Frailty: an in-depth qualitative study exploring the views of community care staff.

BACKGROUND: Frailty is seen across various health and social care settings. However, little is known about how healthcare professionals, particularly those who provide care for older adults living in the community view frailty. There is also a dearth of information about the extent to which a shared understanding of frailty exists across the various disciplines of care. Such an understanding is crucial across care professionals as it ensures consistent assessment of frailty and facilitates interdisciplinary working/collaboration which is a key component in the management of frailty. This study aimed to explore: (i) how community care staff from various specialties viewed frailty; (ii) whether they had a shared understanding; and (iii) how they assessed frailty in everyday practice. METHODS: Semi-structured interviews were conducted with a purposive sample of 22 community care staff from seven specialties, namely: healthcare assistants, therapy assistants, psychiatric nurses, general nurses, occupational therapists, physiotherapists and social workers, recruited from four neighbourhood teams across Cambridgeshire, England. Interviews were analysed thematically. RESULTS: There was a shared narrative among participants that frailty is an umbrella term that encompasses interacting physical, mental health and psychological, social, environmental, and economic factors. However, various specialities emphasised the role of specific facets of the frailty umbrella. The assessment and management of frailty was said to require a holistic approach facilitated by interdisciplinary working. Participants voiced a need for interdisciplinary training on frailty, and frailty tools that facilitate peer-learning, a shared understanding of frailty, and consistent assessment of frailty within and across specialities. CONCLUSIONS: These findings underscore the need to: (i) move beyond biomedical descriptions of frailty; (ii) further explore the interacting nature of the various components of the frailty umbrella, particularly the role of modifiable factors such as psychological and socioeconomic resilience; (iii) care for frail older adults using holistic, interdisciplinary approaches; and (iv) promote interdisciplinary training around frailty and frailty tools to facilitate a shared understanding and consistent assessment of frailty within and across specialities.

Utility of the Spanish version of the Everyday Cognition scale in the diagnosis of mild cognitive impairment and mild dementia in an older cohort from the Argentina-ADNI.

INTRODUCTION: The performance of activities of daily living in elderly patients with memory disorders is directly related to living independently and to autonomy. Documenting and assessing functional capacity through detailed scales is important for both diagnostic and treatment recommendations. The Everyday Cognition (ECog) scale is a relatively new informant-rated measure of cognitive and functional abilities. In the present study, the discriminant validity of the ECog scale was evaluated in cognitively intact controls (CN) and in patients with mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) from the Argentina-ADNI cohort to establish diagnostic accuracy. In addition, we compared the sensitivity and specificity of ECog against Functional Assessment Questionnaire (FAQ) scale to discriminate among the three groups. METHODS: We evaluated 15 CN, 28 MCI, and 13 mild AD subjects. External, convergent and divergent validity and internal consistency were examined. RESULTS: The average total score on the ECog was significantly different across the three diagnostic syndromes (p < .05). The ECog was more sensitive than FAQ in discriminating between CN and MCI patients and between MCI and AD subjects. The ECog showed a strong correlation with FAQ, and moderate correlations with neuropsychological tests. Cronbach's alpha was .98. CONCLUSIONS: The ECog scale is an efficient instrument for the differentiation of individuals with mild dementia or MCI from normal older adults, with good accuracy and good correlation with other tests measuring daily and cognitive functions. Comparing against FAQ, ECog was more useful in assessing changes in functionality in MCI patients.

Substituent and solvent effects on the UV-vis absorption spectrum of the photoactive yellow protein chromophore.

