gebhart/patrepeval huggingface dataset:
The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games (2005)

The members of the tumour necrosis factor (TNF)/tumour necrosis factor receptor (TNFR) superfamily are critically involved in the maintenance of homeostasis of the immune system. The biological functions of this system encompass beneficial and protective effects in inflammation and host defence as well as a crucial role in organogenesis. At the same time, members of this superfamily are responsible for host damaging effects in sepsis, cachexia, and autoimmune diseases. This review summarizes recent progress in the immunobiology of the TNF/TNFR superfamily focusing on results obtained from animal studies using gene targeted mice. The different modes of signalling pathways affecting cell proliferation, survival, differentiation, apoptosis, and immune organ development as well as host defence are reviewed. Molecular and cellular mechanisms that demonstrate a therapeutic potential by targeting individual receptors or ligands for the treatment of chronic inflammatory or autoimmune diseases are discussed.
Establishment of a quantitative mouse dorsal air sac model and its application to evaluate a new angiogenesis inhibitor. (1999)

We have developed an improved mouse dorsal air sac model for quantifying in vivo tumor-induced angiogenesis. In our improved model, tumor angiogenesis is determined by measuring the blood volume in an area of skin held in contact with a tumor cell-containing chamber, using 51Cr-labeled red blood cells (RBC). The blood volume induced by murine B16-BL6 melanoma cells increased linearly with the cell number in the range from 2 x 10(5) to 5 x 10(6). Ten of 11 human tumor cell lines examined induced a significant increment in blood volume. For three representative human tumor cell lines (A549, WiDr. and HT1080 cells) that showed different angiogenic potencies, the levels of vascular endothelial growth factor (VEGF) produced by the tumor cells cultured under conditions of hypoxia and high cell density were correlated with the degree of in vivo angiogenesis. Using the improved model, it was confirmed that TNP-470, a well-known inhibitor, and borrelidin, an antibiotic from Streptomyces rochei, significantly inhibited the WiDr cell-induced angiogenesis. Borrelidin also inhibited spontaneous lung metastasis of B16-BL6 melanoma at the same dose that inhibited angiogenesis. Our results suggest that the improved mouse dorsal air sac model can be used for simple and quantitative measurement of tumor-induced angiogenesis and its inhibition.
Factor VIII:E113A Represents a High Specific Activity Factor VIII Arising from a Single Point Mutation within a Ca2+ Binding Site. (2004)

Abstract We recently identified an acidic-rich segment in the A1 domain of factor VIII (residues 110-126) that functions in the coordination of Ca2+, an ion necessary for cofactor activity (Wakabayashi et al., J. Biol. Chem.279:12677–12684, 2004). Using Ala-scanning mutagenesis, it was determined that replacement of residue E113 with Ala yielded a factor VIII point mutant that possessed an ~2-fold increased affinity for Ca2+ as compared with wild type, suggesting that this residue did not directly contribute to Ca2+ coordination but rather modulated the affinity of the ion at this site. Furthermore, the E113A factor VIII possessed twice the specific activity of wild type as determined by a one-stage clotting assay. This increased activity was not likely a result of increased affinity for Ca2+, since assays were performed at saturating Ca2+ levels. Saturation mutagenesis at position 113 revealed that substitution at this position with relatively small, nonpolar residues were well-tolerated, whereas replacement with a number of polar or charged residues was detrimental to activity. Ala-substitution yielded the greatest activity increase of ~2-fold and this level was observed over a wide range of factor VIII concentrations. Time course experiments of factor VIII activation following reaction with thrombin revealed similar rates of activation and inactivation of E113A as observed for the wild type. Interestingly, results from factor Xa generation assays using purified reactants showed the mutant possessed &lt;10% greater specific activity than wild type and yielded similar values for Km for substrate factor X, kcat for factor Xa generation and Kd for factor IXa. Thus the single amino acid substitution minimally altered cofactor structure or inter-molecular interactions relating to its participation in factor Xase. These results indicate that mutations within this Ca2+ coordination site may selectively enhance cofactor specific activity as measured in a plasma-based assay compared to activity determined in a purified system. The enhanced activity observed for E113A factor VIII may derive from a subtle alteration in conformation affecting a yet to be identified functional parameter.
Measuring the thickness of the human cerebral cortex from magnetic resonance images (2000)

