gebhart/patrepeval huggingface dataset:
Neuronal Genomics Using Mouse Cloning with the Single Neuronal Nucleus (2006)

Brain system is composed of enormous numbers of diversified single neurons. Therefore assessing epigenetic and genetic regulation in the nucleus of single neurons is a new challenge for understanding neuronal commitment, differentiation and maturation. As differentiated neurons are, in nature, postmitotic, neither the genome nor its epigenetic modifications are easy to evaluate fully. The cloning of mammalian cells, which has been used mainly in the fields of assisted reproduction and regenerative medicine, can be applied to propagating the entire genome of single neurons. In addition, embryonic stem (ES) cells derived from embryos cloned from single neuronal nuclei provide an “eternal” resource for assessing the genetic content of individual neurons. Here, we discuss the possible genetic/epigenetic regulation of gene expression in the nuclei of single neurons, and the utility of cloning by neuronal nuclear transfer to assess the genomic constitution of the single nucleus of differentiated neurons during development. This use of cloning technology may be a fruitful approach for analyzing the entire genome of individual single neurons. Keywords: Diversity, ndividuality, developmental potential, differentiated neurons, nuclear transfer, embryonic stem (ES) cells
Cellular neural networks: theory (1988)

A novel class of information-processing systems called cellular neural networks is proposed. Like neural networks, they are large-scale nonlinear analog circuits that process signals in real time. Like cellular automata, they consist of a massive aggregate of regularly spaced circuit clones, called cells, which communicate with each other directly only through their nearest neighbors. Each cell is made of a linear capacitor, a nonlinear voltage-controlled current source, and a few resistive linear circuit elements. Cellular neural networks share the best features of both worlds: their continuous-time feature allows real-time signal processing, and their local interconnection feature makes them particularly adapted for VLSI implementation. Cellular neural networks are uniquely suited for high-speed parallel signal processing.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Identification of the Fc gamma receptor class I binding site in human IgG through the use of recombinant IgG1/IgG2 hybrid and point-mutated antibodies. (1991)

To characterize the region on human IgG1 responsible for its high-affinity interaction with the human Fc gamma receptor class I (Fc gamma RI), we have analyzed the binding properties of a series of genetically engineered chimeric antidinitrophenyl antibodies with identical murine antibody combining sites and hybrid IgG1/IgG2 human constant (C) regions. In addition, we have investigated a panel of reciprocally point-mutated IgG1 and IgG2 chimeric antibodies to identify the amino acid residues that confer cytophilic properties to human IgG1. Our data unambiguously indicate that cytophilic activity of IgG1 is an intrinsic property of its heavy-chain C region 2 (CH2) domain. We report that the entire sequence spanning residues 234-237 (LLGG) is required to restore full binding activity to IgG2 and IgG4 and that individual amino acid substitutions failed to render IgG2 active. Nevertheless, the reciprocal single point mutations in IgG1 either significantly lowered its activity or abolished it completely. Finally, we observed that an IgG2 antibody containing the entire ELLGGP sequence (residues 233-238) was more active than wild-type IgG1. This finding suggests that in addition to the primary contact site identified in the N terminus of the gamma 1 CH2 domain, secondary sites involving residues from the C-terminal half of the domain may also contribute to the IgG1-Fc gamma RI interaction.
Critical Roles for stx 2 , eae , and tir in Enterohemorrhagic Escherichia coli -Induced Diarrhea and Intestinal Inflammation in Infant Rabbits (2003)

Enterohemorrhagic Escherichia coli (EHEC) is a group of food-borne pathogens that can cause diarrhea, colitis, and the hemolytic uremic syndrome (HUS). The importance of several of the proposed EHEC virulence factors lacks experimental verification in animal models. The limitations of current animal models led us to reexamine the infant rabbit model for the study of EHEC pathogenicity. Here, we report that intragastric inoculation of a Shiga toxin 2 (Stx2)-producing E. coli O157:H7 clinical isolate into infant rabbits led to severe diarrhea and intestinal inflammation but no signs of HUS. We constructed a set of isogenic derivatives of this isolate with deletions in several putative virulence genes, including stx(2), eae, tir, and ehxA, to investigate the contribution of individual virulence factors to EHEC pathogenicity. stx(2) increased the severity and duration of EHEC-induced diarrhea. Furthermore, although stx(2) had no role in EHEC intestinal colonization nor was it required for EHEC-induced inflammation, stx(2) altered how the host responded to EHEC infection by promoting heterophilic infiltration of the colonic epithelium and lamina propria. Intragastric inoculation of purified Stx2 also induced inflammation and diarrhea in this model. Diarrhea and intestinal inflammation were also dependent on EHEC colonization, as EHEC derivatives with deletions in eae and tir did not colonize, form attaching and effacing lesions, or develop clinical signs of disease. Our studies indicate that infant rabbits are a useful model for investigation of the intestinal stage of EHEC pathogenesis and suggest that Shiga toxin may play a critical role in causing diarrhea and inflammation in patients infected with EHEC.
A study of fungal endophytes of needles of balsam fir (Abies balsamea) and red spruce (Picea rubens) in New Brunswick, Canada, using culture and electron microscope techniques (1989)