Solvent effects on the UV-vis absorption spectra and molecular properties of four models of the photoactive yellow protein (PYP) chromophore have been studied with ASEP/MD, a sequential quantum mechanics/molecular mechanics method. The anionic trans-p-coumaric acid (pCA(-)), thioacid (pCTA(-)), methyl ester (pCMe(-)), and methyl thioester (pCTMe(-)) derivatives have been studied in gas phase and in water solution. We analyze the modifications introduced by the substitution of sulfur by oxygen atoms and hydrogen by methyl in the coumaryl tail. We have found some differences in the absorption spectra of oxy and thio derivatives that could shed light on the different photoisomerization paths followed by these compounds. In solution, the spectrum substantially changes with respect to that obtained in the gas phase. The n → π1* state is destabilized by a polar solvent like water, and it becomes the third excited state in solution displaying an important blue shift. Now, the π → π1* and π → π2* states mix, and we find contributions from both transitions in S1 and S2. The presence of the sulfur atom modulates the solvent effect and the first two excited states become practically degenerate for pCA(-) and pCMe(-) but moderately well-separated for pCTA(-) and pCTMe(-).

[Nocturnal continuous subcutaneous infusion of apomorphine in advanced Parkinson's disease: a series of 37 cases]. / Uso de infusión subcutánea continua nocturna de apomorfina en la enfermedad de Parkinson avanzada: una serie de 37 casos.

INTRODUCTION: Multiple factors can cause sleep disturbances in Parkinson's disease. The quality of sleep and therefore of life is usually improved with continuous dopaminergic stimulation therapies, such as continuous subcutaneous infusion of apomorphine. PATIENTS AND METHODS: We present an observational retrospective study of patients at our centre with advanced Parkinson's disease, treated with continuous infusion of apomorphine, with treatment extended to nights, between 2011 and 2022. We collected data from 37 patients, and evaluated the indication for nocturnal treatment, efficacy, safety and reasons for withdrawal. RESULTS: Fifty percent of patients began nocturnal treatment for motor complications, 19% for non-motor complications and 31% for both. The most common non-motor symptoms were sleep fragmentation and disturbances, neuropathic pain, psychiatric symptoms and intense nocturia. Twenty of the 37 patients (54%) were continuing treatment at the end of the study follow-up, 16 (43%) discontinued the infusion, and one (3%) was lost to follow-up. The adverse reactions that led to termination of the infusion were severe nodules (two), dopaminergic psychosis (one) and a positive Coombs test with/without anaemia (one). Four patients terminated the nocturnal infusions while continuing the daytime infusions due to suboptimal adaptation to the device. Patients whose symptoms improved without any significant adverse effects continued the treatment. CONCLUSIONS: Continuous infusion of apomorphine during the night was an effective and safe treatment in our series.

TITLE: Uso de infusión subcutánea continua nocturna de apomorfina en la enfermedad de Parkinson avanzada: una serie de 37 casos.Introducción. Existen múltiples factores que pueden causar alteraciones del sueño en la enfermedad de Parkinson. La calidad del sueño y, por ende, de vida suele mejorar con terapias de estimulación dopaminérgica continua, como la infusión subcutánea continua de apomorfina. Pacientes y métodos. Presentamos un estudio observacional, retrospectivo, en pacientes con enfermedad de Parkinson avanzada tratados con infusión continua de apomorfina a los que se extendió el tratamiento al período nocturno en nuestro centro desde 2011 hasta 2022. Recopilamos datos de 37 pacientes en los que evaluamos la indicación de uso nocturno, eficacia, seguridad y motivos de retirada. Resultados. El 50% de los pacientes inició el tratamiento nocturno por complicaciones motoras, el 19% por complicaciones no motoras y el 31% por ambas. Los síntomas no motores más comunes fueron: fragmentación y alteraciones del sueño, dolor neuropático, síntomas psiquiátricos y nicturia intensa. De los 37 pacientes, 20 (54%) continuaban con el tratamiento al final del seguimiento del estudio, 16 (43%) discontinuaron la infusión y se perdió el seguimiento de uno (3%). Las reacciones adversas que llevaron a finalizar la infusión fueron: nódulos graves (dos), psicosis dopaminérgica (uno) y Coombs + con/sin anemia (uno). Cuatro pacientes finalizaron la infusión nocturna manteniendo la infusión diurna por adaptación subóptima al dispositivo. Continuaron el tratamiento los pacientes que presentaron mejoría sintomática sin efectos adversos significativos. Conclusiones. La apomorfina en infusión continua durante el período nocturno fue un tratamiento eficaz y seguro en nuestra serie.

