gebhart/patrepeval huggingface dataset:
Tissue distribution of cyclosporine A in the mouse: a clue to toxicity? (1986)

Four groups of three C57/BL6J mice were each given a single i.p. injection of Cyclosporine A (CYA) 3 mg/kg, containing 3H-CYA with 10 microCi activity. The groups were sacrificed after 5 minutes and at 6, 12 and 24 hours after dosing, respectively. They were immediately flushed with PBS to clear the organs of blood, and the CYA content of blood, kidney, liver, brain, thymus, spleen, heart, lung, muscle and femur were measured by scintillation counting. Hemoglobin concentration in each tissue was negligible. Tissue uptake was expressed as the ratio of activity per gm tissue/activity per ml blood. Organs susceptible to CYA toxicity, e.g., brain, kidney and liver demonstrated retention of CYA relative to blood, as did thymus and spleen. Resistant organs, i.e., heart, lung and muscle did not. The pattern of CYA distribution and clearance corresponded with the known susceptibility of organs to CYA toxicity. CYA kinetics could therefore contribute to its toxicity by means of increased retention and/or accumulation in susceptible organs.
Nitric oxide-mediated cGMP synthesis in oligodendrocytes in the developing rat brain (1997)

We investigated the nature of cGMP-synthesizing cells in the developing rat forebrain using cGMP-immunocytochemistry in combination with in vitro incubation of brain slices. When brain slices of immature rats, aged between 1 and 4 weeks, were incubated with sodium nitroprusside (SNP), a nitric oxide (NO) donor compound, in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), small round cells with a few processes in and around the corpus callosum were visualized with the cGMP-antibody. The morphology and the distribution of the cGMP-positive cells were consistent with the criteria for oligodendrocytes. Furthermore, the cGMP-positive cells expressed 2′3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) and gelsolin, which are marker proteins for oligodendrocytes. Therefore, we concluded that the cGMP-positive cells were oligodendrocytes. A subpopulation of the oligodendrocyte was found to be cGMP-immunoreactive also when slices were incubated in the absence of SNP. Furthermore, incubation of the slice in the presence of L-NAME, an inhibitor of NO synthase, but in the absence of SNP abolished cGMP immunostaining. In addition, some populations of neurons and astrocytes in restricted brain areas produced cGMP in response to the incubation with SNP as previously reported, whereas both ameboid and ramified microglial cells did not respond to the treatment. Atrial natriuretic peptide, a stimulator of particulate guanylyl cyclase, enhanced cGMP synthesis in astrocytes in some brain regions but not in oligodendrocytes. These findings indicate that oligodendrocytes in the immature rat brain express soluble guanylyl cyclase. No cGMP-positive oligodendrocytes were found in the mature rat brain, suggesting that cGMP may mediate signals related to myelinogenesis in the rat brain. GLIA 19:286–297, 1997. © 1997 Wiley-Liss, Inc.
Mouse Reporter Strain for Noninvasive Bioluminescent Imaging of Cells that Have Undergone Cre-Mediated Recombination (2003)

Conditional alleles containing LoxP recombination sites, in conjunction with Cre recombinase delivered by a variety of means, allows for spatial and temporal control of gene expression in mouse models. Here we describe a mouse strain in which a luciferase (Luc) cDNA, preceded by a LoxP-stop-LoxP (L-S-L) cassette, was introduced into the ubiquitously expressed ROSA26 locus. Mouse embryo fibroblasts derived from this strain expressed luciferase after Cre-mediated recombination in vitro. ROSA26 L-S-L-Luc/+ mice expressed luciferase in a diffuse or liver-restricted pattern, as determined by noninvasive, bioluminescent imaging, when crossed to transgenic mice in which Cre was under the control of a zygotically expressed (EIIA-Cre), or a liver-restricted (albumin-Cre), promoter, respectively. Organ-specific luciferase expression was also seen after intraparenchymal administration of an adenovirus encoding Cre. The ROSA26 L-S-L-Luc/+ strain should be useful for characterizing Cre mouse strains and for following the fate of cells that have undergone Cre-mediated recombination in vivo.
A New Concept of Drug Delivery for Acne (1998)

