Prefrontal neurons predict choices during an auditory same-different task

The detection of stimuli is critical for an animal's survival [1]. However, it is not adaptive for an animal to respond automatically to every stimulus that is present in the environment [2-5]. Given that the prefrontal cortex (PFC) plays a key role in executive function [6-8], we hypothesized that PFC activity should be involved in context-dependent responses to uncommon stimuli. As a test of this hypothesis, monkeys participated in a same-different task, a variant of an oddball task [2]. During this task, a monkey heard multiple presentations of a "reference" stimulus that were followed by a "test" stimulus and reported whether these stimuli were the same or different. While they participated in this task, we recorded from neurons in the ventrolateral prefrontal cortex (vPFC; a cortical area involved in aspects of nonspatial auditory processing [9, 10]). We found that vPFC activity was correlated with the monkeys' choices. This finding demonstrates a direct link between single neurons and behavioral choices in the PFC on a nonspatial auditory task.     

The Activity Approach : New Lines of Research

The emotional reactions of an actor that resemble those experienced by the character he is portraying serve as an index of the artist's penetration into the sphere of the needs (motives) of that dramatic character, an indicator of the naturalness, verisimilitude, and accuracy of the behavior ofthat character, which is the most important condition for fruitful creativity in the theater [6]. The ability to transform one's own artistic, creative need (a "meta-meta task," in the terminology of K. S. Stanislavskii) into the motives of the behavior of the portrayed person, into his "metatask," is an extremely important aspect of an actor's talent and also of his professionalism [2,8]. This ability is closely related to a personality trait that may, very provisionally, be designated by the term emotionality, by which is meant the ability to respond forcefully to emotion-producing stimuli. In an actor, emotional responses to the reproduction in the mind of corresponding emotionally colored situations assumes special importance [1,13]. The number of studies employing objective recording of the physiological changes accompanying an actor's emotional responses is still very limited [1,3,5,9,10,15].     

Multi-algebra duplication

This paper was inspired by [5]. First, we define a new kind of duplication which differs from the usual one in that we have different multiplication tables for male and female gametes. [5] deals with the special case where the tables correspond to different recombination rates for males and females for two linked loci. Furthermore, we use the factoring and multilinear technique discussed in [2] and [3] to simplify the proofs in [5].     

The Theory of Set in the Light of Reflex Theory

It is well known to all those acquainted with D. N. Uznadze's theory of set [ustanovka] (1) that this theory was meant to answer the question of "the character and inner structure of human activity" [11; 79]. But, as A. T. Bochorishvili correctly noted, we do not yet have "clarity in basic concepts. … Soviet psychology cannot yet go so far as to speak of the content of the basic concept of the psychology of set, of the content of set itself" [5: 15]. As a panacea for overcoming these differences of opinion, Bochorishvili proposes that we "widely and actively develop investigations of the theoretical bases of the psychology of set as D. N. Uznadze understood if" (ibid.).     

Are respiratory allergic diseases related to atopic dermatitis?

The difference of test results between patients with "pure" atopic dermatitis (AD) and "mixed" AD (with concomitant respiratory allergy, RA) was investigated in 30 AD patients. The results showed the onset of disease that mostly occur in the early infancy [15 (50%) patients had developed the disease under the age of 2-2/10 in "pure" AD, and 13/20 in "mixed" AD]. Twenty (66.6%) of them had a history of RA ("mixed" AD) whereas the remaining 10 (33.3%) had "pure" AD. Seventeen (56.6%) AD patients had one concomitant allergic disease, while 3 (10%) patients had two comorbid conditions (AR and AB) each. Family history was positive for atopy in 22 (73.3%) AD patients [in 14 (46.6%) patients in a first-degree relative]. Twenty-four (80%) patients had positive prick test [9/10 (90%) in "pure" AD and 15/20 (75%) in "mixed" AD], mostly for house dust (20). Positive scratch test was observed in 16 (53.3%) patients [4/10 in "pure" AD, and 12/20 in "mixed" AD]. Nineteen (63.3%) AD patients showed positive patch test reaction [5/10 in "pure" AD, and 14/20 in "mixed" AD]. AD patients had higher serum IgE (21/30) than non-atopic ones but similar in "pure" AD, and "mixed" AD [7/10 (70%) in "pure" AD, and 14/20 (70%) in "mixed" AD]. Determination of CD23 marker on B-lymphocytes showed normal values in 24, and increased values in six patients [2/10 in "pure" AD, and 4/20 in "mixed" AD]. The values of CD21 were decreased in 16 AD patients [6/10 in "pure" AD, and 10/20 in "mixed" AD]. HLA-DR expression was normal in almost all patients. There were no statistically significant differences (p < 0.05) between the "pure" AD and "mixed" AD patient groups, except for the age at onset, which was younger in the group of patients with concomitant RA. Accordingly, study results pointed to the association between AD and RA.     

