Circadian Rhythms of Fetal Liver Transcription Persist in the Absence of Canonical Circadian Clock Gene Expression Rhythms In Vivo

The cellular circadian clock and systemic cues drive rhythmicity in the transcriptome of adult peripheral tissues. However, the oscillating status of the circadian clocks in fetal tissues, and their response to maternal cues, are less clear. Most clock genes do not cycle in fetal livers from mice and rats, although tissue level rhythms rapidly emerge when fetal mouse liver explants are cultured in vitro. Thus, in the fetal mouse liver, the circadian clock does not oscillate at the cellular level (but is induced to oscillate in culture). To gain a comprehensive overview of the clock status in the fetal liver during late gestation, we performed microarray analyses on fetal liver tissues. In the fetal liver we did not observe circadian rhythms of clock gene expression or many other transcripts known to be rhythmically expressed in the adult liver. Nevertheless, JTK_CYCLE analysis identified some transcripts in the fetal liver that were rhythmically expressed, albeit at low amplitudes. Upon data filtering by coefficient of variation, the expression levels for transcripts related to pancreatic exocrine enzymes and zymogen secretion were found to undergo synchronized daily fluctuations at high amplitudes. These results suggest that maternal cues influence the fetal liver, despite the fact that we did not detect circadian rhythms of canonical clock gene expression in the fetal liver. These results raise important questions on the role of the circadian clock, or lack thereof, during ontogeny

T-Cell Immune Responses Against Env from CRF12_BF and Subtype B HIV-1 Show High Clade-Specificity that Can Be Overridden by Multiclade Immunizations

BACKGROUND: The extreme genetic diversity of the human immunodeficiency virus type 1 (HIV-1) poses a daunting challenge to the generation of an effective AIDS vaccine. In Argentina, the epidemic is characterized by the high prevalence of infections caused by subtype B and BF variants. The aim of this study was to characterize in mice the immunogenic and antigenic properties of the Env protein from CRF12_BF in comparison with clade B, employing prime-boost schemes with the combination of recombinant DNA and vaccinia virus (VV) vectors. METHODOLOGY/PRINCIPAL FINDINGS: As determined by ELISPOT from splenocytes of animals immunized with either EnvBF or EnvB antigens, the majority of the cellular responses to Env were found to be clade-specific. A detailed peptide mapping of the responses reveal that when there is cross-reactivity, there are no amino acid changes in the peptide sequence or were minimal and located at the peptide ends. In those cases, analysis of T cell polifunctionality and affinity indicated no differences with respect to the cellular responses found against the original homologous sequence. Significantly, application of a mixed immunization combining both clades (B and BF) induced a broader cellular response, in which the majority of the peptides targeted after the single clade vaccinations generated a positive response. In this group we could also find significant cellular and humoral responses against the whole gp120 protein from subtype B. CONCLUSIONS/SIGNIFICANCE: This work has characterized for the first time the immunogenic peptides of certain EnvBF regions, involved in T cell responses. It provides evidence that to improve immune responses to HIV there is a need to combine Env antigens from different clades, highlighting the convenience of the inclusion of BF antigens in future vaccines for geographic regions where these HIV variants circulate

Mycobacteria Exploit Host Hyaluronan for Efficient Extracellular Replication

In spite of the importance of hyaluronan in host protection against infectious organisms in the alveolar spaces, its role in mycobacterial infection is unknown. In a previous study, we found that mycobacteria interact with hyaluronan on lung epithelial cells. Here, we have analyzed the role of hyaluronan after mycobacterial infection was established and found that pathogenic mycobacteria can grow by utilizing hyaluronan as a carbon source. Both mouse and human possess 3 kinds of hyaluronan synthases (HAS), designated HAS1, HAS2, and HAS3. Utilizing individual HAS-transfected cells, we show that HAS1 and HAS3 but not HAS2 support growth of mycobacteria. We found that the major hyaluronan synthase expressed in the lung is HAS1, and that its expression was increased after infection with Mycobacterium tuberculosis. Histochemical analysis demonstrated that hyaluronan profoundly accumulated in the granulomatous legion of the lungs in M. tuberculosis-infected mice and rhesus monkeys that died from tuberculosis. We detected hyaluronidase activity in the lysate of mycobacteria and showed that it was critical for hyaluronan-dependent extracellular growth. Finally, we showed that L-Ascorbic acid 6-hexadecanoate, a hyaluronidase inhibitor, suppressed growth of mycobacteria in vivo. Taken together, our data show that pathogenic mycobacteria exploit an intrinsic host-protective molecule, hyaluronan, to grow in the respiratory tract and demonstrate the potential usefulness of hyaluronidase inhibitors against mycobacterial diseases

Potential of novel Mycobacterium tuberculosis infection phase-dependent antigens in the diagnosis of TB disease in a high burden setting

