gebhart/patrepeval huggingface dataset:
Hippocampal Neural Disinhibition Causes Attentional and Memory Deficits (2016)

Subconvulsive hippocampal neural disinhibition, that is reduced GABAergic inhibition, has been implicated in neuropsychiatric disorders characterized by attentional and memory deficits, including schizophrenia and age-related cognitive decline. Considering that neural disinhibition may disrupt both intra-hippocampal processing and processing in hippocampal projection sites, we hypothesized that hippocampal disinhibition disrupts hippocampus-dependent memory performance and, based on strong hippocampo-prefrontal connectivity, also prefrontal-dependent attention. In support of this hypothesis, we report that acute hippocampal disinhibition by microinfusion of the GABA-A receptor antagonist picrotoxin in rats impaired hippocampus-dependent everyday-type rapid place learning performance on the watermaze delayed-matching-to-place test and prefrontal-dependent attentional performance on the 5-choice-serial-reaction-time test, which does not normally require the hippocampus. For comparison, we also examined psychosis-related sensorimotor effects, using startle/prepulse inhibition (PPI) and locomotor testing. Hippocampal picrotoxin moderately increased locomotion and slightly reduced startle reactivity, without affecting PPI. In vivo electrophysiological recordings in the vicinity of the infusion site showed that picrotoxin mainly enhanced burst firing of hippocampal neurons. In conclusion, hippocampal neural disinhibition disrupts hippocampus-dependent memory performance and also manifests through deficits in not normally hippocampus-dependent attentional performance. These behavioral deficits may reflect a disrupted control of burst firing, which may disrupt hippocampal processing and cause aberrant drive to hippocampal projection sites.
Xenotransplantation and risks of zoonotic infections (2004)

The shortage of human organs and tissues for transplantation and the advances in immunology of rejection and in genetic engineering have renewed interest in xenotransplantation--the transplantation of animal organs, tissues or cells to humans. Clinical trials have involved the use of non-human primate, porcine, and bovine cells/tissues/organs. In recent years, research has focused mainly on pigs as donors (especially, pigs genetically engineered to carry some human genes). One of the major concerns in xenotransplantation is the risk of transmission of animal pathogens, particularly viruses, to recipients and the possible adaptation of such pathogens for human-to-human transmission. Porcine endogenous retroviruses (PERVs) have been of special concern because of their ability to infect human cells and because, at present, they cannot be removed from the source animal's genome. To date, retrospective studies of humans exposed to live porcine cells/tissues have not found evidence of infection with PERV but more extensive research is needed. This article reviews infectious disease risks associated with xenotransplantation, some measures for minimizing that risk, and microbiological diagnostic methods that may be used in the follow-up of xenotransplant recipients.
12-O-tetradecanoylphorbol-13-acetate promotion of transgenic mice expressing epidermal-targeted v-fos induces rasHA-activated papillomas and carcinomas without p53 mutation: association of v-fos expression with promotion and tumor autonomy. (1995)

Transgenic mice that expressed v-fos exclusively in the epidermis by means of a human keratin K1-based targeting vector (HK1.fos) developed preneoplastic epidermal hyperplasia and hyperkeratosis after long latency and an associated wound promotion stimulus. To assess the requirements for papilloma formation and malignant conversion and determine the sensitivity to a chemical promotion stimulus, HK1.fos mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). HK1.fos mice were sensitive to TPA promotion but developed papillomas only after long latency (20-30 weeks of promotion) and in relatively few numbers per animal, suggesting the necessity of an additional genetic event prior to overt lesion formation. Consistent with this idea, at 60 weeks, on cessation of TPA promotion, these HK1.fos TPA-papillomas were found to be autonomous, TPA-independent tumors which persisted, grew larger, and converted to malignancy. Analysis of HK1.fos tumor RNA and DNA identified endogenous c-rasHa mutations at codons 12 and 61 in papillomas and carcinomas; however, no p53 tumor suppressor gene mutations were detected. These data indicate that epidermal expression of v-fos induces sensitivity to TPA promotion, but since additional genetic events, such as endogenous c-rasHa activation, appear to be required in tumorigenesis, v-fos may predominantly play a role in the mechanism of promotion to achieve papilloma autonomy and TPA independence. Furthermore, spontaneous malignant conversion in this model does not appear to involve mutations in the p53 tumor suppressor gene.
Near-field optical microscope using a silicon-nitride probe (1993)

