gebhart/patrepeval huggingface dataset:
IL-6/IL-6R Axis Plays a Critical Role in Acute Kidney Injury (2008)

The response to tissue injury involves the coordination of inflammatory and repair processes. IL-6 expression correlates with the onset and severity of acute kidney injury (AKI), but its contribution to pathogenesis remains unclear. This study established a critical role for IL-6 in both the inflammatory response and the resolution of AKI. IL-6-deficient mice were resistant to HgCl2-induced AKI compared with wild-type mice. The accumulation of peritubular neutrophils was lower in IL-6-deficient mice than in wild-type mice, and neutrophil depletion before HgCl2 administration in wild-type mice significantly reduced AKI; these results demonstrate the critical role of IL-6 signaling in the injurious inflammatory process in AKI. Renal IL-6 expression and STAT3 activation in renal tubular epithelial cells significantly increased during the development of injury, suggesting active IL-6 signaling. Although a lack of renal IL-6 receptors (IL-6R) precludes the activation of classical signaling pathways, IL-6 can stimulate target cells together with a soluble form of the IL-6R (sIL-6R) in a process termed trans-signaling. During injury,serum sIL-6R levels increased three-fold, suggesting a possible role for IL-6 trans-signaling in AKI. Stimulation of IL-6 trans-signaling with an IL-6/sIL-6R fusion protein activated STAT3 in renal tubular epithelium and prevented AKI. IL-6/sIL-6R reduced lipid peroxidation after injury, suggesting that its protective effect may be largely mediated through amelioration of oxidative stress. In summary, IL-6 simultaneously promotes an injurious inflammatory response and, through a mechanism of trans-signaling, protects the kidney from further injury.
Like Deck Chairs on the Titanic: Why Spectrum Reallocation Won’t Avert the Coming Data Crunch but Technology Might Keep the Wireless Industry Afloat (2012)

Skyrocketing mobile data demands caused by increasing adoption of smartphones, tablet computers, and broadband-equipped laptops will soon swamp the capacity of our nation’s wireless networks, a fact that promises to stagnate a $1 trillion slice of the nation’s economy. Among scholars and policymakers studying this looming “spectrum crisis,” consensus is developing that regulators must swiftly reclaim spectrum licensed to other industries and reallocate those rights to wireless providers. In this interdisciplinary piece, we explain in succinct terms why this consensus is wrong. With data demands increasing at an exponential rate, spectrum reallocation plans that promise only linear growth are destined to fail. What regulators should focus on, instead, are policies that encourage the sluggish incumbents presently dominating the wireless industry to roll out new networking technologies (like tiered network architectures, cognitive radio, and multicell MIMO) that together may allow exponential increases in spectral efficiency.
Allylic and Benzylic Carbanions Substituted by Heteroatoms (1982)

Abstract This review covers allylic and benzylic carbanions in which a heteroatom and the double bond may be part of a conjugated system. Propargylic and allenic systems are also included. The cation is an alkaline or alkaline‐earth element; transition metals are excluded. The chapter by Gilman and Morton in 1954 was restricted to lithium derivatives. Reviews covering part of the subject include those on organometallic compounds, on reagents for nucleophilic acylation, on olefin synthesis with P(O)‐activated reagents, on the formation and reactions of carbanions derived from allylic sulfoxides, dithianes, nitrosoamines, thioethers and ethers, selenium compounds, on base‐catalyzed isomerization, and on rearrangements of carbanions. Allylic and benzylic carbanions adjacent to the following heteroatoms have been described: boron, nitrogen, oxygen, silicon, phosphorus, sulfur, chlorine, selenium, bromine, tellurium. The basicity and structures of these anions are considered first. This discussion is followed by sections on methods of generation of carbanions, reactions occurring during preparation, decomposition, and rearrangements of carbanions, reactions with electrophiles, regioselectivity and stereochemical aspects of the reactions, transformations of the reaction products, and some applications of these carbanions in synthesis.
Benzocaine-induced methemoglobinemia during transesophageal echocardiography. (2005)

