A differential diagnosis of a head and neck bony lesion : Review of a case series with 18 patients with extraintestinal features of familial adenomatous polyposis

Peer reviewe

Retrograde signaling from functionally heterogeneous plastids

Structural and functional components of chloroplast are encoded by genes localized both to nuclear and plastid genomes of plant cell. Development from etioplasts to chloroplasts is triggered by light receptors that activate the expression of photosynthesis-associated nuclear genes (PhaNGs). In addition to photoreceptor-mediated pathways, retrograde signals from the chloroplast to the nucleus activate or repress the expression of nuclear genes involved in acclimatory or stress responses in plant leaves. A plant mesophyll cell contains up to 100 chloroplasts that function autonomously, raising intriguing questions about homogeneity and coordination of retrograde signals transmitted from chloroplast to nucleus. We have previously demonstrated that the knockout of the chloroplast regulatory protein, chloroplast NADPH-dependent thioredoxin reductase (NTRC) leads to a heterogeneous population of chloroplasts with a range of different functional states. The heterogeneous chloroplast population activates both redox-dependent and undifferentiated plastid-generated retrograde signaling pathways in the mutant leaves. Transcriptome data from the ntrc knockout lines suggest that the induction of the redox-dependent signaling pathway depends on light conditions and leads to activation of stress-responsive gene expression. Analysis of mutants in different developmental stages allows to dissect signals from normal and anomalous chloroplasts. Thus, the signals derived from anomalous chloroplasts repress expression of PhaNGs as well as genes associated with light receptor signaling and differentiation of stomata, implying interaction between retrograde pathways and plant development. Analysis of the nuclear gene expression in mutants of retrograde signaling pathways in ntrc background would reveal the components that mediate signals generated from heterogeneous plastids to nucleus.</p

Overexpression of chloroplast NADPH-dependent thioredoxin reductase in Arabidopsis enhances leaf growth and elucidates in vivo function of reductase and thioredoxin domains

Plant chloroplasts have versatile thioredoxin systems including two thioredoxin reductases and multiple types of thioredoxins. Plastid-localized NADPH-dependent thioredoxin reductase (NTRC) contains both reductase (NTRd) and thioredoxin (TRXd) domains in a single polypeptide and forms homodimers. To study the action of NTRC and NTRC domains in vivo, we have complemented the ntrc knockout line of Arabidopsis with the wild type and full-length NTRC genes, in which 2-Cys motifs either in NTRd, or in TRXd were inactivated. The ntrc line was also transformed either with the truncated NTRd or TRXd alone. Overexpression of wild-type NTRC promoted plant growth by increasing leaf size and biomass yield of the rosettes. Complementation of the ntrc line with the full-length NTRC gene containing an active reductase but an inactive TRXd, or vice versa, recovered wild-type chloroplast phenotype and, partly, rosette biomass production, indicating that the NTRC domains are capable of interacting with other chloroplast thioredoxin systems. Overexpression of truncated NTRd or TRXd in ntrc background did not restore wild-type phenotype. Modeling of the three-dimensional structure of the NTRC dimer indicates extensive interactions between the NTR domains and the TRX domains further stabilize the dimeric structure. The long linker region between the NTRd and TRXd, however, allows flexibility for the position of the TRXd in the dimer. Supplementation of the TRXd in the NTRC homodimer model by free chloroplast thioredoxins indicated that TRXf is the most likely partner to interact with NTRC. We propose that overexpression of NTRC promotes plant biomass yield both directly by stimulation of chloroplast biosynthetic and protective pathways controlled by NTRC and indirectly via free chloroplast thioredoxins. Our data indicate that overexpression of chloroplast thiol redox-regulator has a potential to increase biofuel yield in plant and algal species suitable for sustainable bioenergy production

Nitrogen processes in aquatic ecosystems

Executive summary Nature of the problem (science/management/policy) • Freshwater ecosystems play a key role in the European nitrogen (N) cycle, both as a reactive agent that transfers, stores and processes N loadings from the atmosphere and terrestrial ecosystems, and as a natural environment severely impacted by the increase of these loadings. Approaches • This chapter is a review of major processes and factors controlling N transport and transformations for running waters, standing waters, groundwaters and riparian wetlands. Key findings/state of knowledge • The major factor controlling N processes in freshwater ecosystems is the residence time of water, which varies widely both in space and in time, and which is sensitive to changes in climate, land use and management. • The effects of increased N loadings to European freshwaters include acidification in semi-natural environments, and eutrophication in more disturbed ecosystems, with associated loss of biodiversity in both cases. • An important part of the nitrogen transferred by surface waters is in the form of organic N, as dissolved organic N (DON) and particulate organic N (PON). This part is dominant in semi-natural catchments throughout Europe and remains a significant component of the total N load even in nitrate enriched rivers. • In eutrophicated standing freshwaters N can be a factor limiting or co-limiting biological production, and control of both N and phosphorus (P) loading is oft en needed in impacted areas, if ecological quality is to be restored. Major uncertainties/challenges • The importance of storage and denitrifi cation in aquifers is a major uncertainty in the global N cycle, and controls in part the response of catchments to land use or management changes. In some aquifers, the increase of N concentrations will continue for decades even if efficient mitigation measures are implemented now. • Nitrate retention by riparian wetlands has oft en been highlighted. However, their use for mitigation must be treated with caution, since their effectiveness is difficult to predict, and side effects include increased DON emissions to adjacent open waters, N2O emissions to the atmosphere, and loss of biodiversity. • In fact, the character and specific spatial origins of DON are not fully understood, and similarly the quantitative importance of indirect N2O emissions from freshwater ecosystems as a result of N leaching losses from agricultural soils is still poorly known at the regional scale. • These major uncertainties remain due to the lack of adequate monitoring (all forms of N at a relevant frequency), especially – but not only – in the southern and eastern EU countries. Recommendations (research/policy) • The great variability of transfer pathways, buffering capacity and sensitivity of the catchments and of the freshwater ecosystems calls for site specific mitigation measures rather than standard ones applied at regional to national scale. • The spatial and temporal variations of the N forms, the processes controlling the transport and transformation of N within freshwaters, require further investigation if the role of N in influencing freshwater ecosystem health is to be better understood, underpinning the implementation of the EU Water Framework Directive for European freshwaters

