A novel fan-shaped cataract-microcornea syndrome caused by a mutation of CRYAA in an Indian family.
The molecular characterization of an Indian family having 10 members in four generations affected with a unique fan-shaped cataract-microcornea syndrome. Detailed family history and clinical data were recorded. A genome-wide screening by two-point linkage analysis using more than 400 microsatellite markers in combination with multipoint lod score and haplotype analysis was carried out. Mutation screening was performed in the candidate gene by bi-directional sequencing of amplified products. The cataract-microcornea locus in this family was mapped to a 23.5 cM region on chromosome 21q22.3. Direct sequencing of the candidate gene CRYAA revealed a heterozygous C>T transition resulting in the substitution of the highly conserved arginine at position 116 by cysteine (R116C). This study provides the report of mapping a locus for syndromal cataract (cataract-microcornea syndrome) on 21q22.3. The mutation observed in CRYAA in the present family highlights the phenotypic heterogeneity of the disorder in relation to the genotype, as an identical mutation has previously been reported in an American family with a different type of cataract. The "fan-shaped cataract" observed in the present family has not been reported before.


Lighthouse Parenting Programme: Description and pilot evaluation of mentalization-based treatment to address child maltreatment.
This article introduces an innovative mentalization-based treatment (MBT) parenting intervention for families where children are at risk of maltreatment. The Lighthouse MBT Parenting Programme aims to prevent child maltreatment by promoting sensitive caregiving in parents. The programme is designed to enhance parents' capacity for curiosity about their child's inner world, to help parents 'see' (understand) their children clearly, to make sense of misunderstandings in their relationship with their child and to help parents inhibit harmful responses in those moments of misunderstanding and to repair the relationship when harmed. The programme is an adaptation of MBT for borderline and antisocial personality disorders, with a particular focus on attachment and child development. Its strength is in engaging hard to reach parents, who typically do not benefit from parenting programmes. The findings of the pilot evaluation suggest that the programme may be effective in improving parenting confidence and sensitivity and that parents valued the programme and the changes it had helped them to bring about.


Choroidal thickness in normal Indian eyes using swept-source optical coherence tomography.
The purpose of this study is to provide normative database for subfoveal choroidal thickness in Indian eyes using swept-source optical coherence tomography. This is a cross-sectional study based at a tertiary eye care center in Northern India. Two hundred and thirty eight eyes of 119 healthy subjects were examined in terms of axial length, spherical equivalent, and choroidal thickness. Inclusion criteria included age 19-60 years, no retinal or choroidal disorder, and patients with clear media and good fixation. Patients with high hypermetropia (>4 D) or myopia (>6 D) or any systemic disease likely to affect choroidal thickness were excluded. Twelve radial line scans were obtained centered on the fovea that were used to calculate choroidal and retinal thickness in 9 early treatment diabetic retinopathy study (ETDRS) zones. The mean age of all the subjects was 28.70 ± 11.28 years; mean axial length was 23.63 ± 1.96 mm, and mean spherical equivalent was - 0.92 ± 3.08 D. The mean subfoveal choroidal thickness was 299.10 ± 131.2 μ and mean foveal thickness was 239.92 ± 48.16 μ. A negative correlation was found between subfoveal choroidal thickness and age (r = -0.0961, P = 0.1392) and axial length (r = -0.3166, P < 0.001). A statistically significant positive correlation was found between subfoveal choroidal thickness and refractive error (r = 0.2393, P = 0.0002). This study provides normative database for subfoveal choroidal thickness and foveal thickness using swept-source optical coherence tomography. The choroidal thickness measured with swept-source platform is slightly higher than that reported with spectral domain platforms.


Genomics of an extreme psychrophile, Psychromonas ingrahamii.
The genome sequence of the sea-ice bacterium Psychromonas ingrahamii 37, which grows exponentially at -12C, may reveal features that help to explain how this extreme psychrophile is able to grow at such low temperatures. Determination of the whole genome sequence allows comparison with genes of other psychrophiles and mesophiles. Correspondence analysis of the composition of all P. ingrahamii proteins showed that (1) there are 6 classes of proteins, at least one more than other bacteria, (2) integral inner membrane proteins are not sharply separated from bulk proteins suggesting that, overall, they may have a lower hydrophobic character, and (3) there is strong opposition between asparagine and the oxygen-sensitive amino acids methionine, arginine, cysteine and histidine and (4) one of the previously unseen clusters of proteins has a high proportion of "orphan" hypothetical proteins, raising the possibility these are cold-specific proteins. Based on annotation of proteins by sequence similarity, (1) P. ingrahamii has a large number (61) of regulators of cyclic GDP, suggesting that this bacterium produces an extracellular polysaccharide that may help sequester water or lower the freezing point in the vicinity of the cell. (2) P. ingrahamii has genes for production of the osmolyte, betaine choline, which may balance the osmotic pressure as sea ice freezes. (3) P. ingrahamii has a large number (11) of three-subunit TRAP systems that may play an important role in the transport of nutrients into the cell at low temperatures. (4) Chaperones and stress proteins may play a critical role in transforming nascent polypeptides into 3-dimensional configurations that permit low temperature growth. (5) Metabolic properties of P. ingrahamii were deduced. Finally, a few small sets of proteins of unknown function which may play a role in psychrophily have been singled out as worthy of future study. The results of this genomic analysis provide a springboard for further investigations into mechanisms of psychrophily. Focus on the role of asparagine excess in proteins, targeted phenotypic characterizations and gene expression investigations are needed to ascertain if and how the organism regulates various proteins in response to growth at lower temperatures.


Magnetic resonance imaging of the newborn brain: automatic segmentation of brain images into 50 anatomical regions.
We studied methods for the automatic segmentation of neonatal and developing brain images into 50 anatomical regions, utilizing a new set of manually segmented magnetic resonance (MR) images from 5 term-born and 15 preterm infants imaged at term corrected age called ALBERTs. Two methods were compared: individual registrations with label propagation and fusion; and template based registration with propagation of a maximum probability neonatal ALBERT (MPNA). In both cases we evaluated the performance of different neonatal atlases and MPNA, and the approaches were compared with the manual segmentations by means of the Dice overlap coefficient. Dice values, averaged across regions, were 0.81±0.02 using label propagation and fusion for the preterm population, and 0.81±0.02 using the single registration of a MPNA for the term population. Segmentations of 36 further unsegmented target images of developing brains yielded visibly high-quality results. This registration approach allows the rapid construction of automatically labeled age-specific brain atlases for neonates and the developing brain.


