gebhart/patrepeval huggingface dataset:
Identification of a Binding Site in Protease Nexin I (PN1) Required for the Receptor Mediated Internalization of PN1-Thrombin Complexes (1997)

An overlapping synthetic peptide library was constructed representing most of the mature protease nexin I (PN1) sequence from the amino terminus to the reactive center. This library, along with peptides from the heparin binding domain and from the region carboxyl-terminal to the P1 residue of the cleavage site, was screened for the inhibition of 125I-thrombin (Th)-PN1 complex binding and degradation. A peptide corresponding to residues Pro47-Ile58 in the PN1 sequence was identified as a potent inhibitor of 125I-Th-PN1 complex degradation, although it did not affect binding significantly. Pro47-Ile58 was shown to competitively inhibit the low density lipoprotein receptor-related protein (LRP)/alpha2-macroglobulin receptor-mediated endocytosis of 125I-Th-PN1 complexes in mouse embryo fibroblasts. Pro47-Ile58 is an apparent transition sequence in PN1, separating sheet-6B and helix-B. The sequence of Pro47-Ile58, PHDNIVISPHGI, suggests that it forms a loop structure defined by the seven underlined amino acids bordered by proline residues at each end. These studies are the first to identify a putative binding site in a serine protease inhibitor that is required for LRP-mediated internalization.
Integrated Microchannel Cooling for Three-Dimensional Electronic Circuit Architectures (2005)

The semiconductor community is developing three-dimensional circuits that integrate logic, memory, optoelectronic and radio-frequency devices, and microelectromechanical systems. These three-dimensional (3D) circuits pose important challenges for thermal management due to the increasing heat load per unit surface area. This paper theoretically studies 3D circuit cooling by means of an integrated microchannel network. Predictions are based on thermal models solving one-dimensional conservation equations for boiling convection along microchannels, and are consistent with past data obtained from straight channels. The model is combined within a thermal resistance network to predict temperature distributions in logic and memory. The calculations indicate that a layer of integrated microchannel cooling can remove heat densities up to 135W/cm2 within a 3D architecture with a maximum circuit temperature of 85°C. The cooling strategy described in this paper will enable 3D circuits to include greater numbers of active levels while exposing external surface area for functional signal transmission.
PrPCHomodimerization Stimulates the Production of PrPCCleaved Fragments PrPN1 and PrPC1 (2012)

An endoproteolytic cleavage termed α-cleavage between residues 111/112 is a characteristic feature of the cellular prion protein (PrP(C)). This cleavage generates a soluble N-terminal fragment (PrPN1) and a glycosylphosphatidylinositol-anchored C-terminal fragment (PrPC1). Independent studies demonstrate that modulating PrP(C) α-cleavage represents a potential therapeutic strategy in prion diseases. The regulation of PrP(C) α-cleavage is unclear. The only known domain that is essential for the α-cleavage to occur is a hydrophobic domain (HD). Importantly, the HD is also essential for the formation of PrP(C) homodimers. To explore the role of PrP(C) homodimerization on the α-cleavage, we used a well described inducible dimerization strategy whereby a chimeric PrP(C) composed of a modified FK506-binding protein (Fv) fused with PrP(C) and termed Fv-PrP is incubated in the presence of a dimerizer AP20187 ligand. We show that homodimerization leads to a considerable increase of PrP(C) α-cleavage in cultured cells and release of PrPN1 and PrPC1. Interestingly, enforced homodimerization increased PrP(C) levels at the plasma membrane, and preventing PrP(C) trafficking to the cell surface inhibited dimerization-induced α-cleavage. These observations were confirmed in primary hippocampal neurons from transgenic mice expressing Fv-PrP. The proteases responsible for the α-cleavage are still elusive, and in contrast to initial studies we confirm more recent investigations that neither ADAM10 nor ADAM17 are involved. Importantly, PrPN1 produced after PrP(C) homodimerization protects against toxic amyloid-β (Aβ) oligomers. Thus, our results show that PrP(C) homodimerization is an important regulator of PrP(C) α-cleavage and may represent a potential therapeutic avenue against Aβ toxicity in Alzheimer's disease.
Evidence-based guidelines for treating bipolar disorder: revised second edition—recommendations from the British Association for Psychopharmacology (2009)

