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Filter-feeding bivalves, such as the Mytilus species, are exposed to different types of bacteria in the surrounding waters, in particular of the Vibrio genus. Mussels lack an adaptive immune system and hemocytes can recognize pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs) to activate intracellular signaling pathways to trigger the antimicrobial effectors synthesis. Among the areas of bivalve immunity that deserve study include the role of hemocyte subpopulations. Since little information are available on immune responses at the tissue level to human pathogenic vibrios commonly detected in coastal waters involved in seafood-borne diseases, in this work, immunological parameters of the hemocytes from the Mediterranean mussel M. galloprovincialis were evaluated in response to in vivo challenge with Vibrio splendidus. The histological approach has been first used in order to identify the hemocytes recruitment at the infection site and the morphological change of muscular fibers. In addition, using immunolabeling with specific antibody we detected the production of molecules involved in the inflammatory activated cascade: Toll-like receptors 4 (TLR4), the myeloid differentiation factor 88 (MyD88), the Allograft inflammatory factor-1 (AIF-1) and the ribonucleases RNASET2, belonging to the T2 family, that in vertebrates are involved in the recruitment and activation of macrophages. Our results indicate the activation of TLR4 during bacterial infection preparatory to the recruitment of the MyD88 adapter with a putative role in recognition and intracellular signalling. Furthermore, the data presented in this work suggest that challenging with Gram-negative bacteria causes a massive migration of AIF-1+ hemocytes and that the ribonuclease RNASET2 could play a key role in the recruitment of these activated hemocytes. Our approach is useful for further understanding the complex molecular defence mechanisms of the host in invertebrates, especially in relation to the need to develop methods to evaluate the immunological response of bivalve molluscs used in aquaculture. [Display omitted] • Recruitment of hemocytes occurred in mussel M. galloprovincialis in response to Vibrio splendidus bacterial challenge. • Pattern-recognition receptors initiate TLR4 and Myd88 cascades, with a putative role in recognition and intracellular signalling. • The AIF-1 and RNASET2 production significantly increase in the context of bacterial infection. [ABSTRACT FROM AUTHOR]

Drug repositioning, the assignment of new therapeutic purposes to known drugs, is an established strategy with many repurposed drugs on the market and many more at experimental stage. We review three use cases, a herpes drug with benefits in cancer, a cancer drug with potential in autoimmune disease, and a selective and an unspecific drug binding the same target (GPCR). We explore these use cases from a structural point of view focusing on a deep understanding of the underlying drug-target interactions. We review tools and data needed for such a drug-centric structural repositioning approach. Finally, we show that the availability of data on targets is an important limiting factor to realize the full potential of structural drug-repositioning. [ABSTRACT FROM AUTHOR]

We calculate Saturn's quasi-toroidal normal modes of azimuthal order three for several candidate models for the interior stratification. We propose that these oscillations are responsible for exciting a class of slowly propagating spiral density waves observed in the C ring, possessing the same azimuthal symmetry and pattern speeds, that cluster near the rotation rate of the planet. Both prograde and retrograde propagation relative to the planetary rotation are observed. We find that we can construct interior models for which the pattern speeds of the normal modes align with those of a majority of the slow density waves. Excitation of the retrograde density waves requires retrograde toroidal modes with matching pattern speeds. We find that in order to support such modes, the interior model must include a layer of positive static stability in the molecular hydrogen envelope. The model that performs best places the peak of the static stability at a fractional radius of 0.85, near the radius of the semi-conductive layer where Saturn's zonal jets are inferred to decay. The properties of the toroidal modes are less sensitive to the stratification in the deep interior, hence our results neither confirm nor contradict the presence of a dilute core. When differential rotation is included in the form of zonal winds based on analysis of Cassini gravity and magnetic field data, we find that several toroidal modes become inertially unstable, raising the possibility that this instability is the principal mechanism for their excitation. However, while we are able to construct interior models that align the pattern speeds of a few unstable retrograde modes with those of prominent density waves in the ring, the same models fail with respect to the unstable prograde modes. Consequently, the significance of the instability mechanism remains an open question. Our results suggest that the interaction of Saturn's quasi-toroidal modes with the C ring provides an important source of new, complementary constraints on the planet's internal stratification and that further study of these modes is warranted. • We calculate Saturn's quasi-toroidal normal modes for several candidate models for the interior stratification. • We propose that these oscillations are responsible for exciting a class of slowly propagating spiral density waves observed in the C ring. • The results require the interior to possess a layer of positive static stability in the molecular hydrogen envelope. • The quasi-toroidal modes provide an important source of new constraints on the planet's internal stratification. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) is an important medical issue, since it causes serious and sometimes fatal infections in humans. Intensively reared swine may serve as reservoirs for MRSA that can infect swine workers, and also consumers (via contaminated meat). In this study, MRSA strains were isolated from 55 of the 85 (64.7%) intensive pig farms surveyed, and prevalence was greater on pig fattening farms than on breeding farms. In addition, we included in the study 63 foreign pigs imported for slaughter. Overall, the prevalence of MRSA in the 418 sampled swine was 59.1%; 12 genotypes were identified among the isolates; ST398 (96.4%) was most prevalent, followed by ST97 (2%), ST9 (0.8%) and ST1 (0.8%). MRSA isolates were also detected in 26 (17.3%) of the 150 operators included in the study; the genotypes detected were ST398 (85%), ST9 (7.6%), ST5 (3.8%) and ST1 (3.8%). All the strains were pvl negative and pia positive. Both swine and human strains displayed a multi-resistance pattern, and almost all were resistant to tetracycline. The results obtained in this study confirm the high prevalence of MRSA in swine reared and slaughtered in Italy, and underline the public health risk linked to the spread of antimicrobial-resistant Staphylococcus aureus among intensively reared pigs. • Our study shows genetic diversity of MRSA in pigs reared and slaughtered in Italy. • The foodborne risk linked to the consumption or handling the pig meat should be considered. • The professional risk for the farmers and the abattoir workers should be considered. • This is the first international report on the prevalence of MRSA in swine reared in Southern Italy. [ABSTRACT FROM AUTHOR]

