Psychosocial interventions reduce cortisol in breast cancer patients: systematic review and meta-analysis.

Introduction: Cancer initiation, progression and recurrence are intricate mechanisms that depend on various components: genetic, psychophysiological, or environmental. Exposure to chronic stress includes fear of recurrence that can affect biological processes that regulate immune and endocrine systems, increase cancer risk, and influence the survival rate. Previous studies show that psychological interventions might influence the level of cortisol that has been extensively used as a biomarker for measuring hypothalamic-pituitary-adrenal axis functioning and body's immunity response. This meta-analysis aimed to provide a quantitative scrutiny of the effect of certain types of psychosocial interventions on cortisol as a neuroendocrine biomarker in saliva or blood and might predict breast cancer (BC) progression. Methods: A literature search was performed in the following databases: PubMed, The Cohrane Library, Scopus, WOS, PsychInfo, Google Scholar, Ovid Science Direct. After methodical selection of originally generated 2.021 studies, the search yielded eight articles that met inclusion criteria. All these studies explored effects of psychosocial interventions that measured cortisol in total of 366 participants with BC, stages 0-IV, in randomized control trial or quasi experimental study design setting. We applied random effects model to conduct meta-analyses on the parameters of salivary and plasma cortisol and used PRISMA Guidelines as validated methodology of investigation to report the results. Results: Eight studies selected for meta-analysis have shown the reduction of cortisol level due to applied psychosocial intervention. The random effects model showed that interventions produced large effect sizes in reductions of cortisol in blood (Cohen's d = -1.82, 95% Confidence Interval (CI): -3.03, -0.60) and slightly less in saliva (d = -1.73, 95%CI: -2.68, -0.78) with an overall effect of d = -1.76 (95%CI: -2.46, -1.07). Conclusion: Our study concluded that certain types of psychosocial interventions reduce cortisol (indicator of chronic stress) in patients with BC. Application of specific psychosocial support as adjuvant non-invasive therapy for affected females with BC at all phases of treatment could contribute to more cost-effective health care.

Effect of Long-Term Use of Alcohol-Containing Handwashing Gels on the Biofilm-Forming Capacity of Staphylococcus epidermidis.

The spread of coronavirus disease 2019 (COVID-19) has promoted the use of hand sanitizers among the general population as recommended by health authorities. Alcohols, which are used in many hand sanitizers, have been shown to promotes the formation of biofilms by certain bacteria and to increase bacterial resistance to disinfection. We investigated the effect of continued use of alcohol-based gel hand sanitizer on biofilm formation by the Staphylococcus epidermidis resident strain isolated from the hands of health science students. Hand microbes were counted before and after handwashing, and the ability to produce biofilms was investigated. We found that 179 (84.8%) strains of S. epidermidis isolated from hands had the ability to form biofilm (biofilm-positive strains) in an alcohol-free culture medium. Furthermore, the presence of alcohol in the culture medium induced biofilm formation in 13 (40.6%) of the biofilm-negative strains and increased biofilm production in 111 (76.6%) strains, which were classified as low-grade biofilm-producing. Based on our findings, there is no clear evidence that the continued use of alcohol-based gels results in the selection of strains with the capacity to form biofilms. However, other disinfectant formulations that are more commonly used in clinical settings, such as alcohol-based hand-rub solutions, should be tested for their long-term effects.

The STRIPAK Complex Regulates Response to Chemotherapy Through p21 and p27.

The STRIPAK complex has been linked to a variety of biological processes taking place during embryogenesis and development, but its role in cancer has only just started to be defined. Here, we expand on previous work indicating a role for the scaffolding protein STRIP1 in cancer cell migration and metastasis. We show that cell cycle arrest and decreased proliferation are seen upon loss of STRIP1 in MDA-MB-231 cells due to the induction of cyclin dependent kinase inhibitors, including p21 and p27. We demonstrate that p21 and p27 induction is observed in a subpopulation of cells having low DNA damage response and that the p21high/γH2AXlow ratio within single cells can be rescued by depleting MST3&4 kinases. While the loss of STRIP1 decreases cell proliferation and tumor growth, cells treated with low dosage of chemotherapeutics in vitro paradoxically escape therapy-induced senescence and begin to proliferate after recovery. This corroborates with already known research on the dual role of p21 and indicates that STRIP1 also plays a contradictory role in breast cancer, suppressing tumor growth, but once treated with chemotherapeutics, allowing for possible recurrence and decreased patient survival.

