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In this personal memoir of the impact of war and displacement, I tell the story of my father, a Polish-Jewish student from Lwow, then in Poland, who became a refugee after the German invasion of Soviet occupied Poland in 1941. It is the story of loss, survival and reinvention of nationality and family. It is a story familiar to those many refugees through the ages who coped with displacement and loss and made a new and successful life in a foreign country.

Summary: Background: Children whose parents have anxiety problems are at increased risk of developing anxiety themselves. Parenting behaviors are a contributing factor to intergenerational transmission. Interventions which seek to limit anxiogenic parenting behaviors have shown potential in reducing anxiety in offspring but are not widely accessible. This prevention trial aimed to establish the effectiveness of an unguided modular online intervention for highly anxious parents in preventing anxiety in their children. Methods: A parallel group, block-randomised controlled trial of unblinded participants in a 1:1 ratio was conducted to compare efficacy of the online course compared to a no-intervention control. The intervention comprised 8 modules, of approximately 20 min each, and participants progressed through the course at their own pace. The study was conducted entirely online with a self-referred UK-based community sample of parents (child 2–11 years) with substantial anxiety. The primary outcome measure was change in parent-reported child anxiety, as measured by the Spence Children's Anxiety Scale–Parent Report (SCAS-P) or Spence Pre-School Anxiety Scale–Parent Report (Preschool SCAS). Secondary outcomes were child internalising, externalising, and attentional symptoms (Pediatric Symptom Checklist), and parent anxiety (SCARED-Adult). Analyses using complete case analysis following intention to treat principles investigated intervention effects at 6 months (primary analysis) and additionally at 9 to 25-months’ follow-up. Trial registration: ClinicalTrials.Gov NCT04755933, https://clinicaltrials.gov/ct2/show/NCT04755933. Findings: 1811 participants (intervention = 900; control = 911; 92.7% (1677/1810) female; 85.3% (1535/1800) White-British; 66.8% (1201/1799) university educated). Participant retention (based on primary outcome completion) at T2 (6-months post consent) was 67.6% overall (n = 1224) and substantially lower in the intervention arm 57.3% ((516/900) control = 77.8% (708/910)). Child anxiety was lower in the intervention group compared to control at 6-month follow-up (adjusted effect size estimate −0.15 (95% CI: −0.23 to −0.08, p

Background: The use of a second informant (co-respondent) is a common method of identifying potential bias in outcome data (e.g., parent-report child outcomes). There is, however, limited evidence regarding methods of increasing response rates from co-respondents. The use of financial incentives is associated with higher levels of engagement and follow-up data collection in online surveys. This study investigated whether financial incentives paid to index participants in an online trial of a parenting-focused intervention, would lead to higher levels of co-respondent data collection. Methods: A study within a trial (SWAT) using a parallel group RCT design. Participants in the host study (an RCT of an online intervention) were randomised into one of two SWAT arms: received/did not receive a £15 voucher when referred co-respondent completed baseline measures. Primary outcome was completion (No/Yes) of Spence Children's Anxiety Scale (SCAS or SCAS-Pre) at baseline. Additional analysis explored impact of incentives on data quality. Results: Intention to treat analysis of 899 parents (183 co-respondents) in the no-incentive arm, and 911 parents (199 co-respondents) in incentive arm. Nomination of co-respondents was similar between incentive arms. The RR for the incentive arm compared to the no incentive arm was 1.13 (95% CI: 0.91 to 1.41, p = 0.264) indicating that incentives did not impact completion of outcomes by consented co-respondents. There were no indications of different data quality between arms. Discussion: The finding that payment of financial incentives to index participant does not lead to greater levels of co-respondent outcome completion suggests that careful consideration should be made before allocating resources in this way in future trials. Trial registration: The host study was registered at Study Record | ClinicalTrials.gov and the SWAT study was registered in the SWAT Store | The Northern Ireland Network for Trials Methodology Research (qub.ac.uk): SWAT number 143: Filetoupload,1099612,en.pdf (qub.ac.uk).