Abstract Plant defensins are an extensive family of small cysteine rich proteins characterised by a conserved cysteine stabilised alpha beta protein fold which resembles the structure of insect and vertebrate defensins. However, secondary structure and disulphide topology indicates two independent superfamilies of defensins with similar structures that have arisen via an extreme case of convergent evolution. Defensins from plants and insects belong to the cis-defensin superfamily whereas mammalian defensins belong to the trans-defensin superfamily. Plant defensins are produced by all species of plants and although the structure is highly conserved, the amino acid sequences are highly variable with the exception of the cysteine residues that form the stabilising disulphide bonds and a few other conserved residues. The majority of plant defensins are components of the plant innate immune system but others have evolved additional functions ranging from roles in sexual reproduction and development to metal tolerance. This review focuses on the antifungal mechanisms of plant defensins. The activity of plant defensins is not limited to plant pathogens and many of the described mechanisms have been elucidated using yeast models. These mechanisms are more complex than simple membrane permeabilisation induced by many small antimicrobial peptides. Common themes that run through the characterised mechanisms are interactions with specific lipids, production of reactive oxygen species and induction of cell wall stress. Links between sequence motifs and functions are highlighted where appropriate. The complexity of the interactions between plant defensins and fungi helps explain why this protein superfamily is ubiquitous in plant innate immunity. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Singlet oxygen and nitric oxide are simultaneously generated by green light. • The molecular hybrid is not toxic in the dark towards healthy and cancer cells. • Bimodal mortality of cancer cells is observed under green light excitation. Abstract Combination of photosensitizers (PS) for photodynamic therapy with NO photodonors (NOPD) is opening intriguing horizons towards new and still underexplored multimodal anticancer and antibacterial treatments not based on "conventional" drugs and entirely controlled by light stimuli. In this contribution, we report an intriguing molecular hybrid based on a BODIPY light-harvesting antenna that acts simultaneously as PS and NOPD upon single photon excitation with the highly biocompatible green light. The presented hybrid offers a combination of superior advantages with respect to the other rare cases reported to date, meeting most of the key criteria for both PSs and NOPDs in the same molecular entity such as: (i) capability to generate 1O 2 and NO with single photon excitation of biocompatible visible light, (ii) excellent 1O 2 quantum yield and NO quantum efficiency, (iii) photogeneration of NO independent from the presence of oxygen, (iv) large light harvesting properties in the green region. Furthermore, this compound together with its stable photoproduct, is well tolerated by both normal and cancer cells in the dark and exhibits bimodal photomortality of cancer cells under green light excitation due to the combined action of the cytotoxic 1O 2 and NO. [ABSTRACT FROM AUTHOR]

Benign epilepsy with centrotemporal spikes (BECTS) epilepsy, also known as rolandic epilepsy, is the most common childhood type of epilepsy. There is debate on its “benign” definition given the numerous literature data on its correlation to cognitive morbidity. Although its prognosis is often favorable, BECTS can present or evolve however to an atypical form, characterized by a worse prognosis and negative impact on cognitive development. It is possible that abnormal electrical activity, marker of neurological dysfunction, has the potential to disrupt neural network function and development. Numerous studies tried to identify clinical or electroencephalographic criteria for atypical forms and atypical evolution of BECTS in order to guide follow-up and treatment of patients and to predict their outcome. This review provides a compact summery of literature data with a focus on predictive features of future cognitive decline. [ABSTRACT FROM AUTHOR]

This paper assesses the prevalence of MRSA in bulk tank milk (BTM) samples from southern Italy, and the relationship between the Coagulase Positive Staphylococci count (CPS) and MRSA prevalence. Of 486 BTM samples tested, 12 samples (2.5%) resulted positive for the presence of MRSA. Great genetic diversity was found among the isolates: ST1/t127 and t174/IVa, ST5/t688/V, ST8/t unknown/IVa/V, ST45/t015/IVa, ST71/t524/V, ST88/t786/Iva, ST398/t011 and t899/IVa/V and ST2781/t1730/V. All isolates were pvl -negative and ica A positive. The majority of strains (58%) carried the se s ( sec , seh , seg , seo , sem and sen ) genes. All tested strains resulted susceptible to amikacin, cephalotin, cloramphenicol, gentamycin, trimethoprim – sulfamethoxazole, tobramycin and vancomycin, and variably resistant to ampicillin, oxacillin and tetracycline. No statistical association between the CPS count and MRSA detection was found in the MRSA-positive samples. Although some of the spa -types and STs detected in our survey are known to cause human infections, raw milk from Italian herds in the considered area is not a common source of MRSA. Nonetheless, it is necessary to assess the risk of foodborne infection and the risk related to the handling of milk. [ABSTRACT FROM AUTHOR]

Current models of G protein-coupled receptors (GPCRs) signaling describe binding of external agonists to cell surface receptors which, in turn, trigger several biological responses. New paradigms indicate that GPCRs localize to and signal at the nucleus, thus regulating distinct signaling cascades. The formyl-peptide receptor FPR2 belongs to the GPCR super-family and is coupled to PTX-sensitive Gi proteins. We show by western blot analysis, immunofluorescence experiments and radioligand binding assays that FPR2 is expressed at nuclear level in CaLu-6 and AGS cells. Nuclear FPR2 is a functional receptor, since it participates in intra-nuclear signaling, as assessed by decreased G protein-FPR2 association and enhanced ERK2, c-Jun and c-Myc phosphorylation upon stimulation of intact nuclei with the FPR2 agonist, WKYMVm. We analyzed FPR2 sequence for the search of a nuclear localization sequence (NLS) and we found a stretch of basic aminoacids (227-KIHKK-231) in the third cytoplasmic loop of the receptor. We performed single (K230A) and multiple (H229A/K230A/K231A) mutagenesis of NLS. The constructs were individually overexpressed in HEK293 cells and immunofluorescence and western blot analysis showed that nuclear localization or translocation of FPR2 depends on the integrity of the H 229 and K 231 residues within the NLS. [ABSTRACT FROM AUTHOR]

