gebhart/patrepeval huggingface dataset:
Subthalamic Nucleus Neurons Switch from Single-Spike Activity to Burst-Firing Mode (1999)

The modification of the discharge pattern of subthalamic nucleus (STN) neurons from single-spike activity to mixed burst-firing mode is one of the characteristics of parkinsonism in rat and primates. However, the mechanism of this process is not yet understood. Intrinsic firing patterns of STN neurons were examined in rat brain slices with intracellular and patch-clamp techniques. Almost half of the STN neurons that spontaneously discharged in the single-spike mode had the intrinsic property of switching to pure or mixed burst-firing mode when the membrane was hyperpolarized from -41.3 +/- 1.0 mV (range, -35 to -50 mV; n = 15) to -51.0 +/- 1.0 mV (range, -42 to -60 mV; n = 20). This switch was greatly facilitated by activation of metabotropic glutamate receptors with 1S,3R-ACPD. Recurrent membrane oscillations underlying burst-firing mode were endogenous and Ca2+-dependent because they were largely reduced by nifedipine (3 microM), Ni2+ (40 microM), and BAPTA-AM (10-50 microM) at any potential tested, whereas TTX (1 microM) had no effect. In contrast, simultaneous application of TEA (1 mM) and apamin (0.2 microM) prolonged burst duration. Moreover, in response to intracellular stimulation at hyperpolarized potentials, a plateau potential with a voltage and ionic basis similar to those of spontaneous bursts was recorded in 82% of the tested STN neurons, all of which displayed a low-threshold Ni2+-sensitive spike. We propose that recurrent membrane oscillations during bursts result from the sequential activation of T/R- and L-type Ca2+ currents, a Ca2+-activated inward current, and Ca2+-activated K+ currents.
Homogenous junctional sequence of the V14+ T-cell antigen receptor alpha chain expanded in unprimed mice. (1990)

Nucleotide sequences of VJ (variable-joining) junctional regions of V14+ alpha-chain T-cell receptor genes show that most V alpha 14+ T cells use one alpha chain (V alpha 14J alpha 281 with a one-nucleotide N region, which is frequently used in keyhole limpet hemocyanin-specific suppressor T-cell hybridomas) in unprimed mice. Moreover, the frequency of this alpha-chain expression was greater than 1.5% of the total alpha chains found in laboratory strains, including B10 congenic mice. This is about 10(4) times higher than was expected. The V14J281 alpha-chain expression was relatively low but was significant in CD4+/CD8+ immature thymocytes and became quite high in mature single-positive T cells, implying that this alpha chain is selected during T-cell maturation. V14J281 expression increased with time after birth and reached a maximum at around 5 weeks of age. The ligand seems to be a self molecule and to be present in laboratory strains but to be absent in a wild mouse, Mus musculus molossinus, because bone marrow chimeras clearly showed that bone marrow cells derived from Mus musculus molossinus negative for this alpha chain raised V14J281-positive T cells in a C57BL/6 environment. The above results suggest that there are some selection mechanisms for this cell type other than those for conventional alpha beta T cells and also that the homogenous VJ junction of the V14J281 alpha chain plays a pivotal role in the selection of the T cell and its ligand reactivity.
Identification of centromeric antigens in dicentric Robertsonian translocations: CENP-C and CENP-E are necessary components of functional centromeres (1995)

Robertsonian translocations are the most common structural dicentric rearrangements in humans. The stability of these dicentrics is attributed to the inactivation of one centromere by mechanisms which are currently unknown. The presence and amounts of centromeric proteins (CENPs) differ between the centromeres of the few dicentrics which have been studied, providing a limited understanding of the protein components necessary for centromeric function. However, CENP-C previously has been observed only at the active centromeres in two dicentric chromosomes. In the present investigation, the presence and localizations of several centromeric antigens, CENP-B, -C and -E, have been determined in 12 dicentric Robertsonian translocations. Each translocation was studied initially using in situ hybridization with alpha-satellite DNA probes to determine the active centromere. Subsequent immunofluorescence of monoclonal and polyclonal antibodies generated to various centromeric antigens demonstrated that the protein composition differs at the two centromeres of these dicentric translocations. While CENP-B was present at both active and inactive centromeres, CENP-C and -E were located at active centromeres only in the majority of translocations. These results confirm previous observations of CENP-C at active centromeres and provide the first evidence that CENP-E correlates with active centromeres as well, demonstrating that at least two specific centromeric proteins are required for human centromeric function.
Microfluidic high gradient magnetic cell separation (2006)

