gebhart/patrepeval huggingface dataset:
Selection of targeted biological modifiers from a bacteriophage library of random peptides. The identification of novel calmodulin regulatory peptides. (1993)

The interaction of short amino acid sequences is the basis of molecular recognition and biological regulation in many cellular systems. Libraries of random peptides provide an approach to identify peptides that can be used to modulate, in a targeted fashion, the function of specific gene products. We have used a library of random peptides designed and constructed in the M13 bacteriophage to select calcium-dependent calmodulin binding-peptides. Twenty-eight independent sequences were obtained; all contained a tryptophan within the fifteen-amino acid insert. In 11 sequences, the tryptophan was located in the first possible variable position of the inserted sequence and was followed by a proline. The tryptophan-proline combination was also present in six additional isolates but at various other positions within the peptide insert. Synthetic peptides, representative of the calmodulin binding sequences, bound to calmodulin in a calcium-dependent fashion, competed with known calmodulin inhibitors and, when introduced via a patch pipette, inhibited calcium-activated chloride conductance of the colonic epithelial cell line, T84. This report demonstrates the utility of identifying modifiers of biological function and should prove to be a valuable approach in understanding the cellular role of proteins of unknown function.
Mammalian uroplakins. A group of highly conserved urothelial differentiation-related membrane proteins. (1994)

The asymmetric unit membrane (AUM) forms the apical plaques of mammalian urothelium and is believed to play a role in strengthening the urothelial apical surface thus preventing the cells from rupturing during bladder distention. We have shown previously that purified bovine AUMs contain four major integral membrane proteins: the uroplakins Ia (27 kDa), Ib (28 kDa), II (15 kDa), and III (47 kDa). This contradicts some previous reports indicating that some of these proteins are absent in AUMs of several species. Using an improved procedure, we isolated AUMs from, in addition to cattle, eight mammalian species (human, monkey, sheep, pig, dog, rabbit, rat, and mouse). The AUMs of these species appear morphologically similar bearing crystalline patches of 12-nm protein particles with a center-to-center spacing of 16.5 nm. Using antibodies raised against synthetic oligopeptides or individual bovine uroplakins, we established by immunoblotting that the four uroplakins are present in AUMs of all these species. The DNA-deduced amino acid sequences of bovine and mouse uroplakin II revealed 83% identity. These results indicate that uroplakins Ia, Ib, II, and III are the major protein components of probably all mammalian urothelial plaques, and that the sequence and three-dimensional structure of uroplakin molecules are highly conserved during mammalian evolution.
Chronic Nicotine Exposure Upregulates Nicotinic Receptors by a Novel Mechanism (2005)

Nicotine addiction is initiated by its binding to high-affinity nicotinic receptors in brain composed primarily of alpha4 and beta2 subunits. For nicotinic receptors expressed in vivo or heterologously, nicotine exposure over hours to days increases or "upregulates" high-affinity nicotine binding to receptors through a posttranslational mechanism thought to increase receptor numbers. Using heterologous expression, we find nicotine exposure causes a fourfold to sixfold higher binding to alpha4beta2 receptors that does not correspond with any significant change in the number of surface receptors or a change in the assembly, trafficking, or cell-surface turnover of the receptors. However, upregulation does alter the functional state of the receptor, slowing desensitization and enhancing sensitivity to acetylcholine. Based on these findings, we propose an alternative mechanism to explain nicotine-induced upregulation in which nicotine exposure slowly stabilizes alpha4beta2 receptors in a high-affinity state that is more easily activated, thereby providing a memory for nicotine exposure.
Emerging therapeutics for Alzheimer’s disease (2006)

Alzheimer's disease (AD) is the most common form of dementia, with prevalence and the accompanying socioeconomic impact set to increase over the coming decades. Currently available medications result, at best, in modest cognitive improvement. With increasing understanding of the underlying pathology, new therapeutic targets are being identified at an ever-increasing rate. The key pathological events in the AD brain are deposition of insoluble amyloid-beta peptide (Abeta), formation of neurofibrillary tangles and neuroinflammation leading, ultimately, to neuronal cell death. Each of these will be considered, in detail, in terms of the variety of therapeutic approaches currently being investigated and mechanisms that may prove amenable to intervention in the future.
Insulin in type 2 diabetes: promises to keep. (2004)