Are the objectives of Russia’s invasion of Ukraine in 2022 based on Putin’s ideological view of Russia’s history and the place of Ukraine in it in the process re-establishing Russia’s position as a world power challenging US hegemony? Or are there underlying economic objectives shared with Russia’s oligarchs to gain control of Ukraine’s mineral wealth and strategic economic position at the crossroads of Europe and Eurasia? This article compares the economies of Russia and Ukraine and their performance since the end of the Soviet Union and finds that their economic structures and performance are very similar over the last three decades, as is the domination of their respective oligarchs, but that the war has hit Ukraine much more disastrously than sanctions have hit Russia. It concludes that Russia does not need Ukraine’s mineral wealth but that control of Ukraine would bring Russia economic gains. However, the principal reason for the invasion is to push back the potential NATO advance to the Russian border, itself a reaction to US fears of Europe’s increasing dependence on Russia for gas, and in doing so challenge US hegemony not just in Europe by across the world by building bridges to Asia and other parts of the Global South.

ABSTRACTThe study objective was to examine the animal welfare status of Irish beef production farms using an animal welfare index (AWI). Beef production farms (n = 105) including suckler calf-to-beef (n = 30), suckler calf/weaning/finishing (n = 63), dairy calf-to-beef (n = 12) were assessed during the winter housing period using the AWI. Fifty-one indicators were grouped into six categories: ‘locomotion’; six indicators, ‘social interactions’; eight indicators, ‘flooring’; four indicators, ‘environment’; nine indicators, ‘stockperson’; thirteen indicators and ‘husbandry management’ eleven indicators. Two indicators relating to the size of the farm and number of animals on the farm were also collected. The overall mean AWI percentage for the suckler calf-to-beef, suckler calf/weaning/finishing, dairy calf-to-beef farms were 70.3%, 71.9% and 66.6%, respectively. There was no difference (P > 0.05) in AWI between full-time and part-time farmers. This study demonstrated the application of the AWI for use in beef production systems.

Background: Parent-report questionnaires are a common method of generating data on child outcomes in mental health studies. A second report from another person who knows the child (co-respondent) is implemented to reduce bias and increase objectivity. The success of this approach is dependent on the engagement of co-respondents, which can be difficult. Financial incentives are used to increase data return in clinical trials, and to promote referral rates in online marketing. This protocol describes the use of an embedded randomised controlled trial (RCT) to investigate the effect of financial incentives on rates of co-respondent data completion. In the host RCT (of an online intervention designed to reduce the impact of a parent's anxiety on their child) index participants (i.e. parents) are asked to invite a co-respondent to complete measures on the index child. This study will test the hypothesis that providing monetary incentives to index participants will increase the outcome measure completion rate of co-respondents. Methods: Embedded RCT of two parallel groups. Participants in the intervention arm will be sent a £10 voucher if their chosen co-respondent completes online baseline measures. Participants in the control arm will not be offered payment regardless of their chosen co-respondent's behaviour. 1754 participants will take part. Analysis will compare co-respondent outcome measure completion rates between the two arms at baseline and follow-up. Conclusion: Findings from this study will provide evidence on the impact of offering payment to index participants on return rates of co-respondent data. This will inform resource allocation within future clinical trials.

Political discourse around coastal wetland restoration and blue carbon management strategies has increased in the past decade, yet carbon storage has neither been a reason for restoration, nor a criterion to measure the success of current saltmarsh restoration schemes in the UK. To maximise climate change mitigation through saltmarsh restoration, knowledge on the key drivers of carbon stock variability is required. We use restored saltmarshes of similar age, paired with adjacent natural marshes as references, to identify drivers of carbon stocks following managed realignment within an estuary in southeastern England. From surficial soil cores (top 30 cm), we measured carbon stock alongside environmental characteristics. Carbon stock between natural and restored sites were similar after ~ 30 years when restored sites were above mean high water neap (MHWN) tidal levels. Elevated marsh platforms likely provide suitable conditions for the development of mature plant communities associated with greater capture and production of organic carbon. The restored site at Tollesbury (Essex, UK) had a 2-fold lower carbon stock than other restored sites in the estuary. We attribute this to the site’s low position in the tidal frame, below MHWN tidal levels, coupled with low sediment supply and the dominance of pioneer plant communities. As blue carbon is anticipated to become an important facet of saltmarsh restoration, we recommend that sites above MHWN tidal levels are selected for managed realignment or that preference is given to coastlines with a high sediment supply that may rapidly elevate realignment sites above MHWN. Alternatively, elevation could be artificially raised prior to realignment. Restoration schemes aiming to maximise climate change mitigation should also encourage the establishment of key plant species (e.g., Atriplex portulacoides in our study) to enhance carbon stocks. However, the overall goal of restoration ought to be carefully considered as trade-offs in ecosystem services may ensue if restoration for climate change mitigation alone is pursued.