Separation of blood cells by native susceptibility and by the selective attachment of magnetic beads has recently been demonstrated on microfluidic devices. We discuss the basic principles of how forces are generated via the magnetic susceptibility of an object and how microfluidics can be combined with micron-scale magnetic field gradients to greatly enhance in principle the fractionating power of magnetic fields. We discuss our efforts and those of others to build practical microfluidic devices for the magnetic separation of blood cells. We also discuss our attempts to integrate magnetic separation with other microfluidic features for developing handheld medical diagnostic tools.
ROLE OF FAECAL ELASTASE 1 IN PANCREATIC CANCER: A PILOT STUDY. (2004)

Background: Faecal elastase 1 (E1) is an indirect test of pancreatic function. Few study investigated the role of E1 in pancreatic cancer. Aim: 1) To evaluate fecal elastase levels in normal healthy subject in comparison to patients with pancreatic cancer 2) To assess the relationship between faecal elatase 1 and tumor topography in patients with pancreatic cancer. Methods: 26 consecutive patients (15 male, 11 female, mean age 72±21.3) admitted in our G.I. unit between January 2003 and February 2004 with first diagnosis of pancreatic cancer were enrolled in the study. Clinical, laboratory, histologic and imaging data were prospectively collected. Cancer topography was as follow: 14 patients had head cancer; 5 patients had body-tail cancer; 7 patients had head-body cancer. The head-body group of patients was removed from the study when we analized the relationship between fecal elastase levels and pancreatic cancer topography. Control group was composed from 165 normal healthy subject (70 male, 95 female, mean age 68±27.1). All patients and control gave their informed consent. Stool elastase level was measured by an immunoenzymatic method (Meridian Bioscience Europe). According to our normal control group, we considered abnormal E1 values lower than 200 μg/g. Mann-Whitney rank-sum test was used to data analysis. Results: Faecal elastase 1 levels were significantly decreased in pancreatic cancer patients (276.2±234.4) in comparison to normal subjects (504.5±145.3) (p<0.0001). A correlation between E1 levels and cancer topography was found: patients with pancreatic head cancer showed lower E1 levels (189.4±180.7) in comparison to patients with pancreatic body-tail cancer (421.2±229.1) but did not achieve significant level of p (p=0.078) because of low power of the test. Conclusions: Faecal elastase 1 is significantly decreased in patients with pancreatic cancer in comparison to normal healthy subject. Moreover, fecal elastase 1 could have a significant correlation with pancreatic cancer localization.
Studies on Dental Erosion: An in Vitro Model of Root Surface Erosion (2001)

Most research on dental erosion has focused on erosion in enamel. However, the increasing retention of teeth into old age has increased the potential for root surface erosion. The nature and kinetics of root surface erosion have not yet been adequately explored. The objective of this project was to develop an in vitro model of root surface erosion in order to investigate the polarised light microscopy of controlled erosion and the histology and rate of demineralisation of this process in root cementum/dentine. The results demonstrate a process quite different in outcome from that in enamel erosion. Erosion results in loss of volume of enamel. However, it leaves a root surface softened though with little volume loss so long as the demineralised collagen remains hydrated. The polarised light histology was similar to that seen in root surface caries. The rate of erosive demineralisation of tooth roots by selected acids was investigated, with differing rates of demineralisation similar to that seen in enamel erosion observed. The process of erosion showed evidence of significant diffusion control.
5-Lipoxygenase-Activating Protein Inhibitors: Development of 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103) (2009)