Hypertonic Saline for Severe Traumatic Brain Injury With Herniation: A Military Prehospital Case Report.
Severe traumatic brain injury (sTBI) is a devastating injury with limited prehospital therapies available. The Joint Trauma System (JTS) Clinical Practice Guidelines recommend hypertonic saline (HTS) for casualties with sTBI and signs of impending or ongoing herniation (IOH), but its use by combat medics has never been reported in the literature. This report details the management of a pregnant patient with sTBI and signs of IOH, including the use of HTS, by US Air Force pararescumen in an austere prehospital setting. Treatment with HTS was followed by improvement in the patient's neurologic exam and successful evacuation to definitive care where her child was delivered alive. Additionally, we review the pathophysiology and signs of herniation, the mechanism of action of hyperosmotic therapies, and the rationale behind the use of HTS in the combat setting.


Subcellular flux analysis of central metabolism in a heterotrophic Arabidopsis cell suspension using steady-state stable isotope labeling.
The presence of cytosolic and plastidic pathways of carbohydrate oxidation is a characteristic feature of plant cell metabolism. Ideally, steady-state metabolic flux analysis, an emerging tool for creating flux maps of heterotrophic plant metabolism, would capture this feature of the metabolic phenotype, but the extent to which this can be achieved is uncertain. To address this question, fluxes through the pathways of central metabolism in a heterotrophic Arabidopsis (Arabidopsis thaliana) cell suspension culture were deduced from the redistribution of label in steady-state (13)C-labeling experiments using [1-(13)C]-, [2-(13)C]-, and [U-(13)C(6)]glucose. Focusing on the pentose phosphate pathway (PPP), multiple data sets were fitted simultaneously to models in which the subcellular compartmentation of the PPP was altered. The observed redistribution of the label could be explained by any one of three models of the subcellular compartmentation of the oxidative PPP, but other biochemical evidence favored the model in which the oxidative steps of the PPP were duplicated in the cytosol and plastids, with flux through these reactions occurring largely in the cytosol. The analysis emphasizes the inherent difficulty of analyzing the PPP without predefining the extent of its compartmentation and the importance of obtaining high-quality data that report directly on specific subcellular processes. The Arabidopsis flux map also shows that the potential ATP yield of respiration in heterotrophic plant cells can greatly exceed the direct metabolic requirements for biosynthesis, highlighting the need for caution when predicting flux through metabolic networks using assumptions based on the energetics of resource utilization.


An MLST approach to support tracking of plasmids carrying OXA-48-like carbapenemase.
The prevalence of infections caused by OXA-48-like carbapenemase-producing organisms in Ireland has increased dramatically since 2011 and is an urgent public health issue. Genome-based high-resolution genotyping was used to analyse clinical isolates submitted to the Irish Carbapenemase-Producing Enterobacteriaceae Reference Laboratory Service for a 13 month period (2016-17). A total of 109 OXA-48-producing non-duplicate clinical isolates from 16 submitting centres were sequenced. Using a gene-by-gene approach, isolate genomes were characterized by MLST and core genome MLST, and the presence of antimicrobial resistance determinants was determined. Reference mapping and a novel plasmid MLST-type approach was applied to determine plasmid background. The OXA-48-like-producing isolates were Escherichia coli (n = 56), Klebsiella spp. (n = 46) and Enterobacter cloacae (n = 7). Amongst the E. coli isolates there were 37 different STs and amongst the Klebsiella spp. isolates there were 27 different STs. blaOXA-48 was present in 105/109 (96.3%) of isolates. Based on mapping analysis and detection of the pOXA-48 IncL-type plasmid replicon and backbone genes, a pOXA-48-like plasmid was identified in 93/109 isolates (85.3%). The remaining isolates (n = 16; 14.7%) harboured blaOXA-48-like genes in unknown environments. Using a gene-by-gene approach two pOXA-48-like plasmid groups with 2/71 pOXA-48-like locus differences between them were identified. In Ireland we found a diversity of genotypes associated with OXA-48-like-producing clinical isolates with the IncL pOXA-48 plasmid type predominating as the blaOXA-48 genetic environment. A plasmid MLST approach can rapidly identify plasmids associated with outbreaks and monitor spread of types temporally and geographically.


Exudate detection in color retinal images for mass screening of diabetic retinopathy.
The automatic detection of exudates in color eye fundus images is an important task in applications such as diabetic retinopathy screening. The presented work has been undertaken in the framework of the TeleOphta project, whose main objective is to automatically detect normal exams in a tele-ophthalmology network, thus reducing the burden on the readers. A new clinical database, e-ophtha EX, containing precisely manually contoured exudates, is introduced. As opposed to previously available databases, e-ophtha EX is very heterogeneous. It contains images gathered within the OPHDIAT telemedicine network for diabetic retinopathy screening. Image definition, quality, as well as patients condition or the retinograph used for the acquisition, for example, are subject to important changes between different examinations. The proposed exudate detection method has been designed for this complex situation. We propose new preprocessing methods, which perform not only normalization and denoising tasks, but also detect reflections and artifacts in the image. A new candidates segmentation method, based on mathematical morphology, is proposed. These candidates are characterized using classical features, but also novel contextual features. Finally, a random forest algorithm is used to detect the exudates among the candidates. The method has been validated on the e-ophtha EX database, obtaining an AUC of 0.95. It has been also validated on other databases, obtaining an AUC between 0.93 and 0.95, outperforming state-of-the-art methods.


Polarization controller based on embedded optical transformation.
A universal 2D transformation formula for embedded transformation optics is suggested. Linear and nonlinear transformation results using the suggested formula under different conditions reveal several interesting phenomena and potential applications, and designs for various polarization controllers can be achieved based on this idea. For example, an incident Gaussian beam can be transformed into a typical spherical wave, and a "cloak" based on a polarization splitter is proposed for the first time.