Endophytic fungi were isolated from the interiors of surface-sterilized needles of balsam fir (Abies balsamea) and red spruce (Picea rubens) in New Brunswick, Canada. Four different fungi were isolated frequently. One species, designated X-W, was isolated exlusively from the petiole segment of red spruce needles. There was no difference in the variety of species isolated from fir needles from two sites, but a difference in frequency of species did exist. Micrographs of the interior of balsam fir needles showed hyphae occupying intercellular spaces and adhering to the outer walls of parenchyma cells. No penetration of cells by either fungus was observed.
A novel biomarker to predict sensitivity to enzalutamide (ENZA) in TNBC. (2015)

1083 Background: TNBC is a heterogeneous disease with multiple subtypes and drivers. ENZA, a potent inhibitor of AR signaling, is being tested in patients (pts) whose TNBC expresses AR (> 0%) by IHC (NCT01889238). However, AR expression may not confer ENZA sensitivity. Gene profiling was therefore explored to determine whether this could be superior to IHC in predicting benefit from ENZA. Methods: Consent and tissue for AR testing was collected from 404 pts. Next-Gen RNA-sequencing analysis was performed on 175 tissue samples: 122 samples came from pts treated with ENZA (118 unique pts) (ITT); 55 were from untreated pts. A Training Set (TrS, n = 122); and a Validation Set (VS; n = 55) were created. TrS consisted of 80 samples from ENZA treated pts (77 unique pts) + 42 from untreated pts (29 AR = 0%; 13 AR > 0 %). VS consisted of 42 samples from ENZA treated pts (41 unique pts) + 13 from untreated pts (10 AR = 0%; 3 AR > 0 %). A gene expression model of biological subtype (GES) was built directly from the response data in the TrS. Model development utilized the elastic-net algorithm in the context of 500 rounds of Monte-Carlo cross-validation. Tuned parameters were used to validate the gene-expression model in the VS, outcomes were blinded during model validation. Results: The selected GES achieved 80% sensitivity and 65% specificity in prediction of 16 week clinical benefit (CBR16). Utilization of this model to define Diagnostic positive (Dx+) and Dx- populations showed the following results in pts treated with ENZA are shown in the Table. Highest accuracy was demonstrated in pts receiving ENZA as their 1st or 2nd line of therapy. Conclusions: A genomic signature, associated with androgen biology, has been identified that demonstrates the potential to predict clinical response to ENZA in pts with TNBC. Nearly half of the pts enrolled in the phase 2 were classified as Dx+, suggesting a reasonable prevalence of pts who may benefit from this hormonal therapy. This assay may be useful to select TNBC pts for future studies evaluating ENZA. Clinical trial information: NCT01889238. Training Set Validation Set ITT (both sets) Dx+ (n=39) Dx- (n=38) Dx+ (n=17) Dx- (n=24) Dx+ (n=56) Dx- (n=62) CBR16 (% pts; 95% CI) 44 (29-60) 13 (5-27) 29 (12-54) 8 (2-26) 39 (27-53) 11 (5-21) CBR24 (% pts; 95% CI) 39 (24-55) 10 (4-24) 29 (12-54) 0 (0-13) 36 (24-49) 6 (2-16)
High-Efficiency InGaAlP Visible Light-Emitting Diodes (1992)