Adapalene is a stable naphthoic acid derivative that displays a strong retinoid agonist pharmacology. This drug controls cell proliferation and differentiation, and possesses significant anti-inflammatory action. The retinoid action of adapalene are mediated by the ligand-activated gene transcription factors retinoic acid receptors RAR beta and RAR gamma. We describe here how an aqueous gel containing adapalene was selected for the topical treatment of acne.
Obesity and Its Potential Effects on Antidepressant Treatment Outcomes in Patients with Depressive Disorders: A Literature Review (2016)

Accumulating evidence regarding clinical, neurobiological, genetic, and environmental factors suggests a bidirectional link between obesity and depressive disorders. Although a few studies have investigated the link between obesity/excess body weight and the response to antidepressants in depressive disorders, the effect of weight on treatment response remains poorly understood. In this review, we summarized recent data regarding the relationship between the response to antidepressants and obesity/excess body weight in clinical studies of patients with depressive disorders. Although several studies indicated an association between obesity/excess body weight and poor antidepressant responses, it is difficult to draw definitive conclusions due to the variability of subject composition and methodological differences among studies. Especially, differences in sex, age and menopausal status, depressive symptom subtypes, and antidepressants administered may have caused inconsistencies in the results among studies. The relationship between obesity/excess body weight and antidepressant responses should be investigated further in high-powered studies addressing the differential effects on subject characteristics and treatment. Moreover, future research should focus on the roles of mediating factors, such as inflammatory markers and neurocognitive performance, which may alter the antidepressant treatment outcome in patients with comorbid obesity and depressive disorder.
Prevalence and polymorphism of human VH3 genes. (1990)

To better understand heterogeneity of human VH genes, we have studied polymorphism among three homologous genes from VH3, the most complex human VH gene family. Sequence-specific oligonucleotide probes were used to identify the germ-line source of each gene. The fetally expressed gene 56p1, and the germ-line VH element 1.9III, were identified and shown to be distinct. Also identified was T5M10, a VH element that resembles 56p1 and 1.9III, and likely corresponds to the previously described germ-line gene, hv3005. The elements 56p1, 1.9III, and T5M10 were each polymorphic, and in 52 unrelated individuals, their prevalences were 62%, 92%, and 35%, respectively. Among individuals lacking the hybridization bands characteristic of 56p1, 1.9III, or T5M10, alternative RFLP or coding region sequence variants were not found. In the population studied, these three VH elements were present in five different combinations, and at least three haplotypes. The distribution of these VH elements indicated they are not alleles of a single locus, and 56p1 and 1.9III are probably not alleles of each other. These results suggest that polymorphism is commonplace among human VH3 genes, but that a limited number of conserved alleles dominate each locus. We conclude that heterogeneity in the VH germ-line repertoire may derive more from diversity of haplotypes than from diversity of alleles.
Ataxin-3, DNA Damage Repair, and SCA3 Cerebellar Degeneration: On the Path to Parsimony? (2015)

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominant neurodegenerative disorder, characterized by progressive ataxia, spasticity, and ocular movement abnormalities. The SCA3 gene, ATXN3, was identified in 1994 and contains a CAG repeat tract that increases from 12-41 to 62-84 in the disease state to produce ataxin-3 protein containing a polyglutamine (polyQ) expansion SCA3 is the most common inherited ataxia, yet a thorough understanding of the molecular basis of this disease has remained elusive. Initial studies found that ataxin-3 interacts with two proteins, HHR23A and HHR23B, that are both homologs of the DNA repair protein Rad23 Further work revealed ataxin-3 as a bona fide deubiquitinating enzyme More recently, ataxin-3 was shown to interact with the transcription factor FOXO4 as a transcriptional coactivator in the oxidative stress response Thus, while some very basic functions of ataxin-3 have been established, these advances have yielded nonintersecting lines of investigation and have not provided an underlying mechanism for SCA3 disease pathogenesis.
Sub-band coder with a simple adaptive bit-allocation algorithm a possible candidate for digital mobile telephony? (2005)

A sub-band coder for speech digitization with adaptive bit-allocation is studied and described. It contains a uniform filterbank of thirteen 250 Hz channels. The sub-band amplitudes are quantized by the optimal method due to Max (8). Amplitudes in bands with no bits transmitted are regenerated by noise excitation with the respective sub-band power levels. Subjective test-results for bitrates from 4.8 to 16 kbits/s are included. Experiments with background noise and transmission bit-errors are cited.
Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy (2005)

Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal disease caused by a defect of the enzyme arylsulfatase A (ARSA) that disrupts the degradation of sulfatides (Sulf) in neurons and glial cells. Therapy for MLD requires active production of ARSA in the brain to prevent demyelination and neuronal damage, and efficient delivery of ARSA to act faster than disease progression, particularly in the rapidly progressive late infantile form. We used an adeno-associated virus serotype 5 (AAV5) vector to express the human ARSA gene in the brain of MLD mouse model. We achieved rapid, extensive and long-lasting expression of the recombinant ARSA in the brain, cerebellum and brainstem from at least 3 to 15 months post-injection. Analysis of the vector genome and ARSA distribution gave evidence for in vivo cross-correction of many untransduced neurons and astrocytes. ARSA delivery rapidly reversed Sulf storage and prevented neuropathological abnormalities and neuromotor impairment. We believe that AAV5-mediated brain delivery of ARSA is a potentially efficacious therapeutic strategy for MLD patients, especially for those with rapidly progressive form of the disease.
Bovine galactosyltransferase: identification of a clone by direct immunological screening of a cDNA expression library. (1986)

A 1.3-kilobase cDNA clone (7A) coding for bovine galactosyltransferase (glycoprotein 4-beta-galactosyltransferase, EC 2.4.1.38) was isolated from a lambda gt11 expression library by immunological screening with monospecific polyclonal antisera to the affinity-purified bovine enzyme. The nucleotide sequence of this clone predicts an open reading frame that starts at the 5' end of the insert and codes for a polypeptide of 334 amino acids with Mr 37,645. Based on a Mr of 57,000 for the membrane-bound enzyme this clone accounts for approximately 61% of the coding sequence. Portions of the predicted amino acid sequence matched the six tryptic peptides isolated from affinity-purified bovine galactosyltransferase. Clone 7A hybridizes to a 4.8-kilobase bovine mRNA and identifies multiple EcoRI restriction fragments in bovine, murine, and human DNA.
A study of the effect of a resistive heat moisture exchanger (trachinaze) on pulmonary function and blood gas tensions in patients who have undergone a laryngectomy: A randomized control trial of 50 patients studied over a 6‐month period (2003)

Trachinaze is highly superior to placebo at improving subjective pulmonary parameters, including shortness of breath. It is also superior in its ability to maintain an increased peripheral tissue oxygen tension over a 6-month period.
Immunophenotype of human melanoma cells in different metastases. (1985)

The pattern of melanoma-associated antigens (MAAs) expressed on the surface of melanoma cells in 23 metastases, 15 obtained from different patients and 8 from different metastases in two patients, was studied by immunoprecipitation and sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis using monoclonal and polyclonal melanoma antisera. Though there were differences in the MAAs expressed by each melanoma, there were marked similarities as well. No more than two melanomas had a similar pattern of MAAs. However, all melanomas expressed some MAAs, and most MAAs were commonly expressed by several melanomas. Two of the MAAs studied, with molecular weights of approximately 75,000 and 95,000 to 97,000, were particularly well represented, and at least one of these two antigens was expressed by all melanoma cells. These results suggest that complete absence of tumor-associated antigens on metastatic melanoma cells is a rare phenomenon. All melanoma lines we studied expressed at least one of a restricted number of antigens. Thus despite antigenic heterogeneity, sufficient similarity remains between different melanomas to permit specific immunotherapy to be targeted to a limited number of tumor antigens.
Monoclonal antibodies to Cryptococcus neoformans capsular polysaccharide modify the course of intravenous infection in mice (1994)

