases per 100,000 persons, with annual incidence rates of 77, 33, 10, and 11 cases per 100,000 persons aged <1 year, <5 years, 5-14 years, and >or=15 years, respectively. The case-fatality ratio for S. pneumoniae meningitis was 47% (range for age groups, 44%-52%), and 53% of deaths occurred among those aged >5 years. S. pneumoniae meningitis had an epidemic pattern similar to that of N. meningitidis meningitis. Of 48 isolates tested for serotype, 18 were from children aged <5 years; of these 18, 3 isolates (17%) each were serotypes 1, 2, and 5, and 5 isolates (28%) were serotype 6A. The 7-, 10-, and 13-valent pneumococcal conjugate vaccines would cover 6%, 39%, and 67% of serotypes identified among children aged <5 years, respectively. Of the 30 serotypes identified for patients aged >or=5 years, 18 (60%) were serotype 1, whereas no other serotype constituted >10%. The 7-, 10-, and 13-valent vaccines would cover 7%, 70%, and 77% of serotypes. Epidemic pneumococcal meningitis in the African meningitis belt countries of Burkina Faso and Togo is common, affects all age groups, and is highly lethal. On the basis of a modest number of isolates from a limited area that includes only meningitis cases, 7-valent pneumococcal conjugate vaccine might have only a limited and short-term role. By contrast, the proposed 10- and 13-valent vaccines would cover most of the identified serotypes. To better inform vaccine policy, continued and expanded surveillance is essential to document serotypes associated with pneumonia, changes in serotype distribution across time, and the impact of vaccine after vaccine introduction.
Microring resonator channel dropping filters (1997)

Microring resonators side coupled to signal waveguides provide compact, narrow band, and large free spectral range optical channel dropping filters. Higher order filters with improved passband characteristics and larger out-of-band signal rejection are realized through the coupling of multiple rings. The analysis of these devices is approached by the novel method of coupling of modes in time. The response of filters comprised of an arbitrarily large dumber of resonators may be written down by inspection, as a continued fraction. This approach simplifies both the analysis and filter synthesis aspects of these devices.
Regulation of Receptor Activator of NF-κB Ligand-induced Osteoclastogenesis by Endogenous Interferon-β (INF-β) and Suppressors of Cytokine Signaling (SOCS) (2002)

Bone resorption and the immune system are correlated with each other, and both are controlled by a variety of common cytokines produced in the bone microenvironments. Among these immune mediators, the involvement of type I interferons (IFNs) in osteoclastic bone resorption remains unknown. In this study, we investigated the participation of IFN-beta and suppressors of cytokine signaling (SOCS)-1 and -3 in osteoclastogenesis. Addition of exogenous IFN-beta to osteoclast progenitors (bone-derived monocytes/macrophages) inhibited their differentiation toward osteoclasts induced by the receptor activator of NF-kappaB ligand (RANKL) and macrophage colony-stimulating factor with/without transforming growth factor-beta, where inhibition was associated with down-regulation of the gene expressions of molecules related to osteoclast differentiation. In addition, RANKL induced the expression of IFN-beta; furthermore, neutralizing antibody against type I IFNs accelerated the osteoclast formation, indicating type I IFNs as potential intrinsic inhibitors. On the other hand, RANKL also induced the expression of SOCS-1 and -3, suppressors of the IFN signaling. Pretreatment with RANKL for a sufficient time for the induction of SOCSs attenuated phosphorylation of STAT-1 in response to IFN-beta in osteoclast progenitors, causing a decrease in the binding activity of nuclear extracts toward the interferon-stimulated response element. mRNA levels of STAT-1, STAT-2, and IFN-stimulated gene factor-3gamma, comprising IFN-stimulated gene factor-3, were not altered by RANKL. Thus, although the inhibitory cytokine such as IFN-beta is produced in response to RANKL, the inhibition of osteoclastogenesis may be rescued by the induction of signaling suppressors such as SOCSs.
Risk factors for repeated cerebrospinal shunt failures in pediatric patients with hydrocephalus (1999)

