gebhart/patrepeval huggingface dataset:
Molecular Mechanisms of Lipotoxicity in Nonalcoholic Fatty Liver Disease (2008)

Nonalcoholic fatty liver disease (NAFLD) is characterized by insulin resistance, which results in elevated serum concentration of free fatty acids (FFAs). Circulating FFAs provide the substrate for triacylglycerol formation in the liver, and may also be directly cytotoxic. Hepatocyte apoptosis is a key histologic feature of NAFLD, and correlates with progressive inflammation and fibrosis. The molecular pathways leading to hepatocyte apoptosis are not fully defined; however, recent studies suggest that FFA-induced apoptosis contributes to the pathogenesis of nonalcoholic steatohepatitis. FFAs directly engage the core apoptotic machinery by activating the proapoptotic protein Bax, in a c-jun N-terminal kinase-dependent manner. FFAs also activate the lysosomal pathway of cell death and regulate death receptor gene expression. The role of ER stress and oxidative stress in the pathogenesis of nonalcoholic steatohepatitis has also been described. Understanding the molecular mediators of liver injury should promote development of mechanism-based therapeutic interventions.
Inversion of 310‐helix screw sense in a (D‐αMe)Leu homotetrapeptide induced by a guest D‐(αMe)val residue (1995)

The terminally blocked tetrapeptide pBrBz-[D-(alpha Me)Leu]2-D-(alpha Me)Val-D-(alpha Me)Leu-OfBu is folded in the crystal state in a left-handed 3(10)-helical structure stabilized by two consecutive 1<--4 C = O...H-N intramolecular H-bonds, as determined by X-ray diffraction analysis. A CD study strongly supports the view that this conformation is also that largely prevailing in MeOH solution. A comparison with the published conformation of pBrBz-[D-(alpha Me)Leu]4-OfBu indicates that incorporation of a single internal beta-branched (alpha Me)Val guest residue into the host homo-tetrapeptide from the gamma-branched (alpha Me)Leu residue is responsible for a dramatic structural perturbation, i.e. an inversion of the 3(10) screw sense from right to left-handed.
Structural Basis of Inducible Costimulator Ligand Costimulatory Function: Determination of the Cell Surface Oligomeric State and Functional Mapping of the Receptor Binding Site of the Protein (2006)

Inducible costimulator (ICOS) ligand (ICOSL), a B7-related transmembrane glycoprotein with extracellular IgV and IgC domains, binds to ICOS on activated T cells and delivers a positive costimulatory signal for optimal T cell function. Toward determining the structural features of ICOSL crucial for its costimulatory function, the present study shows that ICOSL displays a marked oligomerization potential, resembling more like B7-1 than B7-2. Use of ICOSL constructs lacking either the IgC or IgV domain demonstrates that receptor binding is mediated solely by the IgV domain but requires the IgC domain for maintaining the structural integrity of the protein. To map further the receptor recognition surface on ICOSL, a homology-based protein structure model of the ICOS:ICOSL complex was constructed. Based on predictions from the model, a series of mutations were generated targeting the potential receptor binding surface on ICOSL, and the mutants were tested for their biological function in terms of ICOS binding and T cell costimulation ability. The results provide experimental validation of the model and show that the receptor binding site on ICOSL is constituted chiefly by aromatic/hydrophobic residues. Critical ICOSL residues essential for ICOS binding map to the GFCC'C'' beta-sheet face of the IgV domain and approximately overlap with the B7-1/B7-2 motif(s) that recognize CD28/CTLA-4. Altogether, similar structural features of ICOSL and B7 isoforms suggest a close evolutionary relationship between these costimulatory ligands, yet differences at the same time explain their unique specificity for the cognate binding partners, ICOS and CD28/CTLA-4, respectively.
A design strategy for small molecule-based targeted MRI contrast agents: their application for detection of atherosclerotic plaques (2014)