[Display omitted] • 1O 2 and NO are photogenerated in high yields with an NO fluorescent reporter. • The dyad is entrapped in polymeric nanoparticles and delivered into cancer cells. • The formulation induces cancer cells mortality at very low light doses. The design, synthesis, photochemical properties, and biological evaluation of a novel molecular dyad with double photodynamic action and its formulation within biodegradable polymeric nanoparticles (NPs) are reported. A BODIPY-based singlet oxygen (1O 2) photosensitizer (PS) and a nitric oxide (NO) photodonor (NOPD) based on an amino-nitro-benzofurazan moiety have been covalently joined in a new molecular dyad, through a flexible alkyl spacer. Excitation of the dyad with visible light in the range 400–570 nm leads to the concomitant generation of the cytotoxic 1O 2 and NO with effective quantum yields, being Φ Δ = 0.49 ± 0.05 and Φ NO = 0.18 ± 0.01, respectively. Besides, the non-fluorescent NOPD unit becomes highly fluorescent after the NO release, acting as an optical reporter for the NO photogenerated. The dyad is not soluble in water medium but can be effectively entrapped in water-dispersible, biodegradable polymeric NPs made of mPEG-PCL, ca. 66 nm in diameter. The polymeric nano-environment affects in an opposite way the photochemical performances of the dyad, reducing Φ Δ to 0.16 ± 0.02 and increasing Φ NO to 0.92 ± 0.03, respectively. The NPs effectively deliver the photoactive cargo into the cytoplasm of HepG2 hepatocellular carcinoma cells. A remarkable level of cell mortality is observed for the loaded NPs at very low concentrations of the dyad (1–5 µM) and very low light doses (≤0.8 J cm−2) more likely as the result of the combined photodynamic action of 1O 2 and NO. [ABSTRACT FROM AUTHOR]

Jupiter’s Great Red Spot (GRS) is the most dominant and long-lived feature in Jupiter’s atmosphere. However, whether this is a shallow atmospheric feature or a deeply rooted vortex has remained an open question. In this study, we assess the possibility of inferring the depth of the GRS by the upcoming Juno gravity experiment. This is achieved by an exploration of the possible gravitational signature of the vortex by systematically extending the surface winds into the interior and analyzing the resulting gravity signal. The gravity anomaly is then compared to the expected accuracy in the retrieval of the surface gravity at the GRS location obtained with numerical simulations of the Doppler data inversion based on the expected trajectory of the spacecraft. Starting from observations of the atmospheric velocity at the cloud level, we project the wind using a decay scale height along coaxial cylinders parallel to the spin axis and explore a wide range of decay scale heights in the radial direction. Assuming the large scale vortex dynamics are geostrophic, and therefore thermal wind balance holds, the density anomaly distribution due to Jupiter’s winds can be derived from the velocity maps. The novelty of this approach is in the integration of thermal wind relations over a three-dimensional grid, and in the inclusion of the observed meridional velocity as measured during the Cassini flyby of Jupiter. The perturbations in the mean zonal flow give rise to non zero tesseral spherical harmonics in Jupiter’s gravitational potential. We provide an estimate of this asymmetric gravity coefficients for different values of the wind decay scale height. We conclude that the mass anomaly associated with the GRS is detectable by the Juno gravity experiment if the vortex is deep, characterized by a vertical height larger than 2,000 km below the cloud level of Jupiter, and that the large mass involved with deep winds does not render much the ability to measure the feature. [ABSTRACT FROM AUTHOR]

The evolution of multicellular organisms was marked by adaptations to protect against pathogens. The mechanisms for discriminating the ’’self’’ from ’’non-self” have evolved into a long history of cellular and molecular strategies, from damage repair to the co-evolution of host-pathogen interactions. We investigated the inflammatory response in Anemonia sulcata (Cnidaria: Anthozoa) following injection of substances that varied in type and dimension, and observed clear, strong and specific reactions, especially after injection of Escherichia coli and Vibrio alginolyticus . Moreover, we analyzed enzymatic activity of protease, phosphatase and esterase, showing how the injection of different bacterial strains alters the expression of these enzymes and suggesting a correlation between the appearance of the inflammatory reaction and the modification of enzymatic activities. Our study shows for the first time, a specific reaction and enzymatic responses following injection of bacteria in a cnidarian. [ABSTRACT FROM AUTHOR]

Autonomic signs and symptoms could be of epileptic or nonepileptic origin, and the differential diagnosis depends on a number of factors which include the nature of the autonomic manifestations themselves, the occurrence of other nonictal autonomic signs/symptoms, and the age of the patient. Here, we describe twelve children (aged from ten months to six years at the onset of the symptoms) with Panayiotopoulos syndrome misdiagnosed as gastroesophageal reflux disease. Gastroesophageal reflux disease and Panayiotopoulos syndrome may represent an underestimated diagnostic challenge. When the signs/symptoms occur mainly during sleep, a sleep EEG or, if available, a polysomnographic evaluation may be the most useful investigation to make a differential diagnosis between autonomic epileptic and nonepileptic disorders. An early detection can reduce both the high morbidity related to mismanagement and the high costs to the national health service related to the incorrect diagnostic and therapeutic approaches. To decide if antiseizure therapy is required, one should take into account both the frequency and severity of epileptic seizures and the tendency to have potentially lethal autonomic cardiorespiratory involvement. In conclusion, we would emphasize the need to make a differential diagnosis between gastroesophageal reflux disease and Panayiotopoulos syndrome in patients with “an unusual” late-onset picture of GERD and acid therapy-resistant gastroesophageal reflux, especially if associated with other autonomic symptoms and signs. [ABSTRACT FROM AUTHOR]

Abstract: Data on the relationship between sleep disturbances and refractory epileptic encephalopathies (EEs) are scarce. Our aim was to assess, by means of nocturnal polysomnography, if children with EEs present with objective alterations in sleep organization. Twenty-three children with EEs (12 males; mean age: 8.7±1.4years) and 40 healthy controls (22 males; mean age: 8.8±1.1years) underwent an overnight full polysomnography (PSG). Relative to controls, children with EEs showed a significant reduction in all PSG parameters related to sleep duration time in bed (TIB-min p<0.001), total sleep time (TST-min p<0.001), and sleep percentage (SPT-min p<0.001), as well as significantly higher REM latency (FRL-min p<0.001), rate in stage shifting (p=0.005), and number of awakenings/hour (p=0.002). Relative to controls, children with EEs also showed significant differences in respiratory parameters (AHI/h p<0.001, ODI/h p<0.001, SpO2% p<0.001, SpO2 nadir% p<0.001) and a higher rate of periodic limb movements (PLMs% p<0.001). Our findings suggest that sleep evaluation could be considered mandatory in children with refractory epileptic encephalopathy in order to improve the clinical management and the therapeutic strategies. [Copyright &y& Elsevier]

Abstract: New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype–phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism. [Copyright &y& Elsevier]