Interleukin 5 induces S mu-S gamma 1 DNA rearrangement in B cells activated with dextran-anti-IgD antibodies and interleukin 4: a three component model for Ig class switching.
The cellular signals required for induction of immunoglobulin (Ig) class switching are only partially understood. Two processes that are considered to be necessary for such induction are DNA synthesis and germline constant heavy (CH) gene transcription. We now show that an additional signal, as mediated by interleukin 5 (IL-5), is also required. To induce proliferation of resting B cells, but not Ig secretion, we utilized anti-IgD antibodies conjugated to dextran (alpha delta-dex). The addition of IL-4, a well-established switch factor for the IgG1 subclass, to alpha delta-dex-activated cell cultures failed to induce IgG1 secretion or mIgG1+ cells unless IL-5 was also present. While IL-4 stimulated an increase in germline gamma 1 RNA in alpha delta-dex-activated cells, this effect could neither be induced nor enhanced by IL-5. By contrast, IL-5 strongly enhanced steady-state levels of productive gamma 1 RNA induced by alpha delta-dex and IL-4, suggesting that IL-5 stimulated IgG1 switch rearrangement. To test this possibility we measured switch (S) mu-S gamma 1 DNA recombination events using a newly developed assay, digestion circularization polymerase chain reaction (DC-PCR). We demonstrated that IL-5 was necessary for induction of S mu-S gamma 1 DNA rearrangement in alpha delta-dex plus IL-4-activated cells but that it had little effect on rearrangement in the absence of IL-4. Our data strongly suggest, therefore, a three-component model for induction of Ig class switching. This model includes germline CH gene transcription, DNA synthesis, and a third component that is necessary for recombination.


Visualization of Potential Drug Synergies.
Drug synergy must be taken into account when prescribing several drugs for treating the same disorder. Synergies are sometimes known from clinical trials, but they are not systematically studied. In this paper, we present a visual approach for identifying and explaining the potential synergies between the 2-15 drugs available for a given disorder. It is based on the chaining of two bioinformatics databases, Drug Bank and Signor, and relies on set visualization with rainbow boxes. We apply this approach to antihypertensive drugs, and show that some European recommendations can be visually deduced and explained.


Mammalian DNA polymerase beta: characterization of a 16-kDa transdomain fragment containing the nucleic acid-binding activities of the native enzyme.
The 39-kDa DNA polymerase beta (beta-Pol) molecule can be readily converted into two constituent domains by mild proteolysis; these domains are represented in an 8-kDa N-terminal fragment and a 31-kDa C-terminal fragment [Kumar et al. (1990a) J. Biol. Chem. 265, 2124-2131]. Intact beta-Pol is a sequence-nonspecific nucleic acid-interactive protein that binds both double-stranded (ds) and single-stranded (ss) polynucleotides. These two activities appear to be contributed by separate portions of the enzyme, since the 31-kDa domain binds ds DNA but not ss DNA, and conversely, the 8-kDa domain binds ss DNA but not ds DNA [Casas-Finet et al. (1991) J. Biol. Chem. 266, 19618-19625]. Truncation of the 31-kDa domain at the N-terminus with chymotrypsin, to produce a 27-kDa fragment (residues 140-334), eliminated all DNA-binding activity. This suggested that the ds DNA-binding capacity of the 31-kDa domain may be carried in the N-terminal segment of the 31-kDa domain. We used CNBr to prepare a 16-kDa fragment (residues 18-154) that spans the ss DNA-binding region of the 8-kDa domain along with the N-terminal portion of the 31-kDa domain. The purified 16-kDa fragment was found to have both ss and ds polynucleotide-binding capacity. Thermodynamic binding properties for these activities are similar to those of the intact enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)


Structural relations of language and cognitive skills, and topic knowledge to written composition: A test of the direct and indirect effects model of writing.
Writing involves multiple processes, drawing on a number of language, cognitive, and print-related skills, and knowledge. According to the Direct and Indirect Effects model of Writing (DIEW; Kim & Park, 2019, Reading and Writing, 32, 1319), these multiple factors have hierarchical, interactive, and dynamic relations. I examined the hierarchical relations of language and cognitive skills to written composition as well as the relation of topic knowledge to written composition, using DIEW as a theoretical framework. One hundred thirty-two English-speaking students in Grade 4 were assessed on written composition, topic knowledge, oral language (vocabulary, grammatical knowledge, discourse-level oral production), higher order cognitions (inference, perspective taking [theory of mind], monitoring), domain-general cognitions (working memory and attention), and transcription skills (spelling and handwriting fluency). Structural equation modelling was used to compare hierarchical relations models with a direct or flat relations model. The hierarchical relations model was supported. Discourse oral language skills and transcription skills completely mediated the relations of the other component skills to written composition, and the included component skills explained 82% of variance in written composition. Substantial total effects were found for discourse language, transcription, attention, working memory, vocabulary, theory of mind, and grammatical knowledge. Topic knowledge was moderately related to writing, but this relation became weak once the other skills were accounted for. Component skills have hierarchical structural relations and make direct and indirect contributions to written composition. Furthermore, the role of topic knowledge in written composition appears constrained by language and transcription skills for developing writers.


Benefits and Costs of Context Reinstatement in Episodic Memory: An ERP Study.
This study investigated context-dependent episodic memory retrieval. An influential idea in the memory literature is that performance benefits when the retrieval context overlaps with the original encoding context. However, such memory facilitation may not be driven by the encoding-retrieval overlap per se but by the presence of diagnostic features in the reinstated context that discriminate the target episode from competing episodes. To test this prediction, the encoding-retrieval overlap and the diagnostic value of the context were manipulated in a novel associative recognition memory task. Participants were asked to memorize word pairs presented together with diagnostic (unique) and nondiagnostic (shared) background scenes. At test, participants recognized the word pairs in the presence and absence of the previously encoded contexts. Behavioral data show facilitated memory performance in the presence of the original context but, importantly, only when the context was diagnostic of the target episode. The electrophysiological data reveal an early anterior ERP encoding-retrieval overlap effect that tracks the cost associated with having nondiagnostic contexts present at retrieval, that is, shared by multiple previous episodes, and a later posterior encoding-retrieval overlap effect that reflects facilitated access to the target episode during retrieval in diagnostic contexts. Taken together, our results underscore the importance of the diagnostic value of the context and suggest that context-dependent episodic memory effects are multiple determined.


