gebhart/patrepeval huggingface dataset:
Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain (2012)

Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies.
Overabundance of rare-cutting restriction endonuclease sites in the human genome (1987)

A human chromosome 3-specific cosmid library was constructed from a somatic cell hybrid containing human chromosome 3 as its only human component. This library was screened to identify 230 human recombinants which contained an average insert size of 37 kilobases. DNA prepared from 54 of these cosmids, representing 2000 kilobases of human DNA, was then tested for restriction endonuclease sites for EcoRI, HindIII, KpnI, XhoI, and DraI, as well as those of the rare-cutting restriction endonucleases NotI, SfiI, NruI, MluI, SacII, and BssHII. Sites for the latter enzymes were much more abundant than would be expected from theoretical calculations, reflecting non-random clustering of these sites. This has important implications for the use of these enzymes in the construction of physical maps of chromosomes. Some individual cosmids contained large numbers of rare sites, offering an alternative means of physically mapping chromosomes based upon identifying clusters of rare restriction sites. These clusters appear to be spaced an average of 1000 kb apart.
Codon 12 and codon 13 mutations at the K‐ras gene induce different soft tissue sarcoma types in nude mice (2002)

K-ras codon 12 mutation is more oncogenic in in vitro and in vivo experimental systems than K-ras codon 13 mutation. Moreover, human colorectal tumors bearing a codon 12 mutation are more aggressive, invasive, and metastatic than the same tumor types carrying a codon 13 mutation. However, despite the association between specific sarcoma types and codon 12 or codon 13 mutations, the relationship between the position of the mutated codon at ras genes and tumor aggressiveness has not been studied in this tumor type. Here, we used a nude mice model to evaluate the tumorogenic capacity of stable transfectants of NIH3T3 fibroblasts, expressing K-ras mutated at codon 12 (K12) or 13 (K13), and morphologically, functionally, and molecularly compared these tumors. We found histopathological differences between them, K12-derived tumors showing fibrosarcoma-like features, whereas K13-derived tumors resembled malignant fibrous histiocytomas. Moreover, K12 tumors showed shorter latency of appearance, lower apoptotic and mitotic rates, and higher expression of markers for sarcoma aggressiveness (Ki67, p53 and c-myc) than K13 tumors. They also showed differences in the expression or activation of Ras, Ras downstream pathways [c-Jun N-terminal kinase (JNK), MAPK and AKT], and apoptotic [AKT, Bcl-2, Focal adhesion kinase (FAK)] and mitotic (cyclin B1) regulators, which could explain their functional differences. Most remarkably, the significantly diminished apoptotic rate observed in K12-derived tumors was associated with enhanced antiapoptotic signaling through the AKT pathway. These morphological, functional, and molecular differences demonstrate that codon 12 and codon 13 mutations in the K-ras oncogene can induce two different soft tissue sarcoma types in our in vivo model.
Modulation of Adult Mesenchymal Stem Cells Activity by Toll-Like Receptors: Implications on Therapeutic Potential (2010)

Mesenchymal stem cells (MSCs) are of special interest as therapeutic agents in the settings of both chronic inflammatory and autoimmune diseases. Toll-like receptors (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases due to the permanent exposure of the immune system to TLR-specific stimuli. Therefore, MSCs employed in therapy can be potentially exposed to TLR ligands, which may modulate MSC therapeutic potential in vivo. Recent results demonstrate that MSCs are activated by TLR ligands leading to modulation of the differentiation, migration, proliferation, survival, and immunosuppression capacities. However inconsistent results among authors have been reported suggesting that the source of MSCs, TLR stimuli employed or culture conditions play a role. Notably, activation by TLR ligands has not been reported to modulate the "immunoprivileged" phenotype of MSCs which is of special relevance regarding the use of allogeneic MSC-based therapies. In this review, we discuss the available data on the modulation of MSCs activity through TLR signalling.
Incidence, Predictors, and Outcome of Thrombosis After Successful Implantation of Drug-Eluting Stents (2005)

m e n t s i n a n t i p l a t e l e t therapy, thrombotic events remain the primary cause of death after percutaneous coronary interventions. 1,2][10] We analyzed the incidence, predictors, and
Pharmacokinetics and bioavailabilities of hymecromone in human volunteers (1993)