The concept which has evolved in the management of type 2 diabetes mellitus is early insulin therapy. In type 2 diabetes mellitus first phase insulin response is grossly impaired on eventually absent, overburdening phase 2 responses which obviously fail to compensate in the long run. Perpetuation of the age old practice to continue OHA while almost all beta-cells are exhausted is only buying time for starting insulin. Preservation of beta-cell function by early insulin therapy yields two important benefits: (1) Better glycaemic control at lower medication dose and (2) relative freedom from hypoglycaemia because of well preserved glucagon response. To ensure and to translate the proper action of insulin in the target organs we are now talking about designer insulins which are basically insulin analogues (short and long acting). So type 2 diabetes is a growing menace and is responsible for severe morbidity, mortality and poor quality of life. Good glycaemic control from the very beginning of diabetes has shown to favourably influence all of these and is accepted as a cardinal goal of proper diabetes care.
[Monoclonal immunotherapy with human monoclonal antibody(CLN-IgG) in glioma patients]. (2002)

It is well recognized that malignant gliomas escape an immune response by hiding behind the blood-brain barrier and by producing proteins that suppress systemic immunity. However, if gliomas can be made to be more immunogenic or if a tumor vaccine can be produced, then access to all tumor cells including those that infiltrate into the brain can be achieved through the patient's immune response. Several strategies have been investigated for immunotherapy. Laboratory studies and animal models have shown that these immune cells will attack the tumor cell, reduce the size of implanted tumors, and that the immune memory is sufficient to suppress tumor growth when the animal is rechallenges with a tumor implant. Since the development of hybridoma technology, monoclonal antibodies against human cancer cells have been produced and antigens have been identified. Hagiwara reported the production of a human monoclonal antibody, CLN-IgG, made by fusing UC 729-6, human lymphoblastoid B-cell line, with lymphocytes obtained from a patient with the cervical carcinoma. It has been reported that CLN-IgG recognized the antigen expressed in various histological types of human cancers including malignant gliomas. The effect of human monoclonal antibody(CLN-IgG) on malignant brain tumors was evaluated in patients with malignant glioma. Early phase II study was concluded that this specific immunotherapy with CLN-IgG is safe and effective therapy in patients with malignant glioma. We treated 10 cases of malignant gliomas with CLN-IgG. All patients had received radiotherapy and chemotherapy before this immunotherapy using the human monoclonal antibody. The human monoclonal antibody(CLN-IgG) was administered intravenously once or twice/week during 24 weeks. Six cases of glioblastoma, 1 medulloblastoma and 3 cases of potine glioma histologically unverified, were treated. Five cases of 6 glioblastomas died 4 to 12 months after this treatment, 3 cases of pontine glioma showed good responses, 2 cases showed marked decrease of tumor size and 1 case showed no regrowth of tumor on MRI imaging. For the above reasons, Human monoclonal antibody(CLN-IgG) might be useful as an immunotherapy of malignant gliomas.
Fundamentals of Acoustic Cytometry (2018)

Acoustic cytometry uses radiation pressure forces instead of or in addition to hydrodynamic focusing to position cells or particles in a flowing stream for analysis. Commercial implementations to date combine both hydrodynamic and acoustic focusing together to enable high precision analysis of a broad dynamic range of volumetric sample input rates up to an order of magnitude higher than is practical with hydrodynamic focus alone. This capability allows great flexibility in reducing assay time or modifying or eliminating concentration requirements or concentration steps in sample preparation protocols. It also provides a practical method for processing sub-microliter volumes using sample dilution. In order to take full advantage of this dynamic range, it is necessary to understand the fundamental benefits and limitations of acoustic focusing as applied to flow cytometry. © 2018 by John Wiley & Sons, Inc.
Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization (2002)

Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) characterized by chronic inflammatory demyelination of the central nervous system (CNS). The pathology of EAE involves autoimmune CD4(+) T(h)1 cells. There is a striking inverse correlation between the occurrence of parasitic and autoimmune diseases. We demonstrate that in mice with Schistosoma mansoni ova immunization, the severity of EAE is reduced as measured by decreased clinical scores and CNS cellular infiltrates. Disease suppression is associated with immune deviation in the periphery and the CNS, demonstrated by decreased IFN-gamma and increased IL-4, transforming growth factor-beta and IL-10 levels in the periphery, and increased frequency of IL-4 producing neuroantigen-specific T cells in the brain. S. mansoni helminth ova treatment influenced the course of EAE in wild-type mice, but not in STAT6-deficient animals. This indicates that STAT6 plays a critical role in regulating the ameliorating effect of S. mansoni ova treatment on the autoimmune response, and provides the direct link between helminth treatment, T(h)2 environment and improved EAE. As some intestinal helminthic infections induce minimal pathology, they might offer a safe and inexpensive therapy to prevent and/or ameliorate MS.
Endogenous tumor lectins: overview and perspectives. (1986)

Lectins are carbohydrate-binding proteins of non-immune origin that can be assayed as agglutinins. They are potential mediators in recognitive processes and cell adhesion by interaction with glycoconjugates. These functions are areas of particular relevance to tumor growth and metastatic spread. The presence of lectins in tumors has first been inferred by histochemical and cytological methods. The biochemical analysis for lectins with various specificities reveals differences in the lectin profile between tumors of different classes (eg, mammary adenocarcinoma, rhabdomyosarcoma, or teratoma) and of the same class (eg, testicular germ cell tumors) and differences in relation to normal tissues. The presence of endogenous lectins in tumors, their relation to lectins of normal tissues, and their interaction with glycoconjugates of tumors and normal tissues may contribute to an understanding of intercellular interactions during the complex process of metastatic spread, and may allow to establish a new tool for diagnosis and a lectin-based therapy.
Lignin Chemistry, Technology, and Utilization: A Brief History (1999)

In 1838, Anselme Payen discovered that treatment of wood with nitric acid and then an alkaline solution yielded a major insoluble residue that he called "cellulose," and dissolved incrustants which Schulze later designated "lignin." Following Payen's initial experiments were findings on how to selectively solubilize lignins with either sulfurous acid or alkaline solutions to yield useful cellulose fibers. Klason, Freudenberg, Nimz, Adler, Hibbert, Kratzl, Tischenko, Nakano and others conducted pioneering classical organic chemistry research that revealed much fundamental knowledge about the chemical structure of lignins. The emergence of polymer concepts provided an additional framework that advanced understanding of the physical behavior and chemical nature of lignins. Although much is known about the biosynthesis of lignin, new information is still emerging. Lignins in wood are now known to consist of a family of phenyl propane type polymers in a variety of structural units in combination with carbohydrates. Lignins are widely used as fuels in paper making processes and are sold commercially in expanding markets.
DEVELOPMENTAL PROFILES OF GANGLIOSIDES IN HUMAN AND RAT BRAIN (1971)

Abstract— The developmental profiles of individual gangliosides of human brain were compared with those of rat brain. Interest was focused mainly on the pre‐ and early postnatal development. Human frontal lobe cortex covering the period from 10 foetal weeks to adult age and the cerebrum of rat from birth to 21 days were analysed. Lipid‐NANA and lipid‐P were followed; in the rat, also protein and brain weight. A limited number of samples of human cerebral white matter and cerebellar cortex were also studied. The following major results were obtained: The ganglioside concentration increased approximately three‐fold within a short period: in rat cerebrum, from birth to the 17th day; in human cerebral cortex, from the 15th foetal week to the age of about 6 months. The largest increase in the rat brain occurred by the 11th to the 13th day; in human brain by term. The relative increase of gangliosides during this period was more rapid than that of phospholipids. A hitherto unknown distinct early period of ganglioside and phospholipid formation in rat occurred by the second to fourth day. The changes in brain ganglioside pattern, characteristic of the developmental stages of the rat, were found to be equally pronounced in the human brain. Regional developmental differences in the ganglioside pattern were demonstrated in human brain. A characteristic white matter pattern, rich in monosialogangliosides, had developed by the age of 1 year. The increase in ganglioside concentration and the formation of the definitive ganglioside pattern of cerebellar cortex occurred later than in cerebral cortex. This cerebellar pattern was characterized by a very large trisialoganglioside fraction. The two periods of rapid ganglioside metabolism in rat brain preceded the two periods of rapid protein biosynthesis.
Effect of diazoxide on Friedreich ataxia models (2018)

