gebhart/patrepeval huggingface dataset:
Functional correction of adult mdx mouse muscle using gutted adenoviral vectors expressing full-length dystrophin (2002)

Duchenne muscular dystrophy is a lethal X-linked recessive disorder caused by mutations in the dystrophin gene. Delivery of functionally effective levels of dystrophin to immunocompetent, adult mdx (dystrophin-deficient) mice has been challenging because of the size of the gene, immune responses against viral vectors, and inefficient infection of mature muscle. Here we show that high titer stocks of three different gutted adenoviral vectors carrying full-length, muscle-specific, dystrophin expression cassettes are able to efficiently transduce muscles of 1-yr-old mdx mice. Single i.m. injections of viral vector restored dystrophin production to 25-30% of mouse limb muscle 1 mo after injection. Furthermore, functional tests of virally transduced muscles revealed almost 40% correction of their high susceptibility to contraction-induced injury. Our results show that functional abnormalities of dystrophic muscle can be corrected by delivery of full-length dystrophin to adult, immunocompetent mdx mice, raising the prospects for gene therapy of muscular dystrophies.
Refractory Status Epilepticus (2002)

Refractory status epilepticus occurs in approximately 30% of patients with SE and is associated with increased hospital length of stay and functional disability. Nonconvulsive SE and focal motor seizures at onset are risk factors for RSE. Randomized controlled trials are needed to define the optimal treatment of RSE.
DR3 Regulates Negative Selection during Thymocyte Development (2001)

DR3 (Ws1, Apo3, LARD, TRAMP, TNFSFR12) is a member of the death domain-containing tumor necrosis factor receptor (TNFR) superfamily, members of which mediate a variety of developmental events including the regulation of cell proliferation, differentiation, and apoptosis. We have investigated the in vivo role(s) of DR3 by generating mice congenitally deficient in the expression of the DR3 gene. We show that negative selection and anti-CD3-induced apoptosis are significantly impaired in DR3-null mice. In contrast, both superantigen-induced negative selection and positive selection are normal. The pre-T-cell receptor-mediated checkpoint, which is dependent on TNFR signaling, is also unaffected in DR3-deficient mice. These data reveal a nonredundant in vivo role for this TNF receptor family member in the removal of self-reactive T cells in the thymus.
Does α‐synuclein modulate dopaminergic synaptic content and tone at the synapse? (2004)

alpha-Synuclein is a key component of the pathological process of neurodegeneration in Parkinson's disease. Although its contributions to normal physiological conditions remain elusive, converging observations suggest that a primary function of this protein in dopaminergic neurons may be the regulation of dopamine content and synaptic tone at the synapse. We review here cumulative evidence that demonstrates the participation of alpha-synuclein in the life cycle of dopamine from its synthesis, storage, release, and reuptake. The regulatory role of alpha-synuclein on dopamine metabolism is assessed by discussing the experimental evidence supporting each of these observations in the healthy physiological maintenance of dopaminergic neurons, as well as showing how disruption of these events can initiate the observed neurotoxicity of alpha-synuclein and the genesis of the degenerative processes associated with Parkinson's disease.
Molecular dynamics and protein function (2005)

A fundamental appreciation for how biological macromolecules work requires knowledge of structure and dynamics. Molecular dynamics simulations provide powerful tools for the exploration of the conformational energy landscape accessible to these molecules, and the rapid increase in computational power coupled with improvements in methodology makes this an exciting time for the application of simulation to structural biology. In this Perspective we survey two areas, protein folding and enzymatic catalysis, in which simulations have contributed to a general understanding of mechanism. We also describe results for the F(1) ATPase molecular motor and the Src family of signaling proteins as examples of applications of simulations to specific biological systems.
Thrombin activatable fibrinolysis inhibitor: Not just an inhibitor of fibrinolysis (2004)