Specific and ultrasensitive reverse-phase HPLC assays of the choleretic and biliary antispasmodic hymecromone (down to 0.05 ng ml-1) and its glucuronide, using fluorimetric detection, and sulfate metabolites using UV detection, were developed. Sodium salt solutions of 400 mg (over 3 min) and 800 mg (over 5 min) were infused i.v. into 6-8 normal human volunteers. The half-life of the major rate constant averaged 28 +/- 2 min (SE). Subsequently, less than 0.8 per cent of the dose was eliminated with terminal half-lives of 70-359 min. The apparent volume of distribution of hymecromone, referenced to the total plasma concentration, averaged 20.8 +/- 1.41 (Vc, central compartment volume) and 36.4 +/- 2.11 (Vss steady state volume). Hymecromone's total body clearance averaged 1413 +/- 89 ml min-1. The pharmacokinetics of hymecromone were dose-independent. Only 0.3 +/- 0.3 per cent unchanged hymecromone was renally excreted. Mostly dose-independent glucuronidated drug (93 +/- 4 per cent of the dose) was excreted in the urine; a smaller amount was renally excreted as the sulfate (1.4 +/- 0.3 per cent of the dose). The oral bioavailability estimated from the relative areas under the hymecromone plasma concentration-time curves following oral and i.v. administration of hymecromone to six volunteer subjects showed no dose-dependence and was 1.8 +/- 0.6 per cent. However, an anomalous c. 200 per cent of the glucuronide produced by i.v. hymecromone was produced from orally administered hymecromone as determined from the ratio of the AUC values of glucuronide obtained after peroral and i.v. administration of the same dose of hymecromone to demonstrate a high first-pass effect and implicate renal glucuronidation.
Familial association of breast/ovarian carcinoma (1978)

Twelve pedigrees which show clustering of breast/ovarian cancer among female relatives are analyzed from a medical-genetic standpoint. The significant linear decline in estimates of cumulative breast/ovarian cancer risk to females with diminishing genetic relationship to probands and index cases, plus the lack of excessive site-specific cancer risk to male relatives, supports a sex-limited genetic etiology. Breast/ovarian cancer typically occurred at an early age (x̄ = 50.6 years) in these kindreds compared to the general population, which is another characteristic of hereditary cancer. Examples of apparent mother to daughter and father to daughter genetic transmission of proclivity for breast/ovarian carcinoma were prevalent in the 12 pedigrees. Excluding probands and index cases, the estimated cumulative risk of breast/ovarian cancer to female progeny of affected mothers was 46% for the age interval 20–80 years, suggesting that affected mothers in the pedigrees are transmitting a deleterious cancer-predisposing gene to one-half of their daughters. Eight sibships involving putative carrier males contain a total of 15 female progeny over age 20. Of these, six have manifested breast cancer and five have had ovarian cancer. These results underscore the need for physicians to be cognizant of both males and females as potential transmitters of cancer in this familial tumor association.
Antibody Protects Macaques against Vaginal Challenge with a Pathogenic R5 Simian/Human Immunodeficiency Virus at Serum Levels Giving Complete Neutralization In Vitro (2001)

A major unknown in human immunodeficiency virus (HIV-1) vaccine design is the efficacy of antibodies in preventing mucosal transmission of R5 viruses. These viruses, which use CCR5 as a coreceptor, appear to have a selective advantage in transmission of HIV-1 in humans. Hence R5 viruses predominate during primary infection and persist throughout the course of disease in most infected people. Vaginal challenge of macaques with chimeric simian/human immunodeficiency viruses (SHIV) is perhaps one of the best available animal models for human HIV-1 infection. Passive transfer studies are widely used to establish the conditions for antibody protection against viral challenge. Here we show that passive intravenous transfer of the human neutralizing monoclonal antibody b12 provides dose-dependent protection to macaques vaginally challenged with the R5 virus SHIV(162P4). Four of four monkeys given 25 mg of b12 per kg of body weight 6 h prior to challenge showed no evidence of viral infection (sterile protection). Two of four monkeys given 5 mg of b12/kg were similarly protected, whereas the other two showed significantly reduced and delayed plasma viremia compared to control animals. In contrast, all four monkeys treated with a dose of 1 mg/kg became infected with viremia levels close to those for control animals. Antibody b12 serum concentrations at the time of virus challenge corresponded to approximately 400 (25 mg/kg), 80 (5 mg/kg), and 16 (1 mg/kg) times the in vitro (90%) neutralization titers. Therefore, complete protection against mucosal challenge with an R5 SHIV required essentially complete neutralization of the infecting virus. This suggests that a vaccine based on antibody alone would need to sustain serum neutralizing antibody titers (90%) of the order of 1:400 to achieve sterile protection but that lower titers, around 1:100, could provide a significant benefit. The significance of such substerilizing neutralizing antibody titers in the context of a potent cellular immune response is an important area for further study.
In vitro assessment of long-term reliability of low-cost μΕCoG arrays (2016)