The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vivo activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC(50) of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC(50) of 349 nM in the human blood LTB(4) inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase 1 trials in healthy volunteers.
Arabidopsis NPH1: A Protein Kinase with a Putative Redox-Sensing Domain (1997)

The NPH1 (nonphototropic hypocotyl 1) gene encodes an essential component acting very early in the signal-transduction chain for phototropism. Arabidopsis NPH1 contains a serine-threonine kinase domain and LOV1 and LOV2 repeats that share similarity (36 to 56 percent) with Halobacterium salinarium Bat, Azotobacter vinelandii NIFL, Neurospora crassa White Collar-1, Escherichia coli Aer, and the Eag family of potassium-channel proteins from Drosophila and mammals. Sequence similarity with a known (NIFL) and a suspected (Aer) flavoprotein suggests that NPH1 LOV1 and LOV2 may be flavin-binding domains that regulate kinase activity in response to blue light-induced redox changes.
Dronedaron - eine neue therapeutische Option zur Kontrolle von Vorhofrhythmus und Kammerfrequenz (2006)

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study
On the power spectral density of time-hopping impulse radio (2003)

The power spectral density (PSD) of time-hopping (TH) ultra wide band (UWB) signals plays a major role in key aspects like coexistence with conventional radio systems. In the past, several papers have been published, presenting on the one hand the effects of modulation and timing jitter on the PSD assuming random TH codes. On the other hand, papers have been presented dealing with the PSD of specific TH codes without modulation. This paper presents a mathematical framework that enables the evaluation of the PSD of a modulated impulse radio signal using a deterministic TH code. Besides being of theoretical interest, our results can be the starting point for the development of TH code design criteria aimed at the spectral shaping of the UWB signal.
Receptor tyrosine kinase substrates: src homology domains and signal transduction (1992)

Among the intracellular milieu of proteins are molecules with defined biochemical functions that serve as substrates for ligand‐activated tyrosine kinase receptors. It seems likely that some of these substrate molecules are elements of a critical signaling pathway used by growth factors to control cell proliferation and subverted by oncogenes to deregulate this process. Although the process of cell growth and division is relatively slow compared with other hormonally regulated responses, homeostasis in a human being requires approximately 20 × 10 6 cell divisions per second for the renewal of various cell populations. This review summarizes the present understanding of tyrosine kinase substrates that seem likely to have key roles in the signal transduction pathway that regulates cell proliferation. This includes structural features of these molecules, the influence of tyrosine phosphorylation on their functions, the biological roles of these proteins, and the capacity of these substrates to associate with activated receptor tyrosine kinases.— Carpenter, G. Receptor tyrosine kinase substrates: src homology domains and signal transduction. FASEB J. 6: 3283‐3289; 1992.
T cell receptor grafting allows virological control of hepatitis B virus infection (2019)

T cell therapy is a promising means to treat chronic HBV infection and HBV-associated hepatocellular carcinoma. T cells engineered to express an HBV-specific T cell receptor (TCR) may achieve cure of HBV infection upon adoptive transfer. We investigated the therapeutic potential and safety of T cells stably expressing high affinity HBV envelope- or core-specific TCRs recognizing European and Asian HLA-A2 subtypes. Both CD8+ and CD4+ T cells from healthy donors and from chronic hepatitis B patients became polyfunctional effector cells when grafted with HBV-specific TCRs and eliminated HBV from infected HepG2-NTCP cell cultures. A single transfer of TCR-grafted T cells into HBV-infected, humanized mice controlled HBV infection and virological markers declined 4-5 log or below detection limit. When - as in a typical clinical setting - only a minority of hepatocytes were infected, engineered T cells specifically cleared infected hepatocytes without damaging non-infected cells. Cell death was compensated by hepatocyte proliferation and alanine amino transferase levels peaking at day 5 to 7 normalized again thereafter. Co-treatment with the entry inhibitor Myrcludex B ensured long-term control of HBV infection. Thus, T cells stably transduced with highly functional TCRs have the potential to mediate clearance of HBV-infected cells causing limited liver injury.
Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance) (2019)