Accurate and automated methods for measuring the thickness of human cerebral cortex could provide powerful tools for diagnosing and studying a variety of neurodegenerative and psychiatric disorders. Manual methods for estimating cortical thickness from neuroimaging data are labor intensive, requiring several days of effort by a trained anatomist. Furthermore, the highly folded nature of the cortex is problematic for manual techniques, frequently resulting in measurement errors in regions in which the cortical surface is not perpendicular to any of the cardinal axes. As a consequence, it has been impractical to obtain accurate thickness estimates for the entire cortex in individual subjects, or group statistics for patient or control populations. Here, we present an automated method for accurately measuring the thickness of the cerebral cortex across the entire brain and for generating cross-subject statistics in a coordinate system based on cortical anatomy. The intersubject standard deviation of the thickness measures is shown to be less than 0.5 mm, implying the ability to detect focal atrophy in small populations or even individual subjects. The reliability and accuracy of this new method are assessed by within-subject test-retest studies, as well as by comparison of cross-subject regional thickness measures with published values.
Infection in the bone marrow transplant recipient and role of the microbiology laboratory in clinical transplantation (1997)

Over the past quarter century, tremendous technological advances have been made in bone marrow and solid organ transplantation. Despite these advances, an enduring problem for the transplant recipient is infection. As immunosuppressive regimens have become more systematic, it is apparent that different pathogens affect the transplant recipient at different time points in the posttransplantation course, since they are influenced by multiple intrinsic and extrinsic factors. An understanding of this evolving risk for infection is essential to the management of the patient following transplantation and is a key to the early diagnosis and treatment of infection. Likewise, diagnosis of infection is dependent upon the quality of laboratory support, and services provided by the clinical microbiology laboratory play an important role in all phases of clinical transplantation. These include the prescreening of donors and recipients for evidence of active or latent infection, the timely and accurate microbiologic evaluation of the transplant patient with suspected infection, and the surveillance of asymptomatic allograft recipients for infection. Expert services in bacteriology, mycology, parasitology, virology, and serology are needed and communication between the laboratory and the transplantation team is paramount for providing clinically relevant, cost-effective diagnostic testing.
The Insulin Gene Promoter: A Simplified Nomenclature (1995)

The tools of molecular biology have rapidly expanded our knowledge of how β-cells regulate insulin gene expression. As this work has progressed in parallel in different laboratories, alternate nomenclature systems have been developed to describe the functionally important elements of the insulin gene. This jumble of names is confusing to those outside the field and intimidating to neophytes. Therefore, we have agreed to a simple, uniform set of names for the major insulin gene promoter elements.
Chip level reliability on SOI embedded memory (2002)

In modern DRAM products, stacked-capacitor (STC) cells are widely utilized because the STC cell structure has the advantage of easy fabrication of the storage capacitors. Meanwhile, the drawback of STC cells is the increasing difficulty of the back-end process with each DRAM generation due to the high contact hole aspect ratio resulting from the step height difference between the peripheral circuit regimes and memory array regimes. This paper describes a novel stacked-capacitor cell structure with a simple wiring process which utilizes the virtual flat surface at the bottom of SOI stacked-capacitor cells. The virtual flat surface is made into a real surface by reversing the capacitor and polishing the substrate with bonded-SOI technology (Nishihara et al. 1992). This memory cell is named an embedded memory SOI process (EMSP)(Kim et al. 1996). In this paper, we analyze the problems of capacitor formation under an SOI structure, and confirm the process limitations to improve the embedded memory SOI process, using a 16 Mb SOI DRAM with 0.35 /spl mu/m design rule technology. We have previously reported the basic EMSP. We focus here on chip-level reliability issues for EMSP memory cell structures and present some solutions.
Safety and Feasibility of Balloon Catheter Dilation of Paranasal Sinus Ostia: A Preliminary Investigation (2006)

Dilation of sinus ostial regions via balloon catheter-based technology appears to be relatively safe and feasible. Larger multicenter clinical trials are now warranted to further establish safety and to determine the role of this new technique.
The Midtarsal Joint Locking Mechanism (2005)