The principal physiologic role of TAFI is still a matter of debate. Although TAFI activation can result from proteolysis by a number of proteases, the most likely physiologic activators are thrombin (in complex with the cofactor thrombomodulin) and plasmin (in complex with polysaccharide cofactors). The activated enzyme, TAFIa, displays carboxypeptidase B-like activity and probably regulates both fibrinolysis and inflammation in response to injury and infection. At present, there is limited understanding of the role that TAFI plays in the interrelationships between coagulation, fibrinolysis, and inflammation. Although the potential therapeutic value of TAFIa inhibition/TAFI activation awaits further investigation, the data gathered to date suggest that, like activated protein C, TAFIa may play a pivotal role in regulating the crosstalk between coagulation, fibrinolysis, and inflammation.
Heterogeneity of recombinant antibodies: linking structure to function. (2005)

Structural heterogeneity of recombinant IgG1 antibodies derives from variations in conserved as well as unique structural features. Common sources of heterogeneity include Fc glycosylation, partial heavy chain C-terminal Lys processing, Fc methionine oxidation, hinge-region cleavage, and the glycation of Lys residues. Aspartate residues that are isomerized to iso-aspartate were detected by cation exchange or hydrophobic interaction chromatography for trastuzumab and omalizumab, respectively. Unpaired cysteines were detected in omalizumab using Ellman's reagent, with the thiol-containing Fab resolved using hydrophobic interaction chromatography after papain digestion. Structural variations that cause chromatographic resolution may indicate the presence of a form with reduced potency.
shRNA targeting α-synuclein prevents neurodegeneration in a Parkinson’s disease model (2015)

Multiple convergent lines of evidence implicate both α-synuclein (encoded by SCNA) and mitochondrial dysfunction in the pathogenesis of sporadic Parkinson’s disease (PD). Occupational exposure to the mitochondrial complex I inhibitor rotenone increases PD risk; rotenone-exposed rats show systemic mitochondrial defects but develop specific neuropathology, including α-synuclein aggregation and degeneration of substantia nigra dopaminergic neurons. Here, we inhibited expression of endogenous α-synuclein in the adult rat substantia nigra by adeno-associated virus–mediated delivery of a short hairpin RNA (shRNA) targeting the endogenous rat Snca transcript. Knockdown of α-synuclein by ~35% did not affect motor function or cause degeneration of nigral dopaminergic neurons in control rats. However, in rotenone-exposed rats, progressive motor deficits were substantially attenuated contralateral to α-synuclein knockdown. Correspondingly, rotenone-induced degeneration of nigral dopaminergic neurons, their dendrites, and their striatal terminals was decreased ipsilateral to α-synuclein knockdown. These data show that α-synuclein knockdown is neuroprotective in the rotenone model of PD and indicate that endogenous α-synuclein contributes to the specific vulnerability of dopaminergic neurons to systemic mitochondrial inhibition. Our findings are consistent with a model in which genetic variants influencing α-synuclein expression modulate cellular susceptibility to environmental exposures in PD patients. shRNA targeting the SNCA transcript should be further evaluated as a possible neuroprotective therapy in PD.
Telomerase recognizes its template by using an adjacent RNA motif (2002)

Telomerase adds telomeric repeats to chromosome 3′ ends, forestalling the cellular senescence, apoptosis, and genomic instability that result from telomere loss caused by incomplete DNA replication. The telomerase ribonucleoprotein is dedicated to synthesis of tandem, simple-sequence repeats by virtue of its specialization for copying only a specific template region within the integral RNA. Here, using circularly permuted variants of Tetrahymena thermophila telomerase RNA, we identify the features that allow recognition of the template region within the RNA. We engineered a template-less telomerase ribonucleoprotein that can position and reverse transcribe an exchangeable RNA oligonucleotide template accurately. Only a short “template-recognition” element sequence tag is required to direct efficient use of adjacent 5′ residues as a template for telomeric repeat synthesis. Our findings reveal molecular requirements for template selection by telomerase and physically resolve templating from other RNA functions in catalysis.
Dysregulation of the Protein Tyrosine Kinase LCK in Lymphoproliferative Disorders and in Other Neoplasias (1999)

Initially identified as a T-cell specific member of the Src family of protein tyrosine kinases, Lck has become the object of intensive investigations which have revealed a key role for this kinase in the central processes controlling T-cell development, activation, proliferation and survival. Experimental evidence of the oncogenic potential of Lck, together with the identification of defects in the regulation of Lck expression or activity in T-cell leukemias, suggests that dysregulation of Lck might play a role in neoplastic transformation. Here we review the data documenting a potential role for this kinase in the initiation and maintenance of the transformed state in human cancers.
Immune responses to H-2Kd antigen expressed by recombinant vaccinia virus. (1986)

