gebhart/patrepeval huggingface dataset:
RAP-011 Efficiently Rescues Erythropoiesis In Zebrafish Models Of Diamond Blackfan Anemia (2013)

Abstract Diamond Blackfan Anemia (DBA) is a bone marrow failure disorder characterized by low red blood cell count but normal levels of platelets and white blood cells. Ribosomal mutations in RPS19, RPS26, RPL5, and RPL11 have been identified in approximately 50% of all DBA cases. Corticosteriod therapy and bone marrow transplantion are the most common treatment options for DBA patients. However, corticosteroids have severe side effects and bone marrow transplantation is risky; thus, novel therapeutics for DBA are needed. Sotatercept (ACE-011), an activin receptor IIA ligand trap which rapidly increased hemoglobin and hematocrit in both pharmacologic models and in healthy volunteers, is currently being evaluated in diseases of ineffective erythropoiesis such as ß-thalassemia and MDS. Non-clinical studies in mice have demonstrated that RAP-011, a murine ortholog of sotatercept, stimulates RBC parameters in mice through stimulating expansion of late-stage erythroblasts through a mechanism distinct from EPO. Here, we evaluated the effect of RAP-011 in zebrafish models of ribosome insufficiency in RPS19 and RPL11 that recapitulate the anemic phenotype seen in DBA patients. Treatment with RAP-011 treatment dramatically restored hemoglobin levels compromised by ribosome stress. Furthermore, the beneficial effect of RAP-011 is synergistic with corticosteriod treatment. In zebrafish embryos, RAP-011 likely stimulates erythropoietic activity by altering the microenvironment of erythroid cells, reducing p21 levels through a p53-independent manner. These findings uncover a novel signaling pathway in the pathogenesis of DBA and support the potential use of Sotatercept for the treatment of DBA patients with ribosomal disorders. Our studies also demonstrate, for the first time, that protein drugs can be effectively evaluated in zebrafish human disease models, which offer a unique opportunity to identify the targets and study their mechanisms of action. Disclosures: Sung: Celgene Corp.: Employment. Daniel:Celgene: Employment. Chopra:Celgene: Employment, Equity Ownership. Lin:Celgene: Research Funding.
AN ENZYME-LINKED IMMUNOSORBENT ASSAY FOR CORTISOL IN THE SALIVA OF MAN AND DOMESTIC FARM ANIMALS (1989)

An enzyme-linked immunosorbent assay has been developed for the direct assay of cortisol in the saliva of man, sheep, calf and pig. The assay is sensitive (integral of 1pg), highly specific and reproducible, and has the advantage over radioimmunoassay in being cheaper and quicker to carry out. The relatively-non invasive method of collecting saliva on cotton buds coupled with simple assay equipment provide a good potential for assessing cortisol status in studies on stress and welfare in farm animals as well as the possibility of monitoring cortisol status in mammals generally.
Approaching Real-Time Molecular Diagnostics:  Single-Pair Fluorescence Resonance Energy Transfer (spFRET) Detection for the Analysis of Low Abundant Point Mutations in K-ras Oncogenes (2003)

The aim of this study was to develop new strategies for analyzing molecular signatures of disease states approaching real-time using single pair fluorescence resonance energy transfer (spFRET) to rapidly detect point mutations in unamplified genomic DNA. In addition, the detection process was required to discriminate between normal and mutant (minority) DNAs in heterogeneous populations. The discrimination was carried out using allele-specific primers, which flanked the point mutation in the target gene and were ligated using a thermostable ligase enzyme only when the genomic DNA carried this mutation. The allele-specific primers also carried complementary stem structures with end-labels (donor/acceptor fluorescent dyes, Cy5/Cy5.5, respectively), which formed a molecular beacon following ligation. We coupled ligase detection reaction (LDR) with spFRET to identify a single base mutation in codon 12 of a K-ras oncogene that has high diagnostic value for colorectal cancers. A simple diode laser-based fluorescence system capable of interrogating single fluorescent molecules undergoing FRET was used to detect photon bursts generated from the molecular beacon probes formed upon ligation. LDR-spFRET provided the necessary specificity and sensitivity to detect single-point mutations in as little as 600 copies of human genomic DNA directly without PCR at a level of 1 mutant per 1000 wild type sequences using 20 LDR thermal cycles. We also demonstrate the ability to rapidly discriminate single base differences in the K-ras gene in less than 5 min at a frequency of 1 mutant DNA per 10 normals using only a single LDR thermal cycle of genomic DNA (600 copies). Real-time LDR-spFRET detection of point mutations in the K-ras gene was accomplished in PMMA microfluidic devices using sheath flows.
Hydrogen desorption kinetics from monohydride and dihydride species on silicon surfaces (1988)