Acquired or toxic methemoglobinemia is an uncommon complication of topically administered anesthetic agents in patients of all ages-but particularly in pediatric and elderly patients. This report describes a case of acquired methemoglobinemia that occurred after benzocaine spray was applied orally to a 69-year-old white woman weighing 175 lb who was undergoing transesophageal echocardiography. Patient care was successfully managed. Fundamental concepts regarding methemoglobinemia are also reviewed to heighten physician awareness of this potentially life-threatening complication associated with the application of common topical anesthetic agents.
Antibody-dependent cellular cytotoxicity (ADCC) is mediated by genetically modified antigen-specific human T lymphocytes (2006)

In the context of transplantation, donor and virus-specific T-lymphocyte infusions have demonstrated the dramatic potential of T cells as immune effectors. Unfortunately, most attempts to exploit the T-cell immune system against nonviral malignancies in the syngeneic setting have been disappointing. In contrast, treatments based on monoclonal antibodies (Abs) have been clinically successful and have demonstrated the clinical relevance of several antigens as therapeutic targets and the importance of the antibody-dependent cellular cytotoxicity (ADCC) pathway. In the present study, we considered the possibility of arming specific T cells with a receptor that would enable them to mediate ADCC. After transduction with a CD16/gamma receptor gene, CD4(+) and CD8(+) cytotoxic T lymphocytes displayed stable expression of the CD16 receptor at their surface. In the absence of Ab, CD16/gamma expression did not affect the capacity of specific T lymphocytes to kill their target following "natural" T-cell receptor recognition. When tested against the autologous B-lymphoblastoid cell line (BLCL) coated with anti-CD20 mAb, the newly expressed Fc receptor enabled the T cells to kill the BLCL through ADCC. Adoptive transfer of such newly designed immune effector may be considered to increase antibody efficiency by harnessing the immune potential of T cells.
HIF Prolyl 4-Hydroxylases and their Potential as Drug Targets (2009)

Hypoxia-inducible transcription factor (HIF) is the master regulator of hypoxia-inducible genes involved in the mediation of survival and adaptive responses to insufficient oxygen availability, such as genes involved in hematopoesis, angiogenesis, iron transport, glucose utilization, resistance to oxidative stress, cell proliferation, survival and apoptosis, extracellular matrix homeostasis, and tumor progression. The stability of the HIFalpha subunit is regulated by oxygen-dependent prolyl 4-hydroxylation catalyzed by the HIF prolyl 4-hydroxylases (P4Hs). The 4-hydroxyproline residues generated in normoxic conditions facilitate binding of HIFalpha to the von Hippel-Lindau E3 ubiquitin ligase complex resulting in the attachment of ubiquitin molecules and subsequent rapid proteasomal degradation of HIFalpha. In hypoxia this oxygen-requiring hydroxylation event is inhibited, HIFalpha escapes degradation and can translocate to the nucleus and form a functional dimer with HIFbeta that triggers the hypoxic response. HIF-P4Hs are considered as promising drug development targets in the treatment of diseases such as myocardial infarction, stroke, peripheral vascular disease, inflammation, diabetes and severe anemias. Studies with HIF-P4H inhibitors in various animal models and ongoing clinical trials support this hypothesis by demonstrating efficacy in many applications.
Red Cell Sorbitol: An Indicator of Diabetic Control (1980)

Intact human erythrocytes accumulate intracellular sorbitol in response to the medium's glucose concentration during in vitro incubations. Sorbitol was identified and measured both enzymatically and by gas-liquid chromatography. The sorbitol produced is most likely a result of the activity of aldose reductase, since (1) a low glucose concentration in the medium elicits this response, and (2) this activity is completely blocked by tetramethylene glutaric acid, a specific inhibitor of aldose reductase. Erythrocyte sorbitol levels in insulin-dependent diabetics are clearly above those of nondiabetics after an 8 h fast. A good correlation exists between red cell sorbitol content and coincident plasma glucose concentrations. Individual exceptions to this rule exist, however, and suggest that red cell sorbitol levels may provide information about in vivo polyol pathway activity that may be important in the pathogenesis of diabetes-associated complications.
Genome-wide analysis of disease progression in age-related macular degeneration (2018)