The British Association for Psychopharmacology guidelines specify the scope and target of treatment for bipolar disorder. The second version, like the first, is based explicitly on the available evidence and presented, like previous Clinical Practice guidelines, as recommendations to aid clinical decision making for practitioners: they may also serve as a source of information for patients and carers. The recommendations are presented together with a more detailed but selective qualitative review of the available evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from participants and interested parties. The strength of supporting evidence was rated. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in treatment of episodes, relapse prevention and stopping treatment.
Tertiary Structure of Staphylococcus aureus Cell Wall Murein (2004)

The recently described scaffold model of murein architecture depicts the gram-negative bacterial cell wall as a gel-like matrix composed of cross-linked glycan strands oriented perpendicularly to the plasma membrane while peptide bridges adopt a parallel orientation (B. A. Dmitriev, F. V. Toukach, K. J. Schaper, O. Holst, E. T. Rietschel, and S. Ehlers, J. Bacteriol. 185:3458-3468, 2003). Based on the scaffold model, we now present computer simulation studies on the peptidoglycan arrangement of the gram-positive organism Staphylococcus aureus, which show that the orientation of peptide bridges is critical for the highly cross-linked murein architecture of this microorganism. According to the proposed refined model, staphylococcal murein is composed of glycan and oligopeptide chains, both running in a plane that is perpendicular to the plasma membrane, with oligopeptide chains adopting a zigzag conformation and zippering adjacent glycan strands along their lengths. In contrast to previous models of murein in gram-positive bacteria, this model reflects the high degree of cross-linking that is the hallmark of the staphylococcal cell wall and is compatible with distinguishing features of S. aureus cytokinesis such as the triple consecutive alteration of the division plane orientation and the strictly centripetal mode of septum closure.
Fibroblast Growth Factor-23 Mitigates Hyperphosphatemia but Accentuates Calcitriol Deficiency in Chronic Kidney Disease (2005)

Hyperphosphatemia, calcitriol deficiency, and secondary hyperparathyroidism (SHPT) are common complications of chronic kidney disease (CKD). Fibroblast growth factor-23 (FGF-23) is a novel phosphaturic hormone that also inhibits renal 1alpha-hydroxylase activity and thus may be involved in the pathogenesis of SHPT. Several hypotheses were tested: that FGF-23 increases as renal function declines; is linearly associated with serum phosphate levels; is associated with increased phosphaturia independent of parathyroid hormone (PTH); and is associated with decreased calcitriol levels independent of renal function, hyperphosphatemia, and vitamin D stores. FGF-23, PTH, 25(OH)D3, calcitriol, calcium, phosphate, and urinary fractional excretion of phosphate (Fe(PO4)) were measured in 80 CKD patients. Multiple linear regression was used to test the hypotheses. FGF-23 and PTH were inversely associated with estimated GFR (eGFR), whereas calcitriol levels were linearly associated with eGFR. Hyperphosphatemia and hypocalcemia were present in only 12 and 6% of patients, respectively, all of whose eGFR was <30. Increased Fe(PO4) was associated with decreased eGFR, and both increased FGF-23 and PTH were independently associated with increased Fe(PO4). Increased FGF-23 and decreased 25(OH)D3 were independent predictors of decreased calcitriol, but the effects on calcitriol levels of renal function itself and hyperphosphatemia were completely extinguished by adjusting for FGF-23. It is concluded that FGF-23 levels increase early in CKD before the development of serum mineral abnormalities and are independently associated with serum phosphate, Fe(PO4), and calcitriol deficiency. Increased FGF-23 may contribute to maintaining normal serum phosphate levels in the face of advancing CKD but may worsen calcitriol deficiency and thus may be a central factor in the early pathogenesis of SHPT.
Encodable Activators of Src Family Kinases (2006)