Prevalence of Chronic Diseases among International Travelers Seeking Pretravel Medical Advice in 2018 at Malaga, Spain.

Travelers with preexisting diseases or chronic conditions may be more susceptible to travel-related health risks. They may, therefore, require more attention from specialist travel medicine providers. Our objective was to examine a group of international travelers in Malaga, Spain, quantify the proportion of travelers suffering from chronic conditions, and understand the characteristics of this group. A representative sample of travelers requesting pretravel medical advice at one travel clinic were asked about their preexisting chronic conditions and any immunosuppression. Additional demographic variables were used in an analysis of bivariate correlations. We used a binary logistic regression analysis to identify relationships between independent variables (age, gender, type of trip, travel duration, and destination) and the presence or absence of chronic conditions in travelers. Of the sample of 1,196 travelers, 258 (21.6%) reported having preexisting chronic conditions and 72 (6%) had two or more chronic conditions. Twenty-four of the travelers with chronic conditions (9%) were immunocompromised because of the disease or treatment. The two most common chronic conditions were cardiovascular disease and chronic respiratory conditions (36.8% and 17.1%, respectively). The chronic condition increased by 6.7% for every year of increased age. Travelers with chronic conditions are older, travel mainly to visit friends and relatives, and take shorter trips. More than half of travelers visiting (55.8%) needed more attention from the travel medicine practitioner because of their preexisting chronic conditions, age, or type of travel. Surveillance data based on the population of people traveling would be helpful to provide better advice to travelers.

Trends in the travelers' demand for pre-travel medical advice at a Spanish International Vaccination Center between 2000 and 2017.

Crises and disasters affect the numbers of people traveling either for tourism or other reasons. Many studies have been published on the effects of such events on travel, especially on tourism, and based on the arrivals or departures of travelers to or from countries. Our aim was to assess the influence of these events on the demand for pre-travel medical consultation in an International Vaccination Centre (IVC). Data on 94683 international travelers who visited 113529 international destinations attended at the IVC of Malaga (Spain) during 2000-2017 were studied. A descriptive and time series analyses was conducted. The demand to IVC was 3.47 times higher in 2017 than in 2000. The increase has not been the same for all destinations: Travel to South-East Asia and Western Pacific World Health Organization (WHO) regions has multiplied by 10, while in the same period, Africa WHO region has declined from 36% to 20% of total demand. Thailand, India and Brazil were the countries with the highest demand (21% of all pre-travel consultations). We found out three periods, concurrent with some socioeconomic or health events, in which the number of travellers attend decline with respect to the previous years, or the growth was very slow. Growth in the demand for pre-travel medical advice in parallel with a foreseeable increase in the number of travelers is expected. Pre-travel medical services must be adapted to this increase. This study of the trend of demand for pre-travel medical information should new related problems to travel to be identified and quantified, and should assist improvement of policies and programs aimed at care of travelers.

Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation.

Mice with a keratinocyte-restricted deletion of the actin polymerization-promoting molecule, N-WASP, display cyclic hair loss and skin inflammation. Here, we showed that these mice were also resistant to 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor formation. This resistance correlated with decreased expression of the senescence regulator, DNMT1, and increased expression of the senescence marker, p16Ink4a, in N-WASP-deficient epidermis. Moreover, primary N-WASP-null keratinocytes displayed a premature senescence phenotype in vitro. Expression and activation of p53, a major inducer of senescence, was not significantly altered in N-WASP-null keratinocytes. However, impairment of p53 function effectively rescued the senescence phenotype, indicating that N-WASP was an inhibitor of p53-induced senescence. Mechanistically, N-WASP regulated senescence by preventing p53-dependent degradation of the H3K9 methyltransferases, G9a/GLP, and the DNA methyltransferase, DNMT1, which both control keratinocyte senescence. This pathway collaborated with other N-WASP-independent, senescence-promoting signaling downstream of p53 and allowed the fine tuning of p53-induced senescence by N-WASP. Collectively, these data reveal N-WASP as an inhibitor of p53-induced senescence, which might be of importance for skin tumor formation and cellular aging of keratinocytes. SIGNIFICANCE: These findings demonstrate that N-WASP regulates p53-dependent senescence in keratinocytes in vitro and in vivo.

Notch Signaling Controls Transcription via the Recruitment of RUNX1 and MYB to Enhancers during T Cell Development.