Abstract: The aim of this review was to analyze literature data on the complex association between headache and attention deficit and hyperactivity disorder (ADHD) in children, in order to explore its possible consequences on child neurological development. Headache and ADHD are two common conditions in the pediatric population. They both are disabling diseases that impact the child's quality of life and are associated with severe cognitive, emotional, and behavioral impairments. To assess and analyze literature data about the association of ADHD and headache in children and possible physiopathogenesis relationships, we searched for the following terms: headache, migraine, tension-type headache, ADHD, and children (MESH or text words). We found different studies that assess the clinical, epidemiological, and physiopathogenetic overlap between these two diseases, with contrasting results and unresolved questions. Structural and functional abnormalities in brain networks have been found to be central in both headache and ADHD pathophysiology. It will be crucial to gain a better understanding of how subcortical–cortical and corticocortical network development is altered during the onset of the disorders. [Copyright &y& Elsevier]

Abstract: We propose the use of annotations as a way to flexibly enrich a domain of interest with information concerning different contexts of use for its elements. We provide a formal model of annotation in the framework of typed graphs, in which the presence of annotations is reified through nodes and edges of specific types, relating nodes from different domains. This allows the flexible activation and de-activation of annotations, as well as the addition of several annotations from different domains on the same element. We show that annotations give rise to a category, where pushouts are the basic construct for the composition of annotation-related processes. We prove some properties of annotated graphs and discuss examples drawn from several fields. [Copyright &y& Elsevier]

Abstract: Drosophila dMyc (dMyc) is known for its role in cell-autonomous regulation of growth. Here we address its role in the fat body (FB), a metabolic tissue that functions as a sensor of circulating nutrients to control the release of Drosophila Insulin-like peptides (Dilps) from the brain influencing growth and development. Our results show that expression of dMyc in the FB affects development and animal size. Expression of dMyc, but not of CycD/cdk4 or Rheb, in the FB diminishes the ability to retain Drosophila Insulin-like peptide-2 (DILP2) in the brain during starvation, suggesting that expression of dMyc mimics the signal that remotely controls the release of Dilps into the hemolymph. dMyc also affects glucose metabolism and increases the transcription of Glucose-transporter-1 mRNA, and of Hexokinase and Pyruvate-Kinase mRNAs, key regulators of glycolysis. These animals are able to counteract the increased levels of circulating trehalose induced by a high sugar diet leading to the conclusion that dMyc activity in the FB promotes glucose disposal. dMyc expression induces cell autonomous accumulation of triglycerides, which correlates with increased levels of Fatty Acid Synthase and Acetyl CoA Carboxylase mRNAs, enzymes responsible for lipid synthesis. We also found the expression of Stearoyl-CoA desaturase, Desat1 mRNA significantly higher in FB overexpressing dMyc. Desat1 is an enzyme that is necessary for monosaturation and production of fatty acids, and its reduction affects dMyc's ability to induce fat storage and resistance to animal survival. In conclusion, here we present novel evidences for dMyc function in the Drosophila FB in controlling systemic growth. We discovered that dMyc expression triggers cell autonomous mechanisms that control glucose and lipid metabolism to favor the storage of nutrients (lipids and sugars). In addition, the regulation of Desat1 controls the synthesis of triglycerides in FB and this may affect the humoral signal that controls DILP2 release in the brain. [Copyright &y& Elsevier]

Abstract: Citrin is the liver-specific isoform of the mitochondrial aspartate/glutamate carrier (AGC2). AGC2 deficiency is an autosomal recessive disorder with two age related phenotypes: neonatal intrahepatic cholestasis (NICCD, OMIM#605814) and adult-onset type II citrullinemia (CTLN2, OMIM#603471). NICCD arises within the first few weeks of life resulting in prolonged cholestasis and metabolic abnormalities including aminoacidemia and galactosuria. Usually symptoms disappear within the first year of life, thus making a diagnosis difficult after this time. In this study we report a new Caucasian case of NICCD, a seven week old Romanian boy with prolonged jaundice. Sequencing of the AGC2 gene showed a novel homozygous missense double-nucleotide (doublet) mutation, which produces the change of the glycine at position 437 into glutamate. Functional studies, carried out on the recombinant mutant protein, for the first time demonstrated, that NICCD is caused by a reduced transport activity of AGC2. The presence of AGC2 deficiency in other ethnic groups besides Asian population suggests further consideration for NICCD diagnosis of any neonate with an unexplained cholestasis; a prompt diagnosis is crucial to resolve the metabolic decompensation with an appropriate dietary treatment. [Copyright &y& Elsevier]

Abstract: A December 2010 meeting, “Down Syndrome: National Conference on Patient Registries, Research Databases, and Biobanks,” was jointly sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at the National Institutes of Health (NIH) in Bethesda, MD, and the Global Down Syndrome Foundation (GDSF)/Linda Crnic Institute for Down Syndrome based in Denver, CO. Approximately 70 attendees and organizers from various advocacy groups, federal agencies (Centers for Disease Control and Prevention, and various NIH Institutes, Centers, and Offices), members of industry, clinicians, and researchers from various academic institutions were greeted by Drs. Yvonne Maddox, Deputy Director of NICHD, and Edward McCabe, Executive Director of the Linda Crnic Institute for Down Syndrome. They charged the participants to focus on the separate issues of contact registries, research databases, and biobanks through both podium presentations and breakout session discussions. Among the breakout groups for each of the major sessions, participants were asked to generate responses to questions posed by the organizers concerning these three research resources as they related to Down syndrome and then to report back to the group at large with a summary of their discussions. This report represents a synthesis of the discussions and suggested approaches formulated by the group as a whole. [Copyright &y& Elsevier]

Abstract: This paper provides new estimates of Hispanic–white residential segregation in new destinations and established Hispanic places. New Hispanic destinations are defined broadly to include metropolitan cities, suburban places, and rural communities with unusually rapid Hispanic growth rates. The analysis is framed with the spatial assimilation and place stratification perspectives and is based on block data from the 1990 and 2000 decennial censuses. The analysis confirms our basic hypothesis – that Hispanics are highly segregated in new Hispanic destinations, often at levels greatly exceeding those in established places. Hispanic suburbanization or exurbanization into new destinations is no marker of spatial assimilation. Consistent with the place stratification perspective, differences in Hispanic–white segregation between new destinations and established Hispanic areas cannot be explained by place-to-place differences in ecological location, population composition, economic growth, employment, or Hispanic–white income inequality. Hispanic segregation in new destinations is especially sensitive to the size of the foreign-born population and to preexisting “minority threats” in communities with large black populations. Segregation levels in new destinations also are less responsive to income disparities between Hispanics and whites; economic assimilation does not insure Hispanic spatial assimilation. Understanding how newcomers are spatially incorporated in new destinations will be a continuing challenge for scholars concerned about the spatial diffusion and apparent geographic balkanization of America’s growing Hispanic population. [Copyright &y& Elsevier]