There is considerable current interest in the design of encodable molecules that regulate intracellular protein circuitry and/or activity, ideally with a high level of specificity. Src homology 3 (SH3) domains are ubiquitous components of multidomain signaling proteins, including many kinases, and are attractive drug targets because of the important role their interactions play in diseases as diverse as cancer, osteoporosis, and inflammation. Here we describe a set of miniature proteins that recognize distinct SH3 domains from Src family kinases with high affinity. Three of these molecules discriminate effectively between the SH3 domains of Src and Fyn, which are expressed ubiquitously, and two of these three activate Hck kinase with potencies that rival HIV Nef, one of the most potent kinase activators known. These results suggest that miniature proteins represent a viable, encodable strategy for selective activation of Src family kinases in a variety of cell types.
Detection of aneuploid human sperm by fluorescence in situ hybridization: evidence for a donor difference in frequency of sperm disomic for chromosomes 1 and Y. (1993)

Fluorescence in situ hybridization with repetitive-sequence DNA probes was used to detect human sperm disomic for chromosomes 1 and Y in three healthy men. Data on these same men had been obtained previously, using the human-sperm/hamster-egg cytogenetic technique, providing a cytogenetic reference for validating sperm hybridization measurements. Air-dried smears were prepared from semen samples and treated with DTT and lithium diiodosalicylate to expand sperm chromatin. Hybridization with fluorescently tagged DNA probes for chromosomes 1 (pUC177) or Y (pY3.4) yielded average frequencies of sperm with two fluorescent domains of 14.2 +/- 2.4/10,000 and 5.6 +/- 1.6/10,000 sperm, respectively. These frequencies did not differ statistically from frequencies of hyperploidy observed for these chromosomes with the hamster technique. In addition, frequencies of disomic sperm from one donor were elevated approximately 2.5-fold above those of other donors, for both chromosomes 1 (P = .045) and Y (P = .01), consistent with a trend found with the hamster technique. We conclude that fluorescence in situ hybridization to sperm chromosomes provides a valid and promising measure of the frequency of disomic human sperm.
Prediction of Segregation to Alloy Surfaces from Bulk Phase Diagrams (1976)

Current theories of surface segregation are based on either the difference in the sizes or the heats of sublimation of the alloy components. We show that neither of these theories gives adequate agreement with experiment. A simple rule, based on the melting curve of the alloy, gives good agreement with all available experimental data.
Human Papillomavirus Type 52: a New Virus Associated with Cervical Neoplasia (1988)

Analysis of biopsies of cervical intraepithelial neoplasia (CIN) revealed a high percentage of human papillomavirus (HPV) sequences that would hybridize to a mixture of HPV probes only under conditions of relaxed stringency. The DNA sequences of one of these viruses was molecularly cloned and shown to be a new HPV, type 52 (HPV-52). This virus is most closely related to HPV-33. Hybridization analysis with restriction fragments of HPV-52 showed collinearity with the HPV-33 genome. DNA sequencing revealed a high level of conservation between the two viruses within the L1 open reading frame but significant divergence in the non-coding region of the viral genomes. Prevalence studies indicated that HPV-52 sequences were present in three of 137 (2%) CIN and in one of 48 (2%) cervical squamous cell cancers studied in the U.S.A.
Antibody-Aided Clearance of Extracellular α-Synuclein Prevents Cell-to-Cell Aggregate Transmission (2012)

Abnormal deposition and intercellular propagation of α-synuclein plays a central role in the pathogenesis of disorders such as Parkinson's Disease (PD) and dementia with Lewy bodies (DLB). Previous studies demonstrated that immunization against α-synuclein resulted in reduced α-synuclein accumulation and synaptic loss in a transgenic (tg) mouse model, highlighting the potential for immunotherapy. However, the mechanism by which immunization prevents synucleinopathy-associated deficits remains unknown. Here, we show that antibodies against α-synuclein specifically target and aid in clearance of extracellular α-synuclein proteins by microglia, thereby preventing their actions on neighboring cells. Antibody-assisted clearance occurs mainly in microglia through the Fcγ receptor, and not in neuronal cells or astrocytes. Stereotaxic administration of antibody into the brains of α-synuclein tg mice prevented neuron-to-astroglia transmission of α-synuclein and led to increased localization of α-synuclein and the antibody in microglia. Furthermore, passive immunization with α-synuclein antibody reduced neuronal and glial accumulation of α-synuclein and ameliorated neurodegeneration and behavioral deficits associated with α-synuclein overexpression. These findings provide an underlying mechanistic basis for immunotherapy for PD/DLB and suggest extracellular forms of α-synuclein as potential therapeutic targets.
Seeing double: Crystal structures of the type I TNF receptor (1996)