A new structure for InGaAlP light-emitting diodes (LEDs) which include a GaAlAs current-spreading layer has been designed. Remarkable improvements in external efficiency have been achieved using this structure. The photoluminescence and electroluminescence characteristics of high-Al-content InGaAlP alloys have been investigated. A GaAs substrate with an intentional surface misorientation from the nominally (100) plane towards the [011] direction was found to have a marked effect on the improvement of emission properties. The external quantum efficiency was 1.2% at 592 nm for an In 0.5 (Ga 0.7 Al 0.3 ) 0.5 P active layer LED. These LEDs have been operated for more than 1500 hours at 80°C and 50 mA.
Immunological role of neuronal receptor vanilloid receptor 1 expressed on dendritic cells (2005)

Capsaicin (CP), the pungent component of chili pepper, acts on sensory neurons to convey the sensation of pain. The CP receptor, vanilloid receptor 1 (VR1), has been shown to be highly expressed by nociceptive neurons in dorsal root and trigeminal ganglia. We demonstrate here that the dendritic cell (DC), a key cell type of the vertebrate immune system, expresses VR1. Engagement of VR1 on immature DCs such as by treatment with CP leads to maturation of DCs as measured by up-regulation of antigen-presenting and costimulatory molecules. This effect is present in DCs of VR1+/+ but not VR1-/- mice. In VR1+/+ mice, this effect is inhibited by the VR1 antagonist capsazepine. Further, intradermal administration of CP leads to migration of DCs to the draining lymph nodes in VR1+/+ but not VR1-/- mice. These data demonstrate a powerful influence of a neuroactive ligand on a central aspect of immune function and a commonality of mechanistic pathways between neural and immune functions.
New Insight into Alzheimer’s Disease via Caspase 3-cleaved Tau: Pathogenic Role in Tau Oligomer Formation and Memory Deficits (2017)

Alzheimer’s disease (AD) is the most common and leading cause of dementia. AD has two different pathological hallmarks, extracellular amyloid beta plaques and intracellular neurofibrillary tangles (NFT). NFTs consist of abnormally modified tau protein that forms protein aggregates. Tau protein aggregates are prevalently observed as disease progresses and are believed to cause neuronal dysfunction. The caspase-3 cleaved form of tau, TauC3, is generated in cultured neurons under stress and is found in the brains of patients with AD in the early stages of disease when patients are asymptomatic. TauC3 accelerates tau oligomerization in vitro and in vivo, and induces neuronal degeneration. Moreover, the neuronal expression of TauC3 in transgenic mice causes memory deficits at a young age, which is concomitant with the appearance of tau oligomers. The removal of TauC3-containing oligomers and aggregates using drug treatment improves both memory and synaptic function. These findings demonstrate that TauC3 is critical for the formation of tau oligomers and small aggregates and may ultimately play a role in the rapid memory impairments observed in AD. Overall, TauC3 may represent a new therapeutic target for the prevention of AD.
A critical view of coronary reserve. (1987)

Coronary flow reserve is reduced by pathologic acquired left ventricular hypertrophy, and is less in subendocardial than subepicardial layers of normal or hypertrophied hearts. In normal hearts, pacing-induced tachycardia at a rate of 250 beats/min does not alter coronary reserve in the outer half of the left ventricular wall. Pacing produces a linear decrease in coronary reserve in the inner half, although the decrease is attenuated if perfusion pressure is elevated, as in systemic hypertension. Strenuous exercise can quadruple coronary flow, but modest coronary flow reserve is preserved in normal hearts. Whether this occurs when there is ventricular hypertrophy is unknown and requires study. The concept of coronary flow reserve is important to the understanding of pathophysiology, but data must be interpreted with caution because pharmacologic agents may produce more vasodilatation than can be attained by endogenous stimuli, even when there is marked ischemia.
Muscling in on stem cells (2006)

Skeletal muscle is one of the few adult tissues that possesses the capacity for regeneration (restoration of lost functional tissue) as opposed to repair. This capacity is due to the presence of 'muscle stem cells' known as satellite cells. Detailed investigation of these cells over the past 50 years has revealed that both these and other cells within the skeletal muscle complex are capable of regenerating both muscle and other cell types as well. Here, we review this information, and suggest that skeletal muscle is an exciting reservoir of cells for regenerating skeletal muscle itself, as well as other cell types.
Electrophoretic and Immunological Comparisons of Developmentally Regulated Proteins in Members of the Sclerotiniaceae and Other Sclerotial Fungi (1991)