A recombinant vaccinia virus (VV-H2Kd-6) containing the coding sequence for the murine major histocompatibility complex class I antigen H-2Kd has been constructed and used to express H-2Kd on the surface of infected cells. Vaccinia expressed H-2Kd has been shown to generate an H-2Kd-specific primary cytotoxic T-cell response in mice infected with the recombinant virus and to stimulate an H-2Kd-specific cytotoxic T-cell response in vitro. Cells infected with the recombinant virus acted as targets for specific lysis by appropriate alloreactive cytotoxic T cells, albeit relatively inefficiently when compared with alloreactive recognition and specific lysis of H-2Kd-containing P815 cells. However, H-2Kd expressed by the recombinant virus was recognized efficiently as a restricting element in association with vaccinia virus antigens, while lysis of VV-H2Kd-6-infected L929 (H-2k) cells by CBA/H (H-2k) anti-C3H.OH (H-2KdDk) cytotoxic T cells was comparatively weak. These data suggest that there are quantitative or qualitative differences, or both, between H-2Kd expressed by vaccinia virus and cells of the H-2d haplotype. Qualitative differences have not been demonstrated but cannot be excluded.
Experimental and theoretical analysis of the resonant nonlinearity in ytterbium-doped fiber (1998)

Experimental measurements are described characterizing the nonlinear index change over the range from 500 to 1550 nm induced in an ytterbium (Yb/sup 3+/)-doped twin-core fiber by a 980 nm pump. At 1550 nm, a phase change of /spl pi/ is induced with as little as 14 mW of pump power for a signal loss of only 0.2 dB, By allowing the doped fiber to lase and observing the associated clamping of the induced phase change, we show that a digital nonlinear response can be achieved in which a constant, pump-power-insensitive, phase change is induced for all pump powers above a certain threshold. This lasing induced clamping of the phase change also demonstrates that the nonlinear effect is population dependent as opposed to thermal. The pump-induced phase change is observed to increase for shorter signal wavelengths, which suggests that the effect is due principally to pump-induced changes in the strong ultraviolet (UV) absorptions of Yb/sup 3+/. This observation is accurately predicted by a theoretical analysis that takes into account absorptions in both infrared and ultraviolet regions. This analysis shows that Yb/sup 3+/ may be suitable for low-power all-optical switching applications in both 1300 and 1550 nm telecommunications windows when the speed of response is not a critical parameter.
Improving support for locality and fine-grain sharing in chip multiprocessors (2008)

Both commercial and scientific workloads benefit from concurrency and exhibit data sharing across threads/processes. The resulting sharing patterns are often fine-grain, with the modified cache lines still residing in the writer's primary cache when accessed. Chip multiprocessors present an opportunity to optimize for fine-grain sharing using direct access to remote processor components through low-latency on-chip interconnects. In this paper, we present Adaptive Replication, Migration, and producer-Consumer Optimization (ARMCO), a coherence protocol that, to the best of our knowledge, is the first to exploit direct access to the L1 caches of remote processors (rather than via coherence mechanisms) in order to support fine-grain sharing.
Tissue Expression and Serum Levels of HER-2/neu in Patients with Breast Cancer (1997)

We have analyzed serum levels of soluble HER-2/neu in 42 primary breast cancer patients prior to any therapy and studied the relationship between the overexpression and amplification of HER-2/neu in the primary tumor after surgical excision and data obtained by pathohistological staging. In addition, we have investigated the sera of 62 patients with stage IV breast cancer. Using an enzyme-linked immunosorbent assay, we observed elevated serum HER-2/neu levels in 6/42 (14.2%) preoperative patients. In 42.8% of the patients with HER-2/neu tumor expression/amplification serum levels were increased. In contrast, only 8.5% of the patients without HER-2/neu expression/amplification in the primary tumor presented with elevated serum levels. There was a significant correlation between serum concentrations of soluble HER-2/neu and tumor size (p < 0.0001) or axillary lymph node involvement (p < 0.0001). In patients with stage IV disease, 27 of 62 (43.5%) had elevated soluble HER-2/neu serum levels. A highly significant correlation between soluble HER-2/ neu and CA 15-3 (p < 0.002) was observed. The correlation of serum concentrations of HER-2/neu with estrogen and progesterone receptor status of the primary tumor was not significant in both groups. In conclusion, the measurement of serum HER-2/neu levels at diagnosis defines a small subgroup of breast cancer patients with a relatively advanced stage of disease. Its strong correlation with tumor load in patients with stage II disease and the high prevalence in patients with stage IV disease could make it a promising tool for the assessment of disease activity and biologic behavior in breast cancer.
Immunologic Evaluation of Personalized Peptide Vaccination for Patients with Advanced Malignant Glioma (2005)

