gebhart/patrepeval huggingface dataset:
Impaired Contextual Modulation of Memories in PTSD: An fMRI and Psychophysiological Study of Extinction Retention and Fear Renewal (2014)

Post-traumatic stress disorder (PTSD) patients display pervasive fear memories, expressed indiscriminately. Proposed mechanisms include enhanced fear learning and impaired extinction or extinction recall. Documented extinction recall deficits and failure to use safety signals could result from general failure to use contextual information, a hippocampus-dependent process. This can be probed by adding a renewal phase to standard conditioning and extinction paradigms. Human subjects with PTSD and combat controls were conditioned (skin conductance response), extinguished, and tested for extinction retention and renewal in a scanner (fMRI). Fear conditioning (light paired with shock) occurred in one context, followed by extinction in another, to create danger and safety contexts. The next day, the extinguished conditioned stimulus (CS+E) was re-presented to assess extinction recall (safety context) and fear renewal (danger context). PTSD patients showed impaired extinction recall, with increased skin conductance and heightened amygdala activity to the extinguished CS+ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CS+E and lower activity in amygdala and ventral-medial prefrontal cortex compared with combat controls. Control subjects displayed appropriate contextual modulation of memory recall, with extinction (safety) memory prevailing in the safety context, and fear memory prevailing in the danger context. PTSD patients could not use safety context to sustain suppression of extinguished fear memory, but they also less effectively used danger context to enhance fear. They did not display globally enhanced fear expression, but rather showed a globally diminished capacity to use contextual information to modulate fear expression.
PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding (2000)

The lineage-specific transcription factors GATA-1 and PU.1 can physically interact to inhibit each other's function, but the mechanism of repression of GATA-1 function by PU.1 has not been elucidated. Both the N terminus and the C terminus of PU.1 can physically interact with the C-terminal zinc finger of GATA-1. It is demonstrated that the PU.1 N terminus, but not the C terminus, is required for inhibiting GATA-1 function. Induced overexpression of PU.1 in K562 erythroleukemia cells blocks hemin-induced erythroid differentiation. In this system, PU.1 does not affect the expression of GATA-1 messenger RNA, protein, or nuclear localization. However, GATA-1 DNA binding decreases dramatically. By means of electrophoretic mobility shift assays with purified proteins, it is demonstrated that the N-terminal 70 amino acids of PU.1 can specifically block GATA-1 DNA binding. In addition, PU.1 had a similar effect in the G1ER cell line, in which the GATA-1 null erythroid cell line G1E has been transduced with a GATA-1-estrogen receptor fusion gene, which is directly dependent on induction of the GATA-1 fusion protein to effect erythroid maturation. Consistent with in vitro binding assays, overexpression of PU.1 blocked DNA binding of the GATA-1 fusion protein as well as GATA-1-mediated erythroid differentiation of these G1ER cells. These results demonstrate a novel mechanism by which function of a lineage-specific transcription factor is inhibited by another lineage-restricted factor through direct protein-protein interactions. These findings contribute to understanding how protein-protein interactions participate in hematopoietic differentiation and leukemogenesis. (Blood. 2000;96:2641-2648)
The Role of the Thermal Hysteresis Factor in Tenebrio Molitor Larvae (1978)

ABSTRACT The haemolymph of larvae of Tenebrio molitor contains a factor which produces a thermal hysteresis (a difference between the freezing and melting points) of approximately 0·75 °C. When larvae were acclimated to low temperatures or short photoperiod the thermal hysteresis increased more than twofold. Coincident with the increase in thermal hysteresis the supercooling points and lower lethal temperatures of the larvae were depressed. Therefore, the thermal-hysteresis-producing factor seems to function as an antifreeze. The factor may also act as an adaptation to prevent desiccation. Thermal hysteresis increased almost three-fold in larvae acclimated to low relative humidity. Also, larvae with high levels of the thermal hysteresis factor survived low relative humidities much better than did larvae with lower levels.
Exon Circularization Requires Canonical Splice Signals (2014)

