The article attempts at conceptualizing the basic principles of how adolescents develop, getting out of childhood and proceeding to enter young adulthood. The age period of adolescence is marked with ...intense emotional states, lines of thinking, beliefs and transitions that caregivers often face challenges making sense of or mirroring. Combining mentalization-based approaches with neuropsychoanalytic findings about how basic emotional systems governing playful behavior work can shed additional light into the communication channels and specificities therapists might consider when engaging in such endeavor.
Bifocal attention has been conceptualized differently by various scholars; however, all converge in the idea that the therapeutic process includes the need for the therapist to focus his attention on ...more than one aspect of the therapeutic setting. We propose a novel view in the application of bifocal attention within the mentalizing framework (MBT) of working with children, adolescents, and their families. We start by providing a short history of the evolution of the construct of bifocal attention, followed by a brief description of the structure of MBT for children and adolescents, emphasizing the crucial role of bifocal and multiple attentions in the mentalizing therapist. We close by discussing the importance of continued supervision in facilitating the maintaining of mentalizing glasses in therapy.
Autocrine activation of the complement receptors C3aR and CD46 by complement activation components C3a and C3b produced through C3 cleavage by the protease cathepsin L (CTSL) during T cell ...stimulation is a requirement for IFN-γ production and Th1 induction in human CD4
T cells. Thus, lack of autocrine CD46 activation, such as in CD46-deficient patients, is associated with defective Th1 responses and recurrent infections. We have identified
the gene coding for legumain, also known as asparaginyl endopeptidase (AEP) as one of the key genes induced by CD46 co-stimulation during human CD4
T cell activation. AEP processes and activates a range of proteins, among those α1-thymosin and CTSL, which both drive intrinsically Th1 activity-but has so far not been described to be functionally active in human T cells. Here we found that pharmacological inhibition of AEP during activation of human CD4
T cells reduced CTSL activation and the CTSL-mediated generation of intracellular C3a. This translated into a specific reduction of IFN-γ production without affecting cell proliferation or survival. In line with these findings, CD4
T cells isolated from
mice also displayed a specific defect in IFN-γ secretion and Th1 induction. Furthermore, we did not observe a role for AEP-driven autocrine α1-thymosin activation in T cell-derived IFN-γ production. These data suggest that AEP is an "upstream" activator of the CTSL-C3-IFN-γ axis in human CD4
T cells and hence an important supporter of human Th1 induction.
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Introduction
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Origin of the disease and mechanisms for neuronal death in AD
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Inflammatory reaction
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Aβ‐induced neurotoxicity
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Complement‐mediated neurodegeneration
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Oxidative and ...nitrosylative damage
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Proteasome inhibitor‐induced neurotoxicity
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Cholesterol‐induced neurotoxicity
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Viral infections
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Interrelationship between different aetiopathogenic theories of AD
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Treatment approaches
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Drugs which modify AD symptoms
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Cholinergic treatment
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Antiglutamic treatment
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β‐ and γ‐secretase inhibitors
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Drugs which potentially prevent and modify AD symptoms
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Vitamins and antioxidants
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Non‐steroidal anti‐inflammatory drugs
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Oestrogen replacement therapy
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Inhibitors of complement‐mediated degeneration
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Cobra venom factor (CVF)
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Heparin and other polyionic agents
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Other small molecule inhibitors
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Recombinant protein inhibitors
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Anti‐amyloid therapy (‘vaccination’)
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Targeting proteasome inhibition
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Neuropeptide mixture (Cerebrolysin)
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Conclusions
Alzheimer’s disease (AD) is an age‐related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD; however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. In the past decade, enormous efforts have been devoted to understand the genetics and molecular pathogenesis leading to neuronal death in AD, which has been transferred into extensive experimental approaches aimed at reversing disease progression. Modern medicine is facing an increasing number of treatments available for vascular and neurodegenerative brain diseases, but no causal or neuroprotective treatment has yet been established. Almost all neurological conditions are characterized by progressive neuronal dysfunction, which, regardless of the pathogenetic mechanism, finally leads to neuronal death. The particular emphasis of this review is on risk factors and mechanisms resulting in neuronal loss in AD and current and prospective opportunities for therapeutic interventions. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD.
Inside-Out of Complement in Cancer Kolev, Martin; Das, Madhumita; Gerber, Monica ...