Immunoglobulin G1 (IgG1) monoclonal antibodies (MAbs) to the capsular glucuronoxylomannan (GXM) were studied for their ability to modify the course of intravenous Cryptococcus neoformans infection in mice. A/J mice were given intraperitoneal injection of 1.0 mg of either a GXM-binding IgG1 MAb (2H1 or 2D10 gamma 1) or the irrelevant isotype-matched control MAb 36-65 prior to intravenous infection. Parameters used to study antibody efficacy were lung and brain tissue fungal burden, lung and brain weights, serum GXM levels, and histopathological examination of lung, brain, heart, kidney, and spleen tissues. Mice given GXM-binding MAb had significantly reduced lung tissue fungal burden as measured by CFU. In contrast to the reduction in lung tissue burden, the reduction in brain tissue burden was small and did not achieve statistical significance. Serum GXM levels were reduced in mice receiving GXM-binding MAb. Histopathological examination revealed reduced numbers of granulomas and C. neoformans organisms in the lungs, brains, and kidneys of MAb 2H1-treated mice relative to control mice. The lungs and brains of mice receiving GXM-binding MAb weighed significantly less than those of control animals, consistent with the reduced inflammation noted histologically. Subendocardial inflammation and kidney cortical infarctions were present in control infected mice but not in MAb 2H1-treated mice. Immunocytochemical staining for polysaccharide antigen revealed a marked reduction in the amount of tissue polysaccharide in mice treated with MAb 2H1 relative to control mice. The results support an useful role for passive antibody administration in C. neoformans infections.
A phosphoglycoprotein associated with taxol resistance in J774.2 cells. (1985)

Taxol is an inhibitor of cell replication that promotes the assembly of microtubules in vitro and in cells. In the murine macrophage-like cell line J774.2, a taxol-resistant subline (J7/TAX-50) has been developed in vitro by growing the cells in increasing drug concentrations. These cells, which are approximately 800-fold resistant to taxol, display some cross-resistance to colchicine, vinblastine, puromycin, doxorubicin, and actinomycin D but remain sensitive to bleomycin. Binding of radiolabeled drug to the resistant cells is reduced by approximately 90%. Resistant cells grown in the absence of drug for 10 days (J7/TAX-0D10), 1 month (J7/TAX-0D30), and 8 months (J7/TAX-0D240) regain a major portion (27, 92, and 99%, respectively) of their sensitivity to the drug. However, binding of the drug to the J7/TAX-0D30 and J7/TAX-0D240 cells is increased to only 20 and 70%, respectively, of that measured with sensitive cells. Analysis of plasma membranes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by silver staining reveals the presence of a prominent protein with an approximate molecular weight of 135,000 in the resistant line that is essentially absent from the parental line and from both of the J7/TAX-0D30 and J7/TAX-0D240 lines. Although this protein can be seen in J7/TAX-0D10, its quantity is diminished. The Mr 135,000 protein is also observed in the resistant cells when they are labeled with [3H]leucine, [35S]methionine, [3H]glucosamine, or [32P]orthophosphate. Plasma membranes from colchicine- or vinblastine-resistant J774.2 cells also contain prominent phosphoglycoproteins, with approximate molecular weights of 145,000 and 150,000, respectively. Partial purification of the Mr 135,000 glycoprotein by agarose-bound ricinus communis agglutinin I-agarose affinity chromatography indicates that it accounts for approximately 4 to 5% of total membrane protein. A Mr 100,000 phosphoglycoprotein, present in the membranes of J774.2 cells is essentially absent in J7/TAX-50 cells after labeling with [3H]glucosamine or [32P]orthophosphate. Phosphoamino acid analysis of the Mr 135,000 and 100,000 phosphoglycoproteins reveals that the phosphorylation sites are serine and threonine residues. There appears to be a good correlation between the presence of the Mr 135,000 phosphoglycoprotein in plasma membranes and resistance to taxol.
Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms (2013)

Despite intense efforts to identify cancer-initiating cells in malignant brain tumours, markers linked to the function of these cells have only very recently begun to be uncovered. The notion of cancer stem cell gained prominence, several molecules and signalling pathways becoming relevant for diagnosis and treatment. Whether a substantial fraction or only a tiny minority of cells in a tumor can initiate and perpetuate cancer, is still debated. The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis. In contrast, acute leukaemia transformation of such blood neoplasms appears to derive not only from HSCs but also from committed progenitors that cannot differentiate. This review will focus on putative novel therapy targets represented by markers described to define cancer stem/initiating cells in malignant gliomas, which have been called 'leukaemia of the brain', given their rapid migration and evolution. Parallels are drawn with other cancers, especially haematopoietic, given the similar rampant proliferation and treatment resistance of glioblastoma multiforme and secondary acute leukaemias. Genes associated with the malignant conditions and especially expressed in glioma cancer stem cells are intensively searched. Although many such molecules might only coincidentally be expressed in cancer-initiating cells, some may function in the oncogenic process, and those would be the prime candidates for diagnostic and targeted therapy. For the latter, combination therapies are likely to be envisaged, given the robust and plastic signalling networks supporting malignant proliferation.
The Mitochondrial Permeability Transition Pore is Modulated by Oxidative Agents Through Both Pyridine Nucleotides and Glutathione at Two Separate Sites (1996)

