gebhart/patrepeval huggingface dataset:
Amino Acid Residues in the N-Terminal Region of the PA Subunit of Influenza A Virus RNA Polymerase Play a Critical Role in Protein Stability, Endonuclease Activity, Cap Binding, and Virion RNA Promoter Binding (2006)

The RNA-dependent RNA polymerase of influenza virus is a heterotrimer formed by the PB1, PB2, and PA subunits. Although PA is known to be required for polymerase activity, its precise role is still unclear. Here, we investigated the function of the N-terminal region of PA. Protease digestion of purified recombinant influenza virus A/PR/8/34 PA initially suggested that its N-terminal region is folded into a 25-kDa domain. We then systematically introduced point mutations into evolutionarily conserved amino acids in the N-terminal region of influenza virus A/WSN/33. Most alanine-scanning mutations between residues L109 and F117 caused PA degradation, mediated by a proteasome-ubiquitin pathway, and as a consequence interfered with polymerase activity. Three further PA mutations, K102A, D108A, and K134A, were investigated in detail. Mutation K102A caused a general decrease both in transcription and replication in vivo, whereas mutations D108A and K134A selectively inhibited transcription. Both the D108A and K134A mutations completely inhibited endonuclease activity in vitro, explaining their selective defect in transcription. K102A, on the other hand, resulted in a significant decrease in both cap binding and viral RNA promoter-binding activity and consequently inhibited both transcription and replication. These results suggest that the N-terminal region of PA is involved in multiple functions of the polymerase, including protein stability, endonuclease activity, cap binding, and promoter binding.
Full two-dimensional electroluminescent (EL) analysis of GaAs-AlGaAs HBTs (2003)

This paper describes what is believed to be the first full two-dimensional electroluminescent (EL) analysis of base-emitter junctions in heterojunction bipolar transistors (HBTs). Correlation of the DC and RF characteristics with respect to the changes in EL emission are presented. Special sample preparation techniques and emission microscopy procedures were used to reveal the full electroluminescent pattern from the backside of discrete HBT chips. Sample mounting was optimized to permit inspection at a magnification of 500/spl times/. Two parallel emitter fingers, 3 /spl mu/m by 10 /spl mu/m each, were easily resolved. This technique is utilized to investigate HBT susceptibility to current driven lattice degradation that manifests itself in nonradiative recombination regions. Occurrence of dark line defects (DLDs) is similar to that reported for solid state lasers and light emitting diodes (LEDs). Rapid changes in the EL pattern occur at current densities of 150 kA/cm/sup 2/. Full two-dimensional electroluminescent analysis represents a breakthrough in the investigation and resolution of current driven degradation in HBT devices because dramatic changes in the optical characteristics occur prior to small changes in the electronic characteristics.
Developing Adaptive Applications: The MOST Experience (1999)

Future computer environments will include mobile computers which will either be disconnected, weakly inter-connected by low speed wireless networks such as GSM, or fully inter-connected by high speed networks ranging from Ethernet to ATM. Such enviro
Handbook of Clinical Rating Scales and Assessment in Psychiatry and Mental Health (2009)

Psychiatric clinicians should use rating scales and questionnaires often, for they not only facilitate targeted diagnoses and treatment; they also facilitate links to empirical literature and systemat
Fortimicins A and B, new aminoglycoside antibiotics. III. Structural identification. (1977)

The structures of fortimicins A and B have been determined by PMR, CMR, mass spectra and CD combined with chemical degradations. Both antibiotics are pseudodisaccharides and incorporate a novel aminocyclitol, fortamine. In contrast to the diaminocyclitol moieties of known aminoglycosides, fortamine is a 1,4-diamine, contains both N- and O-methyl groups and possesses chiro stereochemistry. Both antibiotics are glycosides of 6-epi-purpurosamine B, but fortimicin A differs from fortimicin B by being a glycyl amide.
GRP78 Induction in Cancer: Therapeutic and Prognostic Implications (2007)