Analysis of ADP-ribose polymer sizes in intact cells

Poly(ADP-ribose) is a polymer (pADPr) that is synthesized by poly (ADP-ribose) polymerases in response to DNA damaging agents. For instance, chemical alkylating agents such as MNNG [1] or physical stimulation of cells by -rays [2] are well known to induce pADPr synthesis. PARPs are members of a growing family of enzymes which includes PARP-1, PARP-2, S-PARP-1, tankyrase and V-PARP [3]. The association of PARP-1 and PARP-2 in DNA damage signaling pathways has been characterized, but tankyrase and V-PARP seem to be independent of DNA repair mechanisms.Poly(ADP-ribosyl)ation leads to heterogenous chain lengths of up to 200 units (mers) in vitro [3]. While most of these will be covalently bound to proteins, they may be released under alkaline conditions for analysis. Previous immunological methods such as immunoblots [4] showed that about 60–70% of the 6–8 mers pADPr were lost during fixation and that the very short pADPr (2–5 mers) were very weakly bound to the membrane [5]. Furthermore, detection of cellular pADPr using enzyme-linked immunosorbent assay (ELISA) revealed that some molecules of pADPr are also lost during fixation and washings. This phenomenon leads to underestimation of the short pADPr population in cells. Thus, evaluating which pADPr sizes are present in cells and tissues becomes critical.We report here the development of a new highly sensitive immunological method to detect synthesized pADPr sizes distribution in intact cells.     

Trends and Outcome from Radical Therapy for Primary Non-Metastatic Prostate Cancer in a UK Population

Background

Increasing proportions of men diagnosed with prostate cancer in the UK are presenting with non-metastatic disease. We investigated how treatment trends in this demographic have changed.

Patient and Methods

Non-metastatic cancers diagnosed from 2000–2010 in the UK Anglian Cancer network stratified by age and risk group were analysed [n = 10,365]. Radiotherapy [RT] and prostatectomy [RP] cancer specific survival [CSS] were further compared [n = 4755].

Results

Over the decade we observed a fall in uptake of primary androgen deprivation therapy but a rise in conservative management [CM] and radical therapy [p<0.0001]. CM in particular has become the primary management for low-risk disease by the decade end [p<0.0001]. In high-risk disease however both RP and RT uptake increased significantly but in an age dependent manner [p<0.0001]. Principally, increased RP in younger men and increased RT in men ≥ 70y. In multivariate analysis of radically treated men both high-risk disease [HR 8.0 [2.9–22.2], p<0.0001] and use of RT [HR 1.9 [1.0–3.3], p = 0.024] were significant predictors of a poorer CSM. In age-stratified analysis however, the trend to benefit of RP over RT was seen only in younger men [≤ 60 years] with high-risk disease [p = 0.07]. The numbers needed to treat by RP instead of RT to save one cancer death was 19 for this group but 67 for the overall cohort.

Conclusion

This study has identified significant shifts in non-metastatic prostate cancer management over the last decade. Low-risk disease is now primarily managed by CM while high-risk disease is increasingly treated radically. Treatment of high-risk younger men by RP is supported by evidence of better CSM but this benefit is not evident in older men.     

Sensorimotor learning configures the human mirror system

Cells in the "mirror system" fire not only when an individual performs an action but also when one observes the same action performed by another agent [1-4]. The mirror system, found in premotor and parietal cortices of human and monkey brains, is thought to provide the foundation for social understanding and to enable the development of theory of mind and language [5-9]. However, it is unclear how mirror neurons acquire their mirror properties -- how they derive the information necessary to match observed with executed actions [10]. We address this by showing that it is possible to manipulate the selectivity of the human mirror system, and thereby make it operate as a countermirror system, by giving participants training to perform one action while observing another. Before this training, participants showed event-related muscle-specific responses to transcranial magnetic stimulation over motor cortex during observation of little- and index-finger movements [11-13]. After training, this normal mirror effect was reversed. These results indicate that the mirror properties of the mirror system are neither wholly innate [14] nor fixed once acquired; instead they develop through sensorimotor learning [15, 16]. Our findings indicate that the human mirror system is, to some extent, both a product and a process of social interaction.     