Operation of an alternative near-field optical microscope is presented. The microscope uses a microfabricated silicon-nitride probe with integrated cantilever, as originally developed for force microscopy. The cantilever allows routine close contact near-field imaging on arbitrary surfaces without tip destruction. The effect of adhesion forces on the coupling to the evanescent wave has been observed. Images with a lateral resolution of about 50 nm are presented and compared with atomic force images. A specific sample area can be selected using an integrated conventional light microscope.
A gate drive circuit for Normally-On SiC JFETs with self-protection functions against overcurrent and shoot-through fault conditions (2015)

Normally-On Silicon Carbide (SiC) JFETs are considered promising switching semiconductor devices due to their capability to operate in high voltages, frequencies and temperatures. However, an efficient driving and protection scheme is required to fully exploit their potential for use in power converters. In this paper, a proposed self-protection topology is integrated into a fast switching ac-coupled gate drive to minimize fault detection time for the prevention of overcurrent and shoot-through faults caused by the normally-on behavior of the device. The developed topology uses the desaturation principle through a sensing diode to detect drain-source voltage under overcurrent condition. A configuration to keep the device in the off-switching state in case of gate drive power supply failure is also included. The gate drive itself applies forward bias to achieve lower on-state resistance, while design considerations are described in order to achieve fast switching times. A double pulse tester set-up with a phase-leg configuration is used to experimentally verify the performance of the proposed protection schemes under various fault conditions as well as measure switching losses. The standalone nature and easy parameterization of the proposed driving and protection topology makes it suitable for use in any power converter built with normally-On SiC JFETs.
Activating human genes with zinc finger proteins, transcription activator-like effectors and CRISPR/Cas9 for gene therapy and regenerative medicine (2014)

New technologies have recently been developed to control the expression of human genes in their native genomic context by engineering synthetic transcription factors that can be targeted to any DNA sequence. The ability to precisely regulate any gene as it occurs naturally in the genome provides a means to address a variety of diseases and disorders. This approach also circumvents some of the traditional challenges of gene therapy. In this editorial, we review the technologies that have enabled targeted human gene activation, including the engineering of transcription factors based on zinc finger proteins, transcription activator-like effectors and the CRISPR/Cas9 system. Additionally, we highlight examples in which these methods have been developed for therapeutic applications and discuss challenges and opportunities.
RNA Interference-Mediated Knockdown of DNA Methyltransferase 1 Leads to Promoter Demethylation and Gene Re-Expression in Human Lung and Breast Cancer Cells (2004)

DNA methyltransferase 1 (DNMT1) is required to maintain DNA methylation patterns in mammalian cells, and is thought to be the predominant maintenance methyltransferase gene. Recent studies indicate that inhibiting DNMT1 protein expression may be a useful approach for understanding the role of DNA methylation in tumorigenesis. To this end, we used RNA interference to specifically down-regulate DNMT1 protein expression in NCI-H1299 lung cancer and HCC1954 breast cancer cells. RNA interference-mediated knockdown of DNMT1 protein expression resulted in >80% reduction of promoter methylation in RASSF1A, p16(ink4A), and CDH1 in NCI-H1299; and RASSF1A, p16(ink4A), and HPP1 in HCC1954; and re-expression of p16(ink4A), CDH1, RASSF1A, and SEMA3B in NCI-H1299; and p16(ink4A), RASSF1A, and HPP1 in HCC1954. By contrast, promoter methylation and lack of gene expression was maintained when these cell lines were treated with control small interfering RNAs. The small interfering RNA treatment was stopped and 17 days later, all of the sequences showed promoter methylation and gene expression was again dramatically down-regulated, indicating the tumor cells still were programmed for these epigenetic changes. We saw no effects on soft agar colony formation of H1299 cells 14 days after DNMT1 knockdown indicating that either these genes are not functioning as tumor suppressors under these conditions, or that more prolonged knockdown or other factors are also required to inhibit the malignant phenotype. These results provide direct evidence that loss of DNMT1 expression abrogates tumor-associated promoter methylation and the resultant silencing of multiple genes implicated in the pathogenesis of human lung and breast cancer.
Herpes Simplex Virus 1 Immediate-Early and Early Gene Expression during Reactivation from Latency under Conditions That Prevent Infectious Virus Production (2005)

The program of gene expression exhibited by herpes simplex virus during productive infection of cultured cells is well established; however, less is known about the regulatory controls governing reactivation from latency in neurons. One difficulty in examining gene regulation during reactivation lies in distinguishing between events occurring in initial reactivating cells versus events occurring in secondarily infected cells. Thus, two inhibitors were employed to block production of infectious virus: acyclovir, which inhibits viral DNA synthesis, and WAY-150138, which permits viral DNA synthesis but inhibits viral DNA encapsidation. Latently infected murine ganglia were explanted in the presence of either inhibitor, and then amounts of RNA, DNA, or infectious virus were quantified. In ganglia explanted for 48 h, the levels of five immediate-early and early RNAs did not exhibit meaningful differences between acyclovir and WAY-150138 treatments when analyzed by in situ hybridization or quantitative reverse transcription-PCR. However, comparative increases in viral DNA and RNA content in untreated ganglia suggested that virus was produced before 48 h postexplant. This was confirmed by the detection of infectious virus as early as 14 h postexplant. Together, these results suggest that high levels of viral gene expression at 48 h postexplant are due largely to the production of infectious virus and subsequent spread through the tissue. These results lead to a reinterpretation of previous results indicating a role for DNA replication in immediate-early and early viral gene expression; however, it remains possible that viral gene expression is regulated differently in neurons than in cultured cells.
Recombinant Hemoglobin a Produced in Transgenic Swine: Structural Equivalence with Human Hemoglobin A (1994)

Recombinant human hemoglobin A produced by coexpressing human alpha and beta globin genes in swine, and purified from the lysate of transgenic swine has been subjected to detailed protein chemical analysis. These structural studies involving laser desorption mass spectrometry, separation of globin chains by RPHPLC, amino terminal sequence analysis of the isolated globin chains, the tryptic peptide mapping of the purified globin chains and the amino acid composition analysis of the purified tryptic peptides of globin chains have established the primary structural equivalence of the globin chains of the transgenic swine derived hemoglobin A with that of human hemoglobin A. These results demonstrate that the transgenic swine system correctly translates the human alpha and beta globin m-RNA; carries out the correct cotranslational processing of globin chains, and does not introduce any unwanted post translational modifications into the mature chains. Thus, the transgenic swine expression system is an excellent approach for the production of HbA for developing an effective hemoglobin based oxygen carrier.
Implementing self-service business analytics supporting lean manufacturing: A state-of-the-art review (2018)

Piloting lean manufacturing projects requires dynamically tailoring suitable sets of metrics. Quick turnaround in implementing such metrics is critical, as the typical duration of a Lean Six Sigma project is 3 to 6 months. Self-service Business Analytics (SSBA) can provide managers with the much-needed flexibility to efficiently design and redesign comprehensive metrics in fragmented information system contexts. A review of state-of-the-art practices for SSBA implementation is performed, which lays down the foundations for an upcoming framework geared towards lean manufacturing. Key SSBA planning and architecture findings are summarized. Practical evaluation of the framework in a complex information system landscape through Design Science Research (DSR) is projected with the Canadian division of an international steel parts manufacturing company
IL-15 induces CD4+ effector memory T cell production and tissue emigration in nonhuman primates (2006)