This study demonstrated that motion in the forefoot is influenced by hindfoot position through the midtarsal joint. Specifically, the sagittal plane range of motion of the metatarsals is increased when the hindfoot is in valgus.
Bone marrow fibrosis in primary myelofibrosis: pathogenic mechanisms and the role of TGF-β. (2016)

Primary myelofibrosis (PMF) is a Philadelphia chromosome negative myeloproliferative neoplasm (MPN) with adverse prognosis and is associated with bone marrow fibrosis and extramedullary hematopoiesis. Even though the discovery of the Janus kinase 2 (JAK2), thrombopoietin receptor (MPL) and calreticulin (CALR) mutations have brought new insights into the complex pathogenesis of MPNs, the etiology of fibrosis is not well understood. Furthermore, since JAK2 inhibitors do not lead to reversal of fibrosis further understanding of the biology of fibrotic process is needed for future therapeutic discovery. Transforming growth factor beta (TGF-β) is implicated as an important cytokine in pathogenesis of bone marrow fibrosis. Various mouse models have been developed and have established the role of TGF-β in the pathogenesis of fibrosis. Understanding the molecular alterations that lead to TGF-β mediated effects on bone marrow microenvironment can uncover newer therapeutic targets against myelofibrosis. Inhibition of the TGF-β pathway in conjunction with other therapies might prove useful in the reversal of bone marrow fibrosis in PMF.
Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat (2003)

To elucidate the underlying mechanisms involved in AIDS therapy-induced peripheral neuropathy, we have developed a model of nucleoside analog reverse transcriptase inhibitor-induced painful peripheral neuropathy in the rat, using 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI) and 2',3'-didehydro-3'-deoxythymidine (d4T), AIDS chemotherapeutic drugs that are also components of AIDS highly active anti-retroviral therapy. Administration of ddC, ddI and d4T produced dose-dependent mechanical hypersensitivity and allodynia. Peripheral administration of inhibitors of protein kinase A, protein kinase C, protein kinase G, p42/p44-mitogen-activated protein kinase (ERK1/2) and nitric oxide synthase, which have demonstrated anti-hyperalgesic effects in other models of metabolic and toxic painful peripheral neuropathies, had no effect on ddC-, ddI- and d4T-induced hypersensitivity. Since suramin, an anti-parasitic and anti-cancer drug, which shares with the anti-retroviral nucleoside analogs, mitochondrial toxicity, altered regulation of intracellular calcium, and a sensory neuropathy in humans, also produced mechanical hypersensitivity that was not sensitive to the above second messenger inhibitors we evaluated the role of intracellular calcium. Intradermal or spinal injection of intracellular calcium modulators (TMB-8 and Quin-2), which had no effect on nociception in control rats, significantly attenuated and together eliminated ddC and suramin-induced mechanical hypersensitivity. In electrophysiology experiments in ddC-treated rats, C-fibers demonstrated alterations in pattern of firing as indicated by changes in the distribution of interspike intervals to sustained suprathreshold stimuli without change in mechanical activation thresholds or in number of action potentials in response to threshold and suprathreshold stimulation. This study provides evidence for a novel, calcium-dependent, mechanism for neuropathic pain in a model of AIDS therapy-induced painful peripheral neuropathy.
Normalized data nonlinearities for LMS adaptation (1994)

Properly designed nonlinearly-modified LMS algorithms, in which various quantities in the stochastic gradient estimate are operated upon by memoryless nonlinearities, have been shown to perform better than the LMS algorithm in system identification-type problems. The authors investigate one such algorithm given by W/sub k+l/=W/sub k/+/spl mu/(d/sub k/-W/sub k//sup t/X/sub k/)X/sub k/f(X/sub k/) in which the function f(X/sub k/) is a scalar function of the sum of the squares of the N elements of the input data vector X/sub k/. This form of algorithm generalizes the so-called normalized LMS (NLMS) algorithm. They evaluate the expected behavior of this nonlinear algorithm for both independent input vectors and correlated Gaussian input vectors assuming the system identification model. By comparing the nonlinear algorithm's behavior with that of the LMS algorithm, they then provide a method of optimizing the form of the nonlinearity for the given input statistics. In the independent input case, they show that the optimum nonlinearity is a single-parameter version of the NLMS algorithm with an additional constant in the denominator and show that this algorithm achieves a lower excess mean-square error (MSE) than the LMS algorithm with an equivalent convergence rate. Additionally, they examine the optimum step size sequence for the optimum nonlinear algorithm and show that the resulting algorithm performs better and is less complex to implement than the optimum step size algorithm derived for another form of the NLMS algorithm. Simulations verify the theory and the predicted performance improvements of the optimum normalized data nonlinearity algorithm.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Stability of anthracycline antitumour agents in infusion fluids. (1986)