Gadolinium(III) ion (Gd(3+)) complexes are widely used as contrast agents in magnetic resonance imaging (MRI), and many attempts have been made to couple them to sensor moieties in order to visualize biological phenomena of interest inside the body. However, the low sensitivity of MRI has made it difficult to develop practical MRI contrast agents for in vivo imaging. We hypothesized that practical MRI contrast agents could be designed by targeting a specific biological environment, rather than a specific protein such as a receptor. To test this idea, we designed and synthesized a Gd(3+)-based MRI contrast agent, 2BDP3Gd, for visualizing atherosclerotic plaques by linking the Gd(3+)-complex to the lipophilic fluorophore BODIPY to stain lipid-rich environments. We found that 2BDP3Gd was selectively accumulated into lipid droplets of adipocytes at the cellular level. Atherosclerotic plaques in the aorta of Watanabe heritable hyperlipidemic (WHHL) rabbits were clearly visualized in T1-weighted MR images after intravenous injection of 2BDP3Gd in vivo.
Two Distinct Mechanisms of Augmented Antitumor Activity by Modulation of Immunostimulatory/Inhibitory Signals (2010)

This study shows that combined treatment with different immune modulators can augment antitumor immune responses and provides justification for exploring anti-CTLA-4/anti-GITR mAb combination treatment in the clinic.
Angiogenesis as a component of epithelial-mesenchymal interactions (1995)

Here we review the role of angiogenesis as it pertains to the interactions between the epithelium and the mesenchyme, especially during tumor growth and metastasis. We illustrate and discuss several models of angiogenesis including endothelial tube formation on Matrigel. Finally, we examine angiogenic factors using the Matrigel model and investigate several other matrix molecules for their importance in angiogenesis and epithelial/stromal interactions.
Targeted Expression of Bcl-2 in Mouse Oocytes Inhibits Ovarian Follicle Atresia and Prevents Spontaneous and Chemotherapy-Induced Oocyte Apoptosis In Vitro (1999)

Members of the Bcl-2 family serve as central checkpoints for cell death regulation, and overexpression of Bcl-2 is known to inhibit apoptosis in many cell types. To determine whether targeted expression of Bcl-2 could be used to protect female germ cells from apoptosis, we generated transgenic mice expressing fully functional human Bcl-2 protein only in oocytes. Transgenic mice were produced using a previously characterized 480-bp fragment of the mouse zona pellucida protein-3 (ZP3) gene 5'-flanking region to direct oocyte-specific expression of a human bcl-2 complementary DNA. Immunohistochemical analyses using a human Bcl-2-specific antibody showed that transgene expression was restricted to growing oocytes and was not observed in the surrounding ovarian somatic cells or in any other nonovarian tissues. Histomorphometric analyses revealed that ovaries collected from transgenic female mice possessed significantly fewer atretic small preantral follicles compared with wild-type sisters, resulting in a larger population of healthy maturing follicles per ovary. However, the number of oocytes ovulated in response to exogenous gonadotropin priming and the number of pups per litter were not significantly different among wild-type vs. transgenic female mice. Nonetheless, oocytes obtained from transgenic mice and cultured in vitro were found to be resistant to spontaneous and anticancer drug-induced apoptosis. We conclude that targeted expression of Bcl-2 only in oocytes can be achieved as a means to convey resistance of the female germ line to naturally occurring and chemotherapy-induced apoptosis.
RDE-2 interacts with MUT-7 to mediate RNA interference in Caenorhabditis elegans (2005)

In Caenorhabditis elegans, the activity of transposable elements is repressed in the germline. One of the mechanisms involved in this repression is RNA interference (RNAi), a process in which dsRNA targets cleavage of mRNAs in a sequence-specific manner. The first gene found to be involved in RNAi and transposon silencing in C.elegans is mut-7, a gene encoding a putative exoribonuclease. Here, we show that the MUT-7 protein resides in complexes of approximately 250 kDa in the nucleus and in the cytosol. In addition, we find that upon triggering of RNAi the cytosolic MUT-7 complex increases in size. This increase is independent of the presence of target RNA, but does depend on the presence of RDE-1 and RDE-4, two proteins involved in small interfering RNA (siRNA) production. Finally, using a yeast two-hybrid screen, we identified RDE-2/MUT-8 as one of the other components of this complex. This protein is encoded by the rde-2/mut-8 locus, previously implicated in RNAi and transposon silencing. Using genetic complementation analysis, we show that the interaction between these two proteins is required for efficient RNAi in vivo. Together these data support a role for the MUT-7/RDE-2 complex downstream of siRNA formation, but upstream of siRNA mediated target RNA recognition, possibly indicating a role in the siRNA amplification step.
Gradient-index fiber-optic microprobes for minimally invasive in vivo low-coherence interferometry (2002)