BackgroundAnxiety is the most common childhood mental health condition and is associated with impaired child outcomes, including increased risk of mental health difficulties in adulthood. Anxiety runs in families: when a parent has anxiety, their child has a 50% higher chance of developing it themselves. Environmental factors are predominant in the intergenerational transmission of anxiety and, of these, parenting processes play a major role. Interventions that target parents to support them to limit the impact of any anxiogenic parenting behaviors are associated with reduced anxiety in their children. A brief UK-based group intervention delivered to parents within the UK National Health Service led to a 16% reduction in children meeting the criteria for an anxiety disorder. However, this intervention is not widely accessible. To widen access, a 9-module web-based version of this intervention has been developed. This course comprises psychoeducation and home practice delivered through text, video, animations, and practice tasks. ObjectiveThis study seeks to evaluate the feasibility of delivering this web-based intervention and assess its effectiveness in reducing child anxiety symptoms. Methods This is the protocol for a randomized controlled trial (RCT) of a community sample of 1754 parents with self-identified high levels of anxiety with a child aged 2-11 years. Parents in the intervention arm will receive access to the web-based course, which they undertake at a self-determined rate. The control arm receives no intervention. Follow-up data collection is at months 6 and months 9-21. Intention-to-treat analysis will be conducted on outcomes including child anxiety, child mental health symptoms, and well-being; parental anxiety and well-being; and parenting behaviors. ResultsFunding was received in April 2020, and recruitment started in February 2021 and is projected to end in October 2022. A total of 1350 participants have been recruited as of May 2022. ConclusionsThe results of this RCT will provide evidence on the utility of a web-based course in preventing intergenerational transmission of anxiety and increase the understanding of familial anxiety. Trial RegistrationClinicalTrials.gov NCT04755933; https://clinicaltrials.gov/ct2/show/NCT04755933 International Registered Report Identifier (IRRID)DERR1-10.2196/40707

Inequality between nations could be viewed as a major global faultline and although there is evidence that it is slowly being reduced, the gap between countries at the top and bottom remains enormous, with GDP per head of the top 25 high-income countries of the Global North being 52 times that of the bottom 25 countries. Inequality within countries is increasing, with evidence of a growing concentration of income and wealth in the hands of a small number of very rich individuals and senior corporate executives on astronomical salaries and bonuses. The COVID-19 pandemic appears to be reinforcing inequality. These developments are widely considered to be a threat to national and international security. Studies that have sought to find a relationship between inequality and threats to security in the form of terrorism and violent and property crime have found it to be positive. There are, therefore, sound practical reasons why inequality should be reduced, if not moral ones to underpin genuine democracy and human rights.

While there are several published studies for modelling pedestrian behavior at signalized crossings in SUMO, the behavior of pedestrians crossing a road at a location other than a designated crossing, has not been considered to date. This work looks at how to represent pedestrian agents selecting to cross a road at arbitrary locations along the length of the road. The pedestrian agents utilize a gap acceptance model that represents how a pedestrian decides when to cross a road, based on the frequency and speed of approaching vehicles, while considering the spacing between them. Furthermore, the gap acceptance model allows the pedestrians to choose to cross all lanes in one go, when safe to do so, known as Double Gap or one stage crossing. Alternatively, if an agent is identified as a risk-taker, they may choose to cross lane by lane, sometimes waiting in the middle of the road, known as Rolling Gap or risk-taker crossing behavior. The inclusion of these two crossing behaviors allows for situations where urgency plays an important role in behavioral decision making, such as in emergencies, rush hour or in crowd management events. The outlined pedestrian crossing model is attained by integrating the pedestrian model EXODUS with SUMO, via the TraCI API.