Relevance of the serial position effect in the differential diagnosis of mild cognitive impairment, Alzheimer-type dementia, and normal ageing.

UNLABELLED: Serial position effects are observed when a person memorises a series of words exceeding his or her attention span. Cognitively normal individuals recall words at the beginning and end of the list more frequently than those in the middle, which reflects the way that short- and long-term episodic memory works. OBJECTIVE: To study the serial position effect in patients with mild cognitive impairment (MCI) compared to subjects with Alzheimer-type dementia (AD) or normal ageing (NA). METHODS: 30 AD, 25 MCI and 20 NA subjects underwent neurological and neuropsychological assessment. The Rey Auditory Verbal Learning Test (RAVLT) was used to study primacy, middle, and recency effects and delayed recall for each group. RESULTS: The general memory pattern of MCI subjects was very similar to that of AD subjects, and was characterised by reduced learning capacity, rapid forgetfulness and clear recency effect in learning. With regard to delayed recall, however, there were differences in performance; MCI subjects' ability to recall words at the beginning and middle of the list was similar to that of normal subjects, while their memory of words at the end of the list was poor, as in AD subjects. CONCLUSIONS: RAVLT is a tool permitting us to distinguish between MCI and NA subjects. The recency index for the delayed recall task is a valid indicator for distinguishing between MCI patients and patients with normal ageing.

[Bibliometric analysis of the thematic evolution in fibromyalgia and biomechanics (1985-2021)]. / Análisis bibliométrico de la evolución temática en fibromialgia y biomecánica (1985-2021).

The main objective of the study is to analyse the scientific evolution of the research field of fibromyalgia and biomechanics. A search was carried out in Web of Science, from 1985 to 2021. With those results, a bibliometric map of keywords was created with VOSviewer. On top of that, scientific mapping and performance analysis were also conducted using SciMAT. A total of 233 articles from around the world were analysed, highlighting the production of the USA and Spain. The results show great diversity in topics with 54 different topics and 33 keywords. Although most of the topics found are not widely developed except the topics of physical activity and symptomatology. In conclusion, the study of fibromyalgia and biomechanics has generally grown over time.

Quantifying electron temperature distributions from time-integrated x-ray emission spectra.

K-shell x-ray emission spectroscopy is a standard tool used to diagnose the plasma conditions created in high-energy-density physics experiments. In the simplest approach, the emissivity-weighted average temperature of the plasma can be extracted by fitting an emission spectrum to a single temperature condition. It is known, however, that a range of plasma conditions can contribute to the measured spectra due to a combination of the evolution of the sample and spatial gradients. In this work, we define a parameterized model of the temperature distribution and use Markov Chain Monte Carlo sampling of the input parameters, yielding uncertainties in the fit parameters to assess the uniqueness of the inferred temperature distribution. We present the analysis of time-integrated S and Fe x-ray spectroscopic data from the Orion laser facility and demonstrate that while fitting each spectral region to a single temperature yields two different temperatures, both spectra can be fit simultaneously with a single temperature distribution. We find that fitting both spectral regions together requires a maximum temperature of 1310-70 +90 eV with significant contributions from temperatures down to 200 eV.

An optimized MNK1b aptamer, apMNKQ2, and its potential use as a therapeutic agent in breast cancer.