Repeated cerebrospinal fluid (CSF) shunt failures in pediatric patients who have undergone neurosurgical procedures are common, and they are a significant cause of morbidity and occasionally mortality. To date, the risk factors for repeated failure have not been established. By performing survival analysis for repeated events, the authors examined the effects of patient characteristics, shunt hardware, and surgical details in a large cohort of patients. During a 10-year period all pediatric patients with hydrocephalus requiring CSF diversionary procedures were included in a prospective single-institution observational study. Patient characteristics were defined as age, gender, weight, head circumference; American Society of Anesthesiology class, and the cause of hydrocephalus. Surgical details included whether the procedure was performed on an emergency or nonemergency basis, use of antibiotics, concurrent other surgical procedures, and the duration of surgical procedure. Details on shunt hardware included the type of shunt, the valve system, whether the shunt system included multiple or complex components, the type of distal catheter, site of the shunt, and side on which the shunt was placed. Repeated shunt failures were assessed with multivariable time-to-event analysis (using the Cox regression model). Conditional models (as established by Prentice, et al.) were formulated for gap times (that is, times between successive shunt failures). There were 1183 shunt failures in 839 patients. Failure time from the first shunt procedure was an important predictor for the second and third episodes of failures, thus establishing an association between the times to failure within individual patients. Age of less than 40 weeks gestation at time of the first shunt implantion carried a hazard ratio (HR) of 2.49 (95% confidence interval [CI] 1.68-3.68) for the first failure and remained high for subsequent episodes of failure. Age of 40 weeks to 1 year (at the time of the initial surgery) also proved to be an important predictor of first shunt malfunctions (HR 1.77, 95% CI 1.29-2.44). The cause of hydrocephalus was significantly associated with the risk of initial failure and, to a lesser extent, later failures. Concurrent other surgical procedures were associated with an increased risk of failure. The patient's age at the time of initial shunt placement and the time interval since previous surgical revision are important predictors of repeated shunt failures in the multivariable model. Even after adjusting for age at first shunt insertion as well as the cause of hydrocephalus there is significant association between repeated failure times for individual patients.
Human Carboxylesterase Isozymes: Catalytic Properties and Rational Drug Design (2006)

Human carboxylesterase 1 (hCE-1, CES1A1, HU1) and carboxylesterase 2 (hCE-2, hiCE, HU3) are a serine esterase involved in both drug metabolism and activation. Although both hCE-1 and hCE-2 are present in several organs, the hydrolase activity of liver and small intestine is predominantly attributed to hCE-1 and hCE-2, respectively. The substrate specificity of hCE-1 and hCE-2 is significantly different. hCE-1 mainly hydrolyzes a substrate with a small alcohol group and large acyl group, but its wide active pocket sometimes allows it to act on structurally distinct compounds of either large or small alcohol moiety. In contrast, hCE-2 recognizes a substrate with a large alcohol group and small acyl group, and its substrate specificity may be restricted by a capability of acyl-hCE-2 conjugate formation due to the presence of conformational interference in the active pocket. Furthermore, hCE-1 shows high transesterification activity, especially with hydrophobic alcohol, but negligible for hCE-2. Transesterification may be a reason for the substrate specificity of hCE-1 that hardly hydrolyzes a substrate with hydrophobic alcohol group, because transesterification can progress at the same time when a compound is hydrolyzed by hCE-1. From the standpoint of drug absorption, the intestinal hydrolysis by CES during drug absorption is evaluated in rat intestine and Caco2-cell line. The rat in situ single-pass perfusion shows markedly extensive hydrolysis in the intestinal mucosa. Since the hydrolyzed products are present at higher concentration in the epithelial cells rather than blood vessels and intestinal lumen, hydrolysates are transported by a specific efflux transporter and passive diffusion according to pH-partition. The expression pattern of CES in Caco-2 cell monolayer, a useful in vitro model for rapid screening of human intestinal drug absorption, is completely different from that in human small intestine but very similar to human liver that expresses a much higher level of hCE-1 and lower level of hCE-2. Therefore, the prediction of human intestinal absorption using Caco-2 cell monolayers should be carefully monitored in the case of ester and amide-containing drugs such as prodrugs. Further experimentation for an understanding of detailed substrate specificity for CES and development of in vitro evaluation systems for absorption of prodrug and its hydrolysates will help us to design the ideal prodrug.
Potential role of phospholipase A2 in HL-60 cell differentiation to macrophages induced by protein kinase C activation. (1993)

2-Lysophosphatidylcholine and cis-unsaturated fatty acids such as linoleic and linolenic acids, which are the products of the hydrolysis of phosphatidylcholine catalyzed by phospholipase A2 (EC 3.1.1.4), significantly potentiate the differentiation of HL-60 cells to macrophages that is induced by either a membrane-permeant diacylglycerol or a phorbol ester. The cell differentiation was assayed by measuring the expression of CD11b, one of the cell surface markers of macrophages, and also by the appearance of phagocytic activity. Snake venom phospholipase A2 added directly to the cells is also active for this potentiation. Neither lysophosphatidylcholine, fatty acid, nor phospholipase A2 is active unless a membrane-permeant diacylglycerol or a phorbol ester is present. The results presented provide further evidence that activation of phospholipase A2 may be intimately related to the signal transduction pathway through protein kinase C.
Use of Autologous Grafts for Reconstruction of Osteochondral Defects of the Knee (1999)