Diverse sensitivity thresholds in dynamic signaling responses by social amoebae.
The complex transition from a single-cell to a multicellular life form during the formation of a fruiting body by the amoeba Dictyostelium discoideum is accompanied by a pulsatile collective signaling process that instigates chemotaxis of the constituent cells. Although the cells used for the analysis of this phenomenon are normally genetically identical (isogenic), it is not clear whether they are equally responsive to the waves of the signaling stimulus, nor is it clear how responses across the population influence collective cell behavior. Here, we found that isogenic Dictyostelium cells displayed differing sensitivities to the chemoattractant cyclic adenosine monophosphate (cAMP). Furthermore, the resulting signaling responses could be explained by a model in which cells are refractory to further stimulation for 5 to 6 min after the initial input and the signaling output is amplified, with the amplification threshold varying across the cells in the population. This pathway structure could explain intracellular amplification of the chemoattractant gradient during cell migration. The new model predicts that diverse cell responsiveness can facilitate collective cell behavior, specifically due to the presence of a small number of cells in the population with increased responsiveness that aid in propagating the initial cAMP signaling wave across the cell population.


Identification, genetic localization, and allelic diversity of selectively amplified microsatellite polymorphic loci in lettuce and wild relatives (Lactuca spp.).
Selectively amplified microsatellite polymorphic locus (SAMPL) analysis is a method of amplifying microsatellite loci using generic PCR primers. SAMPL analysis uses one AFLP primer in combination with a primer complementary to microsatellite sequences. SAMPL primers based on compound microsatellite sequences provided the clearest amplification patterns. We explored the potential of SAMPL analysis in lettuce to detect PCR-based codominant microsatellite markers. Fifty-eight SAMPLs were identified and placed on the genetic map. Seventeen were codominant. SAMPLs were dispersed with RFLP markers on 11 of the 12 main linkage groups in lettuce, indicating that they have a similar genomic distribution. Some but not all fragments amplified by SAMPL analysis were confirmed to contain microsatellite sequences by Southern hybridization. Forty-five cultivars of lettuce and five wild species of Lactuca were analyzed to determine the allelic diversity for codominant SAMPLs. From 3 to 11 putative alleles were found for each SAMPL; 2-6 alleles were found within Lactuca sativa and 1-3 alleles were found among the crisphead genotypes, the most genetically homogeneous plant type of L. sativa. This allelic diversity is greater than that found for RFLP markers. Numerous new alleles were observed in the wild species; however, there were frequent null alleles. Therefore, SAMPL analysis is more applicable to intraspecific than to interspecific comparisons. A phenetic analysis based on SAMPLs resulted in a dendrogram similar to those based on RFLP and AFLP markers.


Persistent Epstein-Barr virus infection: unrestricted latent and lytic viral gene expression in healthy immunosuppressed transplant recipients.
Posttransplant lymphoproliferative disease (PTLD) is a common Epstein-Barr virus (EBV)-associated complication of transplantation which, despite treatment, is often fatal. This study was undertaken to monitor persistent EBV infection in transplant recipients, to compare EBV load and gene expression in healthy individuals and EBV-associated diseases, and to highlight differences in PTLD that could be used to define those at risk of the disease. A cohort of 96 cardiothoracic transplant recipients was monitored posttransplant for up to 1110 days (median 268 days). Levels of EBV DNA and viral mRNA transcripts in peripheral blood mononuclear cells (PBMs) were measured at regular intervals and compared with those found in healthy individuals, infectious mononucleosis (IM) patients, and 12 PTLD patients bled at the time of diagnosis. Overall posttransplant levels were significantly higher than pretransplant and healthy subjects, and correlate with dose of immunosuppression. EBV DNA levels in both IM and PTLD were significantly higher than in healthy recipients, with the highest levels in PTLD patients. Individual measurements in 12 healthy transplant recipients reached levels seen in PTLD, and thus single estimations are not of predictive significance for PTLD development. Analysis of viral gene expression in peripheral blood mononuclear cells showed a restricted (LMP 2 only) pattern in healthy subjects, and an unrestricted (latency 3) pattern with lytic replication in 14% of IM blood and 45% of cases of PTLD. A total of 55% of healthy transplant recipients had additional transcripts in one or more blood samples, and this finding correlated with high viral load. Analysis of the 12 samples from healthy recipients with viral loads equivalent to those seen in PTLD showed additional transcripts in all cases and latency 3 with lytic replication in 33%. Thus, an isolated finding of high viral load and/or unrestricted latent and lytic gene expression is not indicative of PTLD.


Interactions of small nuclear RNA's with precursor messenger RNA during in vitro splicing.
Precursor messenger RNA splicing requires multiple factors including U1, U2, U4, U5, and U6 small nuclear RNA's. The crosslinking reagent psoralen was used to analyze the interactions of these RNA's with an adenovirus precursor messenger RNA in HeLa nuclear extract. An endogenous U2-U4-U6 crosslinkable complex dissociated upon incubation with precursor messenger RNA. During splicing, U1, U2, U5, and U6 became crosslinked to precursor messenger RNA and U2, U5, and U6 became crosslinked to excised lariat intron. U2 also formed a doubly crosslinked complex with U6 and precursor messenger RNA. The U1, U5, and U6 crosslinks to the precursor messenger RNA mapped to intron sequences near the 5' splice site, whereas the U2 crosslink mapped to the branch site. The kinetics of crosslink formation and disappearance delineates a temporal pathway for the action of small RNA's in the spliceosome. Potential base pairing interactions between conserved sequences in the small nuclear RNA's and precursor messenger RNA at the sites of crosslinking suggest that the 5' splice site is defined in several steps prior to the first cleavage event.