Circular RNAs (circRNAs), an abundant class of noncoding RNAs in higher eukaryotes, are generated from pre-mRNAs by circularization of adjacent exons. Using a set of 15 circRNAs, we demonstrated their cell-type-specific expression and circular versus linear processing in mammalian cells. Northern blot analysis combined with RNase H cleavage conclusively proved a circular configuration for two examples, LPAR1 and HIPK3. To address the circularization mechanism, we analyzed the sequence requirements using minigenes derived from natural circRNAs. Both canonical splice sites are required for circularization, although they vary in flexibility and potential use of cryptic sites. Surprisingly, we found that no specific circRNA exon sequence is necessary and that potential flanking intron structures can modulate circularization efficiency. In combination with splice inhibitor assays, our results argue that the canonical spliceosomal machinery functions in circRNA biogenesis, constituting an alternative splicing mode.
Truth Telling, Confidentiality, and the Dying Patient: New Dilemmas for the Nurse (1989)

The issues of truth telling and confidentiality, although less dramatic than foregoing life-sustaining treatments, are among the most important for any professionally moral relationship between a dying patient and nurse. The ethical dilemmas for the nurse caught in the middle are described. The interdependence of truth telling and keeping confidences is discussed. Guidelines for open communication and empathic listening are suggested.
Interleukin-12 Production Is Required for Chlamydial Antigen-Pulsed Dendritic Cells To Induce Protection against LiveChlamydia trachomatisInfection (1999)

Immunization with dendritic cells pulsed ex vivo with antigens has been successfully used to elicit primary antigen-specific immune responses. We report that mouse bone marrow-derived dendritic cells pulsed with inactivated chlamydial organisms induced strong protection against live chlamydial infection in a mouse lung infection model. Either the dendritic cells or chlamydial organisms alone or macrophages similarly pulsed with chlamydial organisms failed to induce any significant protection. These observations suggest that dendritic cells can efficiently process and present chlamydial antigens to naive T cells in vivo. Mice immunized with the chlamydia-pulsed dendritic cells preferentially developed a Th1 cell-dominant response while mice immunized with the other immunogens did not, suggesting a correlation between a Th1 cell-dominant response and protection against chlamydial infection. We further found that dendritic cells produced a large amount of interleukin 12 (IL-12) upon ex vivo pulsing with inactivated chlamydial organisms, which may allow the dendritic cells to direct a Th1 cell-dominant response. Dendritic cells from mice deficient in the IL-12 p40 gene failed to produce IL-12 after a similar ex vivo pulse with chlamydial organisms, and more importantly, immunization with these dendritic cells failed to induce a Th1 cell-dominant response and did not induce strong protection against chlamydial infection. Thus, the ability of dendritic cells to efficiently process and present chlamydial antigens and to produce IL-12 upon chlamydial-organism stimulation are both required for the induction of protection against chlamydial infection. This information may be useful for the further design of effective chlamydial vaccines.
A Single Residue at the Active Site of CD38 Determines Its NAD Cyclizing and Hydrolyzing Activities (2001)

CD38 is a multifunctional enzyme involved in metabolizing two Ca(2+) messengers, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). When incubated with NAD, CD38 predominantly hydrolyzes it to ADP-ribose (NAD glycohydrolase), but a trace amount of cADPR is also produced through cyclization of the substrate. Site-directed mutagenesis was used to investigate the amino acid important for controlling the hydrolysis and cyclization reactions. CD38 and its mutants were produced in yeast, purified, and characterized by immunoblot. Glu-146 is a conserved residue present in the active site of CD38. Its replacement with Phe greatly enhanced the cyclization activity to a level similar to that of the NAD hydrolysis activity. A series of additional replacements was made at the Glu-146 position including Ala, Asn, Gly, Asp, and Leu. All the mutants exhibited enhanced cyclase activity to various degrees, whereas the hydrolysis activity was inhibited greatly. E146A showed the highest cyclase activity, which was more than 3-fold higher than its hydrolysis activity. All mutants also cyclized nicotinamide guanine dinucleotide to produce cyclic GDP. This activity was enhanced likewise, with E146A showing more than 9-fold higher activity than the wild type. In addition to NAD, CD38 also hydrolyzed cADPR effectively, and this activity was correspondingly depressed in the mutants. When all the mutants were considered, the two cyclase activities and the two hydrolase activities were correlated linearly. The Glu-146 replacements, however, only minimally affected the base-exchange activity that is responsible for synthesizing NAADP. Homology modeling was used to assess possible structural changes at the active site of E146A. These results are consistent with Glu-146 being crucial in controlling specifically and selectively the cyclase and hydrolase activities of CD38.
Glycosylhydrazine, 6. Synthese von Pyrazol‐, Pyrazolo[3,4‐d]pyrimidin‐und 1H‐1,2,4‐Triazolgluconucleosiden aus Glucosehydrazonen (1981)