Hydrogen desorption kinetics from monohydride and dihydride species on crystalline-silicon surfaces were measured using transmission Fourier-transform infrared (FTIR) spectroscopy. The FTIR desorption measurements were performed in situ in an ultrahigh-vacuum chamber using high-surface-area porous-silicon samples. The kinetics for hydrogen desorption from the monohydride and dihydride species was monitored using the SiH stretch mode at 2102 ${\mathrm{cm}}^{\mathrm{\ensuremath{-}}1}$ and the ${\mathrm{SiH}}_{2}$ scissors mode at 910 ${\mathrm{cm}}^{\mathrm{\ensuremath{-}}1}$, respectively. Annealing studies revealed that hydrogen from the ${\mathrm{SiH}}_{2}$ species desorbed between 640 and 700 K, whereas hydrogen from the SiH species desorbed between 720 and 800 K. Isothermal studies revealed second-order hydrogen desorption kinetics for both the monohydride and dihydride surface species. Desorption activation barriers of 65 kcal/mol (2.82 eV) and 43 kcal/mol (1.86 eV) were measured for the monohydride and dihydride species, respectively. These desorption activation barriers yield upper limits of 84.6 kcal/mol (3.67 eV) and 73.6 kcal/mol (3.19 eV) for the Si-H chemical bond energies of the SiH and ${\mathrm{SiH}}_{2}$ surface species.
Designing Biomaterials to Direct Biological Responses (1999)

We have set forth a design strategy for creating biomimetic materials that direct the formation of tissue surrounding implants or regeneration within porous scaffolds. Our studies have established that heterogeneous mimetic peptide surfaces (MPS) containing both the -RGD- (cell-binding) and-FHRRIKA- (putative heparin-binding) peptides, unique to BSP, in the ratio of 75:25 (MPS II) or 50:50 (MPS III) proved to be more biologically relevant and specific for RCO cell function. The initial response of human osteoblast-like cells to these surfaces was mediated by the collagen (alpha 2 beta 1) and vitronectin receptors (alpha v beta 3), whereas the vitronectin receptor alone dominated longer-term events (> 30 min). MPS II and III surfaces enhanced cell spreading and long-term events such as mineralization of the extracellular matrix compared to homogenous peptide surfaces and controls. Furthermore, extensive mineralization of the ECM deposited by RCOs occurred when the peptide was coupled to an interfacial interpenetrating polymer network (IPN) that resisted protein deposition (i.e., non-specific adsorption) and fouling. Work on thermo-reversible P(NIPAAm-co-AAc) hydrogels demonstrated the ability to create materials that can be delivered to the body in a minimally invasive manner and support tissue regeneration. These hydrogels can be modified to incorporate biofunctional components such as the biomimetic peptides, theoretically enhancing their ability to foster tissue regeneration. These results suggest that biomaterials can be engineered to mimic ECM components of bone (e.g., various organs) by grafting peptides in the appropriate ratios of the cell and heparin-binding domains, and ultimately modulate the expression of the osteoblast cell phenotype. Approaches similar to the one presented in this work can be used to design materials for hybrid artificial organs and other tissues.
Induction of Calcium Influx through TRPC5 Channels by Cross-Linking of GM1 Ganglioside Associated with α5β1 Integrin Initiates Neurite Outgrowth (2007)