Atypical Neurophysiology Underlying Episodic and Semantic Memory in Adults with Autism Spectrum Disorder

Individuals with autism spectrum disorder (ASD) show atypicalities in episodic memory (Boucher et al. in Psychological Bulletin, 138 (3), 458-496, 2012). We asked participants to recall the colours of a set of studied line drawings (episodic judgement), or to recognize line drawings alone (semantic judgement). Cycowicz et al. (Journal of Experimental Child Psychology, 65, 171-237, 2001) found early (300 ms onset) posterior old-new event-related potential effects for semantic judgements in typically developing (TD) individuals, and occipitally focused negativity (800 ms onset) for episodic judgements. Our results replicated findings in TD individuals and demonstrate attenuated early old-new effects in ASD. Late posterior negativity was present in the ASD group, but was not specific to this time window. This non-specificity may contribute to the atypical episodic memory judgements characteristic of individuals with ASD

Witnessing Violence Toward Siblings: An Understudied but Potent Form of Early Adversity

Research on the consequences of witnessing domestic violence has focused on inter-adult violence and most specifically on violence toward mothers. The potential consequences of witnessing violence to siblings have been almost entirely overlooked. Based on clinical experience we sought to test the hypothesis that witnessing violence toward siblings would be as consequential as witnessing violence toward mothers. The community sample consisted of unmedicated, right-handed, young adults who had siblings (n = 1,412; 62.7% female; 21.8±2.1 years of age). History of witnessing threats or assaults to mothers, fathers and siblings, exposure to parental and sibling verbal abuse and physical abuse, sexual abuse and sociodemographic factors were assessed by self-report. Symptoms of depression, anxiety, somatization, anger-hostility, dissociation and ‘limbic irritability’ were assessed by rating scales. Data were analyzed by multiple regression, with techniques to gauge relative importance; logistic regression to assess adjusted odds ratios for clinically-significant ratings; and random forest regression using conditional trees. Subjects reported witnessing violence to siblings slightly more often than witnessing violence to mothers (22% vs 21%), which overlapped by 51–54%. Witnessing violence toward siblings was associated with significant effects on all ratings. Witnessing violence toward mother was not associated with significant effects on any scale in these models. Measures of the relative importance of witnessing violence to siblings were many fold greater than measures of importance for witnessing violence towards mothers or fathers. Mediation and structural equation models showed that effects of witnessing violence toward mothers or fathers were predominantly indirect and mediated by changes in maternal behavior. The effects of witnessing violence toward siblings were more direct. These findings suggest that greater attention be given to the effects of witnessing aggression toward siblings in studies of domestic violence, abuse and early adversity

Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer.

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, P=1.68x10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, P=0.49), 0.94 (95% CI: 0.84-1.05, P= 0.27), and 0.98 (95% CI: 0.85-1.12, P=0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR=0.69, 95% CI: 0.49-0.99, P=0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia. This article is protected by copyright. All rights reserved

The LeucoPatch® system in the management of hard-to-heal diabetic foot ulcers: study protocol for a randomised controlled trial

Background: Diabetic foot ulcers are a common and severe complication of diabetes mellitus. Standard treatment includes debridement, offloading, management of infection and revascularisation where appropriate, although healing times may be long. The LeucoPatch® device is used to generate an autologous platelet-rich fibrin and leucocyte wound dressing produced from the patient's own venous blood by centrifugation, but without the addition of any reagents. The final product comprises a thin, circular patch composed predominantly of fibrin together with living platelets and leucocytes. Promising results have been obtained in non-controlled studies this system, but this now needs to be tested in a randomised controlled trial (RCT). If confirmed, the LeucoPatch® may become an important new tool in the armamentarium in the management of diabetic foot ulcers which are hard-to-heal. Methods: People with diabetes and hard-to-heal ulcers of the foot will receive either pre-specified good standard care or good standard care supplemented by the application of the LeucoPatch® device. The primary outcome will be the percentage of ulcers healed within 20 weeks. Healing will be defined as complete epithelialisation without discharge that is maintained for 4 weeks and is confirmed by an observer blind to randomisation group. Discussion: Ulcers of the foot are a major source of morbidity to patients with diabetes and costs to health care economies. The study population is designed to be as inclusive as possible with the aim of maximising the external validity of any findings. The primary outcome measure is healing within 20 weeks of randomisation and the trial also includes a number of secondary outcome measures. Among these are rate of change in ulcer area as a predictor of the likelihood of eventual healing, minor and major amputation of the target limb, the incidence of infection and quality of life. Trial registration: International Standard Randomised Controlled Trial, ISRCTN27665670. Registered on 5 July 2013

Characteristics of Early-Onset vs Late-Onset Colorectal Cancer: A Review.

The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer. Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts. The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes