gebhart/patrepeval huggingface dataset:
Role of PTEN nuclear translocation in excitotoxic and ischemic neuronal injuries following stroke (2012)

Stroke is a leading cause of death and disability in developed countries. About 87% of stroke cases results from blood vessel(s) occlusion in the brain, leading to neuronal death and neurological impairment (Lloyd-Jones et al., 2010). The ischemic progression likely involves multiple events, and increasing evidence showed that the ischemic neuronal death is caused, at least in part, by over-activation of N-methyl-Daspartate subtype glutamate receptors (NMDARs) (Rothman, 1983, Rothman, 1984, Simon et al., 1984). A large number of pre-clinical studies showed that NMDAR antagonists have strong neuroprotective effects against ischemic insults (Park et al., 1988b, Bullock et al., 1990). However, none of the following human clinical trials have succeeded yet (Muir, 2006). Several explanations have been suggested (Gladstone et al., 2002), including the following two major reasons that may be overcome by the novel therapeutics proposed here. First, the stroke patient inclusion periods (&gt;6 hours) used by most clinical trials are beyond the therapeutic time window (&lt;1 hour) of NMDAR antagonists. Second, NMDAR antagonists, when used at the concentration required to block excitotoxicity, also abolish the pro-survival downstream cascades of NMDARs, thus leading to intolerable side effects. Therefore, instead of aiming at the receptor per se, my current study turns to focus on identifying NMDAR’s downstream death signals, which may permit a much wider therapeutic time window and are solely involved in pro-death signaling pathways of NMDARs. My results suggest that PTEN (phosphatase and tensin homolog deleted on chromosome TEN) is such a candidate. Both NMDA stimulation on cultured neurons (in vitro) and ischemic insults in rats (in vivo) can trigger ubiquitination-dependent PTEN translocation into the nucleus. Inhibition of PTEN nuclear translocation using an interfering peptide (Tat-K13) can significantly reduce the excitotoxic/ischemic neuronal injuries both in vitro and in vivo. Most excitingly, the intervention time window of PTEN nuclear translocation (6 hours post-ictus) is much wider than that of the only clinically available anti-stroke drug named tissue plasminogen activator (3 hours) (NINDS, 1995). These findings strongly suggest that PTEN nuclear translocation is a critical step leading to excitotoxic/ischemic neuronal injuries, and Tat-K13 represents a potential therapeutic strategy for stroke treatment.
Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins (2001)

Integrin-mediated adhesion promotes cell survival in vitro, whereas integrin antagonists induce apoptosis of adherent cells in vivo. Here, we demonstrate that cells adherent within a three-dimensional extracellular matrix undergo apoptosis due to expression of unligated integrins, the beta subunit cytoplasmic domain, or its membrane proximal sequence KLLITIHDRKEF. Integrin-mediated death requires initiator, but not stress, caspase activity and is distinct from anoikis, which is caused by the loss of adhesion per se. Surprisingly, unligated integrin or beta integrin tails recruit caspase-8 to the membrane, where it becomes activated in a death receptor-independent manner. Integrin ligation disrupts this integrin-caspase containing complex and increases survival, revealing an unexpected role for integrins in the regulation of apoptosis and tissue remodeling.
Use of Anhydrous Hydrogen Fluoride in Peptide Synthesis. I. Behavior of Various Protective Groups in Anhydrous Hydrogen Fluoride (1967)

Abstract The properties of anhydrous hydrogen fluoride (HF) as a reagent for the acidolysis of various protective groups have been studied. Amino acids with various protective groups were each treated with HF at 0 or 20°C in the presence of anisole, and the reaction products were tested. Thus, HF was found to be much better than the other known reagents, such as hydrogen bromide and trifluoroacetic acid. In the present study, the following groups were shown, for the first time, to be removed safely: the nitro group in nitroarginine, the diphenylmethyl group in diphenylmethylamide, the t-butyl group in S-t-butylcysteine, the isopropyloxycarbonyl group, and the isopropyl ester group. A new and convenient apparatus was designed for the safe handling of HF for peptide synthesis.
Plants, Polysaccharides, and the Treatment and Prevention of Neoplasia (2000)

