gebhart/patrepeval huggingface dataset:
Signalling proteins in enterobacterial AmpC β‐lactamase regulation (1989)

The cloned Citrobacter freundii ampC beta-lactamase is inducible in the presence of its regulatory gene ampR in Escherichia coli (Lindberg et al., 1985). The basal level of expression and inducibility are affected by two E. coli proteins encoded by the closely linked ampD and ampE genes. Deletion of both genes led to constitutive ampR-dependent overproduction of beta-lactamase, whereas an out-of-frame deletion in AmpD caused the basal expression to increase two-fold. This ampD1 mutant was inducible at lower beta-lactam concentrations than the wild type. An IS1 insertion in ampD was polar on ampE expression and increased basal beta-lactamase expression 30-fold while mediating a semi-constitutive phenotype. AmpE expressed from a recombinant plasmid in an ampD-ampE deletion mutant reduced basal beta-lactamase expression to wild-type levels but did not markedly reduce beta-lactam resistance since the cells became hyperinducible. In the absence of AmpD, increasing levels of AmpE therefore decrease the basal expression of AmpC beta-lactamase in an AmpR-dependent manner. AmpD modulated the response exerted on beta-lactamase expression by AmpE. The ampD gene encodes a 20.5kD cytoplasmic protein while the 32.1kD ampE gene product is an integral membrane protein with a likely ATP-binding site between the second and third putative transmembrane region. Since neither AmpD nor AmpE are needed for beta-lactam induction and since these proteins could not be covalently labelled by benzylpenicillin, they are not thought to act as beta-lactam-binding sensory transducers. Instead it is suggested that AmpD and AmpE sense the effect of beta-lactam action on peptidoglycan biosynthesis and relay this signal to AmpR.
Effect of Btk inhibitor PCI-32765 monotherapy on responses in patients with relapsed aggressive NHL: Evidence of antitumor activity from a phase I study. (2010)

8012 Background: Bruton's tyrosine kinase (Btk) is a downstream mediator of B-cell receptor signaling. Based on promising preclinical data in B cell NHL, a study was conducted to test the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of PCI-32765, a potent, selective oral inhibitor of Btk. Methods: Multiple histologic subtypes of B cell NHL were enrolled in this dose escalation study. Cohort I was dosed at 1.25 mg/kg/day, and further dose escalation (2.5, 5.0, 8.3, 12.5, 17.5 mg/kg) based on safety evaluation. In the absence of DLTs, dose escalation was to proceed to three dose levels above the cohort that achieved >90% occupancy of Btk by PCI-32765 assessed using a PD probe assay. Blood was collected for determination of PK and PD of PCI-32765 and responses assessed every two cycles. Results: 29 pts (12 follicular, 7 CLL/SLL, 4 DLBCL, 4 mantle, 2 marginal) with a median of 3 prior therapies have been enrolled on cohorts 1-4. Therapy was well tolerated with most adverse events < grade 2. One protocol defined DLT (dose delay > 7 d due to neutropenia) was observed. 19/22 pts from cohorts 1-3 are evaluable. The ORR is 42%; 1 CR (SLL), 7 PR (4 CLL/SLL, 2 MCL and 1FL). In cohort 2, PD demonstrate complete occupancy of Btk by PCI-32765, with >95% enzyme occupancy 4 hours post dose in all pts. Basophil degranulation, a Btk-dependent cellular process, was completely inhibited up to 24 hrs. T- cell responses were not affected, and no significant depletion of peripheral blood B, T or NK cell counts was observed. Positive correlation (R2 = 0.93) was found between Btk active-site occupancy in PBMCs (mean of Days 1 and 8) and PCI-32765 plasma AUC 0-° (Day 1) at the 1.25 mg/kg dose. Conclusions: PCI-32765 is a novel oral agent that selectively targets Btk, with favorable safety data, and encouraging antitumor activity. Dose escalation to subsequent cohorts is ongoing. Phase II studies of single-agent Btk are planned in relapsed and refractory CLL/SLL and MCL. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmacyclics Pharamacyclics
Selective TBK1/IKKi dual inhibitors with anticancer potency (2013)