<p>Abstract</p> <p>Background</p> <p>Confirming tuberculosis (TB) disease in suspects in resource limited settings is challenging and calls for the development of more suitable diagnostic tools. Different <it>Mycobacterium tuberculosis (M.tb) </it>infection phase-dependent antigens may be differentially recognized in infected and diseased individuals and therefore useful as diagnostic tools for differentiating between <it>M.tb </it>infection states. In this study, we assessed the diagnostic potential of 118 different <it>M.tb </it>infection phase-dependent antigens in TB patients and household contacts (HHCs) in a high-burden setting.</p> <p>Methods</p> <p>Antigens were evaluated using the 7-day whole blood culture technique in 23 pulmonary TB patients and in 19 to 21 HHCs (total n = 101), who were recruited from a high-TB incidence community in Cape Town, South Africa. Interferon-gamma (IFN-γ) levels in culture supernatants were determined by ELISA.</p> <p>Results</p> <p>Eight classical TB vaccine candidate antigens, 51 DosR regulon encoded antigens, 23 TB reactivation antigens, 5 TB resuscitation promoting factors (rpfs), 6 starvation and 24 other stress response-associated TB antigens were evaluated in the study. The most promising antigens for ascertaining active TB were the rpfs (Rv0867c, Rv2389c, Rv2450c, Rv1009 and Rv1884c), with Areas under the receiver operating characteristics curves (AUCs) between 0.72 and 0.80. A combination of <it>M.tb </it>specific ESAT-6/CFP-10 fusion protein, Rv2624c and Rv0867c accurately predicted 73% of the TB patients and 80% of the non-TB cases after cross validation.</p> <p>Conclusions</p> <p>IFN-γ responses to TB rpfs show promise as TB diagnostic candidates and should be evaluated further for discrimination between <it>M.tb </it>infection states.</p

Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go?

In this review we discuss recent progress in the development, testing, and clinical evaluation of new vaccines against tuberculosis (TB). Over the last 20 years, tremendous progress has been made in TB vaccine research and development: from a pipeline virtually empty of new TB candidate vaccines in the early 1990s, to an era in which a dozen novel TB vaccine candidates have been and are being evaluated in human clinical trials. In addition, innovative approaches are being pursued to further improve existing vaccines, as well as discover new ones. Thus, there is good reason for optimism in the field of TB vaccines that it will be possible to develop better vaccines than BCG, which is still the only vaccine available against TB

DC Priming by M. vaccae Inhibits Th2 Responses in Contrast to Specific TLR2 Priming and Is Associated with Selective Activation of the CREB Pathway

The environmental mycobacterium, M. vaccae has been used in mouse models to support the contemporary hygiene hypothesis that non-pathogenic microorganisms reduce allergy associated T helper (Th)2 responses and inflammatory diseases by augmenting regulatory T cells. However, data for human models and possible mechanisms are limited. We tested the effect of innate immune interactions between human DC and M. vaccae on DC-dependent T cell responses. M. vaccae activation of DC via Toll like receptor (TLR)2 was compared to a specific TLR2 ligand (Pam(3)CSK4) and alternative stimulation with a TLR4 ligand (LPS). M. vaccae induced DC dependent inhibition of Th2 responses, in contrast to Pam(3)CSK4, which had the opposite effect and LPS, which had no polarizing effect. DC maturation, gene expression and cytokine production, in response to each stimulus did not correlate with the specific functional effects. Comparable DC transcriptional responses to M. vaccae and Pam(3)CSK4 suggested that TLR2 mediated transcriptional regulation was not sufficient for inhibition of Th2 responses. Transcription factor enrichment analysis and assessment of signaling events, implicated a role for selective early activation of the CREB pathway by M. vaccae. Further study of the CREB pathway may provide novel insight into the molecular mechanisms of DC-dependent T cell polarization

Tratamientos Psicológicos Empíricamente Apoyados Para Adultos: Una Revisión Selectiva [Evidence-Based Psychological Treatments for Adults: A Selective Review]