Friedreich ataxia (FRDA) is an inherited recessive disorder caused by a deficiency in the mitochondrial protein frataxin. There is currently no effective treatment for FRDA available, especially for neurological deficits. In this study, we tested diazoxide, a drug commonly used as vasodilator in the treatment of acute hypertension, on cellular and animal models of FRDA. We first showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mammalian target of rapamycin (mTOR) pathway. We then explored the potential therapeutic effect of diazoxide in frataxin-deficient transgenic YG8sR mice and we found that prolonged oral administration of 3 mpk/d diazoxide was found to be safe, but produced variable effects concerning efficacy. YG8sR mice showed improved beam walk coordination abilities and footprint stride patterns, but a generally reduced locomotor activity. Moreover, they showed significantly increased frataxin expression, improved aconitase activity, and decreased protein oxidation in cerebellum and brain mitochondrial tissue extracts. Further studies are needed before this drug should be considered for FRDA clinical trials.
Clinical management of urinary incontinence in women. (2013)

Most cases of urinary incontinence in women fall under one of three major subtypes: urge, stress, or mixed. A stepped-care approach that advances from least invasive (behavioral modification) to more invasive (surgery) interventions is recommended. Bladder retraining and pelvic floor muscle exercises are first-line treatments for persons without cognitive impairment who present with urge incontinence. Neuromodulation devices, such as posterior tibial nerve stimulators, are an option for urge incontinence that does not respond to behavioral therapy. Pharmacologic therapy with anticholinergic medications is another option for treating urge incontinence if behavioral therapy is unsuccessful; however, because of adverse effects, these agents are not recommended in older adults. Other medication options for urge incontinence include mirabegron and onabotulinumtoxinA. Sacral nerve stimulators, which are surgically implanted, have also been shown to improve symptoms of urge incontinence. Pelvic floor muscle exercises are considered first-line treatment for stress incontinence. Noninvasive electrical and magnetic stimulation devices are also available. Alternatives for treating stress incontinence include vaginal inserts, such as pessaries, and urethral plugs. Limited or conflicting evidence exists for the use of medications for stress incontinence; no medications are approved by the U.S. Food and Drug Administration for this condition. Minimally invasive procedures, including radiofrequency denaturation of the urethra and injection of periurethral bulking agents, can be used if stress incontinence does not respond to less invasive treatments. Surgical interventions, such as sling and urethropexy procedures, should be reserved for stress incontinence that has not responded to other treatments.
Sexual harassment in health care: a major productivity problem. (1997)

Sexual harassment in health care is a problem because of exorbitant legal costs, lost productivity, poor morale, and nonproductive absenteeism or turnover. Sexual harassment is more prevalent in health care. Health care organizations often do little to prevent it and do not respond properly when it occurs. In this article, legal precedents are reviewed, and a model of sexual harassment is developed to illustrate the phenomenon and identify interventions. Harassing and stereotyping behavior can be changed. Victims' responses and willingness to report incidents can be changed. Policies, sanctions, accountability, training, the type of investigations, and changed organizational culture help reduce sexual harassment. It is argued that reduction of sexual harassment in health care is important because it is a major productivity issue.
Molecular basis of the glycoprotein C-negative phenotypes of herpes simplex virus type 1 mutants selected with a virus-neutralizing monoclonal antibody (1986)