Increasing evidence suggests that the noncanonical IKKs play critical roles in tumor genesis and development, leading to the notion that noncanonical IKKs may be good targets for cancer therapy. Here, we demonstrate that although TBK1 is not overexpressed or constitutively activated in some tumor cells, targeting IKKi induces the activation of TBK1. Therefore, simultaneously targeting both kinases is necessary to efficiently suppress tumor cell proliferation. We show that three TBK1/IKKi dual inhibitors, which are based on a structurally rigid 2-amino-4-(3'-cyano-4'-pyrrolidine)phenyl-pyrimidine scaffold, potently inhibit cell viability in human breast, prostate and oral cancer cell lines. Treatment with these TBK1/IKKi dual inhibitors significantly impairs tumor development in xenograft and allograft mouse models. The anticancer function of these inhibitors may be partially due to their suppression of TBK1/IKKi-mediated AKT phosphorylation and VEGF expression. Most importantly, these TBK1/IKKi dual inhibitors have drug-like properties including low molecular weight, low cytochrome P450 inhibition and high metabolic stability. Therefore, our studies provide proof of concept for further drug discovery efforts that may lead to novel strategies and new therapeutics for the treatment of human cancer.
High Quality Silicon-Based AlN Thin Films for MEMS Application (2005)

ABSTRACTAluminum nitride is an attractive piezoelectric material for MEMS devices such as bulk acoustic wave (BAW) devices. (002)-oriented AlN films were deposited on Si, Al and Pt by reactive sputtering. Optimized AlN (002) peak reaches a full width at half maximum (FWHM) of 5.6°. Auger electron spectroscopy is used to analyze the oxygen contamination of films. To find the suitable electrode material for device application, the growth mechanism of AlN crystallites on different substrates is also discussed. Based on sputtered AlN films, the prototype of AlN thin film bulk acoustic resonator (TFBAR) was fabricated successfully.Keywords: Aluminum nitridereactive sputtering(002) orientationthin film bulk acoustic resonator (TFBAR) ACKNOWLEDGMENTSThis work is supported by the National 973' Project (G1999033105) and “985” project of China.
Functional connectivity in the default network during resting state is preserved in a vegetative but not in a brain dead patient (2009)

Recent studies on spontaneous fluctuations in the functional MRI blood oxygen level-dependent (BOLD) signal in awake healthy subjects showed the presence of coherent fluctuations among functionally defined neuroanatomical networks. However, the functional significance of these spontaneous BOLD fluctuations remains poorly understood. By means of 3 T functional MRI, we demonstrate absent cortico-thalamic BOLD functional connectivity (i.e. between posterior cingulate/precuneal cortex and medial thalamus), but preserved cortico-cortical connectivity within the default network in a case of vegetative state (VS) studied 2.5 years following cardio-respiratory arrest, as documented by extensive behavioral and paraclinical assessments. In the VS patient, as in age-matched controls, anticorrelations could also be observed between posterior cingulate/precuneus and a previously identified task-positive cortical network. Both correlations and anticorrelations were significantly reduced in VS as compared to controls. A similar approach in a brain dead patient did not show any such long-distance functional connectivity. We conclude that some slow coherent BOLD fluctuations previously identified in healthy awake human brain can be found in alive but unaware patients, and are thus unlikely to be uniquely due to ongoing modifications of conscious thoughts. Future studies are needed to give a full characterization of default network connectivity in the VS patients population.
Cycloaddition Chemistry of Organic Molecules with Semiconductor Surfaces (2000)

Recent investigations have shown that cycloaddition reactions, widely used in organic chemistry to form ring compounds, can also be applied to link organic molecules to the (001) surfaces of crystalline silicon, germanium, and diamond. While these surfaces are comprised of Si=Si, Ge=Ge, and C=C structural units that resemble the C=C bonds of organic alkenes, the rates and mechanisms of the surface reactions show some distinct differences from those of their organic counterparts This article reviews recent studies of [2 + 2], [4 + 2] Diels-Alder, and other cycloaddition reactions of organic molecules with semiconductor surfaces and summarizes the current understanding of the reaction pathways.
Feline leukemia virus infection as a potentiating cofactor for the primary and secondary stages of experimentally induced feline immunodeficiency virus infection (1990)

