AID: how does it aid antibody diversity?

Activation-induced cytidine deaminase (AID) is an essential enzyme to regulate class switch recombination (CSR), somatic hypermutation (SHM), and gene conversion (GC). AID is known to be required for DNA cleavage of S regions in CSR. However, its molecular mechanism is a focus of extensive debate. RNA editing hypothesis postulates that AID edits yet unknown mRNA to generate specific endonucleases for CSR and SHM. By contrast, DNA deamination hypothesis assumes that AID deaminates cytosine in DNA, followed by DNA cleavage by base excision repair enzymes. We discuss available evidence for the two proposed models. Recent findings, namely requirement of protein synthesis for DNA breakage and dispensability of U removal activity of uracil DNA glycosylase, force us to reconsider DNA deamination hypothesis.     

Tibolone: what does tissue specific activity mean?

Preclinical studies has found that tibolone can display a weak estrogenic, progestational and androgenic activity. The effect produced depends mainly on the target tissue involved. Clinical data indicate that tibolone produces the hormonal effects needed to treat climacteric symptoms and to prevent long-term effects of the menopause without stimulating breast and endometrial tissues. This clinical profile would be produced by the tissue specific activity of tibolone and its main metabolites. Tibolone's tissue specific activity may be explained by the interplay of several mechanisms, such as the metabolic conversion of tibolone to compounds with different biological activity, the classical interaction with the steroid receptor and the specific local metabolism, within the target tissue. Therefore, the tissue response and thus the clinical effect produced by tibolone in a given tissue seem to depend on the predominating mechanisms and interactions present in that tissue.     

Altered thymic activity in early life: how does it affect the immune system in young adults?

The thymus is responsible for the maturation of lymphoid precursors into T cells, and is necessary to establish the T cell pool during prenatal and early postnatal life in humans. With the years, it undergoes a natural shrinking process, referred to as involution, suspected to be central in the decline of immune competence with aging, or immunosenescence. Here, we review the recent studies focusing on the immunological consequences of abnormal thymic development and thymectomy shortly after birth. These works highlight the importance of the thymic function in preserving immune efficacy throughout life, and provide insights into the development of immune aging.     

Staying alive overdosed: How does Helicobacter pylori control urease activity?

Urease, a nickel metalloenzyme is an essential virulence factor of the gastric pathogen, Helicobacter pylori. This enzyme is the major actor in the resistance to acidity and, therefore, plays a central role in colonization and persistence in the host. Urease has till recently been considered to be a constitutive and permanently active enzyme. Recent advances have revealed that the activity of this abundant protein is subtly modulated at different levels. These regulatory mechanisms mainly concern nickel insertion at the urease active site with control of both the availability and incorporation of this metal ion into the structural subunits, whose production itself is induced in some conditions. Another level of regulation is the availability of the urease substrate, urea, which is controlled by UreI, an acid-gated urea channel encoded by the urease gene cluster. We calculated that under in vitro conditions without added nickel only a small proportion of the urease active sites is filled with nickel but that this is sufficient for full acid resistance. This raised the question of why this organism produces this enzyme far in excess of its needs. We propose a model in which the role of excess urease is to maintain a pool of actively bound intracellular Ni2+ ions which can be inherited by the daughter cells to provide sufficient activated urease even in case of long-term nickel deficiency.     

Computational modelling of phonological dyslexia: how does the DRC model fare?

This paper investigates the patterns of reading impairment in phonological dyslexia using computational modelling with the dual-route cascaded model of reading (DRC, Coltheart, Rastle, Perry, Langdon, & Ziegler, 2001). Systematic lesioning of nonlexical and phonological processes in DRC demonstrates that different lesions and severity of those lesions can reproduce features of phonological dyslexia including impaired reading of nonwords, relatively spared reading of words, an advantage for reading pseudohomophones. Using the same stimuli for model and for patients, lesions to DRC were also used to simulate the reading accuracy shown by three individuals with acquired phonological dyslexia. No single lesion could replicate the reading performance of all three individuals. In order to simulate reading accuracy for one individual a phonological impairment was necessary (addition of noise to the phoneme units), and for the remaining two individuals an impairment to nonlexical reading procedures (increasing the time interval between each new letter being processed) was necessary. We argue that no single locus of impairment (neither phonological nor nonlexical) can account for the reading impairments of all individuals with phonological dyslexia. Instead, different individuals have different impairments (and combinations of impairments) that together provide the spectrum of patterns found in phonological dyslexia.     

A deconvolution method to improve automated 3D-analysis of dendritic spines: application to a mouse model of Huntington’s disease

Dendritic spines are postsynaptic structures the morphology of which correlates with the strength of synaptic efficacy. Measurements of spine density and spine morphology are achievable using recent imaging and bioinformatics tools. The three-dimensional automated analysis requires optimization of image acquisition and treatment. Here, we studied the critical steps for optimal confocal microscopy imaging of dendritic spines. We characterize the deconvolution process and show that it improves spine morphology analysis. With this method, images of dendritic spines from medium spiny neurons are automatically detected by the software Neuronstudio, which retrieves spine density as well as spine diameter and volume. This approach is illustrated with three-dimensional analysis of dendritic spines in a mouse model of Huntington’s disease: the transgenic R6/2 mice. In symptomatic mutant mice, we confirm the decrease in spine density, and the method brings further information and show a decrease in spine volume and dendrite diameter. Moreover, we show a significant decrease in spine density at presymptomatic age which so far has gone unnoticed.     