Rates of decay for the survival probability of a mutant gene II The multitype case

This paper extends the results of [1] to the multitype case. For a multitype branching process that is slightly supercritical, approximations for the survival probability in terms of the maximal eigenvalue of the mean matrix and a generalized variance ² are developed. Our results improve upon those of Hoppe [5] and Eshel [3] that seek to validate a conjecture of Ewens [4].Research supported in part by NSF grant DMS 9007182     

A dynamin-related protein required for nuclear remodeling in Tetrahymena

Dynamin-related proteins (DRPs) are GTPases that reversibly assemble on cellular membranes [1]. Individual DRPs (here "DRP" includes authentic dynamins) function in fission or tubulation of the plasma membrane, trans-Golgi network, mitochondria, peroxisomes, chloroplasts, and endosomes [1] and in mitochondrial fusion [2]. Many of these functions are widespread; they are present in animals, plants, trypanosomes, Giardia, ciliates, alga, and slime molds [3-8]. Lineage-specific expansions of the gene family created specialized DRPs. In animals, such DRPs include MxB, which has been reported to regulate nuclear-pore transport [9]. Whereas many unicellular organisms possess a small number of DRPs, expansions occurred in some protist lineages. The eight DRPs in the ciliate Tetrahymena thermophila might contribute to aspects of ciliate complexity. Each ciliate cell contains distinct germline and somatic nuclei, whose differentiation and maintenance must require distinct machinery [10, 11]. Here we show that Drp6p, previously shown to be targeted to the nuclear envelope [3], is required for macronuclear development. Drp6p activity, which is distinct from that of the only other known nuclear DRP, is modulated by a combination of stage-specific subcellular targeting and assembly dynamics. This work demonstrates a novel DRP activity and presents a system in which environmental and developmental cues can be used for manipulating key aspects of regulation.     

Altered fractalkine cleavage results in an organ-specific 17 kDa fractalkine fragment in salivary glands of NOD mice