Abstract Background Coral reefs are rapidly changing in response to local and global stressors. Research to better understand and inform the management of these stressors is burgeoning. However, in situ studies of coral reef ecology are constrained by complex logistics and limited resources. Many reef studies are also hampered by the scale-dependent nature of ecological patterns, and inferences made on causal relationships within coral reef systems are limited by the scales of observation. This is because most socio-ecological studies are conducted at scales relevant to the phenomenon of interest. However, management often occurs across a significantly broader, often geopolitical, range of scales. While there is a critical need for incisive coral reef management actions at relevant spatial and temporal scales, it remains unclear to what extent the scales of empirical study overlap with the scales at which management inferences and recommendations are made. This systematic map protocol will evaluate this potential scale mismatch with the goal of raising awareness about the significance of effectively addressing and reporting the scales at which researchers collect data and make assumptions. Methods We will use the Collaboration for Environmental Evidence (CEE) systematic mapping guidelines to identify relevant studies using a framework-based synthesis to summarise the spatial and temporal scales of coral reef fish ecology research and the scales at which management inferences or recommendations are made. Using tested predefined terms, we will search for relevant published academic and grey literature, including bibliographic databases, web-based search engines, and organisational websites. Inclusion criteria for the evidence map are empirical studies that focus on coral reef fish ecological organisation and processes, those informing management interventions and policy decisions, and management documents that cite coral reef research for management decision-making. Study results will be displayed graphically using data matrices and heat maps. This is the first attempt to systematically assess and compare the scales of socio-ecological research conducted on coral reef systems with their management.

Background Changing demographics across the UK has led to general practitioners (GPs) managing increasing numbers of older patients with multi-morbidity and resultant polypharmacy. Through government led initiatives within the National Health Service, an increasing number of GP practices employ pharmacist support. The purpose of this study is to evaluate the impact of a medicines optimisation intervention, delivered by GP practice-based pharmacists, to patients at risk of medication-related problems (MRPs), on patient outcomes and healthcare costs. Methods A multi-centre, randomised (normal care or pharmacist supplemented care) study in four regions of the UK, involving patients (n = 356) from eight GP practices, with a 6-month follow-up period. Participants were adult patients who were at risk of MRPs. Results Median number of MRPs per intervention patient were reduced at the third assessment, i.e. 3 to 0.5 (p

Impact models projections are used in integrated assessments of climate change. Here the authors test systematically across many important systems, how well such impact models capture the impacts of extreme climate conditions.

Cancer vaccination and immunotherapy revolutionised the treatment of cancer, a result of decades of research into the immune system in health and disease. However, despite recent breakthroughs in treating otherwise terminal cancer, only a minority of patients respond to cancer immunotherapy and some cancers are largely refractive to immunotherapy treatment. This is due to numerous issues intrinsic to the tumour, its microenvironment, or the immune system. CD4+ and CD8+ αβ T-cells emerged as the primary effector cells of the anti-tumour immune response but their function in cancer patients is often compromised. This review details the mechanisms by which T-cell responses are hindered in the setting of cancer and refractive to immunotherapy, and details many of the approaches under investigation to direct T-cell function and improve the efficacy of cancer vaccination and immunotherapy.

Temperature is a dominant factor driving arctic and boreal ecosystem phenology, including leaf budburst and gross primary production (GPP) onset in Alaskan spring. Previous studies hypothesized that both accumulated growing degree day (GDD) and cold temperature (chilling) exposure are important to leaf budburst. We test this hypothesis by combining both satellite and aircraft vegetation measurements with the Community Land Model Version 4.5 (CLM), in which the end of plant dormancy depends on thermal conditions (i.e. GDD). We study the sensitivity of GPP onset of different Alaskan deciduous vegetation types to a GDD model with chilling requirement (GC model) included. The default CLM simulations have a 1–12 d earlier day of year GPP onset over Alaska vegetated regions compared to satellite constrained estimates from the Polar Vegetation Photosynthesis and Respiration Model. Integrating a GC model into CLM shifts the phase and amplitude of GPP. During 2007–2016, mean GPP onset is postponed by 5 ± 7, 4 ± 8, and 1 ± 6 d over Alaskan northern tundra, shrub, and forest, respectively. The GC model has the greatest impact during warm springs, which is critical for predicting phenology response to future warming. Overall, spring GPP high bias is reduced by 10%. Thus, including chilling requirement in thermal forcing models improves northern high-latitude phenology, but leads to other impacts during the growing season which require further investigation.