This study reports on 13 patients (mean age: 31 years) with a femoral condyle defect >1.5 cm2 who underwent treatment with an osteochondral graft of the same size obtained from the superior aspect of the lateral condyle, preserving the patellar groove. Mean follow-up was 61.5 months (range: 13-141 months). Twelve results were rated clinically as satisfactory with patients able to resume their normal pre-injury level of activity, and 1 case was rated as poor. No patient reported any patellar problems. Radiographic and computed tomographic evaluation demonstrated good integration of the graft in the host bone. The results of this technique at relatively long-term follow-up are encouraging, with a high percentage of subjective satisfaction. This technique appears to be reliable and provides a valid solution for treatment of wide cartilage defects when other techniques are too complex or inadequate.
Transgenic rabbits overexpressing growth hormone develop acromegaly and diabetes mellitus (1998)

Transgenic rabbits expressing the bovine growth hormone (bGH) gene in liver and kidney were obtained to study the long-term effects of chronic exposure to GH in nonrodent animals. These rabbits presented high levels of bGH and insulin-like growth factor I in serum. In spite of chronic exposure to bGH, transgenic rabbits had similar body weight to controls. However, enlargement of the head and limbs and reduction of visceral fat were observed in these animals. They also showed marked hyperinsulinemia, hyperglycemia, and hypertriglyceridemia, indicating that they developed insulin resistance. Furthermore, serious histopathological alterations, including marked fibrosis, were observed in liver, kidney, and skeletal muscle. These anatomical, metabolic, and histological alterations closely resemble those found in patients with acromegaly. Thus, transgenic rabbits overexpressing GH may be a good model of the human disease.
Identification, Synthesis, and Activity of Novel Blockers of the Voltage-Gated Potassium Channel Kv1.5 (2003)

The voltage-gated potassium channel Kv1.5 is regarded as a promising target for the development of new atrial selective drugs with fewer side effects. In the present study the discovery of ortho,ortho-disubstituted bisaryl compounds as blockers of the Kv1.5 channel is presented. Several compounds of this new class were synthesized and screened for their ability to block Kv1.5 channels expressed in Xenopus oocytes. The observed structure-activity relationship (SAR) is described by a pharmacophore model that consists of three hydrophobic centers in a triangular arrangement. The hydrophobic centers are matched by a phenyl or pyridyl ring of the bisaryl core and both ends of the side chains. The most potent compounds (e.g., 17c and 17o) inhibited the Kv1.5 channel with sub-micromolar half-blocking concentrations and displayed 3-fold selectivity over Kv1.3 and no significant effect on the HERG channel and sodium currents. In addition, compounds 17c and 17m have already shown antiarrhythmic effects in a pig model.
The ST6GalNAc-I Sialyltransferase Localizes throughout the Golgi and Is Responsible for the Synthesis of the Tumor-associated Sialyl-Tn O-Glycan in Human Breast Cancer (2005)

The functional properties of glycoproteins are strongly influenced by their profile of glycosylation, and changes in this profile are seen in malignancy. In mucin-type O-linked glycosylation these changes can result in the production of mucins such as MUC1, carrying shorter sialylated O-glycans, and with different site occupancy. Of the tumor-associated sialylated O-glycans, the disaccharide, sialyl-Tn (sialic acid alpha2,6GalNAc), is expressed by 30% of breast carcinomas and is the most tumor-specific. The ST6GalNAc-I glycosyltransferase, which can catalyze the transfer of sialic acid to GalNAc, shows a highly restricted pattern of expression in normal adult tissues, being largely limited to the gastrointestinal tract and absent in mammary gland. In breast carcinomas, however, a complete correlation between the expression of RNA-encoding ST6GalNAc-I and the expression of sialyl-Tn is evident, demonstrating that the expression of sialyl-Tn results from switching on expression of hST6GalNAc-I. Endogenous or exogenous expression of hST6GalNAc-I (but not ST6GalNAc-II) always results in the expression of sialyl-Tn. This ability to override core 1/core 2 pathways of O- linked glycosylation is explained by the localization of ST6GalNAc-I, which is found throughout the Golgi stacks. The development of a Chinese hamster ovary (CHO) cell line expressing MUC1 and ST6GalNAc-I allowed the large scale production of MUC1 carrying 83% sialyl-Tn O-glycans. The presence of ST6GalNAc-I in the CHO cells reduced the number of O-glycosylation sites occupied in MUC1, from an average of 4.3 to 3.8 per tandem repeat. The availability of large quantities of this MUC1 glycoform will allow the evaluation of its efficacy as an immunogen for immunotherapy of MUC1/STn-expressing tumors.
Spectral and Regulatory Properties of Biodegradative Threonine Deaminase* (1972)