Plants and Fungi have traditionally been the single largest source of lead compounds for the development of therapeutics by the pharmaceutical industry. Currently mushroom and plant polysaccharides brought to attention by Complementary and Alternative medicine, are undergoing scientific analysis and development to prevent and treat cancer, Two classes of saccharides are under investigation-beta glucan polysaccharides as biological response modifiers for the adjuvant treatment of cancer and "Oligosaccharin"-related oligosaccharides for the prevention of sun-induced skin cancer. Beta glucans already in human trials in the Far East will require mechanistic pharmacologic studies and definition of stucture function relationships before they are ready for clinical trials in the West. Other beta glucans that prime natural killer cells for antibody dependent cell-mediated cytotoxicity are approaching clinical trials. Oligosaccharides that downregulate production of immunosuppressive cytokines by ultraviolet radiation injured keratinocytes are promising agents for the prevention of environmental skin cancer.
Proteogenomics meets cancer immunology: mass spectrometric discovery and analysis of neoantigens (2015)

Cancer proteogenomics is an emerging field that aims to identify and quantify protein sequence changes associated with the cancer genome. Besides being involved in cancer development and progression, such protein variants may serve as neoantigens, which provide the T-cell response against tumors. Mass spectrometry-based proteogenomics may be a promising tool for finding neoantigens in individual specimens. It is partly based on a technical background accumulated from mass spectrometric studies of peptide ligands of major histocompatibility complex proteins. Examples of the use of mass spectrometry in neoantigen identification are reviewed in this article. Some experimental workflows are discussed, which may use shotgun and targeted proteomics for translational human studies of neoepitopes, such as cancer vaccine development and checkpoint therapy response prediction.
Comparison of Soluble Decoy IgG Fusion Proteins of BAFF-R and BCMA as Antagonists for BAFF (2003)

BAFF is considered a therapeutic target because dysregulated production of BAFF can induce systemic lupus erythematosus-like phenotype in mice, and elevated levels of BAFF are associated with disease severity in systemic lupus erythematosus and rheumatoid arthritis patients. Fc fusion decoy receptors, BCMA-Fc and BAFF-R-Fc, are therapeutic candidates for blocking BAFF. While studying their interactions with BAFF, we found that BAFF-R-Fc is more effective than BCMA-Fc for blocking BAFF binding to its receptors. We also found that a trimeric BAFF can bind more than one BAFF-R-Fc but only one BCMA-Fc. Moreover, we show that, in contrast to monovalent BAFF-R-Fc, monovalent BCMA does not form stable complexes with BAFF. Differences in their interaction with BAFF predict BAFF-R-Fc would be a better inhibitor. Indeed, we show BAFF-R-Fc is 10-fold more efficacious than BCMA-Fc for blocking BAFF-induced B cell proliferation in vitro and for blocking BAFF-mediated survival of mouse splenic B lymphocytes in vivo.
Synthesis and Characterization of in Situ Cross-Linkable Hyaluronic Acid-Based Hydrogels with Potential Application for Vocal Fold Regeneration (2004)

Despite a well-recognized clinical need for a material to replace missing or damaged vibratory connective tissue of the vocal fold, materials have yet to be engineered specifically for this purpose. Injectable hydrogels are particularly attractive because they would require a minimally invasive surgical procedure, could fill irregular defects, and could be designed to have viscoelastic properties similar to the normal tissue. We therefore synthesized a series of photo-cross-linkable hydrogels using hyaluronic acid (HA) as the starting material. The hydrogel precursors studied included HA modified with glycidyl methacrylate (HA/GMA), HA partially oxidized by sodium periodate (HAox) followed by GMA conjugation (HAox/GMA), and HA grafted with a synthetic polymer before introduction of GMA. The synthetic polymer employed was oligomeric poly(2-hydroxyethyl methacrylate) (P(HEMA)) with 31 mol % poly(N,N-dimethylacrylamide) (P(DMAM)), and the resulting hydrogel precursors were referred to as (HAox-g-Py)/GMA (y%: grafting percent). The macromonomers were characterized by GPC and 1H NMR. Hydrogels were obtained by subjecting the aqueous macromonomer solutions to UV irradiation in the presence of a photoinitiator. Under physiological conditions HAox/GMA hydrogel exhibited the highest swelling ratio and degraded most readily, whereas (HAox-g-P1.9)/GMA hydrogel swelled to a lesser extent and was most resistant to enzymatic degradation. Mechanical tests using an acoustic shaker yielded viscoelastic properties from 20 to 180 Hz. HAox/GMA hydrogel showed the lowest viscoelastic modulus and viscosity while (HAox-g-P1.9)/GMA hydrogel exhibited the highest values. The interior structures of the fully swollen hydrogels examined by scanning electron microscopy (SEM) showed the presence of fibrous or porous morphology. The cell cytotoxicity study indicated that HAox/GMA macromonomer was cytocompatible at concentrations less than 0.2 mg/mL, and there was no loss of cells when encapsulated in (HAox-g-P1.9)/GMA photo-cross-linked network. These new hydrogels have potential as injectable formulations for regeneration of the vocal fold's mucosal layered microstructure.
Pulmonary Emphysema (1998)