Abstract 2,3,4,6‐Tetra‐ O ‐benzyl‐D‐glucosehydrazon ( 5b ) lieferte mit Acetylaceton, (Ethoxymethylen)malodinitril, (Ethoxymethylen)cyanessigester und (Aminomethylen)cyanacetamid in einem Reaktionsschritt nach zweifachem Ringschluß regio‐ und diastereoselektiv die β‐verknüpften Pyrazolgluconucleoside 6b, 12b, 13b und 14b . Die Nucleoside 12b und 13b wurden in die ungeschützten Pyrazolo[3,4‐ d ]pyrimidingluconucleoside 15a und 16a (Analoge des Adenosins bzw. Inosins) übergeführt. Entsprechend wurde aus 5b und N ‐(Ethoxymethylen)oxalsäureestermonoamid in einem Schritt der β‐verknüpfte Glucopyranosyl‐1 H ‐1,2,4‐triazol‐5‐carbonsäureester 20 und mit aktvierten Ameisensäurederivaten das unsubstituierte 1 H ‐1,2,4‐Triazolderivat 22 erhalten.
Construction and Pre-Clinical Evaluation of An Anti-CD19 Chimeric Antigen Receptor (2008)

Abstract Adoptive T cell immunotherapy can cause regression of established malignancy. One promising approach is to transfer genes encoding chimeric antigen receptors (CARs) that specifically recognize tumor-associated antigens to T cells before the T cells are adoptively transferred to patients. We have constructed a CAR that consists of an anti-CD19 single chain variable region (scFv) that is coupled to a portion of the CD28 costimulatory molecule and the signaling component of the CD3-zeta chain. CD19 is a promising target for immunotherapy because most malignant B cell express CD19, but the only normal cells that express CD19 are B cells, B cell precursors, and perhaps follicular dendritic cells. We have demonstrated that gamma-retroviruses encoding the anti-CD19 CAR can be used to transduce human T cells and that these transduced T cells specifically recognize CD19+ targets. To transduce T cells, we stimulated T cells with the anti-CD3 monoclonal antibody OKT3 on day 0 then conducted sequential retroviral transductions on day 2 and on day 3. Transductions were performed by spin-loading retroviruses onto RetroNectin (Takara) coated culture plates followed by overnight incubation of the OKT3- stimulated T cells on the plates. Forty-five to sixty-seven percent of T cells expressed the anti-CD19 CAR as measured by flow cytometry 7–8 days after transduction (n=8). Anti-CD19-CAR-transduced CD8+ and CD4+ T cells produced IFNg and IL-2 specifically in response to stimulation with CD19+ target cells. The transduced T cells specifically killed primary chronic lymphocytic leukemia (CLL) cells. T cells from CLL patients that were either untreated or previously treated with fludarabine plus rituximab could be transduced and induced to proliferate sufficiently to provide enough cells for clinical adoptive T cell transfer. In addition, we adapted this protocol for use in CLL patients with very high peripheral blood leukemia cell counts by depleting CD19+ cells using magnetic bead sorting prior to OKT3 stimulation. In preparation for a clinical trial that will enroll patients with advanced B cell malignancies, we have generated a producer cell clone that produces GALV (Gibbon ape leukemia virus)-enveloped gamma-retroviruses encoding the anti-CD19 CAR, and we have produced sufficient retroviral supernatant for the proposed clinical trial under good manufacturing practice (GMP) conditions.
INDUCTION OF LONG-TERM SPECIFIC TOLERANCE TO ALLOGRAFTS IN RATS BY THERAPY WITH AN ANTI-CD3-LIKE MONOCLONAL ANTIBODY (1993)