HIV infection selectively targets CD4+ effector memory T (T EM) cells, resulting in dramatic depletion of CD4+ T cells in mucosal effector sites in early infection. Regeneration of the T EM cell compartment is slow and incomplete, even when viral replication is controlled by antiretroviral therapy (ART). Here, we demonstrate that IL-15 dramatically increases in vivo proliferation of rhesus macaque (RM) CD4+ and CD8+ T EM cells with little effect on the naive or central memory T (T CM) cell subsets, a response pattern that is quite distinct from that of either IL-2 or IL-7. T EM cells produced in response to IL-15 did not accumulate in blood. Rather, 5-bromo-2'-deoxyuridine (BrdU) labeling studies suggest that many of these cells rapidly disperse to extralymphoid effector sites, where they manifest (slow) decay kinetics indistinguishable from that of untreated controls. In RMs with uncontrolled SIV infection and highly activated immune systems, IL-15 did not significantly increase CD4+ T EM cell proliferation, but with virologic control and concomitant reduction in immune activation by ART, IL-15 responsiveness was again observed. These data suggest that therapeutic use of IL-15 in the setting of ART might facilitate specific restoration of the CD4 + T cell compartment that is the primary target of HIV with less risk of exhausting precursor T cell compartments or generating potentially deleterious regulatory subsets.
Carbon-Nanotube-Based Voltage-Mode Multiple-Valued Logic Design (2005)

Multivalued logic has always attracted the attention of digital system and logic designers. However, the high-performance and low-power CMOS process, which has been developed over the last two decades, has traditionally assisted successful circuit implementation of binary logic. Consequently, in spite of its large potential multivalued logic design is seldom a circuit designer's choice. This paper presents a novel method of multiple-valued logic design using carbon-nanotube field-effect transistors (CNFETs). The geometry-dependent threshold voltage of CNFETs has been effectively used to design a ternary logic family. We have developed a SPICE-compatible model of ballistic CNFETs that can account for varying geometries and operating conditions. SPICE simulations have been performed on the proposed logic gates, and the transfer characteristics as well as transient behavior have been extensively studied. Finally, a comparison in terms of power and performance of the ternary logic family vis-a/spl grave/-vis traditional complementary field-effect transistor binary logic family has been presented.
Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria (2006)

Twenty percent of the familial form of amyotrophic lateral sclerosis (ALS) is caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1) through the gain of a toxic function. The nature of this toxic function of mutant SOD1 has remained largely unknown. Here we show that WT SOD1 not only hastens onset of the ALS phenotype but can also convert an unaffected phenotype to an ALS phenotype in mutant SOD1 transgenic mouse models. Further analyses of the single- and double-transgenic mice revealed that conversion of mutant SOD1 from a soluble form to an aggregated and detergent-insoluble form was associated with development of the ALS phenotype in transgenic mice. Conversion of WT SOD1 from a soluble form to an aggregated and insoluble form also correlates with exacerbation of the disease or conversion to a disease phenotype in double-transgenic mice. This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are crosslinked through intermolecular disulfide bonds via oxidation of cysteine residues in SOD1. Our data thus show a molecular mechanism by which SOD1, an important protein in cellular defense against free radicals, is converted to aggregated and apparently ALS-associated toxic dimers and multimers by redox processes. These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders. Importantly, rational therapy based on these observations can now be developed and tested.
Medical diagnosis, diagnostic spaces, and fuzzy systems (1997)

The complexity and uncertainty of diagnostic information makes the diagnostic process difficult to learn, teach, and practice. Fuzzy logic methods, used successfully with complex industrial control problems, may be appropriate to model the range of uncertainties found in medical diagnostic information. A fuzzy systems model for use with diagnostic and other medical decisions is described. Combining a state space view of an animal in which each dimension of the space represents a variable of the animal with a fuzzy sets representation of the variables and states of the animal leads to a fuzzy systems model, which can be used to successfully diagnose disease. Partitioning the multidimensional state space of the animal into healthy and specific disease regions provides a diagnostic space for evaluating the health of the animal. When an input vector representing the variables of a sick animal is entered into the system, the model can provide a diagnosis and, potentially, a prognosis for that animal. The model can be implemented on a desktop computer for convenient use, and it provides a helpful geometric interpretation of the concepts of "diagnosis" and "prognosis" for teaching diagnostic reasoning. The fuzzy systems approach has advantages that are unavailable in other methods. The capability of fuzzy systems to act as universal approximators allows them to accommodate complex, nonlinear, imprecise, and even conflicting relationships to provide accurate knowledge representation. With these advantages over standard rule-based methods of modeling the medical diagnostic process, fuzzy expert systems have broad potential for use in medicine and warrant further study to determine their application and possible limitations.
Continuous Subcutaneous Insulin Infusion and Multiple Daily Injection Therapy Are Equally Effective in Type 2 Diabetes (2003)