The chemical stability of six anthracycline cytostatics has been studied in four different, commonly used, infusion fluids. Stability was determined with the use of high performance liquid chromatography. All compounds tested appeared to be stable in 5% dextrose and 3.3% dextrose-0.3% sodium chloride solutions, during a 28 days’ incubation period at 25°C in the dark. When doxorubicin and its 4′-cogeners are stored in Lactated Ringer’s or 0.9% sodium chloride injection considerable degradation occurs. t90 values are presented. Degradation products could be traced by means of thin layer chromatography. Daunorubicin and 4-demethoxy-daunorubicin are apparently stable in Lactated Ringer’s and 0.9% sodium chloride injection.
Withdrawing Life Support from Mechanically Ventilated Recipients of Bone Marrow Transplants: A Case for Evidence-Based Guidelines (1996)

Of the patients who required mechanical ventilation after bone marrow transplantation, no one survived with lung injury combined with either hemodynamic instability or hepatic and renal failure. However, survival after mechanical ventilation seems to be improving.
CHANGES IN CRYSTALLOGRAPHIC STRUCTURE AND THERMOSTABILITY OF A CU,ZN SUPEROXIDE DISMUTASE MUTANT RESULTING FROM THE REMOVAL OF BURIED CYSTEINE (1990)

In principle, protein thermostability depends on efficient interior packing of apolar residues and on avoidance of irreversible denaturation in the unfolded state. To study these effects, the single free cysteine in the highly stable enzyme bovine Cu,Zn superoxide dismutase was mutated to alanine (Cys6----Ala), and the recombinant protein was expressed in yeast, purified, characterized for reversible and irreversible denaturation, crystallized isomorphously to the wild-type enzyme, and used to determine the atomic structure. Removal of the chemically reactive thiol significantly decreased the rate of irreversible denaturation (as monitored by thermal inactivation at 70 degrees C), but the observed energetic cost (delta delta G of 0.7-1.3 kcal/mol as determined by differential scanning calorimetry) was much less than predicted from either the change in hydrophobicity or packing due to removal of the interior sulfur atom. X-ray diffraction data were collected to 2.1-A resolution using an area detector, and the atomic model for the mutant enzyme was determined by fitting to electron density difference maps, followed by reciprocal space refinement both with stereochemical restraints using PROLSQ and with molecular dynamics using X-PLOR. The refined 2.1-A resolution crystallographic structure suggests that small concerted and compensating shifts (less than 0.5 A) of the surrounding side chains and of the adjacent N- and C-terminal beta-strands significantly reduced the energetic cost of the interior mutation by improving packing and stereochemistry in the mutant enzyme. Taken together, these results differentiate between the effects of reversible and irreversible processes as they impact the design of thermostable proteins and suggest that relatively subtle concerted shifts can significantly reduce the energetic cost of evolutionary variation in internal residues of proteins with Greek key beta-barrel folds.
Sustained antibody responses depend on CD28 function in bone marrow–resident plasma cells (2011)