Monoclonal antibodies to CD3 have been shown to activate T cells in vivo and in vitro but have also been shown to render T cells anergic in vitro. In this study G4.18, a mouse IgG3 mAb, was produced that appeared to recognize CD3 by its binding to all peripheral T cells, including a population not recognized by mAb to TCR-alpha/beta that was presumed to be TCR-gamma/delta cells. It precipitated molecules in the 24-26 kd region consistent with the CD3 complex as well as molecules approximately 45 and approximately 49 kd that corresponded to TCR alpha and beta chains and a 92-kd complex. Incubating T cells for 24 hr with saturating concentrations of G4.18 caused modulation of the TCR complex. In vitro, it activated T cells but only if prebound to plastic. In solution it inhibited MLC and CML, but not PHA or Con A activation. In vivo, G4.18 was not toxic even in high doses, and this was thought to be due to the inability of this mAb to activate T cells in vitro because the rat lacks Fc receptors for mouse IgG3. Therapy with G4.18 resulted in transient modulation of TCR/CD3 on T cells and depletion of these cells from blood. G4.18 had no depleting effects by lymph node or spleen cells but caused marked, transient thymic involution. Therapy with G4.18 also induced indefinite survival (> 100 days) of PVG (RTIc) heart grafts but not skin grafts in DA (RTIa) hosts. These hosts with long-surviving cardiac transplants, when grafted from PVG skin, accepted these grafts but rejected third-party skin in first-set. Thus G4.18 was shown to induce long-term specific tolerance to an organ allograft.
An intravitreal biodegradable sustained release naproxen and 5-fluorouracil system for the treatment of experimental post-traumatic proliferative vitreoretinopathy (2004)

The results suggest that this NA/5-FU codrug device effectively inhibits the progression of PVR in a rabbit trauma model that closely resembles PVR in humans. Additional studies to add knowledge to these initial findings and to clarify the potential of the codrug device for the treatment of human PVR are warranted.
Nowcasting Euro Area Economic Activity in Real-Time: The Role of Confidence Indicators (2009)

This paper assesses the role of surveys for the early estimates of GDP in the euro area in a model-based automated procedures which exploits the timeliness of their release. The analysis is conducted using both an historical evaluation and a real time case study on the current conjuncture.
Antioxidant Vitamins and Prevention of Lung Disease (1992)

Although the evidence for oxidative stress for air pollution in the human lung is fragmentary, the hypothesis that oxidative stress is an important, if not the sole, mechanism of toxicity of oxidizing air pollutants and tobacco smoke is compelling and growing. First, biochemical mechanisms have been worked out for oxidation of lung lipids by the gas phase of cigarette smoke, NO2 and O3. The oxidation of lung lipids can be prevented by both vitamins C and E. Vitamin C is more effective in preventing oxidation by NO2, and vitamin E is more effective against O3. Second, multiple species of experimental animals develop lung disease similar to human bronchitis and emphysema from exposure to NO2 and O3, respectively. The development of these diseases occurs over a near lifetime exposure when the levels of NO2 or O3 are at near ambient air pollution values. Third, isolated human cells are protected against oxidative damage from NO2 and O3 by both vitamins C and E. Fourth, the vitamin C level in the lung either declines on exposure to NO2 for short-term exposures or increases on chronic cigarette smoke exposure. The effects of cigarette smoking on serum vitamin C is apparently complex and may be related to the daily intake of vitamin C as well as smoking. Serum vitamin C levels may be poor indicators of lung demands when daily vitamin C intakes are above 100 mg/day. Fifth, vitamin C supplementation protects against the effects of ambient levels of air pollution in adults as measured by histamine challenge. An augmented response to histamine challenge may represent increased lung permeability brought about by air pollution. In experimental animal and human experiments, the amount of vitamin C or E that afforded protection was in excess of the current recommended dietary allowance. Although animal studies do not provide evidence for complete protection against NO2 or O3, they do illustrate that current recommended daily allowances are inadequate for maximum protection against air pollution levels to which over 100 million Americans are exposed. The problem of air pollution and its effects on humans is truly of global concern. Air pollution is not restricted to North America or Japan where it was first recognized, but is a major public health problem in Europe as well. When data are available, air pollution probably will be shown to be a major public health problem in all urban areas of the world.(ABSTRACT TRUNCATED AT 400 WORDS)
Physical and sexual abuse history and addiction treatment outcomes. (2002)

Individuals with substance use disorders who have a history of physical or sexual abuse may have higher risk for problematic treatment outcomes as a result of greater psychiatric problems, deficits in social support and possible difficulties in establishing treatment alliance. Clinicians may consider increasing the duration and intensity of treatment to temper the negative effects of abuse on later functioning.
Prostacyclin Stimulation of the Activation of Blood Coagulation Factor X by Platelets (1986)