1. Highly purified L-threonine deaminase [EC 4. 2. 1. 16] (biodegradative) of Escherichia coli exhibits an absorption maximum at 415 nm due to an aldimine linkage between the ɛ-amino group of lysyl residues and the enzyme-bound pyridoxal phosphate (PLP). When L-threonine was added to the enzyme, a transient bathochromic shift of the absorption was observed. The difference spectroscopy indicated that the new absorp-tion centers at 450 nm. When L-threonine was added in the presence of AMP, a -marked enhancement of the absorption at 450 nm was observed without an appreciable shift of the absorption maximum. In contrast, when D-threonine, a competitive inhibitor was added, a stable and rather weak absorption appeared at around 420–440 nm and this absorption was insensitive to AMP. 2. The threonine deaminase was gradually inactivated during the course of deamina-tion of L-threonine or L-serine. Further addition of the substrate to the inactivated enzyme exhibited no reactivating effect and so was PLP. When AMP was added to the inactivated enzyme in the presence of the substrate, however, instantaneous restoration of the activity was observed. 3. Specific activity of the enzyme markedly decreased as the enzyme concentration increased. In addition, at high enzyme concentrations, the activating effect of AMP also markedly decreased, while the Km for L-threonine remained to be 0.5 M regardless of the presence of the nucleotide. 4. Several structural analogues of the substrates or of possible reaction intermediates, including D-threonine,β-hydroxybutyric, crotonic, tiglic, acrylic, and 2,2′-dimethyl-acrylic acids inhibited the enzyme reaction to considerable extents.
Uptake of a boronated epidermal growth factor-dextran conjugate in CHO xenografts with and without human EGF-receptor expression. (1998)

An epidermal growth factor (EGF)-dextran-boron conjugate for targeting against EGF receptor-rich tumours was investigated regarding uptake and distribution in vivo. EGF served as the tumour-seeking part and dextran was the carrier for the potentially toxic boron. Nude mice carrying subcutaneous tumours on the flanks were injected with conjugate either i.v. or intratumorally. The xenografts were from Chinese hamster ovary cells transfected with the gene for the human EGF-receptor (CHO-EGFR), and these cells expressed the EGFR. Non-transfected cells without EGF-receptors (CHO) were used as controls. No accumulations in tumours could be observed following the i.v. injections but there were, in both tumour types, high accumulations in the liver. Following intratumoral injections the accumulations were higher in the CHO-EGFR tumours than in the CHO tumours. The tumour over blood and liver ratios were also higher for the CHO-EGFR tumours than for the CHO tumours. Thyroid accumulations after the intratumoral injections indicate different degradation patterns of the conjugate in CHO-EGFR animals than in CHO animals. In conclusion, after intratumoral injections the conjugate showed receptor-dependent binding to EGFR-rich tumours, and the tumour-to-blood and tumour-to-liver ratios were promising.
Loran-C: Present and Future* (1982)

Since its inception, the Loran-C Radionavigation System has expanded, and now covers much of the Northern Hemisphere. Coast Guard plans concerning past Loran-C expansion are discussed, as well as the Loran-C user education program, and efforts to verify the accuracy of the system. Plans for possible future expansion and use of Loran-C are also outlined.
Nonpeptide angiotensin II receptor antagonists. 1. Synthesis and in vitro structure-activity relationships of 4-[[[(1H-pyrrol-1-ylacetyl)amino]phenyl]methyl]imidazole derivatives as angiotensin II receptor antagonists (1993)

A novel series of non-biphenylyltetrazole angiotensin II receptor antagonists which contain a 1H-pyrrol-1-ylacetyl residue in place of the benzoyl residue in EXP 6803 have been developed. The receptor binding activity of several members of this new series was in the 10(-8) M range, which was better than that of EXP 6803. Introduction of a carboxylic acid moiety at the 2-position of the pyrrole ring enhanced the in vitro binding affinity at the receptor by 10-fold. Compounds containing an acetic acid (18) or a propionic acid residue (20) at the 5-position of the imidazole were more potent than the carboxylic acid analogue (24). The binding IC50 of the most potent compound 20 was 22 nM. Compounds 18, 20, and 24 in their best fit conformations were manually overlayed on that of the template conformation of EXP 6803 and EXP 8623, respectively. The synthesis and structure-activity relationship data are described.
Management of hypomagnesemia in cancer patients receiving chemotherapy. (2008)

nantly in the ileum) and in the colon. Elimination is predominantly renal. The threshold for urinary excretion is near the normal serum concentration. Therefore, when serum levels exceed 2.5 mEq/L, Mg excretion increases dramatically. Conversely, the kidneys retain a strong capacity to reabsorb Mg, and the main site for reabsorption is the thick ascending loop of Henle (Figure 1). Different fac-tors, such as volume expansion, ethanol ingestion, hypercalcemia, and diuretic administration, may impair renal reabsorption. A minimal daily intake of 0.3 mEq/kg of body weight has been suggested to prevent deﬁciency. Infants and children tend to have higher daily requirements.