The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases

Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1. Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a lower omega-6/omega-3 ratio), exert suppressive effects. In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial. Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition. A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries.     

A UDP-glucose derivative is required for vacuolar autophagic cell death

Autophagic cell death in Dictyostelium can be dissociated into a starvation-induced sensitization stage and a death induction stage. A UDP-glucose pyrophosphorylase (ugpB) mutant and a glycogen synthase (glcS) mutant shared the same abnormal phenotype. In vitro, upon starvation alone mutant cells showed altered contorted morphology, indicating that the mutations affected the pre-death sensitization stage. Upon induction of cell death, most of these mutant cells underwent death without vacuolization, distinct from either autophagic or necrotic cell death. Autophagy itself was not grossly altered as shown by conventional and electron microscopy. Exogenous glycogen or maltose could complement both ugpB(-) and glcS(-) mutations, leading back to autophagic cell death. The glcS(-) mutation could also be complemented by 2-deoxyglucose that cannot undergo glycolysis. In agreement with the in vitro data, upon development glcS(-) stalk cells died but most were not vacuolated. We conclude that a UDP-glucose derivative (such as glycogen or maltose) plays an essential energy-independent role in autophagic cell death.     

Screening of edentulous patients in a dental school population using the prosthodontic diagnostic index

doi:10.1111/j.1741‐2358.2009.00317.x
Screening of edentulous patients in a dental school population using the prosthodontic diagnostic index Purpose: The aim of this study was to classify a number of completely or partially edentulous patients who attended undergraduate clinics at the Dental School of Athens using the prosthodontic diagnostic index (PDI) to identify the complexity of the cases treated by the students. Background: There is a scarcity of studies, concerning prosthodontic patients and screening them according to a classification system such as the PDI. Material and methods: The survey was conducted on 181 patients who attended the clinics for treatment. The PDI categorised the patients into four classes (Class I–IV) according to the severity of certain diagnostic findings. Results: From the 110 completely edentulous patients, 27 patients were in Class I, 21 in Class II, 15 in Class III and 47 in Class IV. From the 71 partially edentulous patients, two were in Class I, 17 in Class II, 29 in Class III and 23 in Class IV. Conclusion: Our results showed that the majority of patients were categorised in Class III (partially edentulous) and IV (completely edentulous). This indicates the need to introduce a proper screening tool, such as the PDIs, during the initial examination, to achieve a successful treatment.     

Genetic structure,admixture and invasion success in a Holarctic defoliator,the gypsy moth (Lymantria dispar,Lepidoptera: Erebidae)

Characterizing the current population structure of potentially invasive species provides a critical context for identifying source populations and for understanding why invasions are successful. Non‐native populations inevitably lose genetic diversity during initial colonization events, but subsequent admixture among independently introduced lineages may increase both genetic variation and adaptive potential. Here we characterize the population structure of the gypsy moth (Lymantria dispar Linnaeus), one of the world's most destructive forest pests. Native to Eurasia and recently introduced to North America, the current distribution of gypsy moth includes forests throughout the temperate region of the northern hemisphere. Analyses of microsatellite loci and mitochondrial DNA sequences for 1738 individuals identified four genetic clusters within L. dispar. Three of these clusters correspond to the three named subspecies; North American populations represent a distinct fourth cluster, presumably a consequence of the population bottleneck and allele frequency change that accompanied introduction. We find no evidence that admixture has been an important catalyst of the successful invasion and range expansion in North America. However, we do find evidence of ongoing hybridization between subspecies and increased genetic variation in gypsy moth populations from Eastern Asia, populations that now pose a threat of further human‐mediated introductions. Finally, we show that current patterns of variation can be explained in terms of climate and habitat changes during the Pleistocene, a time when temperate forests expanded and contracted. Deeply diverged matrilines in Europe imply that gypsy moths have been there for a long time and are not recent arrivals from Asia.     

New phenotypic aspects of the decidual spiral artery wall during early post-implantation mouse pregnancy