Sjögren''s syndrome is a rheumatic disease in which the salivary and lacrimal glands are the principal targets of a pathological autoimmune reaction. Previous studies in mice indicated that delayed organogenesis and aberrant cell physiology followed by an increase in acinar cell apoptosis precede chronic focal inflammation in the salivary glands and the manifestation of impaired exocrine gland secretion. In a recent study by Wildenberg and colleagues, the authors report aberrant proteolytic activity in the salivary glands of non-obese diabetic mice and the generation of a unique organ-specific 17 kDa fragment of the chemokine and adhesion molecule fractalkine.In the previous issue of Arthritis Research & Therapy, aberrant proteolytic activity in the salivary glands of non-obese diabetic (NOD) mice with spontaneous experimental Sjögren''s syndrome (SS) was reported [1]. SS is a rather common systemic autoimmune disease characterized by exocrine gland inflammation and impaired glandular function [2]. The NOD strain has become a commonly used spontaneous model for SS in which several SS-related hypotheses have been developed or tested. Although the initiating event leading to the accumulation of mononuclear cells in the exocrine glands is unknown, studies in NOD mice and related congenic strains carrying the Aec1 and Aec2 loci showed aberrant proteolytic activity [3], elevated apoptosis and activated interferon-γ, Toll-like receptor (TLR)3 and TLR7 associated pathways in the salivary glands prior to manifestation of the disease [4].Wildenberg and colleagues [1] now provide evidence that fractalkine is cleaved to a unique organ-specific 17 kDa fragment in the salivary glands of NOD mice. This phenomenon was observed from as early as 10 weeks of age. At this time-point the mice probably displayed a pre-disease or sub-clinical stage of SS [5]. Altered cleavage was subsequently observed until 20 weeks of age when SS in NOD mice is thought to have advanced to an overt disease stage [5]. Unfortunately, the protease involved in the cleavage of this apparently unique and organ-specific17 kDa fragment has not yet been identified. The cleavage, however, did not seem to depend on Caspase-3, ADAM-10, ADAM-17, MMP-2 and/or MMP-9 activity [1]. Throughout the same period of time, NOD mice presented autoantibodies recognizing 31 kDa fractalkine.The authors mainly discuss their finding from the perspective of fractalkine as a potentially new autoantigen in SS [1]. Although such hypotheses are highly speculative considering the present core of knowledge, we believe that chemokines in general, and fractalkine in particular, deserve more attention in SS research. We recently found specific chemokines to be associated with different aspects of experimental SS [6], and prevention of hyposalivation in NOD mice through administration of heat-shock protein 60 kDa coincided with normalization of multiple chemokine levels in saliva [7].In contrast to other chemokines, fractalkine can be found in two specific forms, which allows fractalkine to participate in very distinct biological processes. Soluble fractalkine acts as a potent chemotactic factor for monocytes, natural killer (NK)-cells, and T-cells expressing CX3C receptor (CX3R)1. In addition, a membrane-anchored form, which is unusual for chemokines, is expressed on endothelial cells and also several cell types associated with exocrine glands [8]. To what extent fractalkine expression patterns might be altered in salivary glands obtained from patients with SS in comparison with viral infections or homeostatic conditions, however, remains to be investigated [8].By acting as an adhesion molecule, membrane-bound frac-talkine may facilitate extravasation of CX3CR1-expressing leukocytes [9,10]. In addition, CX3CR1 appears to be a selective surface marker for leukocyte subsets, which exert cytotoxic effector functions. Fractalkine may also lead to increased interferon-γ, tumor necrosis factor-γ and granulocyte monocyte colony stimulating factor production by NK-cells and other cell subsets that have been suggested to play a role in the initiation phase and pathogenesis of inflammatory conditions, such as atherosclerosis [10], glomerulonephritis [9] and rheumatoid arthritis (RA) [9]. Although these disorders are multifactorial in nature, exposure to microbial agents is thought to play a role in their initiation [2,9,10]. Several viral proteins were reported to bind a broad spectrum of mediators of the immune system, including fractalkine [8]. Specific gene polymorphisms have been reported to be risk factors for coronary heart disease [10] and deletion of CX3CR1 in apolipoprotein E deficient mice reduced atherosclerotic lesion formation [10]. Fractalkine has also been associated with the pathogenesis of RA after fractalkine and CX3CR1 expression were reported to be upregulated in the synovium of patients with RA [9]. Supporting the notion of the disease-modulating activity of fractalkine in RA, administration of anti-fractalkine antibodies ameliorated experimental RA [9]. With regard to diseases involving the kidneys, a viral fractalkine antagonist reduced kidney inflammation and proteinurea in the Wistar-Kyoto crescentic glomerulonephritis model [9]. In concordance, anti-CX3CR1 blocked lymphocytic infiltration and the development of subsequent stages of glomerulonephritis in these rats [9]. In MRL^lpr mice a truncated fractalkine analogue with the capability of antagonizing the actions of fractalkine also significantly ameliorated several aspects of lupus nephritis and vasculitis [9].The findings reported by Wildenberg and colleagues add the aspect of organ-specific cleavage of fractalkine to its potential role in a specific autoimmune condition. Unfortunately, the report does not address the effect of altered cleavage on fractalkine''s biological activities, for example, chemotaxis. Based on the results presented it is therefore difficult to speculate if fractalkine, through altered cleavage, might be rendered either more potent or less efficient with regard to certain of its actions. The study by Wildenberg and colleagues provides, however, a rationale for conducting such functional studies in the future. In parallel, it would be interesting to address if the described autoantibodies might have the potential to modulate fractalkine related inflammatory processes.     

DSAS-6 organizes a tube-like centriole precursor, and its absence suggests modularity in centriole assembly

Centrioles are microtubule-based cylindrical structures that exhibit 9-fold symmetry and facilitate the organization of centrosomes, flagella, and cilia [1]. Abnormalities in centrosome structure and number occur in many cancers [1, 2]. Despite its importance, very little is known about centriole biogenesis. Recent studies in C. elegans have highlighted a group of molecules necessary for centriole assembly [1, 3]. ZYG-1 kinase recruits a complex of two coiled-coil proteins, SAS-6 and SAS-5, which are necessary to form the C. elegans centriolar tube, a scaffold in centriole formation [4, 5]. This complex also recruits SAS-4, which is required for the assembly of the centriolar microtubules that decorate that tube [4, 5]. Here we show that Drosophila SAS-6 is involved in centriole assembly and cohesion. Overexpression of DSAS-6 in syncitial embryos led to the de novo formation of multiple microtubule-organizing centers (MTOCs). Strikingly, the center of these MTOCs did not contain centrioles, as described previously for SAK/PLK4 overexpression [6]. Instead, tube-like structures were present, supporting the idea that centriolar assembly starts with the formation of a tube-like scaffold, dependent on DSAS-6 [5]. In DSAS-6 loss-of-function mutants, centrioles failed to close and to elongate the structure along all axes of the 9-fold symmetry, suggesting modularity in centriole assembly. We propose that the tube is built from nine subunits fitting together laterally and longitudinally in a modular and sequential fashion, like pieces of a layered "hollow" cake.     

