gebhart/patrepeval huggingface dataset:
No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies (2016)

There was no evidence of an effect of alirocumab on transition to new-onset diabetes in 3448 individuals without diabetes at baseline with a follow-up period of 6-18 months, compared to either placebo or ezetimibe. Longer follow-up with larger number of individuals is needed to conclusively rule out an effect.
Erythropoietic Defect Associated with Reduced Cell Proliferation in Mice Lacking the 26S Proteasome Shuttling Factor Rad23b (2013)

Rad23a and Rad23b proteins are linked to nucleotide excision DNA repair (NER) via association with the DNA damage recognition protein xeroderma pigmentosum group C (XPC) are and known to be implicated in protein turnover by the 26S proteasome. Rad23b-null mice are NER proficient, likely due to the redundant function of the Rad23b paralogue, Rad23a. However, Rad23b-null midgestation embryos are anemic, and most embryos die before birth. Using an unbiased proteomics approach, we found that the majority of Rad23b-interacting partners are associated with the ubiquitin-proteasome system (UPS). We tested the requirement for Rad23b-dependent UPS activity in cellular proliferation and more specifically in the process of erythropoiesis. In cultured fibroblasts derived from embryos lacking Rad23b, proliferation rates were reduced. In fetal livers of Rad23b-null embryos, we observed reduced proliferation, accumulation of early erythroid progenitors, and a block during erythroid maturation. In primary wild-type (WT) erythroid cells, knockdown of Rad23b or chemical inhibition of the proteasome reduced survival and differentiation capability. Finally, the defects linked to Rad23b loss specifically affected fetal definitive erythropoiesis and stress erythropoiesis in adult mice. Together, these data indicate a previously unappreciated requirement for Rad23b and the UPS in regulation of proliferation in different cell types.
ε-Decalactone: A Thermoresilient and Toughening Comonomer to Poly(l-lactide) (2013)

The renewable monomer ε-decalactone is an excellent partner to L-lactide, where their copolymers overcome inherent drawbacks of polylactide, such as low thermal stability and brittleness. ε-Decalactone is a seven-membered lactone that was successfully polymerized with Sn(Oct)(2) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene into both an amorphous homopolymer and copolymers with high molecular weight, low dispersity, and predicted macromolecular architecture. The thermoresilient nature of ε-decalactone is reflected in a high polymerization ceiling temperature and increased thermal stability for the prepared copolymers. The high ceiling temperature enables easy modulation of the polymerization rate via temperature while maintaining architectural control. The apparent rate constant was increased 15-fold when the temperature was increased from 110 to 150 °C. Copolymers of L-lactide and ε-decalactone, either with the latter as a central block in triblock polymers or with randomly positioned monomers, exhibited exceptionally tough material characteristics. The triblock copolymer had an elongation-at-break 250 times greater than that of pure poly(L-lactide). The toughness of the copolymers is attributed to the flexible nature of the polymer derived from the monomer ε-decalactone and to the segment immiscibility. These properties result in phase separation to soft and hard domains, which provides the basis for the elastomeric behavior.
Bioinspired Fibers Follow the Track of Natural Spider Silk (2011)

The mechanical behavior and microstructure of bioinspired fibers spun from solutions of recombinant spidroin-like proteins were extensively characterized, and compared with those of natural spider silk fibers. It is confirmed that high performance bioinspired fibers indistinguishable from natural spider silk up to large strains can be produced through genetic engineering and conventional spinning technologies. It is also found that fibers spun from spidroin-like proteins that contain different motifs of sequence exhibit variations in their microstructure in terms of crystallinity and chain alignment, but these differences are not reflected in distinct tensile properties. This similarity in terms of their mechanical behavior indicates that bioinspired fibers are largely independent of their exact sequence of recombinant proteins and, in particular, of their proline content. Finally, it is shown that the largest differences between natural and bioinspired fibers are found at very large deformations, marking the ultimate challenge in the synthesis of silk-like fibers.
Identification of Novel HLA-A*0201–Restricted Epitopes in Recent-Onset Type 1 Diabetic Subjects and Antibody-Positive Relatives (2006)