Previous studies demonstrated that cross-linking of GM1 ganglioside with multivalent ligands, such as B subunit of cholera toxin (CtxB), induced Ca2+ influx through an unidentified, voltage-independent channel in several cell types. Application of CtxB to undifferentiated NG108-15 cells resulted in outgrowth of axon-like neurites in a Ca2+ influx-dependent manner. In this study, we demonstrate that CtxB-induced Ca2+ influx is mediated by TRPC5 channels, naturally expressed in these cells and primary neurons. Both Ca2+ influx and neurite induction were blocked by TRPC5 small interfering RNA (siRNA). Pretreatment of NG108-15 cells with neuraminidase increased cell-surface GM1 and greatly enhanced the signal. GM1 was not directly associated with TRPC5 but rather with alpha5beta1 integrin, which opened the channel through a signaling sequence after cross-linking of the GM1/integrin complex. This cascade included autophosphorylation of focal adhesion kinase and subsequent activation of phospholipase Cgamma (PLCgamma) and phosphoinositide-3 kinase [PI(3)K]. Pharmacological blockers that inhibited tyrosine kinase, PLC, and PI(3)K suppressed both CtxB-induced Ca2+ influx and neurite outgrowth. These were also suppressed by SK&F96365, a nonspecific transient receptor potential channel blocker. Confocal immunocytochemistry revealed that GM1 cross-linking induced colocalization of GM1 with these signaling elements in sprouting regions of plasma membrane. In primary cerebellar granular neurons (CGNs), TRPC5 was detected at 2 d in vitro (2 DIV), a stage corresponding to CtxB-stimulated Ca2+ influx. Neurite outgrowth in CGNs, determined at 3 DIV, was accelerated by CtxB and suppressed by TRPC5 siRNA and the above blockers. The crucial role of GM1 was indicated with CGNs from ganglio-series null mice, in which growth of axons was significantly retarded.
Achievable Rates of FDD Massive MIMO Systems With Spatial Channel Correlation (2015)

It is well known that the performance of frequency-division-duplex (FDD) massive MIMO systems with i.i.d. channels is disappointing compared with that of time-division-duplex (TDD) systems, due to the prohibitively large overhead for acquiring channel state information at the transmitter (CSIT). In this paper, we investigate the achievable rates of FDD massive MIMO systems with spatially correlated channels, considering the CSIT acquisition dimensionality loss, the imperfection of CSIT and the regularized-zero-forcing linear precoder. The achievable rates are optimized by judiciously designing the downlink channel training sequences and user CSIT feedback codebooks, exploiting the multiuser spatial channel correlation. We compare our achievable rates with TDD massive MIMO systems, i.i.d. FDD systems, and the joint spatial division and multiplexing (JSDM) scheme, by deriving the deterministic equivalents of the achievable rates, based on the one-ring model and the Laplacian model. It is shown that, based on the proposed eigenspace channel estimation schemes, the rate-gap between FDD systems and TDD systems is significantly narrowed, even approached under moderate number of base station antennas. Compared to the JSDM scheme, our proposal achieves dimensionality-reduction channel estimation without channel pre-projection, and higher throughput for moderate number of antennas and moderate to large channel coherence block length, though at higher computational complexity.
Rapid microRNA Profiling on Encoded Gel Microparticles (2011)

Sensitive, flexible, and rapid: A post-hybridization labeling scheme was combined with a high-throughput microfluidic scanning system to demonstrate the use of graphically encoded gel particles for rapid microRNA quantification (see picture). A versatile particle encoding scheme allows for scalable multiplexing that provides attomole sensitivity with a simple and efficient workflow.
Spatial variation in risk : a non-parametric binary regression approach. (1998)

A common problem in environmental epidemiology is the estimation and mapping of spatial variation in disease risk. In this paper we analyse data from the Walsall District Health Authority, UK, concerning the spatial distributions of cancer cases compared with controls sampled from the population register. We formulate the risk estimation problem as a nonparametric binary regression problem and consider two different methods of estimation. The first uses a standard kernel method with a cross-validation criterion for choosing the associated bandwidth parameter. The second uses the framework of the generalized additive model (GAM) which has the advantage that it can allow for additional explanatory variables, but is computationally more demanding. For the Walsall data, we obtain similar results using either the kernel method with controls stratified by age and sex to match the age–sex distribution of the cases or the GAM method with random controls but incorporating age and sex as additional explanatory variables. For cancers of the lung or stomach, the analysis shows highly statistically significant spatial variation in risk. For the less common cancers of the pancreas, the spatial variation in risk is not statistically significant.
Endogenous p53 Protects Vascular Smooth Muscle Cells From Apoptosis and Reduces Atherosclerosis in ApoE Knockout Mice (2005)