Cancer cells adapt to chronic stress in the tumor microenvironment by inducing the expression of GRP78/BiP, a major endoplasmic reticulum chaperone with Ca(2+)-binding and antiapoptotic properties. GRP78 promotes tumor proliferation, survival, metastasis, and resistance to a wide variety of therapies. Thus, GRP78 expression may serve as a biomarker for tumor behavior and treatment response. Combination therapy suppressing GRP78 expression may represent a novel approach toward eradication of residual tumors. Furthermore, the recent discovery of GRP78 on the cell surface of cancer cells but not in normal tissues suggests that targeted therapy against cancer via surface GRP78 may be feasible.
Targeted deletion of βIII spectrin impairs synaptogenesis and generates ataxic and seizure phenotypes (2010)

The spectrin membrane skeleton controls the disposition of selected membrane channels, receptors, and transporters. In the brain betaIII spectrin binds directly to the excitatory amino acid transporter (EAAT4), the glutamate receptor delta, and other proteins. Mutations in betaIII spectrin link strongly to human spinocerebellar ataxia type 5 (SCA5), correlating with alterations in EAAT4. We have explored the mechanistic basis of this phenotype by targeted gene disruption of Spnb3. Mice lacking intact betaIII spectrin develop normally. By 6 months they display a mild nonprogressive ataxia. By 1 year most Spnb3(-/-) animals develop a myoclonic seizure disorder with significant reductions of EAAT4, EAAT1, GluRdelta, IP3R, and NCAM140. Other synaptic proteins are normal. The cerebellum displays increased dark Purkinje cells (PC), a thin molecular layer, fewer synapses, a loss of dendritic spines, and a 2-fold expansion of the PC dendrite diameter. Membrane and expanded Golgi profiles fill the PC dendrite and soma, and both regions accumulate EAAT4. Correlating with the seizure disorder are enhanced hippocampal levels of neuropeptide Y and EAAT3 and increased calpain proteolysis of alphaII spectrin. It appears that betaIII spectrin disruption impairs synaptogenesis by disturbing the intracellular pathways selectively regulating protein trafficking to the synapse. The mislocalization of these proteins secondarily disrupts glutamate transport dynamics, leading to seizures, neuronal damage, and compensatory changes in EAAT3 and neuropeptide Y.
New additive solutions for red cells (2016)

Shortly after the introduction of component therapy in the 1960s, the first additives for red cell concentrates (RCC) were introduced. This development resulted in prolongation of RCC shelf life from 21 to 35 or 42 days. Over the years, some new solutions were developed, but still SAGM (Europe) and AS‐1 (United States) are the standard, nearly exclusive in combination with CPD as anticoagulant. Most of these new solutions were minor variations on SAGM or AS‐1, with limited improvement of in vitro quality of erythrocytes. Development of new concepts, resulting in improved quality of RCC, was in first instance focused on achieving longer storage time. However, as a result from the concern about possible negative side effects caused by transfusion of older units, the research on new additive solutions is more focused on having a better quality during the currently accepted maximum storage time of 35–42 days. Around 1990, Meryman developed the concept of the so‐called chloride shift. Through replacement of chloride by impermeable solutes, it is possible to manipulate the intracellular pH of erythrocytes, resulting in high 2,3‐DPG and/or ATP values throughout storage. During the past 15–20 years, several research groups, with the group of Greenwalt and Hess as pioneers, developed new additive solutions based on the Meryman concept. Recently, the first commercial product from these studies was launched, with an improved in vitro quality parameter profile and improved in vivo recovery data. Finally, some recent developments are discussed with respect to alkaline additive solutions and anaerobic storage of erythrocyte concentrates.
Ability of HIV to Promote a T H 1 to T H 0 Shift and to Replicate Preferentially in T H 2 and T H 0 Cells (1994)

Both interferon gamma (IFN-gamma) produced by T helper 1 (TH1) lymphocytes and interleukin-4 (IL-4) produced by TH2 lymphocytes were reduced in either bulk circulating mononuclear cells or mitogen-induced CD4+ T cell clones from the peripheral blood of individuals infected with human immunodeficiency virus (HIV). There was a preferential reduction in clones producing IL-4 and IL-5 in the advanced phases of infection. However, enhanced proportions of CD4+ T cell clones producing both TH1-type and TH2-type cytokines (TH0 clones) were generated from either skin-infiltrating T cells that had been activated in vivo or peripheral blood T cells stimulated by antigen in vitro when cells were isolated from HIV-infected individuals. All TH2 and most TH0 clones supported viral replication, although viral replication was not detected in any of the TH1 clones infected in vitro with HIV. These results suggest that HIV (i) does not induce a definite TH1 to TH2 switch, but can favor a shift to the TH0 phenotype in response to recall antigens, and (ii) preferentially replicates in CD4+ T cells producing TH2-type cytokines (TH2 and TH0).
VirtualPower (2007)