Cytotoxic T-lymphocytes (CTLs) are considered to be essential for beta-cell destruction in type 1 diabetes. However, few islet-associated peptides have been demonstrated to activate autoreactive CTLs from type 1 diabetic subjects. In an effort to identify novel epitopes, we used matrix-assisted algorithms to predict peptides of glial fibrillary acidic protein (GFAP), prepro-islet amyloid polypeptide (ppIAPP), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) that likely bind to HLA-A*0201 with a strong affinity and contain a COOH-terminal proteasomal cleavage site. Seven peptides stabilized HLA-A*0201 expression in binding assays and were used to stimulate peripheral blood mononuclear cells and were evaluated for granzyme B secretion. We found that 5 of 13 type 1 diabetic subjects and 4 of 6 antibody-positive relatives exhibited greater numbers of granzyme B-secreting cells in response to at least one putative epitope compared with healthy control subjects. The most prevalent responses in antibody-positive and type 1 diabetic subjects were to ppIAPP(9-17). Other peptides recognized by type 1 diabetic or antibody-positive subjects included GFAP(143-151), IGRP(152-160), and GFAP(214-222). These data implicate peptides of ppIAPP, GFAP, and IGRP as CTL epitopes for a heterogenous CD8(+) T-cell response in type 1 subjects and antibody-positive relatives.
Role of Conserved Residues within the Carboxy Phosphate Domain of Carbamoyl Phosphate Synthetase (1996)

Carbamoyl phosphate synthetase (CPS) catalyzes the formation of carbamoyl phosphate from glutamine, bicarbonate, and 2 mol of MgATP. The heterodimeric protein is composed of a small amidotransferase subunit and a larger synthetase subunit. The synthetase subunit contains a large tandem repeat for each of the nucleotides used in the overall synthesis of carbamoyl phosphate. A working model for the three-dimensional fold of the carboxy phosphate domain of CPS was constructed on the basis of amino acid sequence alignments and the X-ray crystal structure coordinates for biotin carboxylase and D-alanine:D-alanine ligase. This model was used to select ten residues within the carboxy phosphate domain of CPS for modification and subsequent characterization of the kinetic constants for the mutant proteins. Residues R82, R129, R169, D207, E215, N283, and Q285 were changed to alanine residues; residues E299 and R303 to glutamine; and residue N301 to aspartate. No significant changes in the catalytic constants were observed upon mutation of either R82 or D207, and thus these residues appear to be nonessential for binding and/or catalytic activity. The Michaelis constant for ATP was most affected by modification of residues R129, R169, Q285, and N301. The binding of bicarbonate was most affected by the mutagenesis of residues E215, E299, N301, and R303. The mutation of residues E215, N283, E299, N301, and R303 resulted in proteins which were unable to synthesize carbamoyl phosphate at a significant rate. All of the mutations, with the exception of the N301D mutant, primarily affected the enzyme by altering the step for the phosphorylation of bicarbonate. However, mutation of N301 to aspartic acid also disrupted the catalytic step involved in the phosphorylation of carbamate. These results are consistent with a role for the N-terminal half of the synthetase subunit of CPS that is primarily directed at the initial phosphorylation of bicarbonate by the first ATP utilized in the overall synthesis of carbamoyl phosphate. The active site structure appears to be very similar to the ones previously determined for D-alanine:D-alanine ligase and biotin carboxylase.
Clinical and Cytogenetic Analyses in Uveal Melanoma (2006)

Monosomy 3 and largest tumor diameter are the most significant in determining survival of patients with uveal melanoma. Abnormalities in the q-arm of chromosome 16 are relatively common in uveal melanoma, but are not associated with survival or other cytogenetic or histopathologic parameters.
Parallel transmission for ultrahigh‐field imaging (2015)

The development of MRI systems operating at or above 7 T has provided researchers with a new window into the human body, yielding improved imaging speed, resolution and signal-to-noise ratio. In order to fully realise the potential of ultrahigh-field MRI, a range of technical hurdles must be overcome. The non-uniformity of the transmit field is one of such issues, as it leads to non-uniform images with spatially varying contrast. Parallel transmission (i.e. the use of multiple independent transmission channels) provides previously unavailable degrees of freedom that allow full spatial and temporal control of the radiofrequency (RF) fields. This review discusses the many ways in which these degrees of freedom can be used, ranging from making more uniform transmit fields to the design of subject-tailored RF pulses for both uniform excitation and spatial selection, and also the control of the specific absorption rate. © 2015 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.
Using model-based functional MRI to locate working memory updates and declarative memory retrievals in the fronto-parietal network (2013)