Recent studies have indicated that the tumor suppressor gene p53 limits atherosclerosis in animal models; p53 expression is also increased in advanced human plaques compared with normal vessels, where it may induce growth arrest and apoptosis. However, controversy exists as to the role of endogenous levels of p53 in different cell types that comprise plaques. We examined atherosclerotic plaque development and composition in brachiocephalic arteries and aortas of p53-/-/ApoE-/- mice versus wild type p53 controls. p53-/- mice demonstrated increased aortic plaque formation, with increased rates of cell proliferation and reduced rates of apoptosis in brachiocephalic arteries. Although most proliferating cells were monocyte/macrophages, apoptotic cells were both vascular smooth muscle cells (VSMCs) and macrophages. Transplant of p53 bone marrow to p53-/-/ApoE-/- mice reduced aortic plaque formation and cell proliferation in brachiocephalic plaques, but also markedly reduced apoptosis. To examine p53 regulation of these processes, we studied proliferation and apoptosis in macrophages, bone marrow stromal cells and VSMCs cultured from these mice. Although endogenous p53 promoted apoptosis in macrophages, it protected VSMCs and stromal cells from death, a hitherto unknown function in these cells, in part by inhibiting DNA damage response enzymes. p53 also inhibited stromal cell expression of VSMC markers. We conclude that endogenous levels of p53 protect VSMCs and stromal cells against apoptosis, while promoting apoptosis in macrophages, and protect against atherosclerosis development.
Relative expression of progesterone receptors A and B in premalignant and invasive breast lesions (2000)

While advances in science and technology have increased options for treating breast cancer, current social trends have changed the way people deal with this disease. Women in the United States are no longer simply passive patients, but rather they are survivors, advocates and activists who are speaking up for themselves and speaking out for issues relevant to the treatment and prevention of breast cancer.
Effect of excimer laser annealing on the structural and electrical properties of polycrystalline silicon thin-film transistors (1999)

The structural and electrical properties of excimer laser annealed polycrystalline silicon thin-film transistors (polysilicon TFTs) are investigated in relation to the laser energy density. The devices were fabricated on 50 nm thick polysilicon films prepared by excimer laser crystallization (ELA) of amorphous silicon or by a combined solid phase crystallization (SPC) and ELA process. The structural properties of the polysilicon films have been investigated by transmission electron microscopy analysis. The effective density of states distributions in the polysilicon films and in the oxide traps near the oxide/polysilicon interface have been determined from low frequency noise measurements. The TFT performance parameters are compared with respect to their correlation with the structural properties of the polysilicon films and their electrically active defects, the basic variables being the starting material (amorphous silicon or SPC polysilicon) and the laser energy density.
Microwave-Promoted Lipase-Catalyzed Reactions. Resolution of (±)-1-Phenylethanol (1996)

Microwave irradiation increased enzymatic affinity and selectivity of supported lipases in esterification and transesterification reactions carried out in dry media and at temperature near 100 degrees C.
Exploring Fine-Grained Heterogeneity with Composite Cores (2015)

Heterogeneous multicore systems- comprising multiple cores with varying performance and energy characteristics-have emerged as a promising approach to increasing energy efficiency. Such systems reduce energy consumption by identifying application phases and migrating execution to the most efficient core that meets performance requirements. However, the overheads of migrating between cores limit opportunities to coarse-grained phases (hundreds of millions of instructions), reducing the potential to exploit energy efficient cores. We propose Composite Cores, an architecture that reduces migration overheads by bringing heterogeneity into a core. Composite Cores pairs a big and little compute μEngine that together achieve high performance and energy efficiency. By sharing architectural state between the μEngines, the migration overhead is reduced, enabling fine-grained migration and increasing the opportunities to utilize the little μEngine without sacrificing performance. An intelligent controller migrates the application between μEngines to maximize energy efficiency while constraining performance loss to a configurable bound. We evaluate Composite Cores using cycle accurate microarchitectural simulations and a detailed power model. Results show that, on average, Composite Cores are able to map 30 percent of the execution time to the little μEngine, achieving a 21 percent energy savings while maintaining 95 percent performance.
Quantitative evaluation of liver-specific promoters from retroviral vectors after in vivo transduction of hepatocytes (1994)