These findings highlight the possible clinical utility of CMSs and suggests that refinement of the CMS classification may provide a path toward identifying patients with metastatic CRC who are most likely to benefit from specific targeted therapy as part of the initial treatment.
Cartilage-Derived Morphogenetic Proteins and Osteogenic Protein-1 Differentially Regulate Osteogenesis (1998)

Cartilage-derived morphogenetic proteins-1 and -2 (CDMP-1 and CDMP-2) are members of the bone morphogenetic protein (BMP) family, which play important roles in embryonic skeletal development. We studied the biological activities of recombinant CDMP-1 and CDMP-2 in chondrogenic and osteogenic differentiation and investigated their binding properties to type I and type II serine/threonine kinase receptors. In vivo, CDMP-1 and CDMP-2 were capable of inducing dose-dependently de novo cartilage and bone formation in an ectopic implantation assay. In vitro studies using primary chondrocyte cultures showed that both CDMP-1 and CDMP-2 stimulated equally de novo synthesis of proteoglycan aggrecan in a concentration-dependent manner. This activity was equipotent when compared with osteogenic protein-1 (OP-1). In contrast, CDMPs were less stimulatory than OP-1 in osteogenic differentiation as evaluated by alkaline phosphatase activity and expression levels of bone markers in ATDC5, ROB-C26, and MC3T3-E1 cells. CDMP-2 was the least osteogenic in these assays. Receptor binding studies of CDMP-1 and CDMP-2 revealed that both have affinity for the BMP receptor type IB (BMPR-IB) and BMPR-II, and weakly for BMPR-IA. Moreover, using a promoter/reporter construct, transcriptional activation signal was transduced by BMPR-IB in the presence of BMPR-II upon CDMP-1 and CDMP-2 binding. Our data show that distinct members of the BMP family differentially regulate the progression in the osteogenic lineage, and this may be due to their selective affinity for specific receptor complexes.
Systemic Gene Silencing in Primary T Lymphocytes Using Targeted Lipid Nanoparticles (2015)

Modulating T cell function by down-regulating specific genes using RNA interference (RNAi) holds tremendous potential in advancing targeted therapies in many immune-related disorders including cancer, inflammation, autoimmunity, and viral infections. Hematopoietic cells, in general, and primary T lymphocytes, in particular, are notoriously hard to transfect with small interfering RNAs (siRNAs). Herein, we describe a novel strategy to specifically deliver siRNAs to murine CD4(+) T cells using targeted lipid nanoparticles (tLNPs). To increase the efficacy of siRNA delivery, these tLNPs have been formulated with several lipids designed to improve the stability and efficacy of siRNA delivery. The tLNPs were surface-functionalized with anti-CD4 monoclonal antibody to permit delivery of the siRNAs specifically to CD4(+) T lymphocytes. Ex vivo, tLNPs demonstrated specificity by targeting only primary CD4(+) T lymphocytes and no other cell types. Systemic intravenous administration of these particles led to efficient binding and uptake into CD4(+) T lymphocytes in several anatomical sites including the spleen, inguinal lymph nodes, blood, and the bone marrow. Silencing by tLNPs occurs in a subset of circulating and resting CD4(+) T lymphocytes. Interestingly, we show that tLNP internalization and not endosome escape is a fundamental event that takes place as early as 1 h after systemic administration and determines tLNPs' efficacy. Taken together, these results suggest that tLNPs may open new avenues for the manipulation of T cell functionality and may help to establish RNAi as a therapeutic modality in leukocyte-associated diseases.
The Cosmed K4 Telemetry System as an Accurate Device for Oxygen Uptake Measurements during Exercise (1997)