Family- and population-based genetic studies have successfully identified multiple disease-susceptibility loci for Age-related macular degeneration (AMD), one of the first batch and most successful examples of genome-wide association study. However, most genetic studies to date have focused on case-control studies of late AMD (choroidal neovascularization or geographic atrophy). The genetic influences on disease progression are largely unexplored. We assembled unique resources to perform a genome-wide bivariate time-to-event analysis to test for association of time-to-late-AMD with ∼9 million variants on 2721 Caucasians from a large multi-center randomized clinical trial, the Age-Related Eye Disease Study. To our knowledge, this is the first genome-wide association study of disease progression (bivariate survival outcome) in AMD genetic studies, thus providing novel insights to AMD genetics. We used a robust Cox proportional hazards model to appropriately account for between-eye correlation when analyzing the progression time in the two eyes of each participant. We identified four previously reported susceptibility loci showing genome-wide significant association with AMD progression: ARMS2-HTRA1 (P = 8.1 × 10-43), CFH (P = 3.5 × 10-37), C2-CFB-SKIV2L (P = 8.1 × 10-10) and C3 (P = 1.2 × 10-9). Furthermore, we detected association of rs58978565 near TNR (P = 2.3 × 10-8), rs28368872 near ATF7IP2 (P = 2.9 × 10-8) and rs142450006 near MMP9 (P = 0.0006) with progression to choroidal neovascularization but not geographic atrophy. Secondary analysis limited to 34 reported risk variants revealed that LIPC and CTRB2-CTRB1 were also associated with AMD progression (P < 0.0015). Our genome-wide analysis thus expands the genetics in both development and progression of AMD and should assist in early identification of high risk individuals.
Can long‐term prophylaxis for severe haemophilia be stopped in adulthood? Results from Denmark and the Netherlands (2005)

Prophylaxis is the treatment of choice for children with severe haemophilia. As prophylaxis is especially important during the period of growth, the need for continued prophylaxis in adulthood should be considered. The aim of this study was to describe the incidence and outcome of stopping prophylaxis in patients with severe haemophilia who were offered prophylaxis during childhood. All patients with severe haemophilia (factor VIII/IX <0.01 IU/ml), born 1970-80, treated in two Danish and one Dutch treatment centre were studied. Data on discontinuation of prophylaxis, treatment, joint bleed frequency, clinical scores and radiological scores were collected. Eighty patients were studied. Median follow-up was 19 years (range 7-29). A total of 35% of patients discontinued prophylaxis at a median age of 21.5 years [interquartile range (IQR) 18.4-24.4], experiencing only three joint bleeds per year (IQR 1.4-8.7). Median clinical scores were similar in patients who discontinued prophylaxis [4 points (IQR 0-6)] and those who continued [3 points (IQR 1-6)], as were median Pettersson scores at 13 (IQR 1-24) vs. 13 points (IQR 5-23) respectively. In conclusion one-third of young adults with severe haemophilia on a prophylactic regimen discontinued prophylaxis in early adulthood, while maintaining a low joint bleed frequency and similar arthropathy after 4 years.
Location area planning in cellular networks using simulated annealing (2002)

Location area (LA) planning plays an important role in cellular networks because of the trade-off caused by paging and registration signaling. The upper bound on the size of an LA is the service area of a mobile switching center (MSC). In that extreme case, the cost of paging is at its maximum, but no registration is needed. On the other hand, if each cell is an LA, the paging cost is minimal, but the registration cost is the largest. In general, the most important component of these costs is the load on the signaling resources. Between the extremes lie one or more partitions of the MSC service area that minimize the total cost of paging and registration. In this paper, we try to find an optimal method for determining the location areas. For that purpose, we use the available network information to formulate a realistic optimization problem. We propose an algorithm based on simulated annealing (SA) for the solution of the resulting problem. Then, we investigate the quality of the SA technique by comparing its results to greedy search and random generation methods.
Effect of polysilicon gate on the flatband voltage shift and mobility degradation for ALD-Al/sub 2/O/sub 3/ gate dielectric (2002)

Al/sub 2/O/sub 3/ (EOT=22.7 /spl Aring/) gate dielectric layer formed by Atomic Layer Deposition (ALD) process have been characterized for sub-100 nm CMOS devices. The gate leakage current was 3 orders of magnitude lower than that of SiO/sub 2/ and the hysteresis of C-V curve was not observed. However, the negative fixed charge induced the flat band voltage (Vfb) shift and degraded the channel mobility of MOS transistor. The Vfb shift was reduced and channel mobility was improved by applying P+ gate by BF/sub 2/ implantation. It is suggested that the phosphorous diffused from gate polysilicon has a role of network modifier in Al/sub 2/O/sub 3/ film and formation of the Al-O- dangling bond which may be ascribed to negative fixed charge.
Hydroxylated human homotrimeric collagen I in Agrobacterium tumefaciens‐mediated transient expression and in transgenic tobacco plant (2002)