Power management has become increasingly necessary in large-scale datacenters to address costs and limitations in cooling or power delivery. This paper explores how to integrate power management mechanisms and policies with the virtualization technologies being actively deployed in these environments. The goals of the proposed VirtualPower approach to online power management are (i) to support the isolated and independent operation assumed by guest virtual machines (VMs) running on virtualized platforms and (ii) to make it possible to control and globally coordinate the effects of the diverse power management policies applied by these VMs to virtualized resources. To attain these goals, VirtualPower extends to guest VMs `soft' versions of the hardware power states for which their policies are designed. The resulting technical challenge is to appropriately map VM-level updates made to soft power states to actual changes in the states or in the allocation of underlying virtualized hardware. An implementation of VirtualPower Management (VPM) for the Xen hypervisor addresses this challenge by provision of multiple system-level abstractions including VPM states, channels, mechanisms, and rules. Experimental evaluations on modern multicore platforms highlight resulting improvements in online power management capabilities, including minimization of power consumption with little or no performance penalties and the ability to throttle power consumption while still meeting application requirements. Finally, coordination of online methods for server consolidation with VPM management techniques in heterogeneous server systems is shown to provide up to 34% improvements in power consumption.
Immunotherapy of Cancer: Targeting Cancer During Active Disease or During Dormancy? (2017)

Immunotherapeutic targeting of advanced stage cancers has prolonged the survival of cancer patients, yet its curative efficacy is limited due to tumor immunoediting and escape. On the other hand, human vaccines have been able to eradicate smallpox and control several other infectious diseases. The success has resulted from the administration of vaccines in prophylactic settings, or during latency periods in order to protect an individual during future exposure to the disease rather than curing an established disease. Therefore, administration of immunotherapy at the right time is the key to success. However, instead of focusing on the prevention of cancer, current cancer immunotherapies are often being used in a therapeutic setting with the goal of eliminating tumor cells. The present review of evidence related to cancer immunotherapeutics suggests that immunotherapeutic targeting of tumor dormancy could be more promising than targeting of advanced stage disease to achieve a cure for cancer.
A Critical View on the Role of Migraine Triggers in the Genesis of Migraine Pain (2009)

A number of distinct endogenous and exogenous factors have been implicated in migraine precipitation but the exact nature of the triggering process itself and its relationship to the genesis of the headache remains largely speculative. In this article, we examine the potential sites and downstream cascades through which migraine triggers might exert their action to promote the activation of the migraine pain pathway. We further look at the laterality of the headache as a potential indicator for the site of migraine pain initiation and examine the question of triggering factor specificity in relation to the current understanding of migraine pathophysiology.
New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes (2010)

Notch signaling is an evolutionary conserved pathway that is mediated by cell-cell contact. It is involved in a variety of developmental processes and has an essential role in vascular development and angiogenesis. Delta-like 4 (Dll4) is a Notch ligand that is up-regulated during angiogenesis. It is expressed in endothelial cells and regulates the differentiation between tip cells and stalk cells of neovasculature. Here, we present evidence that Dll4 is incorporated into endothelial exosomes. It can also be incorporated into the exosomes of tumor cells that overexpress Dll4. These exosomes can transfer the Dll4 protein to other endothelial cells and incorporate it into their cell membrane, which results in an inhibition of Notch signaling and a loss of Notch receptor. Transfer of Dll4 was also shown in vivo from tumor cells to host endothelium. Addition of Dll4 exosomes confers a tip cell phenotype on the endothelial cell, which results in a high Dll4/Notch-receptor ratio, low Notch signaling, and filopodia formation. This was further evidenced by increased branching in a tube-formation assay and in vivo. This reversal in phenotype appears to enhance vessel formation and is a new form of signaling for Notch ligands that expands their signaling potential beyond cell-cell contact.
p53 mutation as a source of aberrant β-catenin accumulation in cancer cells (2002)