Previously (Holland et al., J. Virol. 52:566-574, 1984; Kikuchi et al., J. Virol. 52:806-815, 1984) we described the isolation and partial characterization of over 100 herpes simplex virus type 1 mutants which were resistant to neutralization by a pool of glycoprotein C- (gC) specific monoclonal antibodies. The genetic basis for the inability of several of these gC- mutants to express an immunoreactive envelope form of gC is reported here. Comparative nucleotide sequence analysis of the gC gene of the six mutants gC-3, gC-8, gC-49, gC-53, gC-85, and synLD70, which secrete truncated gC polypeptides, with that of the wild-type KOS 321 gC gene revealed that these mutant phenotypes were caused by frameshift or nonsense mutations, resulting in premature termination of gC translation. Secretion of the gC polypeptide from cells infected with these mutants was due to the lack of a functional transmembrane anchor sequence. The six secretor mutants were tested for suppression of amber mutations in mixed infection with a simian virus 40 amber suppressor vector. Mutant gC-85 was suppressed and produced a wild-type-sized membrane-bound gC. Nucleotide sequence analysis of the six gC deletion mutants gC-5, gC-13, gC-21, gC-39, gC-46, and gC-98 revealed that they carried identical deletions which removed 1,702 base pairs of the gC gene. The deletion, which was internal to the gC gene, removed the entire gC coding sequence and accounted for the novel 1.1-kilobase mRNA previously seen in infections with these mutants. The mutant gC-44 was previously shown to produce a membrane-bound gC protein indistinguishable in molecular weight from wild-type gC. This mutant differed from wild-type virus in that it had reduced reactivity with virus-neutralizing monoclonal antibodies. Nucleotide sequence analysis of the gC gene of mutant gC-44 demonstrated a point mutation which changed amino acid 329 of gC from a serine to a phenylalanine.
Microbial products induce autoimmune disease by an IL-12-dependent pathway (1997)

The development and exacerbation of autoimmune diseases are associated with antecedent infectious illness. Microbial products such as LPS, bacterial DNA, or oligonucleotides containing an unmethylated cytosine-guanine dinucleotide have cytokine modulating properties. These products converted quiescent myelin basic protein-specific T cells into effector cells capable of transferring experimental allergic encephalomyelitis. The disease-promoting properties of the microbial products were solely dependent on their capacity to induce the production of IL-12.
A comparison of parathyroid hormone-related protein (1-36) and parathyroid hormone (1-34) on markers of bone turnover and bone density in postmenopausal women: The PrOP study (2013)

Parathyroid hormone-related protein (PTHrP)(1-36) increases lumbar spine (LS) bone mineral density (BMD), acting as an anabolic agent when injected intermittently, but it has not been directly compared with parathyroid hormone (PTH)(1-34). We performed a 3-month randomized, prospective study in 105 postmenopausal women with low bone density or osteoporosis, comparing daily subcutaneous injections of PTHrP(1-36) to PTH(1-34). Thirty-five women were randomized to each of three groups: PTHrP(1-36) 400 µg/day; PTHrP(1-36) 600 µg/day; and PTH(1-34) 20 µg/day. The primary outcome measures were changes in amino-terminal telopeptides of procollagen 1 (PINP) and carboxy-terminal telopeptides of collagen 1 (CTX). Secondary measures included safety parameters, 1,25(OH)2 vitamin D, and BMD. The increase in bone resorption (CTX) by PTH(1-34) (92%) (p < 0.005) was greater than for PTHrP(1-36) (30%) (p < 0.05). PTH(1-34) also increased bone formation (PINP) (171%) (p < 0.0005) more than either dose of PTHrP(1-36) (46% and 87%). The increase in PINP was earlier (day 15) and greater than the increase in CTX for all three groups. LS BMD increased equivalently in each group (p < 0.05 for all). Total hip (TH) and femoral neck (FN) BMD increased equivalently in each group but were only significant for the two doses of PTHrP(1-36) (p < 0.05) at the TH and for PTHrP(1-36) 400 (p < 0.05) at the FN. PTHrP(1-36) 400 induced mild, transient (day 15) hypercalcemia. PTHrP(1-36) 600 required a dose reduction for hypercalcemia in three subjects. PTH(1-34) was not associated with hypercalcemia. Each peptide induced a marked biphasic increase in 1,25(OH)2 D. Adverse events (AE) were similar among the three groups. This study demonstrates that PTHrP(1-36) and PTH(1-34) cause similar increases in LS BMD. PTHrP(1-36) also increased hip BMD. PTH(1-34) induced greater changes in bone turnover than PTHrP(1-36). PTHrP(1-36) was associated with mild transient hypercalcemia. Longer-term studies using lower doses of PTHrP(1-36) are needed to define both the optimal dose and full clinical benefits of PTHrP. © 2013 American Society for Bone and Mineral Research.