In this study, we used model-based functional MRI (fMRI) to locate two functions of the fronto-parietal network: declarative memory retrievals and updating of working memory. Because regions in the fronto-parietal network are by definition coherently active, locating functions within this network is difficult. To overcome this problem, we applied model-based fMRI, an analysis method that uses predictions of a computational model to inform the analysis. We applied model-based fMRI to five previously published datasets with associated computational cognitive models, and subsequently integrated the results in a meta-analysis. The meta-analysis showed that declarative memory retrievals correlated with activity in the inferior frontal gyrus and the anterior cingulate, whereas updating of working memory corresponded to activation in the inferior parietal lobule, as well as to activation around the inferior frontal gyrus and the anterior cingulate.
Carl Prausnitz Memorial Lecture. Suppression of antibody responses by chemically modified antigens. (1991)

Some of the studies employing nonantigenic, nonallergenic and tolerogenic derivatives of antigens and allergens, synthesized by coupling onto them an optimal number (n) of molecules of monomethoxy-polyethylene glycol (mPEG), are briefly reviewed. Administration of antigen (mPEG)n conjugates into mice resulted in specific immunosuppression, which was mediated by antigen-specific suppressor T (Ts) cells and by suppressor factor(s) (TsF) produced by these cells. These Ts cells were cloned and shown to be Thy-1.2+, CD3+, CD4-, CD5-, CD8+, and expressed the alpha beta heterodimer of conventional T cell receptors (TCR). The TsF had the functional activity of Ts cells and possessed at least one epitope related to the alpha-chain of TCR. The results of clinical trials of mPEG conjugates of common allergens are briefly referred to; it is suggested that the time is opportune for the evaluation of the therapeutic efficacy of mPEG conjugates of pure allergens which can be synthesized on an industrial scale by recombinant DNA technology. Finally, possible applications of tolerogenic mPEG conjugates of xenogeneic monoclonal antibodies, immunotoxins and immunogenic recombinant lymphokines to the development of immunotherapeutic strategies in oncology, transplantation, autoimmunity and acquired immunodeficiency syndrome are discussed.
High-resolution definition of the Vibrio cholerae essential gene set with hidden Markov model–based analyses of transposon-insertion sequencing data (2013)

The coupling of high-density transposon mutagenesis to high-throughput DNA sequencing (transposon-insertion sequencing) enables simultaneous and genome-wide assessment of the contributions of individual loci to bacterial growth and survival. We have refined analysis of transposon-insertion sequencing data by normalizing for the effect of DNA replication on sequencing output and using a hidden Markov model (HMM)-based filter to exploit heretofore unappreciated information inherent in all transposon-insertion sequencing data sets. The HMM can smooth variations in read abundance and thereby reduce the effects of read noise, as well as permit fine scale mapping that is independent of genomic annotation and enable classification of loci into several functional categories (e.g. essential, domain essential or 'sick'). We generated a high-resolution map of genomic loci (encompassing both intra- and intergenic sequences) that are required or beneficial for in vitro growth of the cholera pathogen, Vibrio cholerae. This work uncovered new metabolic and physiologic requirements for V. cholerae survival, and by combining transposon-insertion sequencing and transcriptomic data sets, we also identified several novel noncoding RNA species that contribute to V. cholerae growth. Our findings suggest that HMM-based approaches will enhance extraction of biological meaning from transposon-insertion sequencing genomic data.
IDO-Independent Suppression of T Cell Effector Function by IFN-γ–Licensed Human Mesenchymal Stromal Cells (2014)