Tcrd and Tcrg display identical developmental programs that depend on the activity of the enhancers Eδ and Eγ being "on" in pre-ß-selection thymocytes to activate transcription and V(D)J recombination of the unrearranged genes and "off" in post-ß-selection CD4+CD8+ double-positive thymocytes to inhibit transcription of the rearranged genes and avoid the expression of TCR δ- and TCR γ-chains in αß T lymphocytes. Eδ and Eγ activity depends on transcription factor binding to essential Runx and Myb sites and parallels that of Notch signaling. We performed Notch gain- and loss-of-function experiments and found that Notch signaling activates Tcrd and Tcrg transcription by favoring the recruitment of RUNX1 and MYB to the enhancers. Our results suggest that the dissociation of RUNX1 and MYB from Eδ and Eγ chromatin in double-positive thymocytes, which results in enhancer inactivation, is caused by decreased Notch signaling triggered by pre-TCR signaling, thereby deciphering the molecular mechanism of Tcrd and Tcrg silencing during ß-selection. These findings reveal a novel molecular mechanism for gene regulation via Notch signaling through the recruitment of RUNX1 and MYB to enhancer chromatin during thymocyte development.

Carbapenem resistance in Acinetobacter baumannii is associated with enhanced survival on hospital fabrics.

The success of Acinetobacter baumannii as an emerging organism is probably linked to its high resistance to adverse environmental conditions. This study was conducted to analyze the association between some factors that may favor the dissemination of A. baumannii clinical isolates. A total of 47 clinical strains of A. baumannii were evaluated to carbapenem, the ability to produce biofilm, the susceptibility to some antiseptics, and the survival time on cotton fabrics. Most of the isolates were resistant to carbapenem (72.3%), produced biofilm (83%), and survived more than 7 (51%) days on fabrics. A significant association between decreased susceptibility to antiseptics containing chlorhexidine or triclosan and carbapenem resistance and survival on fabrics could be observed. The resistance to carbapenem was significantly associated with survival on fabric, but not with the ability to form biofilm. The survival of the isolates on fabric was not associated with the ability to produce biofilms. Characteristics, such as resistance to antibiotics, ability to form biofilm, and survival on dry surfaces, probably contribute to the proliferation of this organism when selected in the hospital environment and can partly explain its success as responsible for nosocomial infection.

Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation.

The chronic skin inflammation psoriasis is crucially dependent on the IL-23/IL-17 cytokine axis. Although IL-23 is expressed by psoriatic keratinocytes and immune cells, only the immune cell-derived IL-23 is believed to be disease relevant. Here we use a genetic mouse model to show that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation with an IL-17 profile. Furthermore, we reveal a cell-autonomous nuclear function for the actin polymerizing molecule N-WASP, which controls IL-23 expression in keratinocytes by regulating the degradation of the histone methyltransferases G9a and GLP, and H3K9 dimethylation of the IL-23 promoter. This mechanism mediates the induction of IL-23 by TNF, a known inducer of IL-23 in psoriasis. Finally, in keratinocytes of psoriatic lesions a decrease in H3K9 dimethylation correlates with increased IL-23 expression, suggesting relevance for disease. Taken together, our data describe a molecular pathway where epigenetic regulation of keratinocytes can contribute to chronic skin inflammation.

RhoA controls retinoid signaling by ROCK dependent regulation of retinol metabolism.

The ubiquitously expressed small GTPase RhoA is essential for embryonic development and mutated in different cancers. Functionally, it is well described as a regulator of the actin cytoskeleton, but its role in gene regulation is less understood. Using primary mouse keratinocytes with a deletion of the RhoA gene, we have now been exploring how the loss of RhoA affects gene expression. Performing transcription factor reporter assays, we found a significantly decreased activity of a RAR luciferase reporter in RhoA-null keratinocytes. Inhibition of the RhoA effector ROCK in control cells reproduced this phenotype. ATRA and retinal, but not retinol increased RAR reporter activity of keratinocytes with impaired RhoA/ROCK signaling, suggesting that retinol metabolism is regulated by RhoA/ROCK signaling. Furthermore a significant percentage of known ATRA target genes displayed altered expression in RhoA-null keratinocytes. These data reveal an unexpected link between the cytoskeletal regulator RhoA and retinoid signaling and uncover a novel pathway by which RhoA regulates gene expression.

The Maritime Declaration of Health (MDH) as a tool to detect maritime traffic-related health risks: analysis of MDH forms submitted to Spanish ports, October 2014 to March 2015.