Micro-electrocorticographic (μECοG) electrode arrays provide a minimally invasive, high-resolution neural interface with broad cortical coverage. Previously, we fabricated μECoG arrays at a lower cost than commercially available devices using low-cost industrial processes [1], [2]. Here, we report the in vitro electrical performance of five μECoG designs undergoing an accelerated aging protocol. The impedance and yield of the μECoG arrays were tracked over time. The equivalent lifetime at 37°C depended on the manufacturer and material stack-up, and ranged between 30 and greater than 760 days (ongoing). The main failure modes of these devices were delamination at the site of the electrode contact and broken traces due to metal dissolution. Based on these in vitro results, we offer several recommendations for μECoG designs suitable for chronic implantation.
Enabling view-dependent stereoscopic projection in real environments (2005)

We show how view-dependent image-based and geometric warping, radiometric compensation, and multi-focal projection enable a view-dependent stereoscopic visualization on ordinary (geometrically complex, colored and textured) surfaces within everyday environments. Special display configurations for immersive or semi-immersive AR/VR applications that require permanent and artificial projection canvases might become unnecessary. We demonstrate several ad-hoc visualization examples in a real architectural and museum application context.
The effect of sodium, potassium and ammonium ions on the conformation of the dimeric quadruplex formed by the Oxytricha nova telomere repeat oligonucleotide d(G4T4G4) (1999)

The DNA sequence d(G 4 T 4 G 4 ) [Oxy-1.5] consists of 1.5 units of the repeat in telomeres of Oxytricha nova and has been shown by NMR and X-ray crystallographic analysis to form a dimeric quadruplex structure with four guanine-quartets. However, the structure reported in the X-ray study has a fundamentally different conformation and folding topology compared to the solution structure. In order to elucidate the possible role of different counterions in this discrepancy and to investigate the conformational effects and dynamics of ion binding to G-quadruplex DNA, we compare results from further experiments using a variety of counterions, namely K + , Na + and NH 4 + . A detailed structure determination of Oxy-1.5 in solution in the presence of K + shows the same folding topology as previously reported with the same molecule in the presence of Na + . Both conformations are symmetric dimeric quadruplexes with T 4 loops which span the diagonal of the end quartets. The stack of quartets shows only small differences in the presence of K + versus Na + counterions, but the T 4 loops adopt notably distinguishable conformations. Dynamic NMR analysis of the spectra of Oxy-1.5 in mixed Na + /K + solution reveals that there are at least three K + binding sites. Additional experiments in the presence of NH 4 + reveal the same topology and loop conformation as in the K + form and allow the direct localization of three central ions in the stack of quartets and further show that there are no specific NH 4 + binding sites in the T 4 loop. The location of bound NH 4 + with respect to the expected coordination sites for Na + binding provides a rationale for the difference observed for the structure of the T 4 loop in the Na + form, with respect to that observed for the K + and NH 4 + forms.
Nucleophilic Reactions of 2-Methyl-3-( 4' -carbomethoxyphenyl)-4-quinazolinones with 2-lndolinones (1989)

Department of Chemistry, Lucknow University, Lucknow-226 007 <em>Manuscript received 10 March 1989, accepted 20 June 1989</em> 2-Methyl-3-(4'-carbomethoxphenyl)-4-quinazolinone undergoes nucleophilic addition-elimination reactions with different lndolinones leading to 2-(3-methylene- substituted-oxindolyl)-3-(4'-carbomethoxyphenyl)-4-quinazolinones (2a- e), Similarly, <em>N</em>-methylindolinones react with 2-methyl-3-(4'-carbomethoxyphenyl)-4-quinazolinone to give 2- (3-methylene-1- methyl-substituted -oxindolyl)- 3 -( 4' - carbomethoxyphenyl)-4 quinazolinones (4a -e). Mannich reactions were performed on 2 with formaldehyde and morpholine/piperidine to give 2-(3-methylene-1-morpholino/piperidinomethyl· substituted-oxindolyl)-3-(4'-carbomethoxyphenyl)-4-quinazolinones (3a- e). The compouuds have been characterised by ir, nmr and mass spectral data.
Forskolin: unique diterpene activator of adenylate cyclase in membranes and in intact cells. (1981)

The diterpene, forskolin [half-maximal effective concentration (EC50), 5-10 microM] activates adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] in rat cerebral cortical membranes in a rapid and reversible manner. Activation is not dependent on exogenous guanyl nucleotides and is not inhibited by guanosine 5'-O-(2-thiodiphosphate) when assayed with adenosine 5'-[beta, gamma-imido]triphosphate as substrate. GTP and GDP potentiate responses to forskolin. The activations of adenylate cyclase by forskolin and guanosine 5'-[beta, gamma-imido]triphosphate p[NH]ppG are not additive, whereas activations by forskolin and fluoride are additive or partially additive. The responses of adenylate cyclase to forskolin or fluoride are not inhibited by manganese ions, whereas the response to p[NH]ppG is completely blocked. Activation of adenylate cyclase by forskolin is considerably greater than the activation by fluoride in membranes from rat cerebellum, striatum, heart, and liver, while being about equal or less than the activation by fluoride in other tissues. Forskolin (EC50, 25 microM) causes a rapid and readily reversible 35-fold elevation of cyclic AMP in rat cerebral cortical slices that is not blocked by a variety of neurotransmitter antagonists. Low concentrations of forskolin (1 microM) augment the response of cyclic AMP-generating systems in brain slices to norepinephrine, isoproterenol, histamine, adenosine, prostaglandin E2, and vasoactive intestinal peptide. Forskolin would appear to activate adenylate cyclase through a unique mechanism involving both direct activation of the enzyme and facilitation or potentiation of the modulation of enzyme activity by receptors or the guanyl nucleotide-binding subunit, or both.
The Skin (1966)