Human bone marrow-derived mesenchymal stromal cells (MSCs) inhibit proliferation of activated T cells, and IFN-γ plays an important role in this process. This IFN-γ-licensed veto property is IDO-dependent. To further decipher the mechanistic underpinnings of MSC veto function on T cells, we investigated the effect of MSCs and IFN-γ-licensed MSCs on T cell effector function as assayed by cytokine secretion of T cells. Although MSCs and IFN-γ-licensed MSCs inhibit T cell proliferation, only IFN-γ-licensed MSCs significantly inhibit Th1 cytokine (IFN-γ, TNF-α, and IL-2) production by T cells. Additionally, IFN-γ-licensed MSCs inhibit T cell degranulation as well as single, double, and triple cytokine-producing T cells. Although IFN-γ-licensed MSCs upregulate their IDO activity, we found that MSC IDO catalytic function is dispensable with regard to MSC-driven inhibition of T cell effector function. Novel flow cytometry based functional screening of MSC-expressed, IFN-γ-licensed inhibitory molecules identified B7H1 and B7DC/PD1 pathways as essential effectors in blocking T cell function. Small interfering RNA-mediated blocking of B7H1 and B7DC reverses the inhibitory potential of IFN-γ-licensed MSCs on T cell effector function. Mechanistic analysis revealed that clustering of MHC and coinhibitory molecules are indispensable for the inhibitory effect of IFN-γ MSCs. Although exogenous IL-2 reverses B7H1-Ig-mediated inhibition of T cell proliferation, it does not affect the veto function of IFN-γ MSCs on both T cell proliferation and effector function. Our results reveal a new immunosuppressive property of IFN-γ-licensed MSCs that inhibits T cell effector function independent of IDO but through the ligands for PD1.
Analgesic Efficacy of Pentazocine Versus a Pentazocine-Naloxone Combination Following Oral Administration (1988)

The effect of the addition of 0.5 mg naloxone on the analgesic em- cacy of pentazocine 50 mg was studied. A single oral dose of either pentazo- cine, the combination of pentazocine plus naloxone, or placebo was given in a randomized double-blind parallel group study. The study sample consisted of 48 patients with moderate pain and 76 patients with severe pain resulting from episiotomy, cesarean section, or gynecological surgery. An analysis of the entire sample showed both pentazocine and the combination to be significantly more effective than placebo for all measures, including global assessments. In addition, the combination was significantly less efficacious than pentazocine for the sum of the pain intensity difference (SPID), percentage of the sum of the pain intensity difference (%SPID), and for relief and pain intensity difference (PID) at the fourth hour. Because there was a significant interaction between drug and baseline pain intensity for the variable SPID, comparisons were made between pentazocine and the combination within each baseline pain intensity group. For patients with moderate baseline pain, the combina- tion produced significantly less pain relief than pentazocine for SPID and for relief and PID at hours 3 and 4. In patients with severe baseline pain, there was no significant difference between pentazocine and the combination of pentazo- cine plus naloxone. Further studies are needed to confirm the suggestion that naloxone taken orally may decrease the analgesia achieved with pentazocine; clinicians should be aware of this possibility.
Germline mutations in the TP53 gene. (1995)

Since the majority of germline mutations in the TP53 gene seem to occur in LFS or LFL families, and these are rare, research is best conducted in a collaborative setting (Li and Fraumeni, in press). In a report from a meeting at Bethesda in 1993, the following areas were outlined for collaborative study: the correlation (if any) of phenotypes with specific mutation; age specific penetrance; cumulative cancer incidence; gender differences in tumour development in carriers; the effects of DNA damaging agents on individuals with a TP53 mutation; the frequency of TP53 germline mutations in cohorts of patients with rare childhood tumours (eg adrenocortical carcinoma); and the psychosocial aspects of predictive TP53 testing. In addition, if, as seems likely from recent data, X irradiation in these individuals induces DNA damage that is tolerated, urgent collaborative studies are needed to investigate new methods of screening, such as magnetic resonance imaging. Treatment modalities should be carefully chosen, and for this reason alone, predictive testing may be desirable in all LFS and LFL families. Individuals carrying TP53 mutations could be offered chemoprevention within trials in an effort to reduce their mortality from cancer.
Tissue-Engineered Lung: An In Vivo and In Vitro Comparison of Polyglycolic Acid and Pluronic F-127 Hydrogel/Somatic Lung Progenitor Cell Constructs to Support Tissue Growth (2006)