The international maritime traffic of people and goods has often contributed to the spread of pathogens affecting public health. The Maritime Declaration of Health (MDH), according to the International Health Regulations (IHR) (2005), is a document containing data related to the state of health on board a ship during passage and on arrival at port. It is a useful tool for early detection of public health risks. The main objective of our study was to evaluate compliance with the model provided in the IHR, focusing on the format and degree of completion of MDH forms received at Spanish ports. We reviewed the content of 802 MDH forms submitted to nine Spanish ports between October 2014 and March 2015. Study results show that 22% of MDH forms presented did not comply with the recommended model and 39% were incomplete. The proportion of cargo ships with correct and complete MDH forms was lower than passenger ships; thus, the nine health questions were answered less frequently by cargo ships than passenger ships (63% vs 90%, p value < 0.001). The appropriate demand and usage of MDH forms by competent authorities should improve the quality of the document as a tool and improve risk assessment.

Chromium Exposure and Risk of Cardiovascular Disease in High Cardiovascular Risk Subjects　- Nested Case-Control Study in the Prevention With Mediterranean Diet (PREDIMED) Study.

BACKGROUND: Epidemiological data on chromium (Cr) exposure and the risk of cardiovascular disease (CVD) are still limited. Toenail Cr level (TCL) provides a time-integrated measure reflecting long-term Cr exposure. We measured TCL to assess the hypothesis that long-term Cr exposure was inversely associated with incident CVD in a population at high risk for CVD.Methods and Results:The associations between TCL and CVD were evaluated in a case-control study nested within the "PREvención con DIeta MEDiterránea" (PREDIMED) trial. We randomly selected 147 of the 288 patients diagnosed with CVD during follow-up and matched them on age and sex to 271 controls. Instrumental neutron activation analysis was used to assess TCL. In-person interviews, medical record reviews, and validated questionnaires were used to assess covariates. The fully adjusted OR for the highest vs. lowest quartile of toenail Cr was 0.54 (95% CI: 0.26-1.14; Ptrend=0.189) for the nested case-control study. On stratification for diabetes mellitus (DM), OR was 1.37 (95% CI: 0.54-3.46; Ptrend=0.364) for the DM group, and 0.25 (95% CI: 0.08-0.80; Ptrend=0.030) for the non-DM group (P for interaction=0.078). CONCLUSIONS: The present findings, although not statistically significant, are consistent with previously reported inverse associations between TCL and CVD. These results, especially for non-DM patients, increase the limited epidemiological knowledge about the possible protective role of Cr against CVD. (Trial registration: www.controlled-trials.com; ISRCTN35739639.).

Psychiatric Status across Body Mass Index in a Mediterranean Spanish Population.

BACKGROUND: Mental and body weight disorders are among the major global health challenges, and their comorbidity may play an important role in treatment and prevention of both pathologies. A growing number of studies have examined the relationship between psychiatric status and body weight, but our knowledge is still limited. OBJECTIVE: The present study aims to investigate the cross-sectional relationships of psychiatric status and body mass index (BMI) in Málaga, a Mediterranean city in the South of Spain. MATERIALS AND METHODS: A total of 563 participants were recruited from those who came to his primary care physician, using a systematic random sampling, non-proportional stratified by BMI categories. Structured clinical interviews were used to assess current Axes-I and II mental disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). BMI was calculated as weight (Kg) divided by square of height in meters (m2). Logistic regression was used to investigate the association between BMI and the presence of any mental disorder. BMI was introduced in the models using restricted cubic splines. RESULTS: We found that high BMI values were directly associated with mood and adjustment disorders, and low BMI values were directly associated with avoidant and dependent personality disorders (PDs). We observed an inverse relationship between low BMI values and cluster A PDs. There were not significant relationships between anxiety or substance-related disorders and BMI. CONCLUSION: Psychiatric status and BMI are related in a Mediterranean Spanish population. A multidisciplinary approach to both pathologies becomes increasingly more necessary.

Fluorescence assay for evaluating microbicidal activity of hand antiseptics.