beta-catenin is involved in both cell-cell interactions and wnt pathway-dependent cell fate determination through its interactions with E-cadherin and TCF/LEF transcription factors, respectively. Cytoplasmic/nuclear levels of beta-catenin are important in regulated transcriptional activation of TCF/LEF target genes. Normally, these levels are kept low by proteosomal degradation of beta-catenin through Axin1- and APC-dependent phosphorylation by CKI and GSK-3beta. Deregulation of beta-catenin degradation results in its aberrant accumulation, often leading to cancer. Accordingly, aberrant accumulation of beta-catenin is observed at high frequency in many cancers. This accumulation correlates with either mutational activation of CTNNB1 (beta-catenin) or mutational inactivation of APC and Axin1 genes in some tumors. However, there are many tumors that display beta-catenin accumulation in the absence of a mutation in these genes. Thus, there must be additional sources for aberrant beta-catenin accumulation in cancer cells. Here, we provide experimental evidence that wild-type beta-catenin accumulates in hepatocellular carcinoma (HCC) cells in association with mutational inactivation of p53 gene. We also show that worldwide p53 and beta-catenin mutation rates are inversely correlated in HCC. These data suggest that inactivation of p53 is an important cause of aberrant accumulation of beta-catenin in cancer cells.
Clinical method for measurement of light backscattering from the in vivo human lens. (1980)

A simple clinical method for measurement of light backscatter from defined regions of the lens in vivo is described. Light scattering was quantitated in 168 lenses of 85 "normal" subjects spanning 8 decades of life. The results indicate that light scatter from the anterior capsule does not change with age. The light scatter from the anterior cortex is quite significant even in young lenses and gradually increases with age. The backscatter in the nuclear region is minimal in young eyes, increasing gradually up to the age of 40, after which it exhibits a sharp increase.
Treatment of Patients With Metastatic Melanoma With Autologous Tumor-Infiltrating Lymphocytes and Interleukin 2 (1994)

Treatment with TILs and IL-2 with or without cyclophosphamide can result in objective responses in about one third of patients with metastatic melanoma. The side effects of treatment are transient in most patients, and this treatment can be safely administered. These results illustrate the potential value of immune lymphocytes for the treatment of patients with melanoma.
Sensitive Detection of Colorectal Cancer in Peripheral Blood by Septin 9 DNA Methylation Assay (2008)

Analysis of SEPT9 DNA methylation in plasma represents a straightforward, minimally invasive method to detect all stages of CRC with potential to satisfy unmet needs for increased compliance in the screening population. Further clinical testing is warranted.
Innate Recognition of Bacteria in Human Milk Is Mediated by a Milk-Derived Highly Expressed Pattern Recognition Receptor, Soluble Cd14 (2000)

Little is known about innate immunity to bacteria after birth in the hitherto sterile fetal intestine. Breast-feeding has long been associated with a lower incidence of gastrointestinal infections and inflammatory and allergic diseases. We found in human breast milk a 48-kD polypeptide, which we confirmed by mass spectrometry and sequencing to be a soluble form of the bacterial pattern recognition receptor CD14 (sCD14). Milk sCD14 (m-sCD14) concentrations were up to 20-fold higher than serum sCD14 from nonpregnant, pregnant, or lactating women. In contrast, lipopolysaccharide (LPS)-binding protein was at very low levels. Mammary epithelial cells produced 48-kD sCD14. m-sCD14 mediated activation by LPS and whole bacteria of CD14 negative cells, including intestinal epithelial cells, resulting in release of innate immune response molecules. m-sCD14 was undetectable in the infant formulas and commercial (cows') milk tested, although it was present in bovine colostrum. These findings indicate a sentinel role for sCD14 in human milk during bacterial colonization of the gut, and suggest that m-sCD14 may be involved in modulating local innate and adaptive immune responses, thus controlling homeostasis in the neonatal intestine.
Delayed-type hypersensitivity and allograft rejection in the mouse: correlation of effector cell phenotype. (1982)