Personalized peptide vaccinations were recommended for the further clinical study to malignant glioma patients.
KRN633: A selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase that suppresses tumor angiogenesis and growth (2004)

Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 play a central role in angiogenesis, which is necessary for solid tumors to expand and metastasize. Specific inhibitors of VEGFR-2 tyrosine kinase are therefore thought to be useful for treating cancer. We showed that the quinazoline urea derivative KRN633 inhibited tyrosine phosphorylation of VEGFR-2 (IC50 = 1.16 nmol/L) in human umbilical vein endothelial cells. Selectivity profiling with recombinant tyrosine kinases showed that KRN633 was highly selective for VEGFR-1, -2, and -3. KRN633 also blocked the activation of mitogen-activated protein kinases by VEGF, along with human umbilical vein endothelial cell proliferation and tube formation. The propagation of various cancer cell lines in vitro was not inhibited by KRN633. However, p.o. administration of KRN633 inhibited tumor growth in several in vivo tumor xenograft models with diverse tissue origins, including lung, colon, and prostate, in athymic mice and rats. KRN633 also caused the regression of some well-established tumors and those that had regrown after the cessation of treatment. In these models, the trough serum concentration of KRN633 had a more significant effect than the maximum serum concentration on antitumor activity. KRN633 was well tolerated and had no significant effects on body weight or the general health of the animals. Histologic analysis of tumor xenografts treated with KRN633 revealed a reduction in the number of endothelial cells in non-necrotic areas and a decrease in vascular permeability. These data suggest that KRN633 might be useful in the treatment of solid tumors and other diseases that depend on pathologic angiogenesis.
Creating Asymmetric Cell Divisions by Skewing Endocytosis (2002)

How can one cell divide to form two cells, which are genetically identical to the mother cell, with different cell fates? That is the question discussed by Shen and Temple. Specifically, they address how Notch signaling is attenuated in one daughter cell through the asymmetric inheritance of the protein Numb, which may be responsible for mediating the endocytosis of the receptor Notch in the Numb-enriched cell.
Direct Phosphorylation of IκB by IKKα and IKKβ: Discrimination Between Free and NF-κB-Bound Substrate (1998)

A large protein complex mediates the phosphorylation of the inhibitor of kappaB (IkappaB), which results in the activation of nuclear factor kappaB (NF-kappaB). Two subunits of this complex, IkappaB kinase alpha (IKKalpha) and IkappaB kinase beta (IKKbeta), are required for NF-kappaB activation. Purified recombinant IKKalpha and IKKbeta expressed in insect cells were used to demonstrate that each protein can directly phosphorylate IkappaB proteins. IKKalpha and IKKbeta were found to form both homodimers and heterodimers. Both IKKalpha and IKKbeta phosphorylated IkappaB bound to NF-kappaB more efficiently than they phosphorylated free IkappaB. This result explains how free IkappaB can accumulate in cells in which IKK is still active and thus can contribute to the termination of NF-kappaB activation.
Metabolic engineering for improving anthranilate synthesis from glucose in Escherichia coli (2009)

This work constitutes the first example of a microbial system for the environmentally-compatible synthesis of anthranilate generated by metabolic engineering. The results presented here, including the characterization of mutation in the trpD gene from strain W3110 trpD9923 and the development of a fermentation strategy, establish a step forward towards the future improvement of a sustainable process for anthranilate production. In addition, the present work provides very useful data regarding the positive and negative consequences of the evaluated metabolic engineering strategies.
Inactivation, Complementation, and Heterologous Expression ofencP, a Novel Bacterial Phenylalanine Ammonia-Lyase Gene (2002)