Chronic obstructive pulmonary disease (COPD) is defined by the American Thoracic Society as “a disease state characterized by the presence of airflow obstruction due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive, may be accompanied by airflow hyperreactivity, and may be viewed as partially reversible.”
Mastering Windows 3.11 Special Edition (1992)

From the Publisher:
This expanded edition includes approximately 200 pages of expert tips and tricks, to help Windows users save time, avoid pitfalls, and squeeze more power from the system. It's still the best start-to-finish guide to installing, using, and making the most of Windows 3.1-with hands-on coverage of everything from basics to advanced techniques.
The structure and growth of valve-pocket thrombi in femoral veins (1974)

The structure of 50 small thrombi in femoral valve pockets and the microscopic contents of 35 apparently empty pockets were studied in an attempt to ascertain the nature of the microscopic nidi from which thrombi form and their manner of growth to visible thrombi. Sixteen thrombi had little or no cellular invasion. Most of these recent structures had two main regions, red areas restricted distally in the pocket by the vein wall, and larger white regions comprising most of the thrombus length and often covering the red areas. Red areas are the early sites of cellular adhesion and invasion and the likely sites of origin of most thrombi. They were usually dominated by red cells and fibrin. White zones, which represent propagation growth, are characterized by many foci of platelets with fibrin borders (platelet-fibrin units). Some red areas also contained platelet-fibrin units but they were few and tiny; platelets were not seen in others and one small wholly red thrombus was devoid of platelets. Degenerative changes in platelet-fibrin units were observed, and it is postulated that many become purely fibrin structures. There was no significant evidence of preceding intimal damage in the vein wall. Therefore nidi are laid down on normal endothelium probably on the vein wall near the apex of the pocket. Some pockets, empty of thrombi, contained condensed foci of red cells or tiny fibrin fragments surfaced by endothelial cells and considered to be the remnants of aborted thrombi; a few contained clumps of platelets or leucocytes. It is postulated that any of these may represent the nidi from which thrombi grow. Several thrombi also incorporated large fat droplets, numerous in two. Fat embolic globules derived from fractures are their likely source.
Recognition Molecule Directed Interfacing Between Semiconductor Quantum Dots and Nerve Cells (2001)

Attachment of semiconductor quantum dots to living neurons utilizing antibody and peptide recognition molecules has been achieved. It is shown that peptide recognition molecules provide nanometer-scale control over the targeting and separation distance between the quantum dot and the cell. The Figure shows a fluorescence image of CdS quantum dots attached by antibody binding to human neuroblastoma cells.
Protein oxidation and degradation during cellular senescence of human BJ fibroblasts: part I— effects of proliferative senescence (2000)