Abstract: Standardized tools for typing Listeria monocytogenes isolates are required in epidemiological surveys investigating food-borne disease outbreaks and in the food-processing environment to identify the sources of contamination and routes by which the organisms are spread. In this survey Amplified Fragment Length Polymorphism (AFLP) and Multi-Locus Sequence Typing (MLST) have been used to study 103 L. monocytogenes isolates from food and environmental sources. A total of 62 AFLP types and 66 MLST Sequence Types were identified. AFLP and MLST produced similar results in terms of discriminating power. The Discrimination Index calculated for the two techniques was 0.976 for AFLP and 0.972 for MLST. These values were appreciably higher compared to serotyping (0.739). A good congruence was observed between AFLP and MLST. The present study demonstrated that AFLP and MLST subtyping are suitable tools for studying the epidemiology of L. monocytogenes. The great advantage of MLST over AFLP and other molecular typing methods based on fragment fingerprinting lies in the unambiguity of sequence data while AFLP is less costly and highly processive. In conclusion the two methods can be perfectly integrated for high-resolution genotyping of L. monocytogenes. [Copyright &y& Elsevier]

Abstract: Recently described biochemical and structural aspects of fucose-binding lectins from the European eel (Anguilla anguilla) and striped bass (Morone saxatilis) led to the identification of a novel lectin family (“F-type” lectins) characterized by a unique sequence motif and a characteristic structural fold. The F-type fold is shared not only with other members of this lectin family, but also with apparently unrelated proteins ranging from prokaryotes to vertebrates. Here we describe the purification, biochemical and molecular properties, and the opsonic activity of an F-type lectin (DlFBL) isolated from sea bass (Dicentrarchus labrax) serum. DlFBL exhibits two tandemly arranged carbohydrate-recognition domains that display the F-type sequence motif. In situ hybridization and immunohistochemical analysis revealed that DlFBL is specifically expressed and localized in hepatocytes and intestinal cells. Exposure of formalin-killed Escherichia coli to DlFBL enhanced their phagocytosis by D. labrax peritoneal macrophages relative to the unexposed controls, suggesting that DlFBL may function as an opsonin in plasma and intestinal mucus. [Copyright &y& Elsevier]

Abstract: Mussels are filter-feeders living in a bacteria-rich environment. We have previously found that numerous bacterial species are naturally present within the cell-free hemolymph, including several of the Vibrio genus, whereas the intra-cellular content of hemocytes was sterile. When bacteria were injected into the circulation of the mussel, the number of living intra-hemocyte bacteria dramatically increased in less than an hour, suggesting intense phagocytosis, then gradually decreased, with no viable bacteria remaining 12h post-injection for Micrococcus lysodeikticus, 24h for Vibrio splendidus and more than 48h for V ibrio anguillarum. The total hemocyte count (THC) was dramatically lowered by the bacterial injections, as quantified by flow cytometry. V. splendidus induced the strongest decreases with −66% 9h post-injection of living bacteria and −56% 3h post-injection of heat-killed bacteria. Flow cytometry was used to identify three main sub-populations of hemocytes, namely hyalinocytes, small granulocytes and large granulocytes. When THC was minimal, i.e. within the first 9h post-injection, proportions of the three cell categories varied dramatically, suggesting differential involvement according to the targets, but small granulocytes remained the majority. According to a decrease in their number followed by an increase (+90% at 12h with living V. splendidus), hyalinocytes also appeared to be involved as cellular effectors of antibacterial immunity, despite possessing little capacity for phagocytosis and not containing antimicrobial peptides. [Copyright &y& Elsevier]

Women of childbearing age are largely affected by several autoimmune disorders (the estimates range between 1.5 and 10 per 10,000). The increasing number of effective biological agents has dramatically revolutionized the treatment of these clinical conditions, ameliorating the patient's quality of life. The use of these agents by women during pregnancy is growing to ensure the disease activity control and avoid adverse health outcomes. However, for many newer biological agents, the degree of information concerning their use in pregnancy is often incomplete to perform a conclusive risk assessment on fetal and maternal health given the exclusion of this specific population from pharmacological clinical trials. More recently, the COVID-19 pandemic has confirmed the unacceptable inequities of pharmacological research and medical treatment for pregnant and lactating women, exacerbating the need for filling the gaps of quantitative and qualitative pharmacology data in this sensitive population. ere we summarize (i) what is already known about safety and effectiveness of biological agents in this understudied population (with specific focus on pregnancy-related health outcomes), and what we are going to learn from the on-going studies among pregnant women treated with biological agents; (ii) the methodological and ethical considerations that characterize the pharmacological research in pregnancy, also discussing emerging evidence on the use of therapeutic drug monitoring (TDM) in this clinical setting. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to evaluate the expression of the Mytilus galloprovincialis lysozyme gene in different in vivo stress situations, including injection of bacteria Vibrio splendidus LGP32, Vibrio anguillarum or Micrococcus lysodeikticus, as well as heat shock at 30°C and cold stress at 5°C. Injection of V. splendidus LGP32 resulted in: (i) a general down-regulation of lysozyme gene expression, as quantified by Q-PCR; (ii) reduction in the number of circulating hemocytes; (iii) decrease in the percentage of circulating hemocytes expressing lysozyme mRNA which was now restricted to only small cells, as observed by ISH; and (iv) accumulation of hemocytes expressing lysozyme in the muscle sinus where injection took place. Injection of V. anguillarum or M. lysodeikticus induced significant up-regulation of lysozyme gene expression, but only 2–3days post-injection, with no change in the total hemocyte counts but an increased percentage of hemocytes expressing lysozyme mRNA. Neither the control injection of PBS-NaCl nor temperature stress modified the lysozyme expression pattern. Consequently, the hemocyte population appears to be capable of discriminating between stress factors, and even between 2 Vibrio species. [Copyright &y& Elsevier]