In this study, we describe the isolation and characterization of a population of adult-derived or somatic lung progenitor cells (SLPC) from adult mammalian lung tissue and the promotion of alveolar tissue growth by these cells (both in vitro and in vivo) after seeding onto synthetic polymer scaffolds. After extended in vitro culture, differentiating cells expressed Clara cell 10kDa protein, surfactant protein-C, and cytokeratin but did not form organized structures. When cells were combined with synthetic scaffolds, polyglycolic acid (PGA) or Pluronic F-127 (PF-127), and maintained in vitro or implanted in vivo, they expressed lung-specific markers for Clara cells, pneumocytes, and respiratory epithelium and organized into identifiable pulmonary structures (including those similar to alveoli and terminal bronchi), with evidence of smooth muscle development. Although PGA has been shown to be an excellent polymer for culture of specific cell types in vitro, in vivo culture in an immunocompetent host induced a foreign body response that altered the integrity of the developing lung tissue. Use of PF-127/cell constructs resulted in the development of tissue with less inflammatory reaction. These data suggest that the therapeutic use of engineered tissues requires both the use of specific cell phenotypes, as well as the careful selection of synthetic polymers, to facilitate the assembly of functional tissue.
The Dietary Pigment Curcumin Reduces Endothelial Tissue Factor Gene Expression by Inhibiting Binding of AP-1 to the DNA and Activation of NF-κB (1997)

The natural occurring pigment curcumin, a major component of the spice tumeric, has been described to have antioxidative, anti-tumorpromoting, anti-thrombotic and anti-inflammatory properties. It appears, that the pleiotropic effects of curcumin are at least partly due to inhibition of the transcription factors NF-kappa B and AP-1. This study investigates the effect of curcumin on the TNF alpha induced expression of endothelial Tissue Factor (TF), the central mediator of coagulation known to be controlled by AP-1 and NF-kappa B. When bovine aortic endothelial cells (BAEC) were preincubated in the presence of curcumin, TNF alpha induced TF gene transcription and expression were reduced. Transient transfection studies with TF-promoter plasmids revealed that both, NF-kappa B and AP-1 dependent TF expression, were reduced by curcumin action. The observed inhibitions were due to distinct mechanisms. Curcumin inhibited TNF alpha induced I kappa B alpha degradation and the nuclear import of NF-kappa B. In contrast, inhibition of AP-1 was due to a direct interaction of curcumin with AP-1-binding to its DNA binding motif. Thus, curcumin inhibits NF-kappa B and AP-1 by two different mechanisms and reduces expression of endothelial genes controlled by both transcription factors in vitro.
The Interleukin-1α Precursor is Biologically Active and is Likely a Key Alarmin in the IL-1 Family of Cytokines (2013)

Among the 11 members of the IL-1 family cytokines, the precursors of IL-1α, IL-1β, and IL-33 have relatively long N-terminal pro-sequences of approximately 100 amino acid residues prior to the N-terminus of the mature forms. Compared to the mature forms secreted from the cell, 80-90% of the primary translation product is in the intracellular compartment in the precursor form. However, the precursors are readily released from cells during infections but also with non-infectious conditions such a hypoxia and trauma. In this setting, the precursors act rapidly as "alarmins" in the absence of a processing mechanism to remove the pro-sequence and generate a mature form. In the case of IL-1α, the release of the precursor activates adjacent cells via receptor-mediated signaling. However, there are no data comparing the specific activity of the IL-1α precursor to the mature form. In the present study, we compared the precursor and mature forms of recombinant human IL-1α, IL-1β, and IL-33 proteins on the induction of cytokines from A549 cells as well as from human peripheral blood mononuclear cells (PBMC). Similar to the mature form, the IL-1α precursor was active in inducing IL-6 and TNFα, whereas the precursor forms of IL-1β and IL-33 were not active. On PBMC, precursor and mature IL-1α at 0.04 and 0.2 nM were equally active in inducing IL-6. Given the fact that during necrotic cell death, the IL-1α precursor is released intact and triggers IL-1 receptors on tissue macrophages, these data identify the precursor form of IL-1α as a key player in sterile inflammation.