OBJECTIVE—Compare the efficacy, safety, and patient satisfaction of continuous subcutaneous insulin infusion (CSII) therapy with multiple daily injection (MDI) therapy for patients with type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 132 CSII-naive type 2 diabetic patients were randomly assigned (1:1) to CSII (using insulin aspart) or MDI therapy (bolus insulin aspart and basal NPH insulin) in a multicenter, open-label, randomized, parallel-group, 24-week study. Efficacy was assessed with HbA1c and eight-point blood glucose (BG) profiles. Treatment satisfaction was determined with a self-administered questionnaire. Safety assessments included adverse events, hypoglycemic episodes, laboratory values, and physical examination findings. RESULTS—HbA1c values decreased similarly for both groups from baseline (8.2 ± 1.37% for CSII, 8.0 ± 1.08% for MDI) to end of study (7.6 ± 1.22% for CSII, 7.5 ± 1.22% for MDI). The CSII group showed a trend toward lower eight-point BG values at most time points (only significant 90 min after breakfast; 167 ± 48 vs. 192 ± 65 mg/dl for CSII and MDI, respectively; P = 0.019). A total of 93% of CSII-treated subjects preferred the pump to their previous injectable insulin regimen for reasons of convenience, flexibility, ease of use, and overall preference. Safety assessments were comparable for both treatment groups. CONCLUSIONS—Insulin aspart in CSII therapy provided efficacy and safety comparable to MDI therapy for type 2 diabetes. Patients with type 2 diabetes can be trained as outpatients to use CSII and prefer CSII to injections, indicating that pump therapy should be considered when initiating intensive insulin therapy for type 2 diabetes.
Aspartate Transcarbamylase (1971)

Abstract N-(Phosphonacetyl)-l-aspartate (PALA) is a stable analogue of the transition state in the reaction catalyzed by aspartate transcarbamylase from Escherichia coli; it combines in 1 molecule most of the structural features of the two natural substrates, carbamyl phosphate and l-aspartate. The inhibition constant (Ki) for PALA with the catalytic subunit is 2.7 x 10-8m at 28° and pH 7.0 in 0.2 m imidazole acetate; the value of Ki is approximately the same with the native enzyme. PALA binds to aspartate transcarbamylase about 1000 times more tightly than carbamyl phosphate, the substrate bound most tightly. In addition to tight binding, other data indicate that PALA interacts with the enzyme at both the carbamyl phosphate and l-aspartate sites simultaneously and puts the enzyme into the same contracted conformation as do carbamyl phosphate and succinate (an analogue of l-aspartate) acting together. PALA alone or carbamyl phosphate and succinate together produce the same ultraviolet difference spectrum with the catalytic subunit; the binding of PALA alone or carbamyl phosphate and succinate together at some of the catalytic sites in the native enzyme activates the remaining catalytic sites to the same extent. PALA gives competitive inhibition with carbamyl phosphate but not with l-aspartate, indicating an obligatory binding order for the substrates: carbamyl phosphate must bind before l-aspartate for catalysis to occur. Titration of the catalytic subunit with PALA, monitored by ultraviolet difference spectroscopy, indicates that there are 3.07 active sites per 100,000 daltons. The interaction of PALA with the enzyme is consistent with the compression model for aspartate transcarbamylase previously proposed (Collins, K.D., and Stark, G.R., J. Biol. Chem., 244, 1869 (1969)).