Preliminary validity of the modified Cigarette Evaluation Questionnaire in predicting the reinforcing effects of cigarettes that vary in nicotine content.
Validity studies evaluating self-report measures in relation to behavioral preference of cigarettes varying in nicotine content are needed. The current study examined the relationship between ratings on the modified Cigarette Evaluation Questionnaire (mCEQ) and the relative reinforcing effects of Spectrum research cigarettes (15.8, 5.2, 2.4, 0.4 mg per gram of tobacco). Data for this secondary analysis were obtained from a double-blind study (Higgins et al., 2017) evaluating the subjective and reinforcing effects of Spectrum cigarettes under acute smoking abstinence. Current smokers (N = 26) were recruited from three vulnerable smoking populations (economically disadvantaged women of reproductive age, opioid-maintained individuals, individuals with affective disorders). In Phase 1 (five sessions), the mCEQ (Satisfaction, Psychological Reward, Enjoyment of Respiratory Tract Sensations, Craving Reduction, Aversion subscales) was administered following ad lib smoking of Spectrum cigarettes and subscale differences scores were calculated by subtracting ratings of the 15.8 mg/g cigarette from ratings of the reduced nicotine content cigarettes. In Phase 2 (six sessions), participants completed six 2-dose concurrent choice tests. The relationship between mCEQ subscale difference scores from Phase 1 and nicotine dose choice from Phase 2 was examined using mixed-model repeated-measures analyses of variance. Higher Satisfaction and lower Aversion subscale difference scores were associated with choosing the 15.8 mg/g cigarette more than the 5.2, 2.4, and 0.4 mg/g cigarettes. Scores on the other mCEQ subscales were not associated with nicotine choice. These results provide support for validity of the mCEQ Satisfaction and Aversion subscales predicting the relative reinforcing effects and abuse liability of varying nicotine content cigarettes. (PsycINFO Database Record


Porcine IgA allotypes are not equally transcribed or expressed in heterozygous swine.
The prediction of 1:1 expression of constant region allotypes in heterozygous animals assumes that productive VDJ rearrangements occur at random between chromosomes, switch recombination is random, there is no allele-related defect in switching and there is no selection for a B-cell receptor bearing a certain constant region allotype. In data reported here, this prediction was often not fulfilled for the transcripts encoding the IgAa and IgAb alleles of porcine IgA including those from late term fetal piglets that are not in contact with environmental antigens or maternal regulatory factors. In the spleen, thymus, mesenteric lymph node (MLN), ileal Peyer patches, parotid gland and PBLs of 5-week-old conventionally-reared Duroc pigs, ratios of IgAa to IgAb transcripts as high as 4:1 were observed. Since White Cross animals had significantly higher levels of IgAb than IgAa (some >3-fold), a allele-linked switch defect cannot explain the deviation from the expected 1:1 ratio. When the IgAa:IgAb ratios in older Durocs and those reared at a different site were studied, no evidence for breed dependence of differential transcription was found. Total serum IgA levels paralleled total transcript levels in PBLs while particularly in White Cross animals, the IgAa:IgAb ratio in serum was higher in many animals than the IgAa:IgAb transcript ratio in their PBLs. We conclude that deviations from the expected 1:1 ratio of allotype transcripts and secreted IgA in young pigs is normal and deviations from this ratio also occur during fetal life in the absence of environmental antigens and maternal regulatory factors. We speculate that postnatal deviations result from: (A) exposure to environmental antigens that selectively expand B-cells expressing V(H) gene alleles linked to either IgAa or IgAb or (B) some form of colostrum-dependent regulation. Pre-natal regulation may depend on the selection of B-cells bearing certain V(H) or C(H) encoded BCRs by stromal ligands such as fetal B-cell superantigens.


Estrogen deficiency and bone loss: an inflammatory tale.
Estrogen plays a fundamental role in skeletal growth and bone homeostasis in both men and women. Although remarkable progress has been made in our understanding of how estrogen deficiency causes bone loss, the mechanisms involved have proven to be complex and multifaceted. Although estrogen is established to have direct effects on bone cells, recent animal studies have identified additional unexpected regulatory effects of estrogen centered at the level of the adaptive immune response. Furthermore, a potential role for reactive oxygen species has now been identified in both humans and animals. One major challenge is the integration of a multitude of redundant pathways and cytokines, each apparently capable of playing a relevant role, into a comprehensive model of postmenopausal osteoporosis. This Review presents our current understanding of the process of estrogen deficiency-mediated bone destruction and explores some recent findings and hypotheses to explain estrogen action in bone. Due to the inherent difficulties associated with human investigation, many of the lessons learned have been in animal models. Consequently, many of these principles await further validation in humans.


Can healthy fetuses show facial expressions of "pain" or "distress"?
With advances of research on fetal behavioural development, the question of whether we can identify fetal facial expressions and determine their developmental progression, takes on greater importance. In this study we investigate longitudinally the increasing complexity of combinations of facial movements from 24 to 36 weeks gestation in a sample of healthy fetuses using frame-by-frame coding of 4-D ultrasound scans. The primary aim was to examine whether these complex facial movements coalesce into a recognisable facial expression of pain/distress. Fifteen fetuses (8 girls, 7 boys) were observed four times in the second and third trimester of pregnancy. Fetuses showed significant progress towards more complex facial expressions as gestational age increased. Statistical analysis of the facial movements making up a specific facial configuration namely "pain/distress" also demonstrates that this facial expression becomes significantly more complete as the fetus matures. The study shows that one can determine the normal progression of fetal facial movements. Furthermore, our results suggest that healthy fetuses progress towards an increasingly complete pain/distress expression as they mature. We argue that this is an adaptive process which is beneficial to the fetus postnatally and has the potential to identify normal versus abnormal developmental pathways.