We developed a fluorescent ß-d-glucuronidase activity (BGA)-based assay for detecting and quantifying Escherichia coli in samples to assess the biocide efficacy of hand antiseptics. The fluorescence level is proportional to the number of viable E. coli organisms present. We compared our assay results to those of the E. coli plate count method specified by the European standard for testing hygienic hand rub disinfectant products (EN1500). The plate count method requires excessive handling and materials and is not valid if the number of organisms per plate is too low or high for counting in many of the samples. We optimized the fluorescent assay based on the cleavage of 4-methylumbelliferyl-ß-d-glucuronide by adding 4-nitrophenyl-ß-d-glucuronide, a nonfluorogenic BGA substrate, to induce glucuronidase activity and reduce assay time. Furthermore, our method can be automated and eliminates the need for multiple dilutions. Fluorescence was temporally monitored, and the time required to reach a specific value of fluorescence was correlated with the initial number of viable E. coli organisms on the samples. There was a positive correlation (P < 0.05) with a high correlation coefficient (R(2) = 0.82) between the E. coli counts by plate count and fluorescence methods. Reported effects in fluorescent BGA were compared to the EN1500 plate count method with five hand disinfectants. We found our method more advantageous, because it was as sensitive as the EN1500 method, requires less time to complete, and is less expensive and less laborious than conventional plating techniques.

Persistence of nosocomial bacteria on 2 biocidal fabrics based on silver under conditions of high relative humidity.

BACKGROUND: The survival of pathogenic microorganism on fabrics in the health care environment has a important role in nosocomial infections. The use of biocidal fabrics and surfaces could reduce the prevalence of the microorganisms in the hospital environment. METHODS: In this study, the persistence of nosocomial bacteria on 2 fabrics containing biocidal fibers (BF) in the long term following desiccation and subsequent storage was examined at 40% and 90% relative humidity (RH). RESULTS: Very few strains survived more than 7 days at 40% RH on fabrics containing 67% BF, and only strains of Acinetobacter baumanii and Pseudomonas aeruginosa survived on fabric containing 100% BF. None of the strains tested survived 14 days on the 2 fabrics, 67% or 100% BF, under these environmental conditions. In contrast, at higher RH (∼90%), most of the strains tested showed prolonged survival on both fabrics, and all strains of Klebsiella pneumoniae, Enterobacter aerogenes, and A baumannii survived for more than 14 days; however, in a Petri dish, most of the microorganisms tested showed a higher survival even at 28 days. The gram-positive cocci and A baumannii were the most persistent bacteria on the Petri dish. CONCLUSIONS: This study emphasizes the effect of RH on the survival of nosocomial bacteria on 2 commercially available fabrics containing biocide. Evidence of the clinical efficacy of these BF-containing fabrics is lacking.

Weight status and psychological distress in a Mediterranean Spanish population: a symmetric U-shaped relationship.

Psychological disorders in people with extreme weight (low weight or obesity) should be taken into consideration by health professionals in order to practice an effective treatment to these patients. This study evaluates the association between body mass index (BMI) and psychological distress in 563 inhabitants of Málaga (South of Spain). Participants were classified in four categories of BMI: Underweight (BMI <18.5 Kg/m2), Normal weight (BMI 18.5-24.99 Kg/m2), Overweight (BMI 25.0-29.99 Kg/m2) and Obesity (BMI >30 Kg/m2). Psychological distress was measured with the Spanish version of the Derogatis' Symptoms Checklist Revised (SCL-90-R). We observed a symmetric U-shaped relationship between weight status and psychological distress in all SCL-90-R dimensions (p for quadratic trend <0.001) for both men and women. Participants with extreme weight showed the worst psychological status, and participants with normal weight exhibited the best. We found no statistically significant differences between underweight and obese participants in 9 of the 10 SCL-90-R dimensions analyzed among men, and in 8 of the 10 dimensions among women. Underweight and obese participants showed no gender differences in psychological distress levels. Psychological treatment of Mediterranean people with extreme weight, should consider underweight and obese patients at the same level of psychological distress.

Commercializing diarrhea vaccines for travelers.

Continued growth in international travel and forecasts for a great increase in the number of people who travel from industrialized to emerging and developing countries make it necessary to develop and improve the capacity to provide health protection to travelers. Measures available to prevent some diseases include a currently limited number of marketed vaccines which represent extremely useful tools to protect travelers. Travelers very often experience diarrheal and gastrointestinal diseases for which some vaccines are available. Use of these vaccines should be evaluated based on traveler and travel destination and characteristics. Vaccines available include those against cholera, typhoid fever, hepatitis A, hepatitis E (only available in China), and rotavirus. The aim of this review is to provide an updated summary about each of the abovementioned vaccines that may be useful for making decisions regarding their use and assessing their indications in recommendations for travelers.