The fungal stroma is a distinct developmental stage, a compact mass of hyphal cells enveloped by a melanized layer of rind cells which is produced from vegetative mycelium. Two types of stromata that are characteristic of members of the Sclerotiniaceae but are also produced in a wide range of other fungi, i.e., the determinate tuberlike sclerotium and the indeterminate platelike substratal stroma, were compared in these studies. Developmental proteins found in determinate sclerotial and indeterminate substratal stromata, but not in mycelia, were characterized and compared in 52 isolates of fungi, both ascomycetes (including 18 species in the Sclerotiniaceae and 5 species of Aspergillus) and the basidiomycete Sclerotium rolfsii. One-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis of mycelial, stromatal initial, and stromatal extracts demonstrated that all members of the Sclerotiniaceae produced proteins unique to stromatal extracts within a molecular weight range of 31,000 to 39,500 which composed 13 to 58% of the total protein in stromata. Proteins unique to the sclerotial stage were also produced in Sclerotium rolfsii and the Aspergillus species but within a generally lower-molecular-weight range of 11,000 to 30,000. The proteins were then characterized by two-dimensional electrophoresis to determine the number and isoelectric point of polypeptides composing each protein. Polyclonal antibodies were raised to the major 36-kDa sclerotial protein of Sclerotinia sclerotiorum (Ssp). Immunoblots demonstrated that all sclerotial proteins from species in the Sclerotiniaceae cross-reacted with anti-Ssp antibodies, while no cross-reaction was observed with proteins from substratal stromatal species in the Sclerotiniaceae, sclerotial species of Aspergillus, or Sclerotium rolfsii. Results of discriminant analysis of the data from competitive inhibition enzyme-linked immunosorbent assays were consistent with the results of immunoblotting. Three groupings, sclerotial species in the Sclerotiniaceae, substratal stromatal species in the family, and sclerotial species outside the family, were delimited on the basis of relative decreasing ability to compete for anti-Ssp antibody. These data demonstrate that stromatal proteins differ among different taxonomic groups of fungi and suggest that the Sclerotiniaceae may include two distinct lineages of genera.
Pharmacokinetics and Pharmacodynamics of Midazolam and Metabolites in Nonventilated Infants after Craniofacial Surgery (2006)

In nonventilated infants after major surgery, midazolam clearance is two to five times higher than in ventilated children. From the model presented, the recommended initial dosage is a loading dose of 1 mg followed by a continuous infusion of 0.5 mg/h during the night for a COMFORT-Behavior of 12-14 in infants aged 1 yr. Large interindividual variability warrants individual titration of midazolam in these children.
Targeting Activin Receptor-Like Kinase 1 Inhibits Angiogenesis and Tumorigenesis through a Mechanism of Action Complementary to Anti-VEGF Therapies (2011)

Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1) plays an important role in vascular development, remodeling, and pathologic angiogenesis. Here we investigated the role of ALK1 in angiogenesis in the context of common proangiogenic factors [PAF; VEGF-A and basic fibroblast growth factor (bFGF)]. We observed that PAFs stimulated ALK1-mediated signaling, including Smad1/5/8 phosphorylation, nuclear translocation and Id-1 expression, cell spreading, and tubulogenesis of endothelial cells (EC). An antibody specifically targeting ALK1 (anti-ALK1) markedly inhibited these events. In mice, anti-ALK1 suppressed Matrigel angiogenesis stimulated by PAFs and inhibited xenograft tumor growth by attenuating both blood and lymphatic vessel angiogenesis. In a human melanoma model with acquired resistance to a VEGF receptor kinase inhibitor, anti-ALK1 also delayed tumor growth and disturbed vascular normalization associated with VEGF receptor inhibition. In a human/mouse chimera tumor model, targeting human ALK1 decreased human vessel density and improved antitumor efficacy when combined with bevacizumab (anti-VEGF). Antiangiogenesis and antitumor efficacy were associated with disrupted co-localization of ECs with desmin(+) perivascular cells, and reduction of blood flow primarily in large/mature vessels as assessed by contrast-enhanced ultrasonography. Thus, ALK1 may play a role in stabilizing angiogenic vessels and contribute to resistance to anti-VEGF therapies. Given our observation of its expression in the vasculature of many human tumor types and in circulating ECs from patients with advanced cancers, ALK1 blockade may represent an effective therapeutic opportunity complementary to the current antiangiogenic modalities in the clinic.
Cutting Edge: Increased IL-17–Secreting T Cells in Children with New-Onset Type 1 Diabetes (2010)