We studied the modulation of the permeability transition pore (MTP), a cyclosporin-A-sensitive channel, in deenergized mitochondria. Rat liver mitochondria were incubated in a potassium gluconate medium and treated with uncoupler, valinomycin, oligomycin and A23187. Under these conditions the membrane and Donnan potentials are collapsed, and no ion gradients are maintained, allowing the study of the dependence of MTP opening on the Ca2+ concentration under a variety of oxidative conditions without the complexities arising from changes of the membrane potential and matrix pH, and from secondary-ion redistribution. Cross-linking of mitochondrial dithiols with arsenite or phenylarsine oxide, or treatment with tert-butylhydroperoxide leading to complete oxidation of glutathione, increased the sensitivity of MTP opening to Ca2+. This effect could be fully prevented by prior treatment of mitochondria with monobromobimane and restored by reduction with dithiothreitol. The effect of tert-butylhydroperoxide was not additive with that of AsO, and it was completely blocked by modification of reduced glutathione with 1-chloro 2,4-dinitrobenzene through glutathione-S-transferase, indicating that oxidized glutathione affects the pore through the AsO-reactive and PhAsO-reactive dithiol. Oxidation of mitochondrial pyridine nucleotides by a variety of treatments also increased the sensitivity of MTP opening to Ca2+ under conditions where glutathione was maintained in the reduced state. This effect could be fully prevented when reduced pyridine nucleotides levels were reestablished with 2-hydroxybutyrate but not by treatment with monobromobimane or dithiothreitol. The effects of dithiol cross-linking or oxidation, and of pyridine nucleotide oxidation on the MTP were additive. The contribution of each of these two oxidative events, when they were induced at the same time, could still be selectively blocked by monobromobimane and dithiothreitol. The effects of dithiol cross-linking or oxidation, and of pyridine nucleotide oxidation on the MTP were additive. The contribution of each of these two oxidative events,when they were induced at the same time, could still be selectively blocked by monobromobimane and dithiothreitol, or by 2-hydroxybutyrate, respectively. Complete oxidation of pyridine nucleotides did not affect the reactivity of the dithiol towards monobromobimane, indicating that it remained in the reduced state. After transient opening of the MTP, sensitivity to pyridine nucleotide oxidation was lost while sensitivity to dithiol cross-linking was retained. These data indicate that the dithiol belongs to an MTP regulatory component which is larger than the MTP cutoff of about 1500 Da, or is non-diffusible. Taken together, these findings indicate that the MTP is influenced by oxidation-reduction events at two separate sites that can be distinguished experimentally, and that these sites are not connected by common oxidation-reduction intermediates other than glutathione.
Deuterium labelling of the GABA agonists THIP, piperidine‐4‐sulphonic acid and the gaba uptake inhibitor THPO (1982)

Abstract The preparations of deuterium labelled THIP ([7, 7‐ 2 H] 4, 5, 6, 7‐tetrahydroisoxazolo [5, 4‐ c ]pyridin‐3‐ol) ( 7 ) and THPO ([4, 4, 7‐ 2 H] 4, 5, 6, 7‐tetrahydroisoxazo‐lo[4, 5‐ c ]pyridin‐3‐ol) ( 14 ) are described. [7, 7‐ 2 H]‐THIP ( 7 ) was synthesized by triethylamine catalyzed exchange of hydrogen for deuterium in 3‐methoxy‐6‐nitroso‐4, 5, 6, 7‐tetrahydroisoxazolo [5, 4‐ c ] pyridine ( 5 ) using deuterium oxide, followed by acid catalyzed denitrosation and demethylation. A similar reaction sequence was employed for the preparation of [4, 4, 7‐ 2 H]THPO ( 14 ), though the exchange reaction on the N ‐nitroso intermediate 12 required strongly basic conditions. Deuterium labelled P4S (piperidine‐4‐sulphonic acid) ( 17 ) was synthesized by catalytic deuteration of pyridine‐4‐sulphonic acid ( 16 ). The structures of the deuterated compounds 6, 7, 13, 14 , and 17 were established using 1 H NMR spectroscopy, in the case of 17 supported by mass spectrometry.