Abstract: Objective: To determine whether school teachers educated about Primary Prevention of Adult Cardiovascular Disease (PPCVD) could help their students improve their blood lipid profile. Method: Five teachers voluntarily received training about PP-CVD. Thirteen classes of a single high school in Stradella (north Italy) were randomized to receive a 2-month course on PP-CVD (PP-classes; 150 pupils) by their teachers or to a control group (control classes; 130 pupils) during 2004. In all students body weight and fasting venous blood concentrations of total cholesterol (TC), HDL-CHOL, LDL-CHOL, and triglycerides were determined before and 6 months after the completion of the PP-CVD course. Results: Six months after the PP-CVD course, males had significant improvements of all baseline lipid parameters whereas females had improved HDL-CHOL and TC/HDL ratio. No improvements were observed in the control class students. Body weight was unchanged in both groups of students 6 months after the PP-CVD course or the control course. Conclusion: This investigation shows that well-trained school teachers are able to manage PP-CVD education so that students can really improve their lipid profile as a consequence of autonomous changes in dietary habits. [Copyright &y& Elsevier]

Abstract: Menin is a tumor suppressor required to prevent multiple endocrine neoplasia in humans. Mammalian menin protein is associated with chromatin modifying complexes and has been shown to bind a number of nuclear proteins, including the transcription factor JunD. Menin shows bidirectional effects acting positively on c-Jun and negatively on JunD. We have produced protein null alleles of Drosophila menin (mnn1) and have over expressed the Mnn1 protein. Flies homozygous for protein-null mnn1 alleles are viable and fertile. Localized over-expression of Mnn1 causes defects in thoracic closure, a phenotype that sometimes results from insufficient Jun activity. We observed complex genetic interactions between mnn1 and jun in different developmental settings. Our data support the idea that one function of menin is to modulate Jun activity in a manner dependent on the cellular context. [Copyright &y& Elsevier]

The paper presents a computational model of language in which linguistic abilities evolve in organisms that interact with an environment. Each individual’s behavior is controlled by a neural network and we study the consequences in the network’s internal functional organization of learning to process different classes of words. Agents are selected for reproduction according to their ability to manipulate objects and to understand nouns (objects’ names) and verbs (manipulation tasks). The weights of the agents’ neural networks are evolved using a genetic algorithm. Synthetic brain imaging techniques are then used to examine the functional organization of the neural networks. Results show that nouns produce more integrated neural activity in the sensory-processing hidden layer, while verbs produce more integrated synaptic activity in the layer where sensory information is integrated with proprioceptive input. Such findings are qualitatively compared with human brain imaging data that indicate that nouns activate more the posterior areas of the brain related to sensory and associative processing, while verbs activate more the anterior motor areas. [Copyright &y& Elsevier]

Vigabatrin (VGB) has been widely used in patients affected by drug-resistant epilepsy and West syndrome. Following reports of visual field loss associated with vigabatrin therapy, some authors have investigated retinal electrophysiologic variables to identify early electrophysiologic markers and pathogenetic mechanisms of retinal damage. There are no previous reports of a scotopic threshold response (STR) reduction associated with vigabatrin therapy.A 13-year-old male child was submitted to a complete electroretinographic study before and after the start of vigabatrin therapy. Of the electroretinographic responses analyzed, only the scotopic threshold response was altered. The scotopic threshold response is a corneal-negative wave in the electroretinogram (ERG) of a fully dark-adapted eye. In cat, this response has been shown to be mediated by K+ spatial buffer currents that flow from proximal to distal retina in retinal glia as a result of elevated concentration of K+ in proximal retina following depolarization of local neurons in response to light onset.The prospective nature of the study in a previously untreated patient on vigabatrin monotherapy allows us to speculate on the underlying pathogenetic mechanisms and level of action of vigabatrin therapy-related retinal damage. If the predictive value of the scotopic threshold response changes is documented, this ERG response could be used to perform a preliminary evaluation of drugs, which modify gamma-aminobutyric acid (GABA) receptors and/or GABA levels. [Copyright &y& Elsevier]

E. coli O157 is a foodborne pathogen responsible for serious human illnesses, such as hemorrhagic colitic and hemolytic uremic syndrome. Ground beef products are among the foods that are more commonly contaminated, and the strains isolated have been frequently found to carry virulence factors of this pathotype. This paper reports the results of serotyping assays and of investigations performed to screen for virulence factors of 10 E. coli O157 strains isolated from fresh sausages purchased at retail meat outlets in various provinces of Apulia (southern Italy). The presence of verocytotoxins was assessed on VERO cells and ELISA tests. Multiplex PCR assays were performed for the eae, stx1, stx2 and hlyA genes. Six of the 10 strains examined presented the H7 antigen and all of them proved to be potentially pathogenic due to the presence of individual or multiple virulence factors. [Copyright &y& Elsevier]

Although a great deal of interest in the genetics and etiology of cerebral, particularly forebrain, malformations has been generated in the past decade, relatively little is known about the basis of congenital malformations of the structures of the posterior fossa, namely the midbrain, cerebellum, pons, and medulla. In this review, we present a classification scheme for malformations of the midbrain and hindbrain based on their embryologic derivation, highlight four of the conditions associated with such abnormalities, and describe the genetics, prognosis, and recurrence risks for each. We describe several disorders in addition to Joubert syndrome with the distinctive radiologic sign known as the “molar tooth sign,” comprised of midbrain and hindbrain malformations. We discuss Dandy–Walker malformation, its classical definition, and the surprisingly good outcome in the absence of other brain malformations. We consider the heterogeneous entity of cerebellar vermis hypoplasia and describe the recently identified gene associated with an X-linked form of this condition. Finally, the pontocerebellar hypoplasias are discussed in the context of their generally progressive degenerative and severe course, and the differential diagnosis is emphasized. We anticipate that as imaging technologies improve, differentiation of the various disorders should aid in efforts to identify the causative genes. [Copyright &y& Elsevier]

A salicylate-inducible PR-10 gene subclass from apple, designated as APa, was characterized. The APa genes were shown to be highly induced in leaves by abiotic stimuli (ethephon, wounding), as well as by inoculation with a virulent or an avirulent strain of Venturia inaequalis. The up-regulation of APa transcripts occurred earlier in the compatible situation than in the incompatible one, but at higher levels in the latter case. At the protein level, a PR-10 polypeptide band (18 kDa) was detected in both interactions, whereas an additional band (17 kDa) was markedly revealed only after infection with the avirulent strain. Immunodetection of PR-10 proteins on leaf prints indicated their vascular localization and an intensification of the signal in the incompatible condition. Overexpression of APa gene products after infection with the avirulent strain was concomitant with the occurrence of resistance symptoms. For two genes of the APa subclass (Ypr10&ast;Md.b and Ypr10&ast;Md.d), specific patterns of expression were observed: both Ypr10&ast;Md.b and Ypr10&ast;Md.d were transcriptionally activated by ethephon or following inoculation with the avirulent strain of V. inaequalis, whereas after treatment with a salicylate analogue, only Ypr10&ast;Md.d was induced. This suggests that at least a defense pathway involving ethylene is activated in the incompatible situation. [Copyright &y& Elsevier]

The theory of satellite loss resulting from a giant impact on Uranus (Parisi and Brunini 1997, Planet. Space Sci.45, 181–187) is revisited, in the light of the discovery of its five outer moons (Gladman et al. 1998, Nature392, 897–899; Gladman et al. 2000, Icarus147, 320–324; erratum 148, 320). Physical conditions and dynamical constraints in the great collision scenario and restrictions in the possible mechanisms for the origin of the outer uranian satellites are obtained from the knowledge of their actual orbital properties. We conclude that the existence of these moons implies that their origin must be connected to a breakup process. Other scenarios for their origin cast serious doubts on the occurrence of a giant collision at the end of Uranus'' formation process to account for its large spin axis obliquity. [Copyright &y& Elsevier]

The human ARF/INK4a locus encodes two cell cycle inhibitors, p16INK4a and p14ARF, by using separate promoters. A variety of mitogenic stimuli upregulate ARF but a direct modulation at the transcriptional level has been reported only for E2F-1. We show here that the ARF promoter is strongly responsive also to E2F2 and E2F3, thus providing a strong support to their suggested role in the induction of apoptosis. Through the usage of both deletion mutants and/or site-directed mutants, we surprisingly found that none of the four putative E2F consensus sites is strictly necessary for the upregulation of ARF expression, as a minimal deletion mutant, lacking all the putative E2F binding sites, is still transactivated by E2F. Moreover, our data suggest that the ARF promoter is regulated by E2F through both direct binding to the promoter sequences and indirectly, probably by being tethered to the ARF promoter by Sp1-like factors. [Copyright &y& Elsevier]

Graph transformation systems are a formal specification technique for software systems that support the rule based specification of the dynamic behaviour of a system.Their main advantages are the intuitive visual representation of states and state transformations as graphs on the one hand, and the fully formal semantics on the other hand, that allow precise statements about the specification and tool support. In this paper we introduce refinements and modules for typed graph transformation systems to support the software specification development in both dimensions: modules for the horizontal structuring of a specification, i.e., its composition from feasible parts, and refinements for the development over time. [Copyright &y& Elsevier]

The mechanisms of visuospatial attention are mediated by two distinct fronto-parietal networks: a bilateral dorsal network (DAN), involved in the voluntary orientation of visuospatial attention, and a ventral network (VAN), lateralized to the right hemisphere, involved in the reorienting of attention to unexpected, but relevant, stimuli. The present study consisted of two aims: 1) to characterize the spatio-temporal dynamics of attention and 2) to examine the predictive interactions between and within the two attention systems along with visual areas, by using fast optical imaging combined with Granger causality. Data were collected from young healthy participants performing a discrimination task in a Posner-like paradigm. Functional analyses revealed bilateral dorsal parietal (i.e. dorsal regions included in the DAN) and visual recruitment during orienting, highlighting a recursive predictive interplay between specific dorsal parietal regions and visual cortex. Moreover, we found that both attention networks are active during reorienting, together with visual cortex, highlighting a mutual interaction among dorsal and visual areas, which, in turn, predicts subsequent ventral activity. For attentional reorienting our findings indicate that dorsal and visual areas encode disengagement of attention from the attended location and trigger reorientation to the unexpected location. Ventral network activity could instead reflect post-perceptual maintenance of the internal model to generate and keep updated task-related expectations. [ABSTRACT FROM AUTHOR]

The analysis of evolutionary information in a protein family, such as conservation and covariation, is often linked to its structural information. Multiple sequence alignments of distant homologous sequences are used to measure evolutionary variables. Although high structural differences between proteins can be expected in such divergent alignments, most works linking evolutionary and structural information use a single structure ignoring the structural variability within protein families. The goal of this work is to elucidate the relevance of structural divergence when sequence-based measures are integrated with structural information. We found that inter-residue contacts and solvent accessibility undergo large variations in protein families. Our results show that high covariation scores tend to reveal residue contacts that are conserved in the family, instead of protein or conformer specific contacts. We also found that residue accessible surface area shows a high variability between structures of the same family. As a consequence, the mean relative solvent accessibility of multiple structures correlates better with the conservation pattern than the relative solvent accessibility of a single structure. We conclude that the use of comprehensive structural information allows a more accurate interpretation of the information computed from sequence alignments. Therefore, considering structural divergence would lead to a better understanding of protein function, dynamics, and evolution. [ABSTRACT FROM AUTHOR]

Riboprobes ( in situ hybridization) and antibodies (immunohistochemistry), previously used to show the upregulation of Ciona intestinalis (Type A) galectins (CiLgals-a, CiLgals-b) and phenoloxidase (CinPO2) immune-related genes, were tested on histological sections of the ovary. The ovarian follicles are composed of oocytes encased by follicular cells (FCs) and test cells (TCs). Results show the transcription upregulation of both CiLgals and CinPO2 genes in the vitellogenic FCs, conversely distinct cytolocalization of the proteins are shown. At vitellogenic stage, the CiLgals are localized in the FCs, in the oocyte cytoplasm, and close to the germinal vesicle (GV), whereas the CinPO2 was never identified in the FCs. In a presumptive advanced phase and at the post-vitellogenic stage the TCs appear to be labelled by the CinPO2 riboprobe, and the protein identified by the antibody suggesting an mRNA transcytosis process from FCs. At post-vitellogenic stage the CiLgals mainly enrich the GV nucleoplasm, whereas the CinPO2 is contained in TCs and in the ooplasm but never found in the GV. This finding sheds new light on a former paper in which TCs were reported to be the only CinPO2-producing cells in the ovarian follicle. Finally, CiLgals and CinPO2 genes transcription and proteins production seem to be associated with accessory cells during their differentiation from vitellogenic to post-vitellogenic stage. The present findings promote further research on the early upregulation of immune-related genes, and the potential multifunctional role of the produced proteins. In addition further insight on the accessory cells involvement in ascidian oogenesis are reported. [ABSTRACT FROM AUTHOR]