Over the past century, soybean oil (SBO) consumption in the United States increased dramatically. The main SBO fatty acid, linoleic acid (18:2), inhibits in vitro the growth of lactobacilli, beneficial members of the small intestinal microbiota. Human-associated lactobacilli have declined in prevalence in Western microbiomes, but how dietary changes may have impacted their ecology is unclear. Here, we compared the in vitro and in vivo effects of 18:2 on Lactobacillus reuteri and L. johnsonii. Directed evolution in vitro in both species led to strong 18:2 resistance with mutations in genes for lipid biosynthesis, acid stress, and the cell membrane or wall. Small-intestinal Lactobacillus populations in mice were unaffected by chronic and acute 18:2 exposure, yet harbored both 18:2- sensitive and resistant strains. This work shows that extant small intestinal lactobacilli are protected from toxic dietary components via the gut environment as well as their own capacity to evolve resistance.

Agricultural production must increase to feed a growing and wealthier population, as well as to satisfy increasing demands for biomaterials and biomass-based energy. At the same time, deforestation and land-use change need to be minimized in order to preserve biodiversity and maintain carbon stores in vegetation and soils. Consequently, agricultural land use needs to be intensified in order to increase food production per unit area of land. Here we use simulations of AgMIP's Global Gridded Crop Model Intercomparison (GGCMI) phase 1 to assess implications of input-driven intensification (water, nutrients) on crop yield and yield stability, which is an important aspect in food security. We find region- and crop-specific responses for the simulated period 1980-2009 with broadly increasing yield variability under additional nitrogen inputs and stabilizing yields under additional water inputs (irrigation), reflecting current patterns of water and nutrient limitation. The different models of the GGCMI ensemble show similar response patterns, but model differences warrant further research on management assumptions, such as variety selection and soil management, and inputs as well as on model implementation of different soil and plant processes, such as on heat stress, and parameters. Higher variability in crop productivity under higher fertilizer input will require adequate buffer mechanisms in trade and distribution/storage networks to avoid food price volatility.

Abstract Introduction Freely accessible online tests for the diagnosis of Alzheimer's disease (AD) are widely available. The objective of this study was to evaluate these tests along three dimensions as follows: (1) scientific validity; (2) human‐computer interaction (HCI) features; and (3) ethics features. Methods A sample of 16 online tests was identified through a keyword search. A rating grid for the tests was developed, and all tests were evaluated by two expert panels. Results Expert analysis revealed that (1) the validity of freely accessible online tests for AD is insufficient to provide useful diagnostic information; (2) HCI features of the tests are adequate for target users, and (3) the tests do not adhere to accepted ethical norms for medical interventions. Discussion The most urgent concerns raised center on the ethics of collecting and evaluating responses from users. Physicians and other professionals will benefit from a heightened awareness of these tools and their limitations today.

Long-chain PUFAs (LCPUFAs) occur in foods primarily in the natural lipid classes, triacylglycerols (TAGs) or phospholipids (PLs). We studied the relative efficacy of the neural omega-3 DHA provided in formula to growing piglets as a dose of 13C-DHA bound to either TAG or phosphatidylcholine (PC). Piglets were assigned to identical formula-based diets from early life and provided with TAG-13C-DHA or PC-13C-DHA orally at 16 days. Days later, piglet organs were analyzed for 13C-DHA and other FA metabolites. PC-13C-DHA was 1.9-fold more efficacious for brain gray matter DHA accretion than TAG-13C-DHA, and was similarly more efficacious in gray matter synaptosomes, retina, liver, and red blood cells (RBCs). Liver labeling was greatest, implying initial processing in that organ followed by export to other organs, and suggesting that transfer from gut to bloodstream to liver in part drove the difference in relative efficacy for tissue accretion. Apparent retroconversion to 22:5n-3 was more than double for PC-13C-DHA and was more prominent in neural tissue than in liver or RBCs. These data directly support greater efficacy for PC as a carrier for LCPUFAs compared with TAG, consistent with previous studies of arachidonic acid and DHA measured in other species.

This article carefully critiques existing educational literature in relation to simulations, identifying some methodological flaws in the relevant empirical studies, but also pointing to a strong correlation between simulations and student engagement in studies involving a range of methodologies. The article builds on this literature by reporting the findings of empirical research relating to a treaty simulation based on the Paris climate agreement. These findings support the value of treaty simulations in enhancing student engagement. The value of simulations as an effective method to assess both skills and conceptual knowledge is also analysed using a model based on Biggs’ ‘constructive alignment’ approach. The article provides a complete set of materials for running an international treaty negotiation simulation exercise which can be utilized in international law, international relations, international environmental law and negotiation subjects at university. This exercise places an emphasis on the teaching of negotiation skills and developing conceptual knowledge through stimulating student engagement. The simulation is designed to be time-effective, to mitigate any trade-offs with respect to the coverage of other course content. It is also largely free-standing and can be easily adapted to any subjects in which negotiation skills are relevant, including those suggested above.