Follicular dendritic cells: whose children?

At the recent Germinal Centre Conference in Spa, over 200 immunologists gathered to study the fate of lymph follicles, B- and T-cell selection, cell migration, accessory cells, and pathological conditions such as lymphoproliferative diseases and AIDS. Here, Ernst Heinen and Alain Bosseloir report on this fascinating field.     

Tyrosinemia type I treated by NTBC: how does AFP predict liver cancer?

BACKGROUND: Tyrosinemia type I is associated with an increased risk of liver cancer development. The formation of the pathogenic fumarylacetoacetate is prevented by 2-(2-nitro-4-3 trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC). Still, some patients with NTBC treatment develop liver cancer. A rise of alpha-fetoprotein (AFP) is an indicator of liver cancer. AIM: To study the predictive value of AFP in tyrosinemia type I patients for the discrimination between patients at high and low risk of liver cancer development. METHODS: We examined the course of AFP values of 11 Dutch patients with tyrosinemia type I treated by NTBC, of whom four were diagnosed with liver cancer. RESULTS: The four patients with liver cancer had a course of AFP different from the other patients in either velocity of the decrease of AFP, achieving normal AFP and/or having a rise of AFP concentrations. CONCLUSION: Apart from a rise of AFP, a slow AFP decrease, and never normalizing levels of AFP are important predictors of liver cancer development in further life.     

Huntington's disease: how does huntingtin, an anti-apoptotic protein, become toxic?

Huntington's disease belongs to a class of inherited neurological disorders that are caused by the presence of a polyglutamine expansion in apparently unrelated proteins. In Huntington's disease, expansion occurs in the huntingtin protein. Together with the characteristic formation of aggregates in the diseased state, several post-translational modifications affect huntingtin during the pathological process and lead to the dysfunction and eventual death of selective neurons in the brain of patients. These mechanisms are not completely described but could involve the gain of a new toxic function as well as the loss of the beneficial properties of huntingtin.     

Power output in vertical jumps: does optimum loading depend on activity profiles?

The previously proposed maximum dynamic output hypothesis (MDO: i.e. the optimum load for maximizing the power output during jumping is one’s own body) was tested on individuals of various activity profiles. Forty males (10 strength-trained athletes, 10 speed-trained athletes, 10 physically active non-athletes, and 10 sedentary individuals) performed different vertical jumps on a force plate while a pulley system was used to either reduce or increase the subject’s body weight by 10–30 %. As expected, an increase in external loading resulted in a significant increase (p < 0.001) in force output and a concomitant decrease of peak jumping velocity in all groups of participants. The main finding, however, was that all groups revealed the maximum peak and mean power output at approximately the subjects’ own body weight although their weight represented prominently different percentage of their maximum dynamic strength. While a significant (p < 0.05), albeit moderate, ‘group × load’ interaction in one jump was observed for the peak power output, the individual optimum load for maximizing the power output number did not differ among the groups. Although apparently further research on various types of movements is needed, the present results provide, so far, the strongest support of the MDO hypothesis.     

Why does serotonergic activity drastically decrease during REM sleep?

Here, I postulate two hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation. As dendritic spines contain many kinds of serotonin receptors, and the activation of serotonin receptors generally increases the number of spines in the cortex and hippocampus, I postulate that serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. Furthermore, since synaptic consolidation during REM sleep needs long-term potentiation (LTP), and serotonin is reported to inhibit LTP in the cortex, I postulate that serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation. Until now, why serotonergic neurons show these dramatic changes in the sleep–wake cycle remains unexplained; however, making these hypotheses, I can confer physiological meanings on these dramatic changes of serotonergic neurons in terms of spine homeostasis and memory consolidation.     

A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines

Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia in the elderly. Accumulating evidence supports soluble amyloid-β (Aβ) oligomers as the leading candidate for the causative agent in AD and synapses as the primary site of Aβ oligomer action. However, the molecular and cellular mechanisms by which Aβ oligomers cause synaptic dysfunction and cognitive impairments remain poorly understood. Using primary cultures of rat hippocampal neurons as a model system, we show that the partitioning defective-1 (PAR-1)/microtubule affinity-regulating kinase (MARK) family kinases act as critical mediators of Aβ toxicity on synapses and dendritic spines. Overexpression of MARK4 led to tau hyperphosphorylation, reduced expression of synaptic markers, and loss of dendritic spines and synapses, phenotypes also observed after Aβ treatment. Importantly, expression of a non-phosphorylatable form of tau with the PAR-1/MARK site mutated blocked the synaptic toxicity induced by MARK4 overexpression or Aβ treatment. To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels. Our results reveal a critical role for PAR-1/MARK kinases in AD pathogenesis and suggest PAR-1/MARK inhibitors as potential therapeutics for AD and possibly other tauopathies where aberrant tau hyperphosphorylation is involved.