Antecedentes: los tratamientos psicológicos han mostrado su efi cacia, efectividad y efi ciencia para el abordaje de los trastornos mentales; no obstante, considerando el conocimiento científi co generado en los últimos años, no se dispone de trabajos de actualización en español sobre cuáles son los tratamientos psicológicos con respaldo empírico. El objetivo fue realizar una revisión selectiva de los principales tratamientos psicológicos empíricamente apoyados para el abordaje de trastornos mentales en personas adultas. Método: se recogen niveles de evidencia y grados de recomendación en función de los criterios propuestos por el Sistema Nacional de Salud de España (en las Guías de Práctica Clínica) para diferentes trastornos psicológicos. Resultados: los resultados sugieren que los tratamientos psicológicos disponen de apoyo empírico para el abordaje de un amplio elenco de trastornos psicológicos. El grado de apoyo empírico oscila de bajo a alto en función del trastorno psicológico analizado. La revisión sugiere que ciertos campos de intervención necesitan una mayor investigación. Conclusiones: a partir de esta revisión selectiva, los profesionales de la psicología podrán disponer de información rigurosa y actualizada que les permita tomar decisiones informadas a la hora de implementar aquellos procedimientos psicoterapéuticos empíricamente fundamentados en función de las características de las personas que demandan ayuda. // Evidence-Based Psychological Treatments for Adults: A Selective Review. Background: Psychological treatments have shown their effi cacy, effectiveness, and effi ciency in dealing with mental disorders. However, considering the scientifi c knowledge generated in recent years, in the Spanish context, there are no updating studies about empirically supported psychological treatments. The main goal was to carry out a selective review of the main empirically supported psychological treatments for mental disorders in adults. Method: Levels of evidence and degrees of recommendation were collected based on the criteria proposed by the Spanish National Health System (Clinical Practice Guidelines) for different psychological disorders. Results: The results indicate that psychological treatments have empirical support for the approach to a wide range of psychological disorders. These levels of empirical evidence gathered range from low to high depending on the psychological disorder analysed. The review indicates the existence of certain fi elds of intervention that need further investigation. Conclusions: Based on this selective review, psychology professionals will be able to have rigorous, up-to-date information that allows them to make informed decisions when implementing empirically based psychotherapeutic procedures based on the characteristics of the people who require help

[Prevalence of sleep disorders in the elderly]

This study was performed with senior citizens in Greater Metropolitan Guadalajara, Mexico, who live in private homes, alone, or with family. Of these, 58% of men and 76% of women showed at least one symptom of sleep disorder according to the Goldberg General Health Questionnaire, while 8.5% were positive for all survey items. According to DSM IV criteria, 33.3% could be considered "cases" of sleep disorder, and none were under any type of treatment at the time of the study. These possible cases were apparently associated with gender and educational level, but not with marital status or age. In addition, no strong association was detected with the presence of depression, established according to Brink's Geriatric Depression Scale. Given the large amount of "possible cases" found that had not been previously detected and were not in any type of ad hoc treatment, we recommend promoting updated educational courses on this topic for health professionals (mainly doctors and nurses) in such a way as to facilitate timely case detection and thus increase and improve the accessibility of mental health services for the elderly population, increasing health education activities for this age group, their caregivers, and the general population

Trypanosoma cruzi High Mobility Group B (TcHMGB) can act as an inflammatory mediator on mammalian cells

When an infection occurs, the innate immune cells recognize Pathogen Associated Molec ular Patterns (PAMPs) through their Pattern Recognition Receptors. This triggers an inflammatory response intended to kill the foreign microbe. But inflammation can also be triggered by the recognition of endogenous molecules called “Danger (or Damage) Asso ciated Molecular Patterns” (DAMPs) that are released by damaged or necrotic cells to “ring the alarm” of the immune system that repair is needed, so some of them are also known as “alarmins”. High Mobility group box 1 protein (HMGB1) is a prototypical alar min molecule released by injured cells and it is also actively secreted by cells of the innate immune system in response to invasion as well as to sterile damage. Trypanosoma cruzi, the causal agent of Chagas Disease, has its own HMGB protein that we called TcHMGB. Using in vitro and in vivo experimental systems, we demonstrated for the first time that TcHMGB is able to mediate inflammation on mammalian cells, inducing the expression of both pro-inflammatory and anti-inflammatory cytokines. Our results suggest that the parasite´s protein could have a role in the immune response and the pathogenesis of Cha gas disease, probably overlapping to some extent with the host cell DAMP molecules´ functions.Para citar este articulo: Cribb P, Perdomo V, Alonso VL, Manarin R, Barrios-Paya´n J, Marquina-Castillo B, et al. (2017) Trypanosoma cruzi High Mobility Group B (TcHMGB) can act as an inflammatory mediator on mammalian cells. PLoS Negl Trop Dis 11(2): e0005350. doi:10.1371/journal.pntd.0005350Fil: Cribb, Pamela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET); Argentina.Fil: Cribb, Pamela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.Fil: Perdomo, Virginia Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET); Argentina.Fil: Perdomo, Virginia Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.Fil: Alonso, Victoria Lucía. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.Fil: Manarin, Romina. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas; Argentina.Fil: Barrios-Payán, Jorge. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Sección de Patología Experimental; México.Fil: Marquina-Castillo, Brenda. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Sección de Patología Experimental; México.Fil: Tavernelli, Luis. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR -CONICET); Argentina.Fil: Hernández-Pando, Rogelio. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Sección de Patología Experimental; México