The fatty acid desaturase (FADS) genes code for the rate-limiting enzymes required for the biosynthesis of long-chain polyunsaturated fatty acids (LCPUFA). Here we report discovery and function of a novel FADS1 splice variant. FADS1 alternative transcript 1 (FADS1AT1) enhances desaturation of FADS2, leading to increased production of eicosanoid precursors, the first case of an isoform modulating the enzymatic activity encoded by another gene. Multiple protein isoforms were detected in primate liver, thymus, and brain. In human neuronal cells, their expression patterns are modulated by differentiation and result in alteration of cellular fatty acids. FADS1, but not FADS1AT1, localizes to endoplasmic reticulum and mitochondria. Ribosomal footprinting demonstrates that all three FADS genes are translated at similar levels. The noncatalytic regulation of FADS2 desaturation by FADS1AT1 is a novel, plausible mechanism by which several phylogenetically conserved FADS isoforms may regulate LCPUFA biosynthesis in a manner specific to tissue, organelle, and developmental stage.

Saturated branched chain fatty acids (BCFA) are present as complex mixtures in numerous biological samples. The traditional method for structure elucidation, electron ionization (EI) mass spectrometry, sometimes does not unambiguously enable assignment of branching in isomeric BCFA. Zirrolli and Murphy (Zirrolli, J. A., and R. A. Murphy. 1993. Low-energy tandem mass spectrometry of the molecular ion derived from fatty acid methyl esters: a novel method for analysis of branched-chain fatty acids. J. Am. Soc. Mass Spectrom. 4: 223–229.) showed that the molecular ions of four BCFA methyl ester (BCFAME) yield highly characteristic fragments upon collisional dissociation using a triple quadrupole instrument. Here, we confirm and extend these results by analysis using a tabletop 3-D ion trap for activated molecular ion EI-MS/MS to 30 BCFAME. iso-BCFAME produces a prominent ion (30-100% of base peak) for [M-43] (M-C3H7), corresponding to the terminal isopropyl moiety in the original iso-BCFAME. Anteiso-FAME yield prominent ions (20-100% of base peak) corresponding to losses on both side of the methyl branch, [M-29] and [M-57], and tend to produce more prominent m/z 115 peaks corresponding to a cyclization product around the ester. Dimethyl and tetramethyl FAME, with branches separated by at least one methylene group, yield fragment on both sides of the sites of methyl branches that are more than 6 C away from the carboxyl carbon. EI-MS/MS yields uniquely specific ions that enable highly confident structural identification and quantification of BCFAME.

The Δ6 desaturase, encoded by FADS2, plays a crucial role in omega-3 and omega-6 fatty acid synthesis. These fatty acids are essential components of the central nervous system, and they act as precursors for eicosanoid signaling molecules and as direct modulators of gene expression. The polypyrimidine tract binding protein (PTB or hnRNP I) is a splicing factor that regulates alternative pre-mRNA splicing. Here, PTB is shown to bind an exonic splicing silencer element and repress alternative splicing of FADS2 into FADS2 AT1. PTB and FADS2AT1 were inversely correlated in neonatal baboon tissues, implicating PTB as a major regulator of tissue-specific FADS2 splicing. In HepG2 cells, PTB knockdown modulated alternative splicing of FADS2, as well as FADS3, a putative desaturase of unknown function. Omega-3 fatty acids decreased by nearly one half relative to omega-6 fatty acids in PTB knockdown cells compared with controls, with a particularly strong decrease in eicosapentaenoic acid (EPA) concentration and its ratio to arachidonic acid (ARA). This is a rare demonstration of a mechanism specifically altering the cellular omega-3 to omega-6 fatty acid ratio without any change in diet/media. These findings reveal a novel role for PTB, regulating availability of membrane components and eicosanoid precursors for cell signaling.