The purpose of this study was to test the accuracy of oxygen uptake (VO2) measurements using the Cosmed K4 portable telemetry system. This system of higher technology than the original Cosmed K2 device, contains a CO2 electrode allowing measurements alternatively by either the Cosmed K4 system (K4) or the CPX Medical Graphics (CPX) during a maximum oxygen uptake (VO2max) ergocycle test, at rest and during several submaximal exercises (25, 50 and 75% of maximal work rate) in seven subjects. Heart rate values were comparable for exercise at the same work stage during gas collection using the two systems, indicating that the physiological stresses were similar. The VO2 values did not significantly differ at rest (4.40+/-0.83 vs 4.16+/-0.58ml x min(-1) x kg[-1]), at 25% Wmax (20.97+/-1.31 vs 21.32+/-2.54 ml x min(-1) x kg[-1]), at 50% Wmax (33.32+/-3.92 vs 33.50+/-3.51 ml x min(-1) x kg[-1]), at 75% Wmax (47.01+/-7.51 vs 47.49+/-7.11 ml x min(-1) kg[-1]) and at maximal intensities (62.07+/-8.48 vs 62.84+/-11.31 ml x min(-1) kg[-1]) using K4 and CPX devices, respectively. The results of this study indicated that the K4 system was accurate for all oxygen uptake measurements from rest to maximum exercise levels.
Goodness-of-Fit Analysis for the Cox Regression Model Based on a Class of Parameter Estimators (1991)

Abstract In this article we propose a class of estimation functions for the vector of regression parameters in the Cox proportional hazards model with possibly time-dependent covariates by incorporating the weight functions commonly used in weighted log-rank tests into the partial likelihood score function. The resulting estimators behave much like the conventional maximum partial likelihood estimator in that they are consistent and asymptotically normal. When the Cox model is inappropriate, however, the estimators with different weight functions generally converge to nonidentical constant vectors. For example, the magnitude of the parameter estimator using the Kaplan–Meier survival estimator as the weight function will be stochastically larger than that of the maximum partial likelihood estimator if covariate effects diminish over time. Such facts motivate us to develop goodness-of-fit methods for the Cox regression model by comparing parameter estimators with different weight functions. Under the assumed model, the normalized difference between the maximum partial likelihood estimator and a weighted parameter estimator is shown to converge weakly to a multivariate normal with mean zero and with a covariance matrix for which a consistent estimator is proposed. The asymptotic properties of the weighted parameter estimators and those of the related goodness-of-fit tests under misspecified Cox models are also investigated. In particular, it is demonstrated that a goodness-of-fit test with a monotone weight function is consistent against monotone departures from the proportional hazards assumption. Versatile testing procedures with broad sensitivities can be developed based on simultaneous use of several weight functions. Three examples using real data are presented.
DNA Immunization against Experimental Genital Herpes Simplex Virus Infection (1996)

A nucleic acid vaccine, expressing the gene encoding herpes simplex virus (HSV) type 2 glycoprotein D (gD2) under control of the cytomegalovirus immediate-early gene promoter, was used to immunize guinea pigs against genital HSV-2 infection. The vaccine elicited humoral immune responses comparable to those seen after HSV-2 infection. Immunized animals exhibited protection from primary genital HSV-2 disease with little or no development of vesicular skin lesions and significantly reduced HSV-2 replication in the genital tract. After recovery from primary infection, immunized guinea pigs experienced significantly fewer recurrences and had significantly less HSV-2 genomic DNA detected in the sacral dorsal root ganglia compared with control animals. Thus, immunization reduced the burden of latent infection resulting from intravaginal HSV-2 challenge, and a nucleic acid vaccine expressing the HSV-2 gD2 antigen protected guinea pigs against genital herpes, limiting primary infection and reducing the magnitude of latent infection and the frequency of recurrent disease.
Renal cell carcinoma (1997)

Current prognostic factors for renal cell carcinoma yield considerable information for assisting with patient management and predicting clinical outcome. Traditional prognostic factors remain the most valuable, even though a variety of other patient-related and tumor-related factors may significantly contribute to prognostic information. A number of recently described biomarkers show great promise but the current data are insufficient to recommend their use.