The crystal structure of the extracellular domain of the type I tumor necrosis factor receptor (sTNF-R1) has been determined to 2.25 A at pH 7.5. We have also solved the structure of sTNF-R1 at pH 3.7. sTNF-R1 is an elongated molecule consisting of a linear combination of four cysteine-rich motifs. Interestingly, the crystal structure reveals two distinct dimers of the receptor. One dimer is formed by a parallel arrangement of receptors, the other by an antiparallel arrangement of receptors. In the parallel arrangement of the receptors, the tumor necrosis factor (TNF) binding face of the receptor is completely exposed to solvent. However, in the antiparallel arrangement, the TNF binding face is intimately involved in the dimer interactions. Details of these recognition surfaces are discussed. Both these dimer interactions bury substantial surface area, comprise polar and apolar contact surfaces and have complimentary recognition surfaces. Thus these interactions are typical of genuine protein-protein interactions, rather than crystal packing contacts. These dimers may function to inhibit signal transduction in the absence of TNF or in the case of the parallel dimer, promote clustering of TNF/TNF receptor complexes on the cell surface.
Alkali-activated binders: A review (2007)

The disintegration of concrete structures made of ordinary Portland cement (OPC) is a worrying topic of increasing significance. The development of new binders with longer durability is therefore needed. Alkali-activated binders have emerged as an alternative to OPC binders, which seems to have superior durability and environmental impact. This paper reviews current knowledge about alkali-activated binders. The subjects of Part 1 in this paper are historical background, terminology and hydration products. The proper terminology to designate these new binders will be discussed. The influence of the prime materials and the type of alkaline activator on the reaction mechanisms and on the nature of the reaction products will be described.
Generating addressable protein microarrays with PROfusion covalent mRNA-protein fusion technology. (2002)

An mRNA-protein fusion consists of a polypeptide covalently linked to its corresponding mRNA. These species, prepared individually or en masse by in vitro translation with a modified mRNA conjugate (the PROfusion process), link phenotype to genotype and enable powerful directed evolution schemes. We have exploited the informational content of the nucleic acid component of the mRNA-protein fusion to create an addressable protein microarray that self-assembles via hybridization to surface-bound DNA capture probes. The nucleic acid component not only directs the mRNA-protein fusion to the proper coordinate of the microarray, but also positions the protein in a uniform orientation. We demonstrate the feasibility of this protein chip concept with several mRNA-protein fusions, each possessing a unique peptide epitope sequence. These addressable proteins could be visualized on the microarray both by autoradiography and highly specific monoclonal antibody binding. The anchoring of the protein to the chip surface is surprisingly robust, and the system is sensitive enough to detect sub-attomole quantities of displayed protein without signal amplification. Such protein arrays should be useful for functional screening in massively parallel formats, as well as other applications involving immobilized peptides and proteins.
Immune Cell Activation by Bacterial Cpg-DNA through Myeloid Differentiation Marker 88 and Tumor Necrosis Factor Receptor–Associated Factor (Traf)6 (2000)

Transition of immature antigen presenting cells (APCs) to the state of professional APCs is essential for initiation of cell-mediated immune responses to pathogens. Signal transduction via molecules of the Toll-like receptor (TLR)/interleukin 1 receptor (IL-1R) pathway is critical for activation of APCs either by pathogen-derived pattern ligands like lipopolysaccharides (LPS) or by CD40 ligation through T helper cells. The capacity of bacterial DNA (CpG-DNA) to induce APCs to differentiate into professional APCs represents an interesting discovery. However, the signaling pathways involved are poorly understood. Here we show that CpG-DNA activates the TLR/IL-1R signaling pathway via the molecules myeloid differentiation marker 88 (MyD88) and tumor necrosis factor receptor–associated factor 6 (TRAF6), leading to activation of kinases of the IκB kinase complex and the c-jun NH2-terminal kinases. Moreover, cells of TLR2- and TLR4-deficient mice are activated by CpG-DNA, whereas cells of MyD88-deficient mice do not respond. The data suggest that CpG-DNA initiates signaling via the TLR/IL-1R pathway in APCs in a manner similar to LPS and to T helper cell–mediated CD40 ligation. Activation of the TLR/IL-1R signaling pathway by foreign bacterial DNA may be one way to initiate innate defense mechanisms against infectious pathogens in vivo.
Optical design of programmable logic arrays (1988)