Oxidized and cross-linked proteins tend to accumulate in aging cells. Declining activity of proteolytic enzymes, particularly the proteasome, has been proposed as a possible explanation for this phenomenon, and direct inhibition of the proteasome by oxidized and cross-linked proteins has been demonstrated in vitro. We have further examined this hypothesis during both proliferative senescence (this paper) and postmitotic senescence (see the accompanying paper, ref 1 ) of human BJ fibroblasts. During proliferative senescence, we found a marked decline in all proteasome activities (trypsin-like activity, chymotrypsin-like activity, and peptidyl-glutamyl-hydrolyzing activity) and in lysosomal cathepsin activity. Despite the loss of proteasome activity, there was no concomitant change in cellular levels of actual proteasome protein (immunoassays) or in the steady-state levels of mRNAs for essential proteasome subunits. The decline in proteasome activities and lysosomal cathepsin activities was accompanied by dramatic increases in the accumulation of oxidized and cross-linked proteins. Furthermore, as proliferation stage increased, cells exhibited a decreasing ability to degrade the oxidatively damaged proteins generated by an acute, experimentally applied oxidative stress. Thus, oxidized and cross-linked proteins accumulated rapidly in cells of higher proliferation stages. Our data are consistent with the hypothesis that proteasome is progressively inhibited by small accumulations of oxidized and cross-linked proteins during proliferative senescence until late proliferation stages, when so much proteasome activity has been lost that oxidized proteins accumulate at ever-increasing rates. Lysosomes attempt to deal with the accumulating oxidized and cross-linked proteins, but declining lysosomal cathepsin activity apparently limits their effectiveness. This hypothesis, which may explain the progressive intracellular accumulation of oxidized and cross-linked proteins in aging, is further explored during postmitotic senescence in the accompanying paper (1).
Constraint-based watermarking techniques for design IP protection (2001)

Digital system designs are the product of valuable effort and know-how. Their embodiments, from software and hardware description language program down to device-level netlist and mask data, represent carefully guarded intellectual property (IP). Hence, design methodologies based on IP reuse require new mechanisms to protect the rights of IP producers and owners. This paper establishes principles of watermarking-based IP protection, where a watermark is a mechanism for identification that is: (1) nearly invisible to human and machine inspection; (2) difficult to remove; and (3) permanently embedded as an integral part of the design. Watermarking addresses IP protection by tracing unauthorized reuse and making untraceable unauthorized reuse as difficult as recreating given pieces of IP from scratch. We survey related work in cryptography and design methodology, then develop desiderata, metrics, and concrete protocols for constraint-based watermarking at various stages of the very large scale integration (VLSI) design process. In particular, we propose a new preprocessing approach that embeds watermarks as constraints into the input of a black-box design tool and a new postprocessing approach that embeds watermarks as constraints into the output of a black-box design tool. To demonstrate that our protocols can be transparently integrated into existing design flows, we use a testbed of commercial tools for VLSI physical design and embed watermarks into real-world industrial designs. We show that the implementation overhead is low-both in terms of central processing unit time and such standard physical design metrics as wirelength, layout area, number of vias, and routing congestion. We empirically show that the placement and routing applications considered in our methods achieve strong proofs of authorship and are resistant to tampering and do not adversely influence timing.
Uplink Massive MIMO SIR Analysis: How Do Antennas Scale with Users? (2015)

Massive multiple-input multiple-output (MIMO) is a potential physical layer technology for 5G cellular networks. This paper leverages stochastic geometry to derive the uplink signal-to- interference (SIR) distribution in massive MIMO networks. Based on the derived expressions, a scaling law between the number of base station antennas and scheduled users per cell is provided to preserve the uplink SIR distribution, where the impacts of correlation in small-scale fading and power control in the form of fractional path loss compensation are taken account. Numerical results verify the analysis, and show that fractional power control with a compensation fraction of 0.5 is nearly optimal for the average achievable rate in certain cases.
Structure-based design of potent inhibitors of EGF-receptor tyrosine kinase as anti-cancer agents. (1999)

In a systematic effort to design inhibitors of the epidermal growth factor receptor (EGFR) family protein tyrosine kinases (PTK) as anti-cancer agents, we have constructed a three-dimensional homology model of the EGFR kinase domain and used molecular modeling methods for the structure-based design of analogs of the active metabolite of leflunomide (LFM) with potent and specific inhibitory activity against EGFR. These docking studies identified alpha-cyano-beta-hydroxy-beta-methyl-N-[4-(trifluoromethoxy)phenyl]-p ropenamide (LFM-A12) as our lead compound, which was predicted to bind to the EGFR catalytic site in a planar conformation. LFM-A12 inhibited the proliferation (IC50 = 26.3 microM) and in vitro invasiveness (IC50 = 28.4 microM) of EGFR positive human breast cancer cells in a concentration-dependent fashion. Similarly, the model of the EGFR binding pocket was used in combination with docking procedures to predict the favorable placement of chemical groups with defined sizes at multiple modification sites on another class of EGFR inhibitors, the 4-anilinoquinazoline. This approach has led to the successful design of a dibromo quinazoline derivative, WHI-P97, which had an estimated Ki value of 0.09 microM from modeling studies and a measured IC50 value of 2.5 microM in EGFR kinase inhibition assays. WHI-P97 effectively inhibited the in vitro invasiveness of EGFR-positive human cancer cells in a concentration-dependent manner. However, unlike LFM-A12, the quinazoline compounds are not specific for EGFR.
A new PCR‐CGE (size and color) method for simultaneous detection of genetically modified maize events (2006)