Potential contamination of animal‐derived collagen with pathogens has led to the demand for safe recombinant sources of this complex molecule. In continuation of our previous work [Ruggiero et al. (2000) FEBS Lett. 469, 132–136], here we show that it is possible to produce recombinant hydroxylated homotrimeric collagen in tobacco plants that are co‐transformed with a human type I collagen and a chimeric proline‐4‐hydroxylase (P4H). This is to our knowledge the first time that transient expression in tobacco was used to improve the quality of a recombinant protein produced in plants through co‐expression with an animal cell‐derived modifying enzyme. We demonstrated the functionality of the new chimeric P4H and thus improved the thermal stability of recombinant collagen I from plants to 37°C.
A new 'shift and ratio' method for MOSFET channel-length extraction (1992)

A shift-and-ratio method for extracting MOSFET channel length is presented. In this method, channel mobility can be any function of gate voltage, and high source-drain resistance does not affect extraction results. It is shown to yield more accurate and consistent channel lengths for deep-submicrometer CMOS devices at room and low temperatures. It is also found that, for both nFET and pFET, the source-drain resistance is essentially independent of temperature from 300 to 77 K.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Sustained Virological Response after 14 - D Ay Treatment with Danoprevir and 48-Week Treatment with Pegylated Interferon-α2A (40 Kd) plus Ribavirin (2012)

The addition of danoprevir for 14 days to PEG-IFN/RBV treatment results in a high SVR rate in HCV genotype 1 treatment-naive patients.
Direct Analysis and Identification of Proteins in Mixtures by LC/MS/MS and Database Searching at the Low-Femtomole Level (1997)

A method to directly identify proteins contained in mixtures by microcolumn reversed-phase liquid chromatography electrospray ionization tandem mass spectrometry (LC/MS/MS) is studied. In this method, the mixture of proteins is digested with a proteolytic enzyme to produce a large collection of peptides. The complex peptide mixture is then separated on-line with a tandem mass spectrometer, acquiring large numbers of tandem mass spectra. The tandem mass spectra are then used to search a protein database to identify the proteins present. Results from standard protein mixtures show that proteins present in simple mixtures can be readily identified with a 30-fold difference in molar quantity, that the identifications are reproducible, and that proteins within the mixture can be identified at low femtomole levels. Based on these studies, methodology has been developed for direct LC/MS/MS analysis of proteins enriched by immunoaffinity precipitation, specific interaction with a protein-protein fusion product, and specific interaction with a macromolecular complex. The approach described in this article provides a rapid method for the direct identification of proteins in mixtures.
The Low Density Lipoprotein Receptor-1, LRP1, Interacts with the Human Frizzled-1 (HFz1) and Down-regulates the Canonical Wnt Signaling Pathway (2004)

Members of the low density lipoprotein receptor family (LDLR), LRP5/6, were shown to interact with the Frizzled (Fz) receptors and to function as Wnt coreceptors. Here we show that mLRP4T100, a minireceptor of LRP1, another member of the LDLR family, interacts with the human Fz-1 (HFz1), previously shown to serve as a receptor transmitting the canonical Wnt-3a-induced signaling cascade. However, in contrast to LRP5/6, mLRP4T100, as well as the full-length LRP1, did not cooperate with HFz1 in transmitting the Wnt-3a signaling but rather repressed it. mLRP4T100 inhibitory effect was displayed also by endocytosis-defective mLRP4T100 mutants, suggesting that LRP1 repressive effect is not attributable to LRP1-mediated enhanced HFz1 internalization and subsequent degradation. Enforced expression of mLRP4T100 decreased the capacity of HFz1 cysteine-rich domain (CRD) to interact with LRP6, in contrast to HFz1-CRD/Wnt-3a interaction that was not disrupted by overexpressing mLRP4T100. These data suggest that LRP1, by sequestering HFz1, disrupts the receptor/coreceptor complex formation, leading to the repression of the canonical Wnt signaling. Thus, this study implies that the ability to interact with Fz receptors is shared by several members of the LDLR family. However, whereas some members of the LDLR family, such as LRP5/6, interact with Fz and serve as Wnt coreceptors, others negatively regulate Wnt signaling, presumably by sequestering Fz.
Synthesis of novel 13-methyl-13-dihydroanthracyclines. (1986)