Acyl group specificity at the active site of tetrahydridipicolinate N-succinyltransferase.
Tetrahydrodipicolinate N-succinyltransferase (DapD) catalyzes the succinyl-CoA-dependent acylation of L-2-amino-6-oxopimelate to 2-N-succinyl-6-oxopimelate as part of the succinylase branch of the meso-diaminopimelate/lysine biosynthetic pathway of bacteria, blue-green algae, and plants. This pathway provides meso-diaminopimelate as a building block for cell wall peptidoglycan in most bacteria, and is regarded as a target pathway for antibacterial agents. We have solved the X-ray crystal structures of DapD in ternary complexes with pimelate/succinyl-CoA and L-2-aminopimelate with the nonreactive cofactor analog, succinamide-CoA. These structures define the binding conformation of the cofactor succinyl group and its interactions with the enzyme and place its thioester carbonyl carbon in close proximity to the nucleophilic 2-amino group of the acceptor, in support of a direct attack ternary complex mechanism. The acyl group specificity differences between homologous tetrahydrodipicolinate N-acetyl- and N-succinyltransferases can be rationalized with reference to at least three amino acids that interact with or give accessible active site volume to the cofactor succinyl group. These residues account at least in part for the substrate specificity that commits metabolic intermediates to either the succinylase or acetylase branches of the meso-diaminopimelate/lysine biosynthetic pathway.


Interleukin-10 and soluble tumor necrosis factor receptor II are potential biomarkers of Plasmodium falciparum infections in pregnant women: a case-control study from Nanoro, Burkina Faso.
Diagnosis of malaria in pregnancy is problematic due to the low sensitivity of conventional diagnostic tests (rapid diagnostic test and microscopy), which is exacerbated due to low peripheral parasite densities, and lack of clinical symptoms. In this study, six potential biomarkers to support malaria diagnosis in pregnancy were evaluated. Blood samples were collected from pregnant women at antenatal clinic visits and at delivery. Microscopy and real-time PCR were performed for malaria diagnosis and biomarker analyses were performed by ELISA (interleukin 10, IL-10; tumor necrosis factor-α, TNF-α; soluble tumor necrosis factor receptor II, sTNF-RII; soluble fms-like tyrosine kinase 1, sFlt-1; leptin and apolipoprotein B, Apo-B). A placental biopsy was collected at delivery to determine placental malaria. IL-10 and sTNF-RII were significantly higher at all time-points in malaria-infected women (p < 0.001). Both markers were also positively associated with parasite density (p < 0.001 and p = 0.003 for IL-10 and sTNF-RII respectively). IL-10 levels at delivery, but not during pregnancy, were negatively associated with birth weight. A prediction model was created using IL-10 and sTNF-RII cut-off points. For primigravidae the model had a sensitivity of 88.9% (95%CI 45.7-98.7%) and specificity of 83.3% (95% CI 57.1-94.9%) for diagnosing malaria during pregnancy. For secundi- and multigravidae the sensitivity (81.8% and 56.5% respectively) was lower, while specificity (100.0% and 94.3% respectively) was relatively high. Sub-microscopic infections were detected in 2 out of 3 secundi- and 5 out of 12 multigravidae. The combination of biomarkers IL-10 and sTNF-RII have the potential to support malaria diagnosis in pregnancy. Additional markers may be needed to increase sensitivity and specificity, this is of particular importance in populations with sub-microscopic infections or in whom other inflammatory diseases are prevalent.


Lifestyles in suburban populations: A systematic review.
Lifestyle and suburban population are important issues in the field of health. The living conditions of informal settlements can lead to acquisition of an unhealthy lifestyle. This study has been designed to investigate the articles that have been published regarding lifestyle in suburban populations. The present research was a systematic review of studies in databases including Iranmedex, Magiran, SID, Irandoc, PubMed, Google Scholar, Science Direct and Scopus, in 2017. All Persian and English papers written from 2000 to 2017 were evaluated by two reviewers using an advanced search of the databases with keywords related to lifestyles and suburban population. After completion of the search, the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist was used to evaluate the articles. In total, 19 articles were found to have addressed the lifestyle in suburban populations. The results of these studies showed an unhealthy lifestyle in the most informal settlements. There was no food diversity. Malnutrition was common, especially overweight. The majority of the people did not have enough physical activity, and smoking and alcohol consumption were common, especially in men. Studies showed that suburban populations are among the groups that have unfavorable environmental conditions to acquiring healthy lifestyle and maintaining appropriate health. Therefore, developing infrastructure, improving health services (environment, treatment of diseases, reduction of malnutrition and infant mortality, access to safe drinking water and sanitation, improving waste disposal and recycling it), improving education and smoking prevention programs in improving lifestyle is recommended.


Severe acute kidney injury associated with non-steroidal anti-inflammatory drugs in cirrhosis: A case-control study.
Non-steroidal anti-inflammatory drugs (NSAIDs) may cause impairment of kidney function in patients with cirrhosis. Investigational studies demonstrated reversibility of kidney dysfunction after drug withdrawal, but information based on clinical practice is lacking. The aim of the study was to investigate the characteristics and outcome of Acute Kidney Injury (AKI) developing in patients with cirrhosis treated with NSAIDs. Prospective cohort study in a tertiary referral center of all patients with NSAIDs-associated AKI seen from 2002 to 2014. For comparison, three control groups of patients with hypovolemic-induced AKI, type-1 HRS and ATN, respectively, were also evaluated. Urinary excretion of neutrophil gelatinase-associated lipocalin (uNGAL) was measured in a subset of patients. Thirty patients with cirrhosis and NSAIDs-associated AKI were identified. In 19 patients (63%) AKI was transient and kidney function rapidly recovered (4±3 days) after NSAIDs withdrawal. In the remaining 11 patients (37%) AKI was more severe and persisted during hospitalization despite drug withdrawal. Patients with persistent AKI had remarkably higher uNGAL levels compared with those of patients with transient AKI (953±1,198 vs. 83±79 μg/g of creatinine, respectively, p=0.008). Moreover, seven of the 11 patients with persistent AKI (64%) died within three months compared with only one of the 19 (5%) patients with transient AKI (p=0.001). Mortality of persistent AKI was similar in NSAIDs patients compared to control groups. The only independent predictive factor of three-month mortality was persistent AKI. Patients with cirrhosis treated with NSAIDs may develop severe AKI which may be irreversible and associated with poor short-term outcome.