PREVIOUS ARTICLENational Academy of Sciences: Abstracts of papers presented at the autumn meeting, Durham, North Carolina, 17-19 October 1966
Printed two-dimensional micro-zone plates for chemical analysis and ELISA (2011)

In this study we report a new concept of printing low-cost two-dimensional micro-zone plates for chemical and biochemical assays and ELISA. It is different from the concept of forming multi-zone micro-zones on paper by hydrophobic barriers first reported by Yagoda. Instead, the desired multi-zone micro-zone pattern was first printed using a UV-curable varnish onto a polymer film; then fine powders of cellulose or other materials were applied onto the uncured varnish, allowing the powder to stick to the varnish layer. After UV-curing, the powder particles were fixed by the cured varnish, leading to the formation of porous, water absorbing micro-zones on the polymer film. This type of micro-zone plate has the required liquid handling capacity for a variety of low-volume and portable two-dimensional plates for chemical, biochemical assays and ELISA. By suitably spacing porous micro-zones on a non-porous substrate, this type of plate eliminates inter-zone sample leaking. Rapid colorimetric analysis of the results can be performed using a portable battery-powered colour densitometer or a desktop scanner. By introducing a refractive-index-matching liquid into the micro-zones, the plate can be easily analyzed using transmission instruments. A major advantage of this plate fabrication method is that it enables the printing of different powders or functionalized powders to form micro-zones on a same plate, potentially allowing certain more difficult functionalization of materials to be performed before printing. We demonstrate the assaying performance of the plates using an analytical system that aims to clarify the analytical interference between NO(2)(-) and uric acid (UA) in the analysis of samples where both chemical species are present. We also show that ELISA assays can be performed using this type of plates.
Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates (2014)

siRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ∼ 0.002 mg/kg), rats (ED50 < 0.01 mg/kg), and nonhuman primates (over 95% silencing at 0.3 mg/kg). Apolipoprotein E plays a significant role in the potency of cKK-E12 both in vitro and in vivo. cKK-E12 was highly selective toward liver parenchymal cell in vivo, with orders of magnitude lower doses needed to silence in hepatocytes compared with endothelial cells and immune cells in different organs. Toxicity studies showed that cKK-E12 was well tolerated in rats at a dose of 1 mg/kg (over 100-fold higher than the ED50). To our knowledge, this is the most efficacious and selective nonviral siRNA delivery system for gene silencing in hepatocytes reported to date.
Activation of an alternative NF‐ΚB pathway in skeletal muscle during disuse atrophy (2002)

Although cytokine-induced nuclear factor kappaB (NF-kappaB) pathways are involved in muscle wasting subsequent to disease, their potential role in disuse muscle atrophy has not been characterized. Seven days of hind limb unloading led to a 10-fold activation of an NF-kappaB-dependent reporter in rat soleus muscle but not the atrophy-resistant extensor digitorum longus muscle. Nuclear levels of p50 were markedly up-regulated, c-Rel was moderately up-regulated, Rel B was down-regulated, and p52 and p65 were unchanged in unloaded solei. The nuclear IkappaB protein Bcl-3 was increased. There was increased binding to an NF-kappaB consensus oligonucleotide, and this complex bound antibodies to p50, c-Rel, and Bcl-3 but not other NF-kappaB family members. Tumor necrosis factor alpha (TNF-alpha) and TNF receptor-associated factor 2 protein were moderately down-regulated. There was no difference in p38, c-Jun NH(2)-terminal kinase or Akt activity, nor were activator protein 1 or nuclear factor of activated T cell-dependent reporters activated. Thus, whereas several NF-kappaB family members are up-regulated, the prototypical markers of cytokine-induced activation of NF-kappaB seen with disease-related wasting are not evident during disuse atrophy. Levels of an anti-apoptotic NF-kappaB target, Bcl-2, were increased fourfold whereas proapoptotic proteins Bax and Bak decreased. The evidence presented here suggests that disuse muscle atrophy is associated with activation of an alternative NF-kappaB pathway that involves the activation of p50 but not p65.