Exposure to erythemally-effective solar ultraviolet radiation (UVR) that contributes to malignant keratinocyte cancers and associated health-risk is best mitigated through innovative decision-support systems, with global solar UV index ( UVI ) forecast necessary to inform real-time sun-protection behaviour recommendations. It follows that the UVI forecasting models are useful tools for such decision-making. In this study, a model for computationally-efficient data-driven forecasting of diffuse and global very short-term reactive (VSTR) (10-min lead-time) UVI , enhanced by drawing on the solar zenith angle ( θ s ) data, was developed using an extreme learning machine (ELM) algorithm. An ELM algorithm typically serves to address complex and ill-defined forecasting problems. UV spectroradiometer situated in Toowoomba, Australia measured daily cycles (0500–1700 h) of UVI over the austral summer period. After trialling activations functions based on sine, hard limit, logarithmic and tangent sigmoid and triangular and radial basis networks for best results, an optimal ELM architecture utilising logarithmic sigmoid equation in hidden layer, with lagged combinations of θ s as the predictor data was developed. ELM’s performance was evaluated using statistical metrics: correlation coefficient ( r ), Willmott’s Index ( WI ), Nash-Sutcliffe efficiency coefficient ( E NS ), root mean square error ( RMSE ), and mean absolute error ( MAE ) between observed and forecasted UVI . Using these metrics, the ELM model’s performance was compared to that of existing methods: multivariate adaptive regression spline (MARS), M5 Model Tree, and a semi-empirical ( Pro6UV ) clear sky model. Based on RMSE and MAE values, the ELM model (0.255, 0.346, respectively) outperformed the MARS (0.310, 0.438) and M5 Model Tree (0.346, 0.466) models. Concurring with these metrics, the Willmott’s Index for the ELM, MARS and M5 Model Tree models were 0.966, 0.942 and 0.934, respectively. About 57% of the ELM model’s absolute errors were small in magnitude (±0.25), whereas the MARS and M5 Model Tree models generated 53% and 48% of such errors, respectively, indicating the latter models’ errors to be distributed in larger magnitude error range. In terms of peak global UVI forecasting, with half the level of error, the ELM model outperformed MARS and M5 Model Tree. A comparison of the magnitude of hourly-cumulated errors of 10-min lead time forecasts for diffuse and global UVI highlighted ELM model’s greater accuracy compared to MARS, M5 Model Tree or Pro6UV models. This confirmed the versatility of an ELM model drawing on θ s data for VSTR forecasting of UVI at near real-time horizon. When applied to the goal of enhancing expert systems, ELM-based accurate forecasts capable of reacting quickly to measured conditions can enhance real-time exposure advice for the public, mitigating the potential for solar UV-exposure-related disease. [ABSTRACT FROM AUTHOR]

In December 2014, a workshop entitled “Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base” was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD. [ABSTRACT FROM AUTHOR]

Aquatic animals are continuously exposed to chemical pollutants but the effects evoked in skin surfaces, which receive the most direct contact with them, are poorly investigated. Terminal carbohydrate composition and immunological components present in skin mucus of gilthead seabream ( Sparus aurata L.) specimens exposed to waterborne sublethal dosages of heavy metals [arsenic (As 2 O 3 ), cadmium (CdCl 2 ) and mercury (CH 3 HgCl) at 5, 5 and 0.04 μM, respectively for 2, 10 and 30 days were analysed. Moreover, the presence of a fucose binding lectin (FBL) was evaluated by western blot and the protein profiles were by SDS-PAGE and HPLC. Results showed little effects of heavy metals in the presence of several terminal carbohydrates with few increments or decrements. Most of the enzyme activities related to immune responses were increased upon heavy metal exposure in the skin mucus including bactericidal activity. Methylmercury produced the most dramatic changes increasing all the activities. Moreover, the FBL was undetected in any of the control fish skin mucus but was evident in all the heavy metal exposed fish. In addition, As and Cd produced a clear change in the protein profile as evidenced by the lack of a protein band of around 12 kDa which is absent. These protein changes were more evident with the HPLC study showing the presence of different peaks and differences in intensity. The present results could be useful for better understanding the role and their behaviour of the mucosal immunity in skin as a key component of the innate immune system against pollutants. [ABSTRACT FROM AUTHOR]

Abstract: We address the issue of incorporating a particular yet expressive form of integrity constraints (namely, denial constraints) into probabilistic databases. To this aim, we move away from the common way of giving semantics to probabilistic databases, which relies on considering a unique interpretation of the data, and address two fundamental problems: consistency checking and query evaluation. The former consists in verifying whether there is an interpretation which conforms to both the marginal probabilities of the tuples and the integrity constraints. The latter is the problem of answering queries under a “cautious” paradigm, taking into account all interpretations of the data in accordance with the constraints. In this setting, we investigate the complexity of the above-mentioned problems, and identify several tractable cases of practical relevance. [Copyright &y& Elsevier]

Pseudomonas syringae is a phytopathogenic bacterium that causes diseases of monocots, herbaceous dicots, and woody dicots, worldwide. On woody plants, reports of disease due to P. syringae have markedly increased in the last years and the diseases have been recognized as a major threat to the primary products of agroforestry practices. Detection in Italy of a new highly aggressive population of P. syringae in 2008 on kiwifruit, which caused severe epidemics in the following years throughout the kiwifruit-growing areas of Asia, Europe, Oceania, and South America, rendered the entire kiwifruit industry vulnerable to the disease. Similarly, occurrence of an aggressive population of P. syringae on horse chestnut in 2002 in the Netherlands has rapidly established itself as a major threat to horse chestnut throughout Northwest Europe. To better understand the origin of such disease epidemics, a thorough knowledge of the pathogen is needed in sensu lato. Here, we report the most important features of the pathogen and its hosts in an attempt to clarify some key aspects. In particular, the diseases and the economic losses they cause, disease epidemiology, pathogen diversity, and the possible means of disease control have been discussed throughout the manuscript. In addition to the ability to cause the disease, the damage caused to woody plants through the ice nucleation activity of this bacterium is discussed. [ABSTRACT FROM AUTHOR]