Generación de diversidad de los receptores de antígeno en linfocitos: validación del «modelo de accesibilidad» en el control de la recombinación V(D)J / Generation of lymphocyte antigen receptor diversity: Validation of the “accessibility model” in controlling V(D)J recombination

La recombinación V(D)J consiste en el ensamblaje de los segmentos génicos presentes en los genes de las cadenas variables de los receptores de antígeno para generar la diversidad del reconocimiento antigénico en linfocitos. El conocimiento de su regulación en condiciones normales es esencial para entender los casos en que este proceso se desregula, dando lugar a transformaciones leucémicas. La recombinación V(D)J se inicia por acción de una endonucleasa específica presente exclusivamente en linfocitos inmaduros. Según el «modelo de accesibilidad» propuesto hace más de 25 años, la recombinación V(D)J está regulada a través del control de la accesibilidad de esta endonucleasa a sus sitios de corte en el ADN, de acuerdo con unos programas de diferenciación celular muy definidos. En esta revisión se resumen los hallazgos descubiertos en este campo en los últimos años, tales como el importante papel que tiene la conformación génica y la posición de estos genes en el núcleo celular, así como aquellos que muy recientemente han permitido la validación definitiva del «modelo de accesibilidad» (AU)

V(D)J recombination is the assembly of gene segments at the antigen receptor loci in order to generate antigen receptor diversity in T and B lymphocytes. Detailed knowledge of how V(D)J recombination is normally regulated during lymphocyte development is essential to understand the cases of dysregulation of this process that result in leukemic transformation. V(D)J recombination is triggered by action of a specific endonuclease which is exclusively expressed in immature lymphocytes. According to the “accessibility model” proposed more than 25 years ago, DNA cleavage by this endonuclease is very strictly controlled during cell differentiation by regulating its accessibility to chromatin. This review summarizes the advances in the field over the last few years, including the important role of the genomic conformation and position of the antigen receptor loci within the nucleus, as well as those that have recently culminated with the validation of the “accessibility model” to control this process (AU)

Tcra enhancer activation by inducible transcription factors downstream of pre-TCR signaling.

The Tcra enhancer (Eα) is essential for pre-TCR-mediated activation of germline transcription and V(D)J recombination. Eα is considered an archetypical enhanceosome that acts through the functional synergy and cooperative binding of multiple transcription factors. Based on dimethylsulfate genomic footprinting experiments, there has been a long-standing paradox regarding Eα activation in the absence of differences in enhancer occupancy. Our data provide the molecular mechanism of Eα activation and an explanation of this paradox. We found that germline transcriptional activation of Tcra is dependent on constant phospholipase Cγ, as well as calcineurin- and MAPK/ERK-mediated signaling, indicating that inducible transcription factors are crucially involved. NFAT, AP-1, and early growth response factor 1, together with CREB-binding protein/p300 coactivators, bind to Eα as part of an active enhanceosome assembled during pre-TCR signaling. We favor a scenario in which the binding of lymphoid-restricted and constitutive transcription factors to Eα prior to its activation forms a regulatory scaffold to recruit factors induced by pre-TCR signaling. Thus, the combinatorial assembly of tissue- and signal-specific transcription factors dictates the Eα function. This mechanism for enhancer activation may represent a general paradigm in tissue-restricted and stimulus-responsive gene regulation.

Control of V(D)J Recombination through Transcriptional Elongation and Changes in Locus Chromatin Structure and Nuclear Organization.

V(D)J recombination is the assembly of gene segments at the antigen receptor loci to generate antigen receptor diversity in T and B lymphocytes. This process is regulated, according to defined developmental programs, by the action of a single specific recombinase complex formed by the recombination antigen gene (RAG-1/2) proteins that are expressed in immature lymphocytes. V(D)J recombination is strictly controlled by RAG-1/2 accessibility to specific recombination signal sequences in chromatin at several levels: cellular lineage, temporal regulation, gene segment order, and allelic exclusion. DNA cleavage by RAG-1/2 is regulated by the chromatin structure, transcriptional elongation, and three-dimensional architecture and position of the antigen receptor loci in the nucleus. Cis-elements specifically direct transcription and V(D)J recombination at these loci through interactions with transacting factors that form molecular machines that mediate a sequence of structural events. These events open chromatin to activate transcriptional elongation and to permit the access of RAG-1/2 to their recombination signal sequences to drive the juxtaposition of the V, D, and J segments and the recombination reaction itself. This chapter summarizes the advances in this area and the important role of the structure and position of antigen receptor loci within the nucleus to control this process.