During pregnancy the walls of decidual spiral arteries (SAs) undergo clinically important structural modifications crucial for embryo survival/growth and maternal health. However, the mechanisms of SA remodeling (SAR) are poorly understood. Although an important prerequisite to this understanding is knowledge about the phenotype of SA muscular wall prior to and during the beginning of mouse SAR, this remains largely unexplored and was the main aim of this work. Using histological and immunohistochemical techniques, this study shows for the first time that during early mouse gestation, from embryonic day 7.5 (E7.5) to E10.5, the decidual SA muscular coat is not a homogeneous structure, but consists of two concentric layers. The first is a largely one cell-thick sub-endothelial layer of contractile mural cells (positive for α-smooth muscle actin, calponin and SM22α) with pericyte characteristics (NG2 positive). The second layer is thicker, and evidence is presented that it may be of the synthetic/proliferative smooth muscle phenotype, based on absence (α-smooth muscle actin and calponin) or weak (SM22α) expression of contractile mural cell markers, and presence of synthetic smooth muscle characteristics (expression of non-muscle Myosin heavy chain-IIA and of the cell proliferation marker PCNA). Importantly, immunohistochemistry and morphometrics showed that the contractile mural cell layer although prominent at E7.5-E8.5, becomes drastically reduced by E10.5 and is undetectable by E12.5. In conclusion, this study reveals novel aspects of the decidual SA muscular coat phenotype prior to and during early SAR that may have important implications for understanding the mechanisms of SAR.     

Validation of a new test for Schistosoma haematobium based on detection of Dra1 DNA fragments in urine: evaluation through latent class analysis

Background

Diagnosis of urogenital schistosomiasis in chronically infected adults is challenging but important, especially because long term infection of the bladder and urinary tract can have dire consequences. We evaluated three tests for viable infection: detection of parasite specific DNA Dra1 fragments, haematuria and presence of parasite eggs for sensitivity (Se) and specificity (Sp).

Methods

Over 400 urine specimens collected from adult volunteers in an endemic area in Western Nigeria were assessed for haematuria then filtered in the field, the filter papers dried and later examined for eggs and DNA. The results were stratified according to sex and age and subjected to Latent Class analysis.

Conclusions

Presence of Dra1 in males (Se = 100%; Sp = 100%) exceeded haematuria (Se = 87.6%: Sp = 34.7%) and detection of eggs (Se = 70.1%; Sp = 100%). In females presence of Dra1 was Se = 100%: Sp = 100%, exceeding haematuria (Se = 86.7%: Sp = 77.0%) and eggs (Se = 70.1%; Sp = 100%). Dra1 became undetectable 2 weeks after praziquantel treatment. We conclude detection of Dra1 fragment is a definitive test for the presence of Schistosoma haematobium infection.     

Plasma Membrane Localization of Solanum tuberosum Remorin from Group 1, Homolog 3 Is Mediated by Conformational Changes in a Novel C-Terminal Anchor and Required for the Restriction of Potato Virus X Movement]