Delayed-type hypersensitivity (DTH) responses to alloantigens were found to correlate with both skin and tumour allograft rejection in 224 reconstituted ATXBM-CBA mice. Furthermore, DTH responses and allograft rejection were observed only in mice that had received Ly-1 cells. Depletion of Thy-1+ or Ly-1+ cells led to indefinite graft survival and the absence of DTH responses, whereas depletion of Ly-2+ cells led to rapid graft rejection and strong DTH responses. The same result was obtained with CBA mice responding to grafts of either C57BL/6 skin, the B16 melanoma, or the EL4 lymphoma; and for (CBA X A)F1 mice responding to H-2K region alloantigens of AQR skin grafts. Thus, DTH and allograft rejection are both mediated by a Ly-1 T cell and it is considered that these are two different manifestations of the same transplantation response.
Physicochemical Stability of the Antibody−Drug Conjugate Trastuzumab-DM1: Changes due to Modification and Conjugation Processes (2010)

In the manufacture of the antibody-drug conjugate Trastuzumab-DM1 (T-DM1), the lysine residues on the antibody trastuzumab (Tmab) are modified to form the intermediate Tmab-MCC (T-MCC) and then conjugated with the drug DM1. Our goal is to understand the effects of modification and conjugation steps on the physicochemical stability of the antibody. The structural stability of Tmab relative to its modified and conjugated forms was assessed, employing thermally induced stress conditions to formulations containing Tmab, T-MCC, and T-DM1. DSC, SEC, CE-SDS, and LC-MS were used to study the stability of Tmab, T-MCC, and T-DM1 to thermal stress. The DSC thermograms show a decrease in melting temperature for the CH2 transition, in the order Tmab > T-MCC > T-DM1. As per SEC analysis, a significant increase in level of aggregation was detected in T-MCC (∼32%) and T-DM1 (∼5%) after 14 days at 40 °C. Tmab did not show significant aggregate formation. CE-SDS and LC-MS data demonstrate that the aggregation in the case of T-MCC is largely covalent and involves mechanisms other than formation of intermolecular disulfide cross-links. The aggregation observed for T-MCC was significantly inhibited upon addition of amino acids with nucleophilic side chains containing thiol (Cys) and hydroxyl moieties (Ser, Tyr). The covalent aggregation observed for T-MCC and the ability of nucleophilic amino acids, particularly Cys, to inhibit it indicate that the maleimide moiety in the MCC linker may react to form intermolecular covalent cross-links between T-MCC molecules, possibly through a Michael addition mechanism. In addition, DSC results demonstrate that the conjugation of the drug moiety DM1 to Tmab results in destabilization of the CH2 domain of the antibody.
Macrophage damage in relation to the pathogenesis of lung diseases. (1980)

Pulmonary macrophages are important since their migratory patterns and behavior are often pivotal events in the pathogenesis of pulmonary disease. Alveolar macrophages act to decrease the probability of particle penetration through epithelial barriers, and their phagocytic and lytic potentials provide most of the known bactericadal properties of the lung. Macrophages are also involved in immune responses and in defense against neoplasms. Increased inert or infectious particles stimulate the recruitment of additional macrophages. Most free cells containing particles eventually reach the airways and are quickly carried to the pharynx and swallowed. In addition, evidence has now accumulated that macrophages play a part in the pathogenesis of pulmonary diseases. For example, the ingestion of some particles by macrophages causes a release of lysosomal enzymes into the macrophage cytoplasm. These enzymes may kill the macrophage, and dead or dying macrophages release a substance with attracts fibroblasts that elicit fibrogenic responses. Other toxic particles, such as cigarette smoke, my lead to a release of proteases and other toxic enzymes. All particles are capable of competitive inhibition of phagocytosis in macrophages and many may be cytotoxic and further depress phagocytosis. In addition, connective tissue macrophages may contribute to lung disease by concentrating and storing potent carcinogens or other toxic particles close to a reactive bronchial epithelium for long periods. Thus, even through macrophages serve as a first line of defense for the alveolar surface, they may also be capable of injuring the host while exercising their defensive role.