Preexistent feline leukemia virus (FeLV) infection greatly potentiated the severity of the transient primary and chronic secondary stages of feline immunodeficiency virus (FIV) infection. Of 10 FeLV-FIV carrier cats, 5 died of experimentally induced FIV infection, compared with 2 deaths in 10 cats infected only with FeLV and 1 death in 7 cats infected only with FIV. FIV-infected cats with preexistent FeLV infections developed severe depression, anorexia, fever, diarrhea, dehydration, weight loss, and leukopenia 4 to 6 weeks after infection and were moribund within 2 weeks of the onset of signs, whereas cats infected only with FIV developed much milder self-limiting gross and hematologic abnormalities. Pathologic findings in dually infected cats that died were similar to those observed previously in cats dying from uncomplicated primary FIV infection but were much more widespread and severe. Coinfection of asymptomatic FeLV carrier cats with FIV did not increase the levels of FeLV p27 antigen present in their blood over that seen in cats infected with FeLV alone. The amount of proviral FIV DNA was much higher, however, in dually infected cats than in cats infected only with FIV; there was a greater expression of FIV DNA in lymphoid tissues, where the genome was normally detected, and in nonlymphoid tissues, where FIV DNA was not usually found. Dually infedted cats that recovered from the primary stage of FIV infection remained more leukopenic than cats infected with FIV or FeLV alone, and their CD4+/CD8+ T-lymphocyte ratios were inverted. One of these cats developed what was considered to be an opportunistic infection. It was concluded, therefore, that a preexistent FeLV infection in some way enhanced the expression and spread of FIV in the body and increased the severity of both the resulting transient primary and chronic secondary stages of FIV infection. This study also demonstrated the usefulness of the FIV model in studying the role of incidental infectious diseases as cofactors for immunodeficiency-causing lentiviruses.
The Investment Performance of Mutual Funds: An Empirical Investigation of Timing, Selectivity, and Market Efficiency (1979)

Stanley J. Kon, Frank C. Jen, The Investment Performance of Mutual Funds: An Empirical Investigation of Timing, Selectivity, and Market Efficiency, The Journal of Business, Vol. 52, No. 2 (Apr., 1979), pp. 263-289
Enzyme-Linked Immunosorbent Assay Based on a Monoclonal Antibody for the Detection of the Insecticide Triazophos:  Assay Optimization and Application to Environmental Samples (2007)

A direct competitive enzyme-linked immunosorbent assay (ELISA) for triazophos was developed, which was based on the THHe monoclonal antibody (McAb) and a heterologous enzyme tracer (THBu-HRP). The influence of several physicochemical factors (temperature, time, pH, salt, detergent, and solvent) on the immunoassay was studied. For the standard curve, an I50 of 0.21 microg/L and a limit of detection (I20) of 0.02 microg/L was obtained in a high salt concentration buffer (0.05 M PBS, pH 6.0) with 0.05% BSA, which means an almost 3-fold improvement in the assay sensitivity in comparison with the nonoptimized conditions. The optimized ELISA has been used to quantify triazophos in water and soil samples spiked at different amounts. The excellent recoveries achieved confirmed the potential of the immunoassay for environmental monitoring of triazophos in waters and soils without purification steps.
Pharmacodynamic enhancement of the anti-platelet antibody Fab abciximab by site-specific pegylation (2004)

Monoclonal antibodies have been firmly established as human therapeutics. Their high affinity and specificity for target antigens minimize adverse reactions and their molecular size results in extended circulation times relative to small molecule pharmaceuticals. The ability to customize the pharmacokinetics in a rational manner can enhance the potential for these and other classes of biologicals. We have systematically studied the effect of site-specific pegylation of the Fab' fragment of the anti-GPIIb/IIIa, alphavbeta3 antibody c7E3. Regardless of the molecular weight of the PEG molecules, the intrinsic affinity of the resulting constructs remained unchanged. However, in functional assays measuring inhibition of platelet aggregation, the calculated IC50 values of the conjugates decreased with increasing molecular weight of the conjugated PEG. It was determined that the molecular size of the conjugates affects antigen accessibility and whereas high levels of binding to antigen molecules on cells with high antigen density can be demonstrated with the Fab fragment, comparable levels are not achievable with large molecular weight conjugates. In spite of the inability of the larger PEG constructs to achieve saturation binding, functional inhibition of platelet aggregation consistent with saturation binding was demonstrated and the increased molecular size of the conjugates led to predictably prolonged inhibition of platelet aggregation.
Iterative in Situ Click Chemistry Assembles a Branched Capture Agent and Allosteric Inhibitor for Akt1 (2011)