An expanded biological repertoire for Ins(3,4,5,6)P4 through its modulation of ClC-3 function

Ins(3,4,5,6)P(4) inhibits plasma membrane Cl(-) flux in secretory epithelia [1]. However, in most other mammalian cells, receptor-dependent elevation of Ins(3,4,5,6)P(4) levels is an "orphan" response that lacks biological significance [2]. We set out to identify Cl(-) channel(s) and/or transporter(s) that are regulated by Ins(3,4,5,6)P4 in vivo. Several candidates [3-5] were excluded through biophysical criteria, electrophysiological analysis, and confocal immunofluorescence microscopy. Then, we heterologously expressed ClC-3 in the plasma membrane of HEK293-tsA201 cells; whole-cell patch-clamp analysis showed Ins(3,4,5,6)P4 to inhibit Cl(-) conductance through ClC-3. Next, we heterologously expressed ClC-3 in the early endosomal compartment of BHK cells; by fluorescence ratio imaging of endocytosed FITC-transferrin, we recorded intra-endosomal pH, an in situ biosensor for Cl(-) flux across endosomal membranes [6]. A cell-permeant, bioactivatable Ins(3,4,5,6)P4 analog elevated endosomal pH from 6.1 to 6.6, reflecting inhibition of ClC-3. Finally, Ins(3,4,5,6)P(4) inhibited endogenous ClC-3 conductance in postsynaptic membranes of neonatal hippocampal neurones. Among other ClC-3 functions that could be regulated by Ins(3,4,5,6)P4 are tumor cell migration [7], apoptosis [8], and inflammatory responses [9]. Ins(3,4,5,6)P4 is a ubiquitous cellular signal with diverse biological actions.     

Rebalancing the marketing of healthier versus less healthy food products

Jean Adams discusses the evidence around food marketing restrictions and how they may be an effective way to support public health.