Hepatic gene therapy could be used to treat a number of inherited blood diseases such as hemophilia or thrombophilia. Although liver-directed retroviral transduction can result in long-term gene expression in vivo, the low level of protein production has limited its clinical application. We reasoned that the insertion of liver-specific promoters into retroviral vectors would increase gene expression in vivo. The 347-bp human alpha 1-antitrypsin (hAAT), the 810-bp murine albumin (mAIb), the 490-bp rat phosphoenolpyruvate carboxykinase (rPECK), and the 596-bp rat liver fatty acid binding protein promoters were inserted into a Moloney murine leukemia retroviral backbone containing the hAAT reporter gene. Vectors that produced appropriately sized RNA and hAAT protein in vitro were tested in vivo by transducing regenerating rat livers. Long-term serum expression of the hAAT reporter gene was normalized to retroviral transduction efficiency as determined by using a polymerase chain reaction-based assay of genomic DNA from transduced rat livers. The hAAT, mAIb, and rPEPCK promoters were, respectively, 35-, 8-, and 0.02-fold as strong as the previously studied constitutive Pol-II promoter. We conclude that the hAAT promoter resulted in the highest expression from a retroviral vector and may result in therapeutically significant expression of other clinically significant blood proteins.
Role of Membrane Potential and Hydrogen Bonding in the Mechanism of Translocation of Guanidinium-Rich Peptides into Cells (2004)

The results described herein support a mechanistic hypothesis for how guanidine-rich transporters attached to small cargos (MW ca. <3000) can migrate across the lipid membrane of a cell and directly enter the cytosol. Arginine oligomers are found to partition almost completely into the aqueous layer of a water-octanol bilayer. However, when the same partitioning experiment is conducted in the presence of sodium laurate, a representative negatively charged membrane constituent, the arginine oligomer partitions almost completely (>95%) into the octanol layer. In contrast, ornithine oligomers partition almost exclusively into the water layer with and without added sodium laurate. The different partitioning between guanidinium-rich and ammonium-rich oligomers in the presence of sodium laurate is consistent with the ability of the former to form a bidentate hydrogen bonded ion pair. Mono- and dimethylated arginine oligomers, which like ornithine can only efficiently form monodentate hydrogen bonds, were prepared and found to exhibit poor cellular uptake. Ion pair formation converts a once water-soluble agent to a lipid-soluble agent, thereby reducing the energetic penalty for passage of guanidine-rich transporters through the lipid bilayer. Uptake of guanidine-rich transporters is known to be an energy-dependent process, and this requirement for cellular ATP is now rationalized by the inhibition of guanidine-rich transporter uptake in the presence of agents that reduce the membrane potential. Specifically, incubation of cells in buffers with high potassium ion concentrations or pretreatment of cells with gramicidin A reduces the cellular uptake of Fl-aca-arg8-CONH2 by >90%. Furthermore, the reciprocal experiment of hyperpolarizing the cell with valinomycin increased uptake by >1.5 times. In summary, we propose that the water-soluble, positively charged guanidinium headgroups of the transporter form bidentate hydrogen bonds with H-bond acceptor functionality on the cell surface. The resultant ion pair complexes partition into the lipid bilayer and migrate across at a rate related to the membrane potential. The complex dissociates on the inner leaf of the membrane, and the transporter enters the cytosol. This hypothesis does not preclude uptake by other mechanisms, including endocytosis, which is likely to dominate with large cargos.
Getting to Know You: Reputation and Trust in a Two-Person Economic Exchange (2005)

Using a multiround version of an economic exchange (trust game), we report that reciprocity expressed by one player strongly predicts future trust expressed by their partner-a behavioral finding mirrored by neural responses in the dorsal striatum. Here, analyses within and between brains revealed two signals-one encoded by response magnitude, and the other by response timing. Response magnitude correlated with the "intention to trust" on the next play of the game, and the peak of these "intention to trust" responses shifted its time of occurrence by 14 seconds as player reputations developed. This temporal transfer resembles a similar shift of reward prediction errors common to reinforcement learning models, but in the context of a social exchange. These data extend previous model-based functional magnetic resonance imaging studies into the social domain and broaden our view of the spectrum of functions implemented by the dorsal striatum.