We describe the use of iterative in situ click chemistry to design an Akt-specific branched peptide triligand that is a drop-in replacement for monoclonal antibodies in multiple biochemical assays. Each peptide module in the branched structure makes unique contributions to affinity and/or specificity resulting in a 200 nM affinity ligand that efficiently immunoprecipitates Akt from cancer cell lysates and labels Akt in fixed cells. Our use of a small molecule to preinhibit Akt prior to screening resulted in low micromolar inhibitory potency and an allosteric mode of inhibition, which is evidenced through a series of competitive enzyme kinetic assays. To demonstrate the efficiency and selectivity of the protein-templated in situ click reaction, we developed a novel QPCR-based methodology that enabled a quantitative assessment of its yield. These results point to the potential for iterative in situ click chemistry to generate potent, synthetically accessible antibody replacements with novel inhibitory properties.
Image and Video Compression for Multimedia Engineering: Fundamentals, Algorithms, and Standards (1999)

Part I: Fundamentals Introduction Quantization Differential Coding Transform Coding Variable-Length Coding: Information Theory Results (II) Run-Length and Dictionary Coding: Information Theory Results (III) Part II: Still Image Compression Still Image Coding: Standard JPEG Wavelet Transform for Image Coding: JPEG2000 Nonstandard Still Image Coding Part III: Motion Estimation and Compensation Motion Analysis and Motion Compensation Block Matching Pel-Recursive Technique Optical Flow Further Discussion and Summary on 2-D Motion Estimation Part IV: Video Compression Fundam
Polyunsaturated fatty acid deficiency in liver cirrhosis: its relation to associated protein-energy malnutrition (preliminary report). (1988)

Plasma fatty acids (FA) from C14:0 to C22:6 omega 3 were measured in five healthy subjects and in 27 patients with liver cirrhosis. According to the assessment of triceps skinfold, mid-arm muscle circumference, and serum albumin concentration, patients were prospectively included in three groups: group A (n = 7) with acceptable nutritional status (including good nutrition and mild malnutrition), group B (n = 10) with moderate malnutrition, and group C (n = 10) with severe malnutrition. Plasma levels of total FA, saturated FA, linoleic acid, and omega 6 greater than 18C and omega 3 greater than 18 polyunsaturated fatty acids (PUFA) were lower in cirrhotics than in controls. Linoleic:arachidonic ratio was increased and delta 5-desaturation precursors:products ratio did not change, suggesting a reduction in delta 6-desaturase and/or C18-C20 elongase activities. In addition, a stepwise fall in plasma levels of all but saturated FA was found as the nutritional status worsened, suggesting that, in cirrhosis, impairment in PUFA biosynthesis is related to the severity of associated malnutrition. Since PUFA have important biological functions as components of cell membranes and precursors of eicosanoids, the results reported here may open new perspectives in the understanding of the cirrhosis-malnutrition relationship.
Protection of Neonatal Chicks Against a Lethal Challenge of Escherichia coli Using DNA Containing Cytosine-Phosphodiester-Guanine Motifs (2004)

Oligodeoxynucleotides (ODN) containing cytosine-phosphodiester-guanine (CpG) motifs have been shown to be effective immunoprotective agents in murine models for a variety of viral, intracellular bacterial, and protozoan infections. We recently have shown that CpG ODN protects against extracellular bacterial infections in mature chickens. The objective of this study was to investigate the effect of CpG ODN on Escherichia coli septicemia in neonatal broiler chicks. Two-day-old chicks, or embryonated eggs that had been incubated for 18 or 19 days, received 50 microg CpG ODN. Three days after exposure to CpG ODN, a virulent isolate of E. coli was inoculated subcutaneously in the neck of each bird. Birds were examined for 7 days post-E. coli challenge and dinical, pathologic, and bacteriologic assessments were conducted. The control group of birds that received no CpG ODN had a survival rate of 0% to 20%. In contrast, groups that received CpG ODN, either by intramuscular or in ovo routes, had significantly higher survival rates (P < 0.0001). Bacterial counts in air sacs were significantly lower when birds or embryos were treated with CpG ODN as compared with controls. A dose as low as 10 microg of CpG ODN, administered intramuscularly, was able to protect birds significantly against E. coli challenge. Formulation of CpG ODN with 30% Emulsigen did not enhance the protection. This study demonstrates that CpG ODN has systemic protective effects in broiler chicks against E. coli infections. This is the first time that CpG ODN has been demonstrated to have an immunoprotective effect against a bacterial infection in chicks following in ovo delivery.
PDX-1/VP16 Fusion Protein, Together With NeuroD or Ngn3, Markedly Induces Insulin Gene Transcription and Ameliorates Glucose Tolerance (2005)