CD4(+)FOXP3(+) regulatory T cells are essential for immune tolerance, and murine studies suggest that their dysfunction can lead to type 1 diabetes (T1D). Human studies assessing regulatory T cell dysfunction in T1D have relied on analysis of FOXP3-expressing cells. Recently, distinct subsets of CD4(+)FOXP3(+) T cells with differing function were identified. Notably, CD45RA(-)CD25(int)FOXP3(low) T cells lack suppressive function and secrete the proinflammatory cytokine IL-17. Therefore, we evaluated whether the relative fractions of CD4(+)FOXP3(+) subsets are altered in new-onset T1D subjects. We report that children with new-onset T1D have an increased proportion of CD45RA(-)CD25(int)FOXP3(low) cells that are not suppressive and secrete significantly more IL-17 than other FOXP3(+) subsets. Moreover, these T1D subjects had a higher proportion of both CD4(+) and CD8(+) T cells that secrete IL-17. The bias toward IL-17-secreting T cells in T1D suggests a role for this proinflammatory cytokine in the pathogenesis of disease.
p53 Expression Induces Apoptosis in Hippocampal Pyramidal Neuron Cultures (1997)

The tumor suppressor gene p53 has been implicated in the induction of apoptosis in dividing cells. We now show that overexpression of p53 using an adenoviral vector in cultured rat hippocampal pyramidal neurons causes widespread neuronal death with features typical of apoptosis. p53 overexpression did not induce p21, bax, or mdm2 in neurons. X-irradiation of hippocampal neurons induced p53 immunoreactivity and cell death associated with features typical of apoptosis. Overexpression of a constitutively active nonphosphorylatable form of the retinoblastoma gene product blocked x-irradiation-induced neuronal death. However, overexpression of the cyclin-dependent kinase inhibitor p21 did not. Treatment of neurons with transforming growth factor-beta1 protected them from x-irradiation. These results are consistent with a role for p53 in nerve cell death that is distinct from its actions relating to cell cycle arrest.
A Common Nuclear Signal Transduction Pathway Activated by Growth Factor and Cytokine Receptors (1993)

Growth factors and cytokines act through cell surface receptors with different biochemical properties. Yet each type of receptor can elicit similar as well as distinct biological responses in target cells, suggesting that distinct classes of receptors activate common gene sets. Epidermal growth factor, interferon-gamma, and interleukin-6 all activated, through direct tyrosine phosphorylation, latent cytoplasmic transcription factors that recognized similar DNA elements. However, different ligands activated different patterns of factors with distinct DNA-binding specificities in the same and different cells. Thus, unrelated receptors may activate a common nuclear signal transduction pathway that, through differential use of latent cytoplasmic proteins, permits these receptors to regulate both common and unique sets of genes.
Laser-scanning optical-resolution photoacoustic microscopy (2009)

We have developed a laser-scanning optical-resolution photoacoustic microscopy method that can potentially fuse with existing optical microscopic imaging modalities. To acquire an image, the ultrasonic transducer is kept stationary during data acquisition, and only the laser light is raster scanned by an x-y galvanometer scanner. A lateral resolution of 7.8 microm and a circular field of view with a diameter of 6 mm were achieved in an optically clear medium. Using a laser system working at a pulse repetition rate of 1,024 Hz, the data acquisition time for an image consisting of 256 x 256 pixels was less than 2 min.
Myristoyl-Based Transport of Peptides into Living Cells (2007)

Translocation of membrane-impermeant molecules to the interior of living cells is a necessity for many biochemical investigations. Myristoylation was studied as a means to introduce peptides into living cells. Uptake of a myristoylated, fluorescent peptide was efficient in the B lymphocyte cell line BA/F3. In contrast, this cell line was resistant to uptake of a cell-penetrating peptide derived from the TAT protein. In BA/F3 cells, membrane association was shown to be rapid, reaching a maximum within 30 min. Cellular uptake of the peptide lagged the membrane association but occurred within a similar time frame. Experiments performed at 37 versus 4 degrees C demonstrated profound temperature dependence in the cellular uptake of myristoylated cargo. Myristoylated peptides with either positive or negative charge were shown to load efficiently. In contrast to TAT-conjugated cargo, pyrenebutyrate did not enhance cellular uptake of the myristoylated peptide. The myristoylated peptide did not adversely affect cell viability at concentrations up to 100 muM. This assessment of myristoyl-based transport provides fundamental data needed in understanding the intracellular delivery of myristoylated peptide cargoes for cell-based biochemical studies.