The enzyme phenylalanine ammonia-lyase, which catalyzes the nonoxidative deamination of l-phenylalanine to trans-cinnamic acid, is ubiquitously distributed in plants. We now report its characterization for the first time in a bacterium. The phenylalanine ammonia-lyase homologous gene encP from the "Streptomyces maritimus" enterocin biosynthetic gene cluster was functionally characterized and shown to encode the first enzyme in the pathway to the enterocin polyketide synthase starter unit benzoyl-coenzyme A. The disruption of the encP gene completely inhibited the production of cinnamate and enterocin, whereas complementation of the mutant with benzoyl-coenzyme A pathway intermediates or with the wild-type gene encP restored the formation of the benzoate-primed polyketide antibiotic enterocin. Heterologous expression of the encP gene under the control of the ermE* promoter in Streptomyces coelicolor furthermore led to the production of cinnamic acid in the fermented cultures, confirming that the encP gene indeed encodes a novel bacterial phenylalanine ammonia-lyase.
Fully Enclosed Microfluidic Paper-Based Analytical Devices (2012)

This article introduces fully enclosed microfluidic paper-based analytical devices (microPADs) fabricated by printing toner on the top and bottom of the devices using a laser printer. Enclosing paper-based microfluidic channels protects the channels from contamination, contains and protects reagents stored on the device, contains fluids within the channels so that microPADs can be handled and operated more easily, and reduces evaporation of solutions from the channels. These benefits extend the capabilities of microPADs for applications as low-cost point-of-care diagnostic devices.
Symmetric and a-symmetric slepian-wolf codes with systematic and non-systematic linear codes (2005)

We propose a constructive approach for distributed source coding of correlated binary sources using linear channel codes that can achieve any point of the Slepian-Wolf achievable rate region. Our approach is very intuitive and can be used with systematic and nonsystematic linear codes. Moreover, the proposed coding strategy can easily be extended to the case of more than two sources.
Selective Open-Channel Block of Shaker (Kv1) Potassium Channels by S-Nitrosodithiothreitol (Sndtt) (2001)

Large quaternary ammonium (QA) ions block voltage-gated K(+) (Kv) channels by binding with a 1:1 stoichiometry in an aqueous cavity that is exposed to the cytoplasm only when channels are open. S-nitrosodithiothreitol (SNDTT; ONSCH(2)CH(OH)CH(OH)CH(2)SNO) produces qualitatively similar "open-channel block" in Kv channels despite a radically different structure. SNDTT is small, electrically neutral, and not very hydrophobic. In whole-cell voltage-clamped squid giant fiber lobe neurons, bath-applied SNDTT causes reversible time-dependent block of Kv channels, but not Na(+) or Ca(2)+ channels. Inactivation-removed ShakerB (ShBDelta) Kv1 channels expressed in HEK 293 cells are similarly blocked and were used to study further the action of SNDTT. Dose-response data are consistent with a scheme in which two SNDTT molecules bind sequentially to a single channel, with binding of the first being sufficient to produce block. The dissociation constant for the binding of the second SNDTT molecule (K(d2) = 0.14 mM) is lower than that of the first molecule (K(d1) = 0.67 mM), indicating cooperativity. The half-blocking concentration (K(1/2)) is approximately 0.2 mM. Steady-state block by this electrically neutral compound has a voltage dependence (about -0.3 e(0)) similar in magnitude but opposite in directionality to that reported for QA ions. Both nitrosyl groups on SNDTT (one on each sulfur atom) are required for block, but transfer of these reactive groups to channel cysteine residues is not involved. SNDTT undergoes a slow intramolecular reaction (tau approximately 770 s) in which these NO groups are liberated, leading to spontaneous reversal of the SNDTT effect. Competition with internal tetraethylammonium indicates that bath-applied SNDTT crosses the cell membrane to act at an internal site, most likely within the channel cavity. Finally, SNDTT is remarkably selective for Kv1 channels. When individually expressed in HEK 293 cells, rat Kv1.1-1.6 display profound time-dependent block by SNDTT, an effect not seen for Kv2.1, 3.1b, or 4.2.