J.B. Wolffe Memorial Lecture. "Why exercise?".
There is a pronounced plasticity and adaptability in the structural and/or functional properties of cells, tissues, and organ systems in the human body when exposed to various stimuli. While there is unanimous agreement that regular exercise is essential for optimal function of the human body, it is evident that extrinsic factors, such as diet and exercise habits, are reflected in the morbidity and mortality statistics, especially in the aged. Aging is obligatorily associated with reduced maximal aerobic power and reduced muscle strength, i.e., with reduced physical fitness. As a consequence of diminished exercise tolerance, a large and increasing number of elderly persons will be living below, at, or just above "thresholds" of physical ability, needing only a minor intercurrent illness to render them completely dependent. Physical training can readily produce a profound improvement of functions essential for physical fitness in old age. Adaptability to regular physical activity serves to cause less disruption of the cell's "milieu interieur" and minimizes fatigue, thereby enhancing performance and the economy of energy output during exercise.


Effects of arousal and movement on secondary somatosensory and visual thalamus.
Neocortical sensory areas have associated primary and secondary thalamic nuclei. While primary nuclei transmit sensory information to cortex, secondary nuclei remain poorly understood. We recorded juxtasomally from secondary somatosensory (POm) and visual (LP) nuclei of awake mice while tracking whisking and pupil size. POm activity correlated with whisking, but not precise whisker kinematics. This coarse movement modulation persisted after facial paralysis and thus was not due to sensory reafference. This phenomenon also continued during optogenetic silencing of somatosensory and motor cortex and after lesion of superior colliculus, ruling out a motor efference copy mechanism. Whisking and pupil dilation were strongly correlated, possibly reflecting arousal. Indeed LP, which is not part of the whisker system, tracked whisking equally well, further indicating that POm activity does not encode whisker movement per se. The semblance of movement-related activity is likely instead a global effect of arousal on both nuclei. We conclude that secondary thalamus monitors behavioral state, rather than movement, and may exist to alter cortical activity accordingly.


Isolation of the complementary DNA encoding a mouse heparin-binding growth factor receptor with the use of a unique kinase insert sequence.
With the use of reverse transcriptase-polymerase chain reaction techniques focused on a unique kinase insert sequence, the complementary DNA for a mouse tyrosine kinase receptor gene, designated sam3, was isolated from a mouse brain complementary DNA library as a member of the heparin-binding growth factor receptor family or fibroblast growth factor receptor family. The kinase insert region was selected as the probe synthesized by polymerase chain reaction techniques because it composes a unique structure in this receptor family. The sam3 protein, 800 amino acids long, has high homology to mouse K-sam/bek (67%) and N-sam/flg (63%), which we also cloned as the mouse counterparts of human K-sam/bek and N-sam/flg genes, other members of this family. The sam3 protein also has high homology to human FGFR3 (92%) and chicken cek2 (80%) proteins. The sam3 protein is most likely to be a mouse counterpart of human FGFR3 and chicken cek2 proteins. mRNAs of K-sam/bek, N-sam/flg, and sam3/FGFR3 genes were detected in mouse embryo through some adult tissues. The relative amounts of these mRNAs were different depending on the organs examined. Thus, these gene products may have different biological functions in organ development including the central nervous system.


Risk factors for tuberculosis after highly active antiretroviral therapy initiation in the United States and Canada: implications for tuberculosis screening.
Screening for tuberculosis prior to highly active antiretroviral therapy (HAART) initiation is not routinely performed in low-incidence settings. Identifying factors associated with developing tuberculosis after HAART initiation could focus screening efforts. Sixteen cohorts in the United States and Canada contributed data on persons infected with human immunodeficiency virus (HIV) who initiated HAART December 1995-August 2009. Parametric survival models identified factors associated with tuberculosis occurrence. Of 37845 persons in the study, 145 were diagnosed with tuberculosis after HAART initiation. Tuberculosis risk was highest in the first 3 months of HAART (20 cases; 215 cases per 100000 person-years; 95% confidence interval [CI]: 131-333 per 100000 person-years). In a multivariate Weibull proportional hazards model, baseline CD4+ lymphocyte count <200, black race, other nonwhite race, Hispanic ethnicity, and history of injection drug use were independently associated with tuberculosis risk. In addition, in a piece-wise Weibull model, increased baseline HIV-1 RNA was associated with increased tuberculosis risk in the first 3 months; male sex tended to be associated with increased risk. Screening for active tuberculosis prior to HAART initiation should be targeted to persons with baseline CD4 <200 lymphocytes/mm³ or increased HIV-1 RNA, persons of nonwhite race or Hispanic ethnicity, history of injection drug use, and possibly male sex.


Long-term observation of endodontic surgical intervention to treat root perforation and apical periodontitis: a case report of an amalgam-restored tooth.
A case of crestal root perforation and periapical lesion in a maxillary left lateral incisor is reported. Teeth with root perforation present technical difficulties in their clinical management because of their complex defects. In the present case, surgical endodontic treatment was chosen. The apical and lateral pathology was curetted, the tooth root was resected, and a retrograde root restoration of amalgam was placed in a root-end cavity and perforation site. A 10-year follow-up clinical and radiographic examination showed an asymptomatic tooth with osseous healing proceeding.


Rab35 and its effectors promote formation of tunneling nanotubes in neuronal cells.
Tunneling nanotubes (TNTs) are F-actin rich structures that connect distant cells, allowing the transport of many cellular components, including vesicles, organelles and molecules. Rab GTPases are the major regulators of vesicle trafficking and also participate in actin cytoskeleton remodelling, therefore, we examined their role in TNTs. Rab35 functions with several proteins that are involved in vesicle trafficking such as ACAP2, MICAL-L1, ARF6 and EHD1, which are known to be involved in neurite outgrowth. Here we show that Rab35 promotes TNT formation and TNT-mediated vesicle transfer in a neuronal cell line. Furthermore, our data indicates that Rab35-GTP, ACAP2, ARF6-GDP and EHD1 act in a cascade mechanism to promote TNT formation. Interestingly, MICAL-L1 overexpression, shown to be necessary for the action of Rab35 on neurite outgrowth, showed no effect on TNTs, indicating that TNT formation and neurite outgrowth may be processed through similar but not identical pathways, further supporting the unique identity of these cellular protrusions.