Frontiers in immunology,
07/2022, Letnik:
13
Journal Article
Recenzirano
Odprti dostop
The role of complement in cancer has received increasing attention over the last decade. Recent studies provide compelling evidence that complement accelerates cancer progression. Despite the pivotal ...role of complement in fighting microbes, complement seems to suppress antitumor immunity
via
regulation of host cell in the tumor microenvironment. Although most studies link complement in cancer to complement activation in the extracellular space, the discovery of intracellular activation of complement, raises the question: what is the relevance of this process for malignancy? Intracellular activation is pivotal for the survival of immune cells. Therefore, complement can be important for tumor cell survival and growth regardless of the role in immunosuppression. On the other hand, because intracellular complement (the complosome) is indispensable for activation of T cells, these functions will be essential for priming antitumor T cell responses. Here, we review functions of complement in cancer with the consideration of extra and intracellular pathways of complement activation and spatial distribution of complement proteins in tumors and periphery and provide our take on potential significance of complement as biomarker and target for cancer therapy.
The complement system is an evolutionary old and crucial component of innate immunity, which is key to the detection and removal of invading pathogens. It was initially discovered as a liver-derived ...sentinel system circulating in serum, the lymph, and interstitial fluids that mediate the opsonization and lytic killing of bacteria, fungi, and viruses and the initiation of the general inflammatory responses. Although work performed specifically in the last five decades identified complement also as a critical instructor of adaptive immunity-indicating that complement's function is likely broader than initially anticipated-the dominant opinion among researchers and clinicians was that the key complement functions were in principle defined. However, there is now a growing realization that complement activity goes well beyond "classic" immune functions and that this system is also required for normal (neuronal) development and activity and general cell and tissue integrity and homeostasis. Furthermore, the recent discovery that complement activation is not confined to the extracellular space but occurs within cells led to the surprising understanding that complement is involved in the regulation of basic processes of the cell, particularly those of metabolic nature-mostly
novel crosstalks between complement and intracellular sensor, and effector, pathways that had been overlooked because of their spatial separation. These paradigm shifts in the field led to a renaissance in complement research and provide new platforms to now better understand the molecular pathways underlying the wide-reaching effects of complement functions in immunity and beyond. In this review, we will cover the current knowledge about complement's emerging relationship with the cellular metabolism machinery with a focus on the functional differences between serum-circulating versus intracellularly active complement during normal cell survival and induction of effector functions. We will also discuss how taking a closer look into the evolution of key complement components not only made the functional connection between complement and metabolism rather "predictable" but how it may also give clues for the discovery of additional roles for complement in basic cellular processes.
•Recent, evidence have demonstrated presence of intracellular complement proteins and their activation (the complosome).•The complosome plays a role in basic cell processes such as metabolism.•The ...interaction between the complosome and intracellular pathogens needs to be further elucidated.
The complement system was defined over a century ago based on its ability to “complement” the antibody-mediated and cell-mediated immune responses against pathogens. Today our understanding of this ancient part of innate immunity has changed substantially and we know now that complement plays an undisputed pivotal role in the regulation of both innate and adaptive immunity. The complement system consists of over 50 blood-circulating, cell-surface expressed and intracellular proteins. It is key in the recognition and elimination of invading pathogens, also in the removal of self-derived danger such as apoptotic cells, and it supports innate immune responses and the initiation of the general inflammatory reactions. The long prevailing classic view of complement was that of a serum-operative danger sensor and first line of defence system, however, recent experimental and clinical evidences have demonstrated that “local” tissue and surprisingly intracellular complement (the complosome) activation impacts on normal cell physiology. This review will focus on novel aspects of intracellular complement activation and its unexpected roles in basic cell processes such as metabolism. We also discuss what the existence of the complosome potentially means for how the host handles intracellular pathogens such as viruses.
Alzheimers disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD, however, ...neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimers dementia. This review emphasizes on the dual key roles of complement system and complement regulators (CRegs) in disease pathology and progression. The particular focus of this review is on currently evolving strategies for design of complement inhibitors that might aid therapy by restoring the fine balance between activated components of complement system, thus improving the cognitive performance of patients. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD.
Complement is traditionally known to be a system of serum proteins that provide protection against pathogens through direct cell lysis and the mobilization of innate and adaptive immunity. However, ...recent work indicates that the complement system has additional physiological roles beyond those in host defence. In this Opinion article, we describe the new modes and locations of complement activation that enable it to interact with other cell effector systems, such as growth factor receptors, inflammasomes and metabolic pathways. We propose that the location of complement activation dictates its function.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The following article examines the image of nature, reflected in parts of Matvey Valev's Brazilian prose, and focuses on the walking man's gaze. Two main manifestations of nature are observed: „wild ...nature“, characterized by abundance and dominance; and „tamed nature“, in which dominance had been taken away by man. The alienation of Valev's emigrant characters is tied to the broken connection between the character of the modern man and nature.
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