Breast cancer is the most commonly diagnosed and leading cause of cancer death among women worldwide. Mitogen-activated protein kinase-interacting kinases (MNKs) promote the expression of several oncogenic proteins and are overexpressed in several types of cancer. In human cells, there are four isoforms of MNKs. The truncated isoform MNK1b, first described in our laboratory, has a higher basal activity and is constitutively active. Aptamers are emerging in recent years as potential therapeutic agents that show significant advantages over drugs of other nature. We have previously obtained and characterized a highly specific aptamer against MNK1b, named apMNK2F, with a dissociation constant in the nanomolar range, which produces significant inhibition of proliferation, migration, and colony formation in breast cancer cells. Furthermore, its sequence analysis predicted two G-quadruplex structures. In this work, we show the optimization process of the aptamer to reduce its size, improving its stability. The obtained aptamer, named apMNKQ2, is able to inhibit proliferation, colony formation, migration, and invasion in breast cancer cells. In murine models of breast cancer, apMNKQ2 has demonstrated its efficacy in reducing tumor volume and the number of metastases. In conclusion, apMNKQ2 could be used as an anti-tumor drug in the future.

Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH.

At least five adult-onset neurodegenerative diseases, including Huntingtin disease (HD), and dentatorubral-pallidoluysian atrophy (DRPLA) are produced by genes containing a variably increased CAG repeat within the coding region. The size range of the repeats is similar in all diseases; unaffected individuals have fewer than 30 CAG repeats, whereas affected patients usually have more than 40 repeats. The size of the inherited CAG repeat correlates with the severity and age of disease onset. The CAG triplet repeat produces a polyglutamine domain in the expressed proteins. All of these diseases are inherited in a dominant fashion, and a pathologic gain of function in gene carriers has been proposed. We sought to identify proteins in the brain that selectively interact with polyglutamine-domain proteins, hypothesizing that the polyglutamine domain may determine protein-protein interactions.

Canopy nitrogen, carbon assimilation, and albedo in temperate and boreal forests: Functional relations and potential climate feedbacks.

The availability of nitrogen represents a key constraint on carbon cycling in terrestrial ecosystems, and it is largely in this capacity that the role of N in the Earth's climate system has been considered. Despite this, few studies have included continuous variation in plant N status as a driver of broad-scale carbon cycle analyses. This is partly because of uncertainties in how leaf-level physiological relationships scale to whole ecosystems and because methods for regional to continental detection of plant N concentrations have yet to be developed. Here, we show that ecosystem CO(2) uptake capacity in temperate and boreal forests scales directly with whole-canopy N concentrations, mirroring a leaf-level trend that has been observed for woody plants worldwide. We further show that both CO(2) uptake capacity and canopy N concentration are strongly and positively correlated with shortwave surface albedo. These results suggest that N plays an additional, and overlooked, role in the climate system via its influence on vegetation reflectivity and shortwave surface energy exchange. We also demonstrate that much of the spatial variation in canopy N can be detected by using broad-band satellite sensors, offering a means through which these findings can be applied toward improved application of coupled carbon cycle-climate models.

A computer-aided design tool for biomedical OBT sensor tuning in cell-culture assays.

BACKGROUND AND OBJECTIVES: The biomedical engineering must frequently develop sensor designs by including information from performance of bio-samples (cell cultures or tissues), technical specifications of transducers, and constrains from electronic circuits. A computer program for real-time cell culture monitoring system design is developed; analyzing, modelling and integrating into the program design flow the electrodes, cell culture and test circuit's influences. METHODS: The computer tool, first, generates an equivalent electric circuit model for the cell-electrode bio-systems based on the area covered by cells, which also considers the cell culture dynamics. Second, proposes an Oscillation Based Test (OBT) parameterized circuit, for Electrical Cell-Substrate Sensing (ECIS) measurements of the cell culture system bioimpedance. Third, simulates electrically the full system to define the best system parameter values for the sensor. RESULTS: Reported experimental results are based on commercial gold electrodes and the AA8 cell line. Characteristics of the cell lines, as time-division or cell size, are incorporated into the program design flow, showing that for a given assay, the optimal OBT circuit parameters can be selected with the help of the computer tool. The electrical simulations of the full system demonstrate that the can be correctly predicted the output frequency and amplitude ranges of the voltage response, obtaining accurate results when cell culture approaches to confluence phase. CONCLUSION: It is proposed a computer program for system design of biosensors applied to monitoring cell culture dynamics. The program allows obtaining confident system information by electrical stimulation. All system components (electrodes, cell culture and test circuits) are properly modelled. The employed procedure can be applied to any other 2D electrode layout or alternative circuit technique for ECIS test. Finally, deep insight information on cell size, number, and time-division can be extracted from the comparison with real cell culture assays in the future.