Prevalence, incidence, and mortality of PD: a door-to-door survey in Ilan county, Taiwan.
The reported prevalence and incidence rates of PD were significantly lower in China than those in Western countries. People in China and Taiwan have a similar ethnic background. To investigate the prevalence, incidence, and mortality rate of PD in Taiwan. The authors conducted a population-based survey using a two-stage door-to-door approach for patients aged 40 years or older in Ilan, Taiwan. Patients were diagnosed with PD by having at least two of the four cardinal signs of parkinsonism and exclusion of seconddary parkinsonism. To identify new cases of PD after the survey, patients with negative results of parkinsonism in the first stage were matched to the information on clinical diagnosis of PD from the Bureau of National Health Insurance toward the end of December 31, 1997. All cases of PD were linked to the Taiwan mortality registration to ascertain causes of deaths until December 31, 1999. The participation rate was 88.1% among the 11,411 contacted individuals. Thirty-seven cases of PD were identified. The age-adjusted prevalence rate of PD for all age groups was 130.1 per 100,000 population after being adjusted to the 1970 US census, assuming no cases of PD would be found among those younger than 40 years of age. Of 9972 non-PD subjects in the first screen, 15 new cases of PD were ascertained. The age-adjusted incidence rate was 10.4 per 100,000 population for all age groups. The case fatality rate of PD after a 7-year follow-up was 40.4% (21 deaths in 52 patients with PD). The relative risk of death for PD cases versus non-PD cases was 3.38 (95% CI: 2.05-4.34). The 5-year cumulative survival rate in PD cases (78.85%) was statistically lower than that in non-PD cases (92.84%). The prevalence and incidence rates of PD in Taiwan were much higher than those reported in China, but closer to those in Western countries. These results suggest that environmental factors may be more important than racial factors in the pathogenesis of PD.


Genome-wide association and functional follow-up reveals new loci for kidney function.
Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.


Rescuing the N-cadherin knockout by cardiac-specific expression of N- or E-cadherin.
Cell-cell adhesion mediated by some members of the cadherin family is essential for embryonic survival. The N-cadherin-null embryo dies during mid-gestation, with multiple developmental defects. We show that N-cadherin-null embryos expressing cadherins using muscle-specific promoters, alpha- or beta-myosin heavy chain, are partially rescued. Somewhat surprisingly, either N-cadherin or E-cadherin was effective in rescuing the embryos. The rescued embryos exhibited an increased number of somites, branchial arches and the presence of forelimb buds; however, in contrast, brain development was severely impaired. In rescued animals, the aberrant yolk sac morphology seen in N-cadherin-null embryos was corrected, demonstrating that this phenotype was secondary to the cardiac defect. Dye injection studies and analysis of chimeric animals that have both wild-type and N-cadherin-null cells support the conclusion that obstruction of the cardiac outflow tract represents a major defect that is likely to be the primary cause of pericardial swelling seen in null embryos. Although rescued embryos were more developed than null embryos, they were smaller than wild-type embryos, even though the integrity of the cardiovascular system appeared normal. The smaller size of rescued embryos may be due, at least in part, to increased apoptosis observed in tissues not rescued by transgene expression, indicating that N-cadherin-mediated cell adhesion provides an essential survival signal for embryonic cells. Our data provide in vivo evidence that cadherin adhesion is essential for cell survival and for normal heart development. Our data also show that E-cadherin can functionally substitute for N-cadherin during cardiogenesis, suggesting a critical role for cadherin-mediated cell-cell adhesion, but not cadherin family member-specific signaling, at the looping stage of heart development.


Rodent ultrasonic vocalizations as biomarkers of future alcohol use: A predictive analytic approach.
Excessive alcohol consumption has a vast, negative impact on society. Rodent models have been successful in furthering our understanding of the biological underpinnings that drive alcohol consumption. Rodents emit ultrasonic vocalizations (USVs) that are each composed of several acoustic characteristics (e.g., frequency, duration, bandwidth, power). USVs reflect neurotransmitter activity in the ascending limb of the mesolimbic dopaminergic and cholinergic neurotransmitter systems and serve as noninvasive, real-time biomarkers of dopaminergic and cholinergic neurotransmission in the limbic system. In the present study, we recorded spontaneously emitted USVs from alcohol-naïve Long-Evans (LE) rats and then measured their alcohol intake. We compared the USV acoustic characteristics and alcohol consumption data from these LE rats with previously published data from selectively bred high-alcohol (P and HAD-1) and low-alcohol (NP and LAD-1) drinking lines from studies with the same experimental method. Predictive analytic techniques were applied simultaneously to this combined data set and revealed that (a) USVs emitted by alcohol-naïve rats accurately discriminated among high-alcohol consuming, LE, and low-alcohol consuming rat lines, and (b) future alcohol consumption in these same rat lines was reliably predicted from the USV data collected in an alcohol-naïve state. To our knowledge, this is the first study to show that alcohol consumption is predicted directly from USV profiles of alcohol-naïve rats. Because USV acoustic characteristics are sensitive to underlying neural activity, these findings suggest that baseline differences in mesolimbic cholinergic and dopaminergic tone could determine the propensity for future alcohol consumption in rodents.


Neural, mechanical, and geometric factors subserving arm posture in humans.
When the hand is displaced from an equilibrium posture by an external disturbance, a force is generated to restore the original position. We developed a new experimental method to measure and represent the field of elastic forces associated with posture of the hand in the horizontal plane. While subjects maintained a given posture, small displacements of the hand along different directions were delivered by torque motors. The hand was held in the displaced positions and, at that time, we measured the corresponding restoring forces before the onset of any voluntary reaction. The stiffness in the vicinity of the hand equilibrium position was estimated by analyzing the force and displacement vectors. We chose to represent the stiffness both numerically, as a matrix, and graphically, as an ellipse characterized by three parameters: magnitude (the area), shape (the ratio of axis) and orientation (direction of the major axis). The latter representation captures the main geometrical features of the elastic force field associated with posture. We also evaluated the conservative and nonconservative components of this elastic force field. We found that the former were much larger than the latter and concluded that the behavior of the neuromuscular system of the multiarticular arm is predominantly spring-like. Our data indicated that