We present a novel multiplex PCR assay for simultaneous detection of multiple transgenic events in maize. Initially, five PCR primers pairs specific to events Bt11, GA21, MON810, and NK603, and Zea mays L. (alcohol dehydrogenase) were included. The event specificity was based on amplification of transgene/plant genome flanking regions, i.e., the same targets as for validated real-time PCR assays. These short and similarly sized amplicons were selected to achieve high and similar amplification efficiency for all targets; however, its unambiguous identification was a technical challenge. We achieved a clear distinction by a novel CGE approach that combined the identification by size and color (CGE-SC). In one single step, all five targets were amplified and specifically labeled with three different fluorescent dyes. The assay was specific and displayed an LOD of 0.1% of each genetically modified organism (GMO). Therefore, it was adequate to fulfill legal thresholds established, e.g., in the European Union. Our CGE-SC based strategy in combination with an adequate labeling design has the potential to simultaneously detect higher numbers of targets. As an example, we present the detection of up to eight targets in a single run. Multiplex PCR-CGE-SC only requires a conventional sequencer device and enables automation and high throughput. In addition, it proved to be transferable to a different laboratory. The number of authorized GMO events is rapidly growing; and the acreage of genetically modified (GM) varieties cultivated and commercialized worldwide is rapidly increasing. In this context, our multiplex PCR-CGE-SC can be suitable for screening GM contents in food.
The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells (2004)

Recent studies have revealed new roles for NAD and its derivatives in transcriptional regulation. The evolutionarily conserved Sir2 protein family requires NAD for its deacetylase activity and regulates a variety of biological processes, such as stress response, differentiation, metabolism, and aging. Despite its absolute requirement for NAD, the regulation of Sir2 function by NAD biosynthesis pathways is poorly understood in mammals. In this study, we determined the kinetics of the NAD biosynthesis mediated by nicotinamide phosphoribosyltransferase (Nampt) and nicotinamide/nicotinic acid mononucleotide adenylyltransferase (Nmnat), and we examined its effects on the transcriptional regulatory function of the mouse Sir2 ortholog, Sir2alpha, in mouse fibroblasts. We found that Nampt was the rate-limiting component in this mammalian NAD biosynthesis pathway. Increased dosage of Nampt, but not Nmnat, increased the total cellular NAD level and enhanced the transcriptional regulatory activity of the catalytic domain of Sir2alpha recruited onto a reporter gene in mouse fibroblasts. Gene expression profiling with oligonucleotide microarrays also demonstrated a significant correlation between the expression profiles of Nampt- and Sir2alpha-overexpressing cells. These findings suggest that NAD biosynthesis mediated by Nampt regulates the function of Sir2alpha and thereby plays an important role in controlling various biological events in mammals.
Isolation and partial characterization of an unusual human immunodeficiency retrovirus from two persons of west-central African origin (1990)

An unusual human retrovirus was isolated from two patients with persistent generalized lymphadenopathy who originate from West-Central Africa and are currently residing in Belgium. Although the virus shared a number of the same biological and morphological properties as human immunodeficiency retrovirus type 1 (HIV-1) and HIV-2, significant antigenic differences could be demonstrated. Several of the viral proteins also differed in molecular weight from the corresponding HIV-1 and HIV-2 proteins. Partial chemical cleavage of the most highly conserved viral proteins resulted in patterns which differed from those of HIV-1 and HIV-2. Furthermore, nucleic acid hybridization experiments were capable of discriminating between the virus types. Sequence analysis of the viral U3 region revealed a unique enhancer organization not found in other immunodeficiency viruses. The data indicated that the new isolate is more closely related to HIV-1 than to HIV-2 but clearly differs in a number of important respects.