When platelets were incubated with prostacyclin, prostaglandin E1, or prostaglandin D2 at concentrations insufficient to increase the level of adenosine 3',5'-monophosphate (cyclic AMP), coagulation factor X was activated by a platelet cysteine protease. Prostacyclin or prostaglandin E1 at higher concentrations increased the cyclic AMP level and inhibited the activation of factor X by platelets. Inhibition of platelet adenylate cyclase by 2',5'-dideoxyadenosine allowed the activation of the protease at higher concentrations of the autocoids. Prostaglandins A1, A2, B1, B2, E2, F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2, which do not affect platelet cyclic AMP level, did not stimulate the protease.
Current progress and future prospects of liposomes in dermal drug delivery (1993)

Liposomes were introduced first in 1980 for topical drug delivery and since then have attracted considerable interest and generated many speculative claims concerning their potential utility both as a drug carrier and reservoir for controlled release of drugs within various layers of the skin. A number of clinical studies have now demonstrated the superiority of liposomal drug formulations over conventional delivery systems. In this respect, liposomal formulations have been successful in treatment of a number of dermatological diseases and disorders such as psoriasis, mycoses, idiopathic hirsutism and cutaneous infections. This review emphasizes the evaluation of topically applied liposomal formulation both at experimental and clinical levels. Mechanism(s) by which liposomes facilitate deposition of drugs in various layers of the skin is also discussed.
Chronic Sinus Disease with Associated Reactive Airway Disease in Children (1984)

Sinus disease has been described as one of several aggravating factors for chronic adult-onset asthma. Forty-eight children whose reactive airway disease (asthma) was significantly improved with treatment of their sinusitis have been observed. All of the subjects were seen in the office with chronic (more than 3 months) respiratory symptoms; all had daytime and nighttime cough and/or wheeze. The 48 children (32 male and 16 female) had a mean age of 8.2 +/- 1.2 (SD) years (range 4 to 13 years). Fourteen (35%) were nonatopic as determined by family history, personal history, and skin test reactivity to inhalant and pollen antigens. Eighteen of the patients were receiving or had recently received oral corticosteroids. All had been taking bronchodilators daily for at least 3 months without adequate control of the asthma. Sinus radiographs (Waters view) revealed the following abnormalities of the maxillary sinuses: greater than 6 mm of mucosal thickening (ten children [21%]), one opacified (12 children [25%]), bilateral opacification (18 children [38%]) and air fluid level(s) (eight children [17%]). All children were treated with antimicrobial agents for 2 to 5 weeks. Thirty-nine responded both clinically and radiologically. Antral lavage was performed in nine children. Of the 48 subjects, 38 (79%) were able to discontinue taking the bronchodilators with resolution of their sinusitis. It is concluded that sinus disease in children may be an aggravating factor for chronic reactive airway disease and that proper, aggressive treatment of the former will notably improve the latter.
A Molecular Switch in Amyloid Assembly:  Met35and Amyloid β-Protein Oligomerization (2003)

Aberrant protein oligomerization is an important pathogenetic process in vivo. In Alzheimer's disease (AD), the amyloid β-protein (Aβ) forms neurotoxic oligomers. The predominant in vivo Aβ alloforms, Aβ40 and Aβ42, have distinct oligomerization pathways. Aβ42 monomers oligomerize into pentamer/hexamer units (paranuclei) which self-associate to form larger oligomers. Aβ40 does not form these paranuclei, a fact which may explain the particularly strong linkage of Aβ42 with AD. Here, we sought to determine the structural elements controlling paranucleus formation as a first step toward the development of strategies for treating AD. Because oxidation of Met35 is associated with altered Aβ assembly, we examined the role of Met35 in controlling Aβ oligomerization. Oxidation of Met35 in Aβ42 blocked paranucleus formation and produced oligomers indistinguishable in size and morphology from those produced by Aβ40. Systematic structural alterations of the Cγ35-substituent group revealed that its electronic nature, rather than its size (van der Waals volume), was the factor controlling oligomerization pathway choice. Preventing assembly of toxic Aβ42 paranuclei through selective oxidation of Met35 thus represents a potential therapeutic approach for AD.