The title compounds, (+)-13-methyl-13-dihydro-4-demethoxydaunorubicin hydrochloride (8·HCl) and (+)-13-methyl-13-dihydrodaunorubicin hydrochloride (9·HCl), were prepared from (+)-4-demethoxydaunomycinone (13) and (+)-daunomycinone (18), respectively, by silylation of the C7-hydroxy group, addition of methylmagnesium bromide to the C13-carbonyl group, and direct glycosidation of the 7-O-silyl anthracyclinones with the daunosamine derivative (anthracycline numbering). In the P388 in vitro test, 8·HCl was several hundred-fold more active than adriamycin hydrochloride (1·HCl). Notable anticancer activity, equivalent to that of adriamycin hydrochloride, was also observed in the P388 in vivo test of 8·HCl.
Projections from the thoracic cord to the cerebellar nuclei in the rat, studied by anterograde axonal tracing (1997)

The dorsal spinocerebellar tract (DSCT) of the thoracic cord (the thoracic DSCT) consists of uncrossed ascending axons originating from Clarke's column, marginal neurons of Clarke's column, and lamina V neurons, and crossed ascending axons originating from neurons in lamina VIII and the ventromedial part of lamina VII. The present study has examined, by using anterograde labeling with biotinylated dextran, whether the thoracic DSCT projects to the cerebellar nuclei. The tracer was injected into the thoracic cord, for two to four segments at levels between the T4 and T9 segments in the rat. The distribution of anterogradely labeled axons and terminals was bilateral but predominantly ipsilateral to the injections. Labeled axons entered the medial nucleus from its rostromedial aspect and terminated widely in medial and ventral parts of the middle subdivision. Furthermore, they terminated in the medial and ventral part of the caudomedial subdivision. Labeled terminals were seen in rostromedial parts of the anterior interpositus nucleus and in medial to caudal parts of the posterior interpositus nucleus. A small number of labeled terminals were consistently seen in the ventral part of the lateral nucleus and the dorsolateral hump region. The present study shows that the thoracic DSCT projects bilaterally, but predominantly ipsilaterally, to the medial and the anterior and posterior interpositus nuclei and suggests that it conveys input related to posture and movement of the trunk and respiratory movement of the thorax. J. Comp. Neurol. 386:409-421, 1997. © 1997 Wiley-Liss, Inc.
Design and Validation of a Novel Generic Platform for the Production of Tetravalent IgG1-like Bispecific Antibodies (2016)

We have designed and validated a novel generic platform for production of tetravalent IgG1-like chimeric bispecific Abs. The VH-CH1-hinge domains of mAb2 are fused through a peptidic linker to the N terminus of mAb1 H chain, and paired mutations at the CH1-CL interface mAb1 are introduced that force the correct pairing of the two different free L chains. Two different sets of these CH1-CL interface mutations, called CR3 and MUT4, were designed and tested, and prototypic bispecific Abs directed against CD5 and HLA-DR were produced (CD5xDR). Two different hinge sequences between mAb1 and mAb2 were also tested in the CD5xDR-CR3 or -MUT4 background, leading to bispecific Ab (BsAbs) with a more rigid or flexible structure. All four Abs produced bound with good specificity and affinity to CD5 and HLA-DR present either on the same target or on different cells. Indeed, the BsAbs were able to efficiently redirect killing of HLA-DR(+) leukemic cells by human CD5(+) cytokine-induced killer T cells. Finally, all BsAbs had a functional Fc, as shown by their capacity to activate human complement and NK cells and to mediate phagocytosis. CD5xDR-CR3 was chosen as the best format because it had overall the highest functional activity and was very stable in vitro in both neutral buffer and in serum. In vivo, CD5xDR-CR3 was shown to have significant therapeutic activity in a xenograft model of human leukemia.
Oxidant-mediated lung injury in the acute respiratory distress syndrome (1999)

Matthay, Michael A. MD; Geiser, Thomas MD; Matalon, Sadis PhD; Ischiropoulos, Harry PhD Author Information
The cumate gene-switch: a system for regulated expression in mammalian cells. (2006)

We report the generation of a new versatile inducible expression system.