We describe the design, construction, and application of what are believed to be the smallest fiber-optic probes used to date during imaging or diagnosis involving low-coherence interferometry (LCI). The probes use novel fiber-optic gradient-index (GRIN) lenses fabricated by a recently developed modified chemical-vapor-deposition (MCVD) process that avoids on-axis aberrations commonly marring MCVD-fabricated GRIN substrate. Fusing GRIN fiber lenses onto single-mode fiber yields automatically aligned all-fiber probes that insert into tissue through hypodermic needles as small as 31-gauge (inner diameter, 127 mum). We demonstrate the use of such probes with LCI by measuring microscopic brain motions in vivo.
Encrypted key exchange: password-based protocols secure against dictionary attacks (2003)

Classic cryptographic protocols based on user-chosen keys allow an attacker to mount password-guessing attacks. A combination of asymmetric (public-key) and symmetric (secret-key) cryptography that allow two parties sharing a common password to exchange confidential and authenticated information over an insecure network is introduced. In particular, a protocol relying on the counter-intuitive motion of using a secret key to encrypt a public key is presented. Such protocols are secure against active attacks, and have the property that the password is protected against offline dictionary attacks.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Selective Hydrolysis of Cellulose and Polysaccharides into Sugars by Catalytic Hydrothermal Method Using Sulfonated Activated-carbon (2012)

Mildly hydrothermal reaction using solid acid catalysts for cellulose hydrolysis into glucose has potential abilities to be one of the key technologies for a future sustainable society using cellulose biomass. Among the solid acid catalysts tested, such as H-form zeolite catalysts and sulfated and sulfonated catalysts, sulfonated activated-carbon (AC–SO3H) catalyst showed remarkably high yield of glucose in the hydrolysis of cellulose with β-1,4-glycosidic bonds under hydrothermal conditions at temperatures around 423 K. The AC–SO3H catalyst with hydrothermal pre-treatment had excellent catalytic properties attributed to the high hydrothermal stability and the strong acid sites of the sulfo functional groups and the activated carbon surfaces for polysaccharide adsorption. A bifunctional sulfonated activated-carbon supported platinum (Pt/AC–SO3H) was prepared by impregnation of platinum on activated carbon (AC) and sulfonation of the prepared Pt/AC. Gluconic acid was produced from polysaccharides, such as starch and cellobiose, in water at 393 K under air by a one-pot process using the Pt/AC–SO3H catalyst.
A 3D Sphere Culture System Containing Functional Polymers for Large-Scale Human Pluripotent Stem Cell Production (2014)

Utilizing human pluripotent stem cells (hPSCs) in cell-based therapy and drug discovery requires large-scale cell production. However, scaling up conventional adherent cultures presents challenges of maintaining a uniform high quality at low cost. In this regard, suspension cultures are a viable alternative, because they are scalable and do not require adhesion surfaces. 3D culture systems such as bioreactors can be exploited for large-scale production. However, the limitations of current suspension culture methods include spontaneous fusion between cell aggregates and suboptimal passaging methods by dissociation and reaggregation. 3D culture systems that dynamically stir carrier beads or cell aggregates should be refined to reduce shearing forces that damage hPSCs. Here, we report a simple 3D sphere culture system that incorporates mechanical passaging and functional polymers. This setup resolves major problems associated with suspension culture methods and dynamic stirring systems and may be optimal for applications involving large-scale hPSC production.
The biology of breast carcinoma (2003)

The biology of breast carcinoma is complex, with multiple factors contributing to its development and progression. The current review focuses on the role of several critical genes including estrogen receptor, progesterone receptor, retinoic acid receptor-beta, epidermal growth factor receptor family members, p53, BRCA1, and BRCA2 as risk factors for the development of disease, predictors of prognosis and response to therapy, and as therapeutic targets. Studies of the biology of these and other genes that contribute to the development and progression of breast carcinoma have had and will continue to have great impact on all aspects of disease management.
On Convergence of Cognitive and Non-cognitive Behavior in Collaborative Activity. (2015)