Diabetes is the most prevalent and serious metabolic disease, and the number of diabetic patients worldwide is increasing. The reduction of insulin biosynthesis in pancreatic beta-cells is closely associated with the onset and progression of diabetes, and thus it is important to search for ways to induce insulin-producing cells in non-beta-cells. In this study, we showed that a modified form of the pancreatic and duodenal homeobox factor 1 (PDX-1) carrying the VP16 transcriptional activation domain (PDX-1/VP16) markedly increases insulin biosynthesis and induces various pancreas-related factors in the liver, especially in the presence of NeuroD or neurogenin 3 (Ngn3). Furthermore, in streptozotocin-induced diabetic mice, PDX-1/VP16 overexpression, together with NeuroD or Ngn3, drastically ameliorated glucose tolerance. Thus PDX-1/VP16 expression, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. This approach warrants further investigation and may have utility in the treatment of diabetes.
C9-R95X Polymorphism in Patients with Neovascular Age-Related Macular Degeneration (2011)

These findings support the notion that the haploinsufficiency of C9, a terminal complement complex component, engenders reduced intraocular secretion of VEGF and decreased risk for CNV development.
Eradication of Established Tumors by Vaccination With RecombinantBordetella pertussisAdenylate Cyclase Carrying the Human Papillomavirus 16 E7 Oncoprotein (2005)

High-risk human papillomaviruses (HPV) such as HPV16 are associated with the development of cervical cancer. The HPV16-E6 and HPV16-E7 oncoproteins are expressed throughout the replicative cycle of the virus and are necessary for the onset and maintenance of malignant transformation. Both these tumor-specific antigens are considered as potential targets for specific CTL-mediated immunotherapy. The adenylate cyclase (CyaA) of Bordetella pertussis is able to target dendritic cells through specific interaction with the alpha(M)beta(2) integrin. It has been previously shown that this bacterial protein could be used to deliver CD4(+) and CD8(+) T cell epitopes to the MHC class II and class I presentation pathways to trigger specific Th and CTL responses in vivo, providing protection against subsequent viral or tumoral challenge. Here, we constructed recombinant CyaA containing either the full sequence or various subfragments from the HPV16-E7 protein. We show that, when injected to C57BL/6 mice in absence of any adjuvant, these HPV16-recombinant CyaAs are able to induce specific Th1 and CTL responses. Furthermore, when injected into mice grafted with HPV16-E7-expressing tumor cells (TC-1), one of these recombinant proteins was able to trigger complete tumor regression in 100% of the animals tested. This therapeutic efficacy compared favorably to that of strongly adjuvanted peptide and was marginally affected by prior immunity to CyaA protein. This study represents the first in vivo demonstration of the antitumoral therapeutic activity of recombinant CyaA proteins carrying human tumor-associated antigens and paves the way for the testing of this vector in clinical trials.
Differentiation of embryonic stem cells towards hematopoietic cells: progress and pitfalls (2008)

Concrete evidence has shown that embryonic stem cells provide a powerful approach to study the early stage of hematopoiesis. Multiple hematopoietic lineages can be generated from embryonic stem cells, although most of the evidence suggests that hematopoietic development from embryonic stem cells mimics an embryonic/fetal stage of hematopoiesis.
Negative Differential Resistance in GaN/AlN Heterostructure Nanowires (2012)

III-V semiconductor nanowire heterostructures have experienced great progress in numerous mid-and far-infrared ranges. In this work, the electrical properties of GaN/AlN nanowire heterostructures, oriented along the [0001] polar direction and grown vertically on a Si substrate by molecular beam epitaxy, were studied in the context of resonant tunneling. The negative differential resistance was observed in I-V measurements at room temperature and at 78 K for single nanowire devices, confirming the presence of resonant tunneling through AlN barriers. A peak-to-valley ratio of 1.4 was achieved. Effects of different doping profiles have been investigated, showing slight improvement of the resonant tunneling in the presence of silicon doping. This work represents a preliminary step in developing GaN nanowire based intersubband devices for far-infrared and telecom wavelength lasers and photodetectors.