Regular free-space interconnects such as the perfect shuffle and banyan provided by beam splitters, lenses, and mirrors connect optical logic gates arranged in 2-D arrays. An algorithmic design technique transforms arbitrary logic equations into a near-optimal depth circuit. Analysis shows that an arbitrary interconnect makes little or no improvement in circuit depth and can even reduce throughput. Gate count is normally higher with a regular interconnect, and we show cost bounds. We conclude that regularly interconnected circuits will have a higher gate count compared with arbitrarily interconnected circuits using the design techniques presented here and that regular free-space interconnects are comparable with arbitrary interconnects in terms of circuit depth and are preferred to arbitrary interconnects for maximizing throughput.
Transplantation of Umbilical-Cord Blood in Babies with Infantile Krabbe's Disease (2005)

Transplantation of umbilical-cord blood from unrelated donors in newborns with infantile Krabbe's disease favorably altered the natural history of the disease. Transplantation in babies after symptoms had developed did not result in substantive neurologic improvement.
A novel recovery system for cultured cells using plasma‐treated polystyrene dishes grafted with poly(N‐isopropylacrylamide) (1993)

Poly(N-isopropyl acrylamide) (PIPAAm) demonstrated a fully expanded chain conformation below 32 degrees C and a collapsed, compact conformation at high temperatures. This unique temperature responsive polymer was grafted onto surfaces of commercial polystyrene dishes and used as temperature switches for creating hydrophilic surfaces below 32 degrees C and hydrophobic surfaces above 32 degrees C. Cell attachment and the growth of bovine endothelial cells and rat hepatocytes on PIPAAm-grafted surfaces at 37 degrees C demonstrated similar behavior to the commercialized culture dishes. Both cell types were observed to detach from the PIPAAm-grafted surface simply by reducing the temperature below the polymer transition temperature (collapse). Cells recovered by this method maintained substrate adhesivity, growth, and secretion activities nearly identical to those found in primary cultured cells in contrast to the compromised function found in cultured cells damaged by trypsinization. These results provide strong evidence that PIPAAm-grafted surfaces, as thermal switches are very effective for reversing cell attachment and detachment without cell damage. Properties of cell culture surfaces can be readily transformed by this technique reversibly into hydrophilic and hydrophobic coatings of PIPAAm-grafted polymers.
The heat-shock response co-inducer arimoclomol protects against retinal degeneration in rhodopsin retinitis pigmentosa (2014)

Retinitis pigmentosa (RP) is a group of inherited diseases that cause blindness due to the progressive death of rod and cone photoreceptors in the retina. There are currently no effective treatments for RP. Inherited mutations in rhodopsin, the light-sensing protein of rod photoreceptor cells, are the most common cause of autosomal-dominant RP. The majority of mutations in rhodopsin, including the common P23H substitution, lead to protein misfolding, which is a feature in many neurodegenerative disorders. Previous studies have shown that upregulating molecular chaperone expression can delay disease progression in models of neurodegeneration. Here, we have explored the potential of the heat-shock protein co-inducer arimoclomol to ameliorate rhodopsin RP. In a cell model of P23H rod opsin RP, arimoclomol reduced P23H rod opsin aggregation and improved viability of mutant rhodopsin-expressing cells. In P23H rhodopsin transgenic rat models, pharmacological potentiation of the stress response with arimoclomol improved electroretinogram responses and prolonged photoreceptor survival, as assessed by measuring outer nuclear layer thickness in the retina. Furthermore, treated animal retinae showed improved photoreceptor outer segment structure and reduced rhodopsin aggregation compared with vehicle-treated controls. The heat-shock response (HSR) was activated in P23H retinae, and this was enhanced with arimoclomol treatment. Furthermore, the unfolded protein response (UPR), which is induced in P23H transgenic rats, was also enhanced in the retinae of arimoclomol-treated animals, suggesting that arimoclomol can potentiate the UPR as well as the HSR. These data suggest that pharmacological enhancement of cellular stress responses may be a potential treatment for rhodopsin RP and that arimoclomol could benefit diseases where ER stress is a factor.