We present results from a pilot study to investigate the evidence for convergence and synchrony in cognitive and noncognitive behavior of dyads engaged in a collaborative activity. Our approach utilizes multimodal data including video and participant action log files retrieved from the collaborative activity, an online educational simulation on science topics. The log files captured cognitive behavior including frequency and content of chat messages between dyads, as well system help requests. The video data recorded participant nonverbal behavior that was processed on a frame-by-frame basis using automated facial expression classifiers and coded by trained human raters on high-level noncognitive behaviors including: affect display gestures, engagement, anxiety and curiosity. The data were analyzed at individual and dyad levels and results using hierarchical clustering analysis demonstrate evidence of cognitive and noncognitive behavioral convergence among dyads.
Role of threading dislocation structure on the x-ray diffraction peak widths in epitaxial GaN films (1996)

In this letter we demonstrate that the anomalously low (002) x-ray rocking curve widths for epitaxial hexagonal GaN films on (001) sapphire are a result of a specific threading dislocation (TD) geometry. Epitaxial GaN films were grown on c-plane sapphire by atmospheric pressure metalorganic chemical vapor deposition (MOCVD) in a horizontal flow reactor. Films were grown with (002) rocking curves (ω-scans) widths as low as 40 arcsec and threading dislocation densities of ∼2×1010 cm−2. The threading dislocations in this film lie parallel to the [001] direction and within the limit of imaging statistics, all are pure edge with Burgers vectors parallel to the film/substrate interface. These TDs will not distort the (002) planes. However, distortion of asymmetric planes, such as (102), is predicted and confirmed in (102) rocking curve widths of 740 arcsec. These results are compared with films with (002) rocking curves of ∼270 arcsec and threading dislocation densities of ∼7×108 cm−2.
Effect of long‐term belimumab treatment on b cells in systemic lupus erythematosus: Extension of a phase II, double‐blind, placebo‐controlled, dose‐ranging study (2009)

Our data confirm the dependence of newly formed B cells on BLyS for survival in humans. In contrast, memory B cells and plasma cells are less susceptible to selective BLyS inhibition.
Apolipoprotein E Isoform-Specific Differences in Outcome from Focal Ischemia in Transgenic Mice (1998)

Apolipoprotein E (apoE), a 34-KD glycosylated lipid-binding protein, is expressed as three common isoforms in humans (E2, E3, or E4). Clinical evidence suggests that the apoE genotype (APOE) may be a risk factor for poor outcome after acute central nervous system injury. This was examined further in transgenic mice constructed with the human APOE3 or APOE4 gene under the control of human promoter and tissue expression elements. Presence of human apoE3 and apoE4 proteins in brains of human APOE homozygous transgenic mice was confirmed by Western blotting. APOE3 (n = 12) and APOE4 (n = 10) mice underwent 60 minutes of middle cerebral artery occlusion. After 24-hour recovery, infarct size was measured. Infarct volumes (mean +/- standard deviation) were smaller in the APOE3 group (cortex: APOE3 = 18 +/- 4 mm3; APOE4 = 30 +/- 11 mm3, P = 0.04; subcortex: APOE3 = 12 +/- 4 mm3; APOE4 = 18 +/- 4 mm3, P = 0.003). Hemiparesis was less severe in APOE3 mice (P = 0.02). These data indicate that human isoform-specific effects of apoE are relevant to acute pathomechanisms of focal ischemic brain damage when examined in the mouse. APOE transgenic mice may provide an appropriate model to examine the mechanistic basis for the differential effects of human apoE isoforms in acute central nervous system injury.
Developing privacy guidelines for social location disclosure applications and services (2005)

In this article, we describe the design process of Reno, a location-enhanced, mobile coordination tool and person finder. The design process included three field experiments: a formative Experience Sampling Method (ESM) study, a pilot deployment and an extended user study. These studies were targeted at the significant personal security, privacy and data protection concerns caused by this application. We distil this experience into a small set of guidelines for designers of social mobile applications and show how these guidelines can be applied to a different application, called Boise. These guidelines cover issues pertaining to personal boundary definition, control, deception and denial, and group vs. individual communication. We also report on lessons learned from our evaluation experience, which might help practitioners in designing novel mobile applications, including the choice and characterization of users for testing security and privacy features of designs, the length of learning curves and their effect on evaluation and the impact of peculiar deployment circumstances on the results of these finely tuned user studies.
A Novel Chromosomal Translocation t(4; 14)(p16.3; q32) in Multiple Myeloma Involves the Fibroblast Growth-Factor Receptor 3 Gene (1997)

Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus at chromosome 14q32 represent a common mechanism of oncogene activation in lymphoid malignancies. In multiple myeloma (MM), the most consistent chromosomal abnormality is the 14q+ marker, which originates in one third of cases through a t(11; 14)(q13; q32) chromosomal translocation; in the remaining cases, the identity of the partner chromosomes has not been well established. We used a Southern blot approach based on the linkage analysis of the joining (J) and the constant (C) mu, alpha, and gamma regions to detect cases bearing IGH switch-mediated chromosomal translocations. We evaluated DNA of 88 nonkaryotyped patients with MM (78 cases) or plasma cell leukemia (PCL) (10 cases) and found the presence of "illegitimate" rearranged IGH fragments (no comigration between the J and C regions) in 21 cases. To confirm this analysis, we cloned the illegitimate rearranged fragments from three samples, and the molecular and fluorescent in situ hybridization (FISH) analyses indicated the presence of chromosomal translocations juxtaposing a switch IGH region to sequences from chromosomes 11q13 (one PCL case) or 4p16.3 (two MM cases). Interestingly, the breakpoints on 4p16.3 occurred about 14 kb apart in a genomic region located approximately 50 kb centromeric to the fibroblast growth-factor receptor 3 (FGFR3) gene. Moreover, Southern blot analysis using 4p16.3 genomic probes detected a rearrangement in an additional MM tumor. FISH analysis of the MM-derived KMS-11 cell line, reported to be associated with a t(4; 14)(p16.3; q32), showed that the FGFR3 gene was translocated on 14q32. High levels of FGFR3 mRNA expression were observed in the cloned MM tumors and KMS-11 cell line, but not in the cases that were apparently negative for this lesion. Furthermore, a point mutation at codon 373 in the transmembrane domain of the FGFR3 gene resulting in an amino acid substitution (Tyr --> Cys) was detected in the KMS-11 cell line. These findings indicate that the t(4; 14)(p16.3; q32) represents a novel, recurrent chromosomal translocation in MM, and suggest that the FGFR3 gene may be the target of this abnormality and thus contribute to tumorigenesis in MM.
Covalent Modification of Cyclooxygenase-2 (COX-2) by 2-Acetoxyphenyl Alkyl Sulfides, a New Class of Selective COX-2 Inactivators (1998)

All of the selective COX-2 inhibitors described to date inhibit the isoform by binding tightly but noncovalently at the substrate binding site. Recently, we reported the first account of selective covalent modification of COX-2 by a novel inactivator, 2-acetoxyphenyl hept-2-ynyl sulfide (70) (Science 1998, 280, 1268-1270). Compound 70 selectively inactivates COX-2 by acetylating the same serine residue that aspirin acetylates. This paper describes the extensive structure-activity relationship (SAR) studies on the initial lead compound 2-acetoxyphenyl methyl sulfide (36) that led to the discovery of 70. Extension of the S-alkyl chain in 36 with higher alkyl homologues led to significant increases in inhibitory potency. The heptyl chain in 2-acetoxyphenyl heptyl sulfide (46) was optimum for COX-2 inhibitory potency, and introduction of a triple bond in the heptyl chain (compound 70) led to further increments in potency and selectivity. The alkynyl analogues were more potent and selective COX-2 inhibitors than the corresponding alkyl homologues. Sulfides were more potent and selective COX-2 inhibitors than the corresponding sulfoxides or sulfones or other heteroatom-containing compounds. In addition to inhibiting purified COX-2, 36, 46, and 70 also inhibited COX-2 activity in murine macrophages. Analogue 36 which displayed moderate potency and selectivity against purified human COX-2 was a potent inhibitor of COX-2 activity in the mouse macrophages. Tryptic digestion and peptide mapping of COX-2 reacted with [1-14C-acetyl]-36 indicated that selective COX-2 inhibition by 36 also resulted in the acetylation of Ser516. That COX-2 inhibition by aspirin resulted from the acetylation of Ser516 was confirmed by tryptic digestion and peptide mapping of COX-2 labeled with [1-14C-acetyl]salicyclic acid. The efficacy of the sulfides in inhibiting COX-2 activity in inflammatory cells, our recent results on the selectivity of 70 in attenuating growth of COX-2-expressing colon cancer cells, and its selectivity for inhibition of COX-2 over COX-1 in vivo indicate that this novel class of covalent modifiers may serve as potential therapeutic agents in inflammatory and proliferative disorders.