A dominant repressor version of the tomatoSl-ERF.B3gene confers ethylene hypersensitivity via feedback regulation of ethylene signaling and response components

Ethylene Response Factors (ERFs) are downstream components of the ethylene signal transduction pathway, although their role in ethylene-dependent developmental processes remains poorly understood. As the ethylene-inducible tomato Sl-ERF.B3 has been shown previously to display a strong binding affinity to GCC-box-containing promoters, its physiological significance was addressed here by a reverse genetics approach. However, classical up- and down-regulation strategies failed to give clear clues to its roles in planta, probably due to functional redundancy among ERF family members. Expression of a dominant repressor ERF.B3-SRDX version of Sl-ERF.B3 in the tomato resulted in pleiotropic ethylene responses and vegetative and reproductive growth phenotypes. The dominant repressor etiolated seedlings displayed partial constitutive ethylene response in the absence of ethylene and adult plants exhibited typical ethylene-related alterations such as leaf epinasty, premature flower senescence and accelerated fruit abscission. The multiple symptoms related to enhanced ethylene sensitivity correlated with the altered expression of ethylene biosynthesis and signaling genes and suggested the involvement of Sl-ERF.B3 in a feedback mechanism that regulates components of ethylene production and response. Moreover, Sl-ERF.B3 was shown to modulate the transcription of a set of ERFs and revealed the existence of a complex network interconnecting different ERF genes. Overall, the study indicated that Sl-ERF.B3 had a critical role in the regulation of multiple genes and identified a number of ERFs among its primary targets, consistent with the pleiotropic phenotypes displayed by the dominant repression lines

UC-1V150, a potent TLR7 agonist capable of activating macrophages and potentiating mAb-mediated target cell deletion

Toll‐like receptors (TLR) are critical mediators of the immune system with their activation linked to infection, inflammation and the pathogenesis of immune diseases including autoimmunity and cancer. For this reason, over the last 2 decades, TLR and their associated signalling pathways have been targeted therapeutically to enhance innate and adaptive immunity. Several TLR ligands, both endogenous and synthetic are at various phases of clinical testing, and new ligands are continually emerging. Agonists of TLR7 are known immune response modifiers, simultaneously stimulating several cell types, resulting in immune cell activation and cytokine and chemokine release. The immune stimulating properties of the TLR7 agonist Imiquimod has also been exploited for use in the treatment of malignant superficial tumours of the skin. Here, we investigated a novel TLR7 agonist UC‐1V150 and demonstrate it activates both human and mouse myeloid cells in vitro and in vivo, to deliver potent FcγR‐mediated engulfment of opsonized target cells

Comprehensive, Multimodal Characterization of an Imiquimod-Induced Human Skin Inflammation Model for Drug Development

Imiquimod (IMQ) is often used as a topical challenge agent to provoke local skin inflammation. The objective of this study was to develop and refine a rapid, temporary, and reversible human skin inflammation model with IMQ for application in clinical drug development. A randomized, vehicle-controlled, open-label, dose-ranging study was conducted in 16 healthy male subjects. IMQ (5 mg) was applied once daily for 72 hours under occlusion to intact skin (n = 8) or tape stripped (TS) skin (n = 8). Although IMQ alone induced limited effects, TS+IMQ treatment showed larger responses in several domains, including erythema and perfusion (P < 0.0001), mRNA expression of inflammatory markers (P < 0.01), and inflammatory cell influx compared with vehicle. In conclusion, a rapid, human IMQ skin inflammation challenge model was successfully developed with a clear benefit of TS prior to IMQ application. Future interaction studies will enable proof-of-pharmacology of novel compounds targeting the innate immune system

TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is characterized by proliferation of malignant T cells in a chronic inflammatory environment. With disease progression, bacteria colonize the compromised skin barrier and half of CTCL patients die of infection rather than from direct organ involvement by the malignancy. Clinical data indicate that bacteria play a direct role in disease progression, but little is known about the mechanisms involved. Here, we demonstrate that bacterial isolates containing staphylococcal enterotoxin A (SEA) from the affected skin of CTCL patients, as well as recombinant SEA, stimulate activation of signal transducer and activator of transcription 3 (STAT3) and upregulation of interleukin (IL)-17 in immortalized and primary patient-derived malignant and nonmalignant T cells. Importantly, SEA induces STAT3 activation and IL-17 expression in malignant T cells when cocultured with nonmalignant T cells, indicating an indirect mode of action. In accordance, malignant T cells expressing an SEA-nonresponsive T-cell receptor variable region β chain are nonresponsive to SEA in monoculture but display strong STAT3 activation and IL-17 expression in cocultures with SEA-responsive nonmalignant T cells. The response is induced via IL-2 receptor common γ chain cytokines and a Janus kinase 3 (JAK3)-dependent pathway in malignant T cells, and blocked by tofacitinib, a clinical-grade JAK3 inhibitor. In conclusion, we demonstrate that SEA induces cell cross talk-dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism whereby SEA-producing bacteria promote activation of an established oncogenic pathway previously implicated in carcinogenesis

Intra-individual variability and continuity of action and perception measures in infants

The development of action and perception, and their relation in infancy is a central research area in socio-cognitive sciences. In this Perspective Article, we focus on the developmental variability and continuity of action and perception. At group level, these skills have been shown to consistently improve with age. We would like to raise awareness for the issue that, at individual level, development might be subject to more variable changes. We present data from a longitudinal study on the perception and production of contralateral reaching skills of infants aged 7, 8, 9, and 12 months. Our findings suggest that individual development does not increase linearly for action or for perception, but instead changes dynamically. These non-continuous changes substantially affect the relation between action and perception at each measuring point and the respective direction of causality. This suggests that research on the development of action and perception and their interrelations needs to take into account individual variability and continuity more progressively

Chronic wounds and advanced therapies, compatible in primary care?

RESUMEN: El envejecimiento progresivo de la población ha aumentado el riesgo de padecer enfermedades crónicas como patologías vasculares de extremidades inferiores. La aparición de úlceras vasculares arteriales, venosas y de pie diabético son complicaciones de gran morbilidad y mortalidad. Los cambios fisiológicos que padecen las personas mayores y la inmovilidad, son factores de riesgo que favorecen otras como las úlceras por presión. Su cronificación es la consecuencia de la prolongación de la fase inflamatoria. La cicatrización es un proceso endógeno que depende del paciente, el tipo de lesión y el tratamiento escogido. La curación supone un verdadero reto para el personal de enfermería de Atención Primaria de Salud y altos costes económicos. Las terapias avanzadas para el manejo de heridas crónicas están basadas en evidencias científicas que demuestran elevadas tasas de curación, reducción del tamaño de la lesión y mejora en la calidad de vida. Se deben establecer protocolos que disminuyan la variabilidad en la práctica enfermera y fomentar la investigación para poder introducirlas. Es importante que la Atención Primaria de Salud disponga de conocimientos y productos de cura convencional y avanzada, que permitan un tratamiento único, ya que ofrece los cuidados más continuados y evita las derivaciones innecesarias a especialistas.ABSTRACT: The progressive aging of the population has increased the risk of suffering chronic diseases such as vascular diseases of the lower extremities. The appearance of vascular arterial ulcers, venous ulcers and diabetic foot are complications of great morbidity and mortality. Physiological changes in the elderly and immobility, are risk factors that favor others such as pressure ulcers. Its chronification is the consequence of the prolongation of the inflammatory phase. The healing is an endogenous process that depends on the patient, the type of wound and the treatment chosen. The curation of the wound is a real challenge for nurses of Primary Health Care and means high economic costs. Advanced therapies for the management of chronic wounds are based on scientific evidence that proves high rates of healing, reduction of the size of the wound and better quality of life. Protocols should be established due to the reduction of the variability in nursing practice and encourage research to be able to introduce them. It is important that Primary Health Care have knowledge of conventional and advanced healing products, which allow a unique treatment. It provides the most continuous care and avoids unnecessary referrals to specialists.Grado en Enfermerí