Sustained long-term antibody levels are the cornerstone of protective immunity, yet it remains unclear how they are durably maintained. A predominant theory implicates antigen-independent antibody production by a subset of long-lived plasma cells (LLPCs) that survive within bone marrow (BM). Central tenets of this model--that BM LLPCs constitute a subset defined by intrinsic biology distinct from PCs in other tissues and contribute to long-term antibody titers--have not been definitively demonstrated. We now report that long-term humoral immunity depends on the PC-intrinsic function of CD28, which selectively supports the survival of BM LLPC but not splenic short-lived PC (SLPC). LLPC and SLPC both express CD28, but CD28-driven enhanced survival occurred only in the LLPC. In vivo, even in the presence of sufficient T cell help, loss of CD28 or its ligands CD80 and CD86 caused significant loss of the LLPC population, reduction of LLPC half-life from 426 to 63 d, and inability to maintain long-term antibody titers, but there was no effect on SLPC populations. These findings establish the existence of the distinct BM LLPC subset necessary to sustain antibody titers and uncover a central role for CD28 function in the longevity of PCs and humoral immunity.
CD4 + T-Cell Responses Are Required for Clearance of West Nile Virus from the Central Nervous System (2006)

ABSTRACT Although studies have established that innate and adaptive immune responses are important in controlling West Nile virus (WNV) infection, the function of CD4 + T lymphocytes in modulating viral pathogenesis is less well characterized. Using a mouse model, we examined the role of CD4 + T cells in coordinating protection against WNV infection. A genetic or acquired deficiency of CD4 + T cells resulted in a protracted WNV infection in the central nervous system (CNS) that culminated in uniform lethality by 50 days after infection. Mice surviving past day 10 had high-level persistent WNV infection in the CNS compared to wild-type mice, even 45 days following infection. The absence of CD4 + T-cell help did not affect the kinetics of WNV infection in the spleen and serum, suggesting a role for CD4-independent clearance mechanisms in peripheral tissues. WNV-specific immunoglobulin M (IgM) levels were similar to those of wild-type mice in CD4-deficient mice early during infection but dropped ∼20-fold at day 15 postinfection, whereas IgG levels in CD4-deficient mice were ∼100- to 1,000-fold lower than in wild-type mice throughout the course of infection. WNV-specific CD8 + T-cell activation and trafficking to the CNS were unaffected by the absence of CD4 + T cells at day 9 postinfection but were markedly compromised at day 15. Our experiments suggest that the dominant protective role of CD4 + T cells during primary WNV infection is to provide help for antibody responses and sustain WNV-specific CD8 + T-cell responses in the CNS that enable viral clearance.
Site-specific recombination in cells and mice (1999)

The use of site-specific recombinase systems has revolutionized our ability to genetically manipulate embryonic stem (ES) cells and mice. Recent advances using the Cre-loxP and Flp-FRT systems have now made it possible to generate ‘clean’ germline mutations following a single gene targeting event, as well as to (in)activate genes in a conditional manner in the living mouse. Not only can target gene mutations be induced in a spatially and temporally restricted fashion, but lineage tracers can be activated in specific progenitor populations to chart cell fate directly in the wild-type or mutant mouse. This chapter introduces site-specific recombination and details a variety of applications, many of which are extensions of the gene targeting vectors and manipulations presented by Hasty et al. in Chapter 1. Many of the mutagenesis techniques which exploit the Cre-loxP system have been compiled earlier in an excellent book by Torres and Kühn (1). In this chapter, I present the Flp-FRT system in addition to the Cre-loxP system, for individual or combined uses. Together, these surveys and protocols should provide a basis for a wide variety of studies on gene function in vivo. As novel recombinase based applications continue to be developed, the possibilities for genome engineering appear without limit. The simplest site-specific recombination systems are comprised of two elements: the recombinase enzyme and a small stretch of DNA specifically recognized by the particular recombinase. These two elements work together to either delete, insert, invert, or translocate associated DNA. Two such recombinase systems have been established in mice (2-5) providing the basic tools for in vivo genetic engineering: the Cre-loxP system from the bacteriophage P1 and the Flp-FRT system from the budding yeast Saccharomyces cerevisiae. Both Cre and Flp are members of the λ integrase superfamily of site-specific recombinases (6) that cleave DNA at a distinct target sequence and then ligate it to the cleaved DNA of a second identical site to generate a contiguous strand. This recombination reaction is carried out with absolute fidelity, such that not a single nucleotide is gained or lost overall, and with no other requirements than the recombinase, the specific target DNA sequence, and some mono- or divalent cations (7).