The formation of plasma membrane (PM) microdomains plays a crucial role in the regulation of membrane signaling and trafficking. Remorins are a plant-specific family of proteins organized in six phylogenetic groups, and Remorins of group 1 are among the few plant proteins known to specifically associate with membrane rafts. As such, they are valuable to understand the molecular bases for PM lateral organization in plants. However, little is known about the structural determinants underlying the specific association of group 1 Remorins with membrane rafts. We used a structure-function approach to identify a short C-terminal anchor (RemCA) indispensable and sufficient for tight direct binding of potato (Solanum tuberosum) REMORIN 1.3 (StREM1.3) to the PM. RemCA switches from unordered to α-helical structure in a nonpolar environment. Protein structure modeling indicates that RemCA folds into a tight hairpin of amphipathic helices. Consistently, mutations reducing RemCA amphipathy abolished StREM1.3 PM localization. Furthermore, RemCA directly binds to biological membranes in vitro, shows higher affinity for Detergent-Insoluble Membranes lipids, and targets yellow fluorescent protein to Detergent-Insoluble Membranes in vivo. Mutations in RemCA resulting in cytoplasmic StREM1.3 localization abolish StREM1.3 function in restricting potato virus X movement. The mechanisms described here provide new insights on the control and function of lateral segregation of plant PM.Protein-lipid interactions are increasingly recognized as key regulatory processes for signal perception and cellular signaling cascades (Cho and Stahelin, 2005). During signal transduction and trafficking, a number of soluble proteins dynamically associate with plasma membranes (PMs) to deliver their cargo and to recruit pathway components to the sites of action (Seong et al., 2011). For such proteins, membrane association can be critical for function (Porter and Koelle, 2010).PM targeting of peripheral proteins is achieved through (1) binding to integral membrane proteins, (2) posttranslational modifications, or (3) directly by intrinsic membrane anchor domains. Posttranslational modifications function as auxiliary modifications for transient or weak association of soluble proteins to the intracellular face of the PM. In plants, these include N-myristoylation, S-palmitoylation, prenylation by farnesyl or geranylgeranyl moieties, or attachment of glycosylphosphatidylinositol (GPI) anchors (Thompson and Okuyama, 2000). GPI anchors, for example, tightly associate proteins to the extracellular face of PMs by interaction of the inositol head group of the membrane lipid phosphatidylinositol with a glucosamine residue linked to the C-terminal amino acid of the protein (Paulick and Bertozzi, 2008). As an alternative mechanism, globular structures either recognize phospholipids in a stereospecific manner or associate with membranes by their biophysical properties (for review, see Lemmon, 2008). Other proteins expose unstructured clusters of basic and hydrophobic residues to mediate PM binding (McLaughlin et al., 2002; McLaughlin and Murray, 2005).Selective recognition of membrane compartments or domains by protein anchors can be critical in triggering the appropriate downstream trafficking and signaling events (for review, see Gruenberg, 2003; De Matteis and Godi, 2004). Membrane domain selectivity can be specified by the anchoring posttranslational modification or by a protein anchor domain. For instance, proteins carrying GPI anchors are overrepresented in membrane rafts, indicating that addition of this lipid anchor directs proteins to these microdomains (Cordy et al., 2003; Kierszniowska et al., 2009). Membrane rafts are enriched in highly saturated long-chain sphingolipids, sterols, and saturated phospholipids, creating tightly packed domains, designated as “liquid ordered.” These lipids display a stronger affinity to saturated acyl chains as found in GPI-anchored and acylated proteins (Brown, 2006). The composition of membrane rafts also prevents solubilization by detergent at low temperature with nonionic detergent and allows the partial purification of rafts in so-called Detergent-Insoluble Membrane (DIM) fractions, which are supposedly biochemical counterparts of membrane rafts. Many signaling proteins are found in membrane rafts, supporting the hypothesis that they serve as key platforms for cellular signal transduction and cell-to-cell communication (Lingwood and Simons, 2010; Simon-Plas et al., 2011). For example, in human (Homo sapiens) cells, key soluble signaling components such as the Ser/Thr kinase Akt (protein kinase B) are recruited to membrane rafts where they activate signal transduction cascades (Lasserre et al., 2008). Nevertheless, few protein motifs were described to contribute to raft targeting (Rossin et al., 2010), although the 6-amino-acid-long raft target signal from human Tyr phosphatase Src homology 2-containing phosphatase1 is the only known motif sufficient to anchor soluble proteins specifically to domains of the intracellular face of the PM (Sankarshanan et al., 2007). However, the anchoring mechanism itself remains to be unraveled in plants even though DIMs also exist (Mongrand et al., 2010) and functional PM domains have been reported (Bhat et al., 2005). The molecular basis for specific targeting and binding of proteins to membrane rafts has never been described.Remorins form a diverse family of plant-specific proteins organized in six distinct phylogenetic groups (Raffaele et al., 2007). Remorins from group 1 have been reported to localize to the PM despite their overall hydrophilic nature (Reymond et al., 1996; Raffaele et al., 2007). Moreover, group 1 Remorins almost exclusively associate to DIMs and localize to membrane microdomains in a sterol-dependent manner (Lefebvre et al., 2007; Kierszniowska et al., 2009; Raffaele et al., 2009). The function of Remorins is mostly unknown, but we showed in a previous study that StREM1.3 (for potato (Solanum tuberosum) Remorin from group 1, homolog 3; initially described in Reymond et al., 1996) regulates cell-to-cell propagation of the potato virus X (PVX), likely by directly interacting with the viral movement protein Triple Gene Block protein1 (TGBp1; Raffaele et al., 2009). StREM1.3 localizes to the inner leaflet of PMs and along plasmodesmata, bridges connecting neighbor cells essential for cell-to-cell communication in plants (Maule, 2008). Other members of the Remorin family group 1 are likely involved in innate immune responses (Liu et al., 2009; Widjaja et al., 2009; Keinath et al., 2010). Remorins from group 2 are involved in the control of infection by symbiotic bacteria at nodular infection threads and the peribacteroid membrane (Lefebvre et al., 2010) These data suggest general roles for Remorins in regulating signaling in plant-microbe interactions (Jarsch and Ott, 2011).Elucidating the mechanisms driving StREM1.3 association with PM microdomains therefore provides a unique opportunity for understanding the regulation and function of membrane lateral segregation in plants. StREM1.3 does not contain predictable transmembrane or membrane-associated domains. The bases for its association to PMs and selective targeting to DIMs are unknown. Here we identified a novel membrane anchor domain required for StREM1.3 tight and direct association with the detergent-insoluble fraction of the PM. We combined biophysics, in silico analysis, and directed mutagenesis to unravel the molecular bases of StREM1.3 membrane binding and its biological significance in the control of PVX propagation.