This paper presents the Wavelia microwave breast imaging system that has been recently installed at the Galway University Hospital, Ireland, for a first-in-human pilot clinical test. Microwave breast imaging has been extensively investigated over the last two decades as an alternative imaging modality that could potentially bring complementary information to state-of-the-art modalities such as X-ray mammography. Following an overview of the main working principles of this technology, the Wavelia imaging system architecture is presented, as are the radar signal processing algorithms that are used in forming the microwave images in which small tumors could be detectable for disease diagnosis. The methodology and specific quality metrics that have been developed to properly evaluate and validate the performance of the imaging system using complex breast phantoms that are scanned at controlled measurement conditions are also presented in the paper. Indicative results from the application of this methodology to the on-site validation of the imaging system after its installation at the hospital for pilot clinical testing are thoroughly presented and discussed. Given that the imaging system is still at the prototype level of development, a rigorous quality assessment and system validation at nominal operating conditions is very important in order to ensure high-quality clinical data collection.

Delta-6 desaturase (D6D) catalyzes the first step in the synthesis of highly unsaturated fatty acids (HUFA) such as arachidonic (AA), docosapentaenoic (DPAn-6), and docosahexaenoic (DHA) acids, as well as the last desaturation of DPAn-6 and DHA. We created D6D-null mice (−/−), which enabled us to study HUFA deficiency without depleting their precursors. In −/−, no in vivo AA synthesis was detected after administration of [U-13C]linoleic acid (LA), indicating absence of D6D isozyme. Unexpectedly, all of the −/− developed ulcerative dermatitis when fed a purified diet lacking D6D products but containing ample LA. The −/− also exhibited splenomegaly and ulceration in duodenum and ileocecal junction. Male −/− lacked normal spermatozoa with a severe impairment of spermiogenesis. Tissue HUFAs in −/− declined differentially: liver AA and DHA by 95%, and a smaller decrease in brain and testes. Dietary AA completely prevented dermatitis and intestinal ulcers in −/−. DPAn-6 was absent in −/− brain under AA supplementation, indicating absence of D6D isozyme for DPAn-6 synthesis from AA. This study demonstrated a distinct advantage of the D6D-null mice (−/−) to elucidate (1) AA function without complication of LA deprivation and (2) DHA function in the nervous system without AA depletion or DPAn-6 replacement seen in traditional models.—Stroud, C. K., T. Y. Nara, M. Roqueta-Rivera, E. C. Radlowski, P. Lawrence, Y. Zhang, B. H. Cho, M. Segre, R. A. Hess, J. T. Brenna, W. M. Haschek, and M. T. Nakamura. Disruption of FADS2 gene in mice impairs male reproduction and causes dermal and intestinal ulceration.

The mammalian Δ6-desaturase coded by fatty acid desaturase 2 (FADS2; HSA11q12-q13.1) catalyzes the first and rate-limiting step for the biosynthesis of long-chain polyunsaturated fatty acids. FADS2 is known to act on at least five substrates, and we hypothesized that the FADS2 gene product would have Δ8-desaturase activity. Saccharomyces cerevisiae transformed with a FADS2 construct from baboon neonate liver cDNA gained the function to desaturate 11,14-eicosadienoic acid (20:2n-6) and 11,14,17-eicosatrienoic acid (20:3n-3) to yield 20:3n-6 and 20:4n-3, respectively. Competition experiments indicate that Δ8-desaturation favors activity toward 20:3n-3 over 20:2n-6 by 3-fold. Similar experiments show that Δ6-desaturase activity is favored over Δ8-desaturase activity by 7-fold and 23-fold for n-6 (18:2n-6 vs 20:2n-6) and n-3 (18:3n-3 vs 20:3n-3), respectively. In mammals, 20:3n-6 is the immediate precursor of prostaglandin E1 and thromboxane B1. 20:3n-6 and 20:4n-3 are also immediate precursors of long-chain polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid, respectively. These findings provide unequivocal molecular evidence for a novel alternative biosynthetic route to long-chain polyunsaturated fatty acids in mammals from substrates previously considered to be dead-end products.

Infant formulas supplemented with docosahexaenoic acid (DHA) and arachidonic acid (ARA) are now available in the United States; however, little is known about the factors that affect biosynthesis. Baboon neonates were assigned to one of four treatments: term, breast-fed; term, formula-fed; preterm (155 of 182 days gestation), formula-fed; and preterm, formula+DHA/ARA-fed. Standard formula had no DHA/ARA; supplemented formula had 0.61%wt DHA (0.3% of calories) and 1.21%wt ARA (0.6% of calories), and baboon breast milk contained 0.68 ± 0.22%wt DHA and 0.62 ± 0.12%wt ARA. At 14 days adjusted age, neonates received a combined oral dose of [U-13C]α-linolenic acid (LNA*) and [U-13C]linoleic acid (LA*), and tissues were analyzed 14 days after dose. Brain accretion of linolenic acid-derived DHA was ∼3-fold greater for the formula groups than for the breast-fed group, and dietary DHA partially attenuated excess DHA synthesis among preterms. A similar, significant pattern was found in other organs. Brain linoleic acid-derived ARA accretion was significantly greater in the unsupplemented term group but not in the preterm groups compared with the breast-fed group.These data show that formula potentiates the biosynthesis/accretion of DHA/ARA in term and preterm neonates compared with breast-fed neonates and that the inclusion of DHA/ARA in preterm formula partially restores DHA/ARA biosynthesis to lower, breast-fed levels. Current formula DHA concentrations are inadequate to normalize long-chain polyunsaturated fatty acids synthesis to that of breast-fed levels.

Dietary arachidonic acid (20:4n-6) utilization in-vivo for carbon recycling into de-novo lipogenesis and conversion to n-6 long chain polyunsaturates was investigated in baboon neonates using [U-13C]20:4n-6. Neonates consuming a formula typical of human milk received a single oral dose of [13C]arachidonic acid in sn-2 position of either triglyceride or phosphatidylcholine at 18–19 days of postnatal life. Neonate brain, retina, liver, and plasma were obtained 10 days later (28–29 days of life). Low isotopic enrichment (0.27–1.0%Total label) was detected in dihomo-γ-linolenic acid (20:3n-6) in all tissues, but label incorporation into saturates or monounsaturates was not detected. In neonate brain and retina, 16% and 11% of total label was recovered in 22:4n-6, respectively. The relative contribution of dietary fatty acids to postnatal brain 22:4n-6 accretion can be estimated for dietary 20:4n-6 and preformed 22:4n-6 as 17% and 8%, respectively, corresponding to efficiencies of 0.48% and 0.54% of dietary levels, respectively. These results demonstrate in term baboon neonates that in vivo 1) 20:4n-6 was retroconverted to 20:3n-6, 2) 20:4n-6 did not contribute significantly to de novo lipogenesis of saturates and monounsaturates, and 3) the preformed 20:4n-6 contribution to brain 22:4n-6 accumulation was quantitatively a significant metabolic fate for dietary 20:4n-6.—Wijendran, V., P. Lawrence, G-Y. Diau, G. Boehm, P. W. Nathanielsz, and J. T. Brenna. Significant utilization of dietary arachidonic acid is for brain adrenic acid in baboon neonates. J. Lipid Res. 2002. 43: 762–767.

BACKGROUND: Genes coding for the fatty acid desaturases (FADS1, 2, 3) localized at the cancer genomic hotspot 11q13 locus are required for the biosynthesis of 20 carbon polyunsaturated fatty acids (PUFA) that are direct eicosanoid precursors. In several cancer cell lines, FADS2 encoded Δ6 and Δ8 desaturation is not functional. METHODOLOGY/PRINCIPAL FINDINGS: Analyzing MCF7 cell fatty acids with detailed structural mass spectrometry, we show that in the absence of FADS2 activity, the FADS1 product Δ5-desaturase operates to produce 5,11,14-20∶3 and 5,11,14,17-20∶4. These PUFA are missing the 8-9 double bond of the eicosanoid signaling precursors arachidonic acid (5,8,11,14-20∶4) and eicosapentaenoic acid (5,8,11,14,17-20∶5). Heterologous expression of FADS2 restores Δ6 and Δ8-desaturase activity and normal eicosanoid precursor synthesis. CONCLUSIONS/SIGNIFICANCE: The loss of FADS2-encoded activities in cancer cells shuts down normal PUFA biosynthesis, deleting the endogenous supply of eicosanoid and downstream docosanoid precursors, and replacing them with unusual butylene-interrupted fatty acids. If recapitulated in vivo, the normal eicosanoid and docosanoid cell signaling milieu would be depleted and altered due to reduction and substitution of normal substrates with unusual substrates, with unpredictable consequences for cellular communication.