We live in a world increasingly saturated with marketing for less healthy foods [1]. One study found that children in New Zealand see an average of 27 instances of marketing for less healthy foods and only 12 for healthier foods, each day [2]. Food marketing involves activities across the 4 Ps of the marketing mix: product, place, price, and promotion. We are encouraged to buy less healthy food products through their placement in prominent store locations such as checkouts, end of aisles, and store entrances; price discounts; and promotions including advertising, cartoon tie-ins, and celebrity endorsements.Systematic reviews have confirmed the effectiveness of these marketing techniques to influence purchasing and consumption of less healthy foods [3–5]. Indeed, the documented power of food marketing has led the World Health Organisation to recommended limiting exposure as an overarching and enabling “best buy” to improve diets [6].Supermarkets remain the location of about 70% of food spend in the United Kingdom [7]. The concentration of food marketing in grocery stores can feel particularly overwhelming with parents describing the “temptation” as “like a trip to the zoo every week” for their children [8]. As such, supermarkets may be particularly important venues for addressing food marketing.In 2 accompanying Research Articles in PLOS Medicine, Piernas and colleagues used nonrandomised approaches to study the impacts on sales of a range of strategies to rebalance the marketing of healthier versus less healthy products in 3 large UK supermarket chains [9,10]. Across the 2 papers, 7 different interventions were implemented that changed the relative availability of healthier versus less healthy products (2 interventions), removed less healthy products from prominent positions, placed healthier products at eye level, offered price discounts on healthier products, increased signage on healthier products, and applied a range of entertainment tie-in promotions on healthier products (one intervention each). These variously had the intention to encourage substitution of less healthy products with healthier alternatives or to reduce purchasing of less healthy foods without substitution.Increasing the relative availability of healthier products, removing less healthy products from prominent positions and price promotions on healthier products were all associated with changes in unit sales in the expected direction, although associations with changes in nutrients purchased were sometimes more modest. In contrast, moving healthier products to eye level and increasing signage were not associated with changes in sales. These findings are particularly timely in England where a range of measures to reduce exposure to marketing of less healthy foods in retail environments are due to be implemented from October 2022 [11].Piernas and colleagues worked in collaboration with large UK supermarket chains. That the chains were prepared to innovate to support public health indicates that rebalancing marketing towards healthier products may not be as burdensome to the sector as it has sometimes claimed [12]. It also strengthens the external validity of these studies giving an indication of how customers react in real-world environments.However, that the supermarket chains decided what the interventions should be also imposes limitations on wider interpretation of the findings. Each of the 7 different interventions applied to different categories of foods without any rationale made explicit to the research team—for example, chocolate confectionary was removed from prominent positions, higher fibre breakfast cereals were placed at eye level, and price discounts were applied to fruit and vegetables. This makes it hard to determine whether observed impacts were unique to specific combinations of intervention and food category. Indeed, rather than particular marketing interventions being more effective than others across the board, it is possible that complex interplays between food category, marketing intervention, and other contextual aspects (such as shop and customer characteristics) interact to produce changes in sales.The “squeezed balloon effect” proposes that restrictions on specific aspects of marketing may lead to compensatory increases in others [13]. For example, restricting television advertising of less healthy foods during and around children’s programmes in the UK was associated with increased exposure of adults to these adverts [14]. Wider compensation between, as well as within, media (for example, TV restrictions leading to more online marketing) may also be expected. It is possible that supermarkets willing to engage in university-assessed marketing changes may have self-policed any simultaneous compensatory activities, and, anyway, these would not necessarily have been identified in the studies by Piernas and colleagues. Any real-life compensation as the whole grocery sector adapts to government-imposed marketing restrictions may be difficult to predict. This reinforces the need for postimplementation evaluation.The squeezed balloon effect means that the most effective marketing restrictions may be those that target marketing of the same products through multiple simultaneous interventions. In Chile, near-simultaneous implementation of front-of-pack warning labels, advertising restrictions, and a prohibition of sales in schools of products high in calories, sodium, sugar, or saturated fat were associated with substantial declines in purchases of targeted foods and nutrients [15]. This approach is also the underlying strategy in England where near-simultaneous restrictions on TV and online advertising of less healthy foods are planned for the whole of the UK alongside the England-specific bans on location and price-based promotions [16].Despite the innovative approach in England, neither the regulations on TV and online advertising of less healthy foods nor on price and location-based promotions of these foods have cleared the parliamentary process. The UK government recently accepted an amendment to the TV and online advertising restrictions to give the Secretary of State for Health and Social Care power to delay implementation [17]. The restrictions on price and location-based promotions may be under threat of being dropped altogether [18].Piernas and colleagues’ studies add to the accumulating evidence that restricting marketing on less healthy foods and encouraging marketing on healthier foods may be an effective way to support public health. Theory and a range of evidence suggest that simultaneous restrictions on a variety of different types of less healthy food marketing are likely to be the most effective ways of reducing exposure to this marketing. The UK government has proposed this approach in England on a number of occasions. That implementation continues to hang in the balance is a sad indictment of our collective inability to create a world that supports everyone to eat in the way they want to, rather than the way the marketers want for us.     

S-nitrosylation of surfactant protein D as a modulator of pulmonary inflammation

Background

Surfactant protein D (SP-D) is a member of the family of proteins termed collagen-like lectins or “collectins” that play a role in non-antibody-mediated innate immune responses [1]. The primary function of SP-D is the modulation of host defense and inflammation [2].

Scope of review

This review will discuss recent findings on the physiological importance of SP-D S-nitrosylation in biological systems and potential mechanisms that govern SP-D mediated signaling.

Major conclusions

SP-D appears to have both pro- and anti-inflammatory signaling functions.SP-D multimerization is a critical feature of its function and plays an important role in efficient innate host defense. Under baseline conditions, SP-D forms a multimer in which the N-termini are hidden in the center and the C-termini are on the surface. This multimeric form of SP-D is limited in its ability to activate inflammation. However, NO can modify key cysteine residues in the hydrophobic tail domain of SP-D resulting in a dissociation of SP-D multimers into trimers, exposing the S-nitrosylated N-termini. The exposed S-nitrosylated tail domain binds to the calreticulin/CD91 receptor complex and initiates a pro-inflammatory response through phosphorylation of p38 and NF-κB activation [3,4]. In addition, the disassembled SP-D loses its ability to block TLR4, which also results in activation of NF-κB.

General significance

Recent studies have highlighted the capability of NO to modify SP-D through S-nitrosylation, causing the activation of a pro-inflammatory role for SP-D [3]. This represents a novel mechanism both for the regulation of SP-D function and NO's role in innate immunity, but also demonstrates that the S-nitrosylation can control protein function by regulating quaternary structure. This article is part of a Special Issue entitled Regulation of Cellular Processes by S-nitrosylation.