Early events in human T cell ontogeny. Phenotypic characterization and immunohistologic localization of T cell precursors in early human fetal tissues.

During early fetal development, T cell precursors home from fetal yolk sac and liver to the epithelial thymic rudiment. From cells that initially colonize the thymus arise mature T cells that populate T cell zones of the peripheral lymphoid system. Whereas colonization of the thymus occurs late in the final third of gestation in the mouse, in birds and humans the thymus is colonized by hematopoietic stem cell precursors during the first third of gestation. Using a large series of early human fetal tissues and a panel of monoclonal antibodies that includes markers of early T cells (CD7, CD45), we have studied the immunohistologic location and differentiation capacity of CD45+, CD7+ cells in human fetal tissues. We found that before T cell precursor colonization of the thymus (7-8 wk of gestation), CD7+ cells were present in yolk sac, neck, upper thorax, and fetal liver, and were concentrated in mesenchyme throughout the upper thorax and neck areas. By 9.5 wk of gestation, CD7+ cells were no longer present in upper thorax mesenchyme but rather were localized in the lymphoid thymus and scattered throughout fetal liver. CD7+, CD2-, CD3-, CD8-, CD4-, WT31- cells in thorax and fetal liver, when stimulated for 10-15 d with T cell-conditioned media and rIL-2, expressed CD2, CD3, CD4, CD8, and WT31 markers of the T cell lineage. Moreover, CD7+ cells isolated from fetal liver contained all cells in this tissue capable of forming CFU-T colonies in vitro. These data demonstrate that T cell precursors in early human fetal tissues can be identified using a mAb against the CD7 antigen. Moreover, the localization of CD7+ T cell precursors to fetal upper thorax and neck areas at 7-8.5 wk of fetal gestation provides strong evidence for a developmentally regulated period in man in which T cell precursors migrate to the epithelial thymic rudiment.

Addenbrooke's Cognitive Examination validation in Parkinson's disease.

BACKGROUND: There is a clear need for brief, sensitive and specific cognitive screening instruments in Parkinson's disease (PD). OBJECTIVES: To study Addenbrooke's Cognitive Examination (ACE) validity for cognitive assessment of PD patient's using the Mattis Dementia Rating Scale (MDRS) as reference method. A specific scale for cognitive evaluation in PD, in this instance the Scales for Outcomes of Parkinson's disease-Cognition (SCOPA-COG), as well as a general use scale the Mini-mental state examination (MMSE) were also studied for further correlation. METHODS: Forty-four PD patients were studied, of these 27 were males (61%), with a mean (SD) age of 69.5 (11.8) years, mean (SD) disease duration of 7.6 (6.4) years (range 1-25), mean (SD) total Unified Parkinson's Disease Rating Scale (UPDRS) score 37 (24) points, UPDRS III 16.5 (11.3) points. MDRS, ACE and SCOPA-COG scales were administered in random order. All patients remained in on-state during the study. RESULTS: Addenbrooke's Cognitive Examination correlated with SCOPA-COG (r = 0.93, P < 0.0001), and MDRS (r = 0.91 P < 0.0001) and also with MMSE (r = 0.84, P < 0.001). Area under the receiver-operating curve, taking MDRS as the reference test, was 0.97 [95% confidence interval (CI): 0.92-1.00] for ACE, 0.92 (95% CI: 0.83-1.00) for SCOPA-COG and 0.91 (95% CI: 0.83-1.00) for MMSE. Best cut-off value for ACE was 83 points [Sensitivity (Se) = 92%; Specificity (Sp) = 91%; Kappa concordance (K) = 0.79], 20 points for the SCOPA-COG (Se = 92%; Sp = 87%; K = 0.74) and 26 points for MMSE (Se = 61%; Sp = 100%; K = 0.69). CONCLUSION: Addenbrooke's Cognitive Examination appears to be a valid tool for dementia evaluation in PD, with a cut-off point which should probably be set at 83 points, displaying good correlation with both the scale specifically designed for cognitive deficits in PD namely SCOPA-COG, as well as with less specific tests such as MMSE.

Update on radioguided surgery: from international consensus on sentinel node in head and neck cancer to the advances on gynaecological tumors and localization of non-palpable lesions. / Actualización en cirugía radioguiada: del consenso internacional en ganglio centinela de cabeza y cuello a los avances en tumores ginecológicos y localización de lesiones no palpables.

The aim of this review is to provide an updated perspective on different fields of radioguided surgery. With reference to the sentinel lymph node biopsy in oral squamous cell carcinoma, we present the results of the interactive debate held at the recent Congress of our specialty about the more relevant aspects of the London Consensus. Drainage peculiarities and indications according to the current guidelines on gynaecological tumours, endometrial and cervical cancer, are detailed and new scenarios for nuclear medicine physicians are presented; robotic surgery and hybrid tracers, for instance. Moreover, the notable growth in radioguided surgery indications for non-palpable lesions, widely used in mammary pathology, make it advisable to update two procedures which have shown satisfying results, such as the solitary pulmonary nodule and the osteoid osteoma.

Choroidal metastasis of a minor salivary gland adenoid cystic carcinoma: A case report. / Metástasis coroideas de un carcinoma adenoide quístico de glándula salival menor: caso clínico.

CASE REPORT: A 61-year-old man with a lower lip minor salivary gland adenoid cystic carcinoma, suffered from a unilateral progressive visual acuity loss due to choroidal metastasis. DISCUSSION: Adenoid cystic carcinoma is a rare primary tumour with significant metastatic potential. Our patient presented with a unilateral choroidal metastasis. According to the current literature, 8 cases of choroidal metastasis of salivary gland adenoid cystic carcinoma have been reported. This is the second case reported of choroidal metastasis with origin in a minor salivary gland, and the first one with origin in the minor salivary glands of the lower lip.

Review of the role of the sentinel node biopsy in neoadjuvant chemotherapy in women with breast cancer and negative or positive axillary node at diagnosis. / Actualización de la biopsia del ganglio centinela tras quimioterapia neoadyuvante en el cáncer de mama sin y con afectación ganglionar al diagnóstico.

The role of the selective sentinel node biopsy (SNB) is increasing in relevance in breast cancer women with indication of neoadjuvant chemotherapy (NAC). The Radiosurgery Working Group of the SEMNIM is aware of the necessity of establishing the need for SNB before or after NAC, and also how to manage patients with axillary node-negative or node-positive. There is sufficient data to assess that the SNB with radioisotope techniques are feasible and safe in all these scenarios. An adequate axilla evaluation prior to surgery and the possibility of marking prior to NAC the nodes infiltrated must be the two main pillars to guarantee the success of the SNB. It has been shown that to incorporate the SNB in breast cancer women with indication of NAC increases the rate of a conservative treatment of the axilla that will be a clear benefit for these patients.

Transient trochlear nerve palsy following percutaneous angioplasty. / Paresia transitoria del nervio troclear tras angioplastia percutánea.

CASE REPORT: A case is presented of a 63-year-old man who suffered a unilateral isolated trochlear nerve palsy with vertical diplopia following an elective radial coronary angiography and percutaneous coronary intervention, which resolved spontaneously within 2 months. DISCUSSION: Ophthalmoplegia following coronary percutaneous angioplasty is rare. Only internuclear ophthalmoplegia, III and VI cranial nerve palsy have been previously reported following percutaneous angioplasty. This is the first reported case of unilateral isolated trochlear nerve ophthalmoplegia following this procedure.

Induction of Fanconi anemia cellular phenotype in human 293 cells by overexpression of a mutant FAC allele.

The polypeptide encoded by the Fanconi anemia (FA) complementation group C gene, FAC, binds to a group of cytoplasmic proteins in vitro and may form a multimeric complex. A known mutant allele of FAC resulting from the substitution of Pro for Leu at codon 554 fails to correct the sensitivity of FA group C cells to mitomycin C. We reasoned that overexpression of the mutant protein in a wild-type cellular background might induce the FA phenotype by competing with endogenous FAC for binding to the accessory proteins. After stable transfection of 293 cells with wild-type and a mutant FAC allele containing the L554P substitution, four independent clones that expressed four-to-fifteen fold higher levels of transcript from the mutant transgene relative to the endogenous FAC gene showed hypersensitivity to mitomycin C. By contrast, both parental and FAC-overexpressing cells maintained their relative resistance to mitomycin C. No differences in the biosynthesis, subcellular localization and protein interactions of the normal and mutant proteins were detected. The induction of the FA phenotype in this system is compatible with the competition hypothesis and provides support for a functional role of the FAC-binding proteins in vivo.

N-acetyl-cysteine abolishes hydrogen peroxide-induced modification of eukaryotic initiation factor 4F activity via distinct signalling pathways.

During the oxidative stress generated by hydrogen peroxide (H2O2) in nerve growth factor (NGF)-differentiated PC12 cells, eIF4E binding protein (4E-BP1) and initiation factor 4E (eIF4E) phosphorylated levels decrease significantly, and an enhancement of the association of 4E-BP1 to eIF4E, which in turn decreases eIF4F formation is observed. The treatment with N-acetyl-cysteine (NAC) completely abolishes the H2O2-induced decrease in eIF4E phosphorylated levels, whereas the decrease in 4E-BP1 phosphorylated levels and eIF4F activity inhibition are significantly but not fully reversed. Rapamycin, the mammalian target of rapamycin (FRAP/mTOR) inhibitor, prevents the effect of NAC on H2O2-induced eIF4F complex formation inhibition. Besides the inhibitor induces a similar decrease in 4E-BP1 phosphorylated levels to that promote by H2O2. However, rapamycin has no effect on the NAC-induced recovery in phosphorylated eIF4E levels. Neither the MAP kinase inhibitors, PD98056 and SB203580, or the protein phosphatase 2A inhibitor, okadaic acid, mimic NAC effect on the H2O2-induced eIF4E dephosphorylation. Altogether our findings suggest that the effects caused by oxidative stress on eIF4s factors depends on two MAP kinase-independent signal transduction pathways, being at least one of them rapamycin-dependent.

Corepressor required for adenovirus E1B 55,000-molecular-weight protein repression of basal transcription.

Adenovirus E1B 55,000-molecular-weight protein (55K) binds to host cell p53, stabilizing it, greatly increasing its affinity for its cognate DNA-binding site, and converting it from a regulated activator to a constitutive repressor. Here we analyzed the mechanism of repression by the p53-E1B 55K complex. E1B 55K repression requires that 55K be tethered to the promoter by binding directly to DNA-bound p53. Transcription from an assembled, p53-activated preinitiation complex was not repressed by the subsequent addition of E1B 55K, suggesting that either sites of 55K interaction with p53 or targets of 55K in the preinitiation complex are blocked. Specific E1B 55K repression was observed in reactions lacking TFIIA and with recombinant TATA-binding protein in place of TFIID, conditions under which p53 does not activate transcription. Thus, E1B 55K does not simply inhibit a p53-specific activation mechanism but rather blocks basal transcription. As a consequence, E1B 55K may repress transcription from any promoter with an associated p53-binding site, no matter what other activators associate with the promoter. E1B 55K did not repress basal transcription in reactions with recombinant and highly purified general transcription factors and RNA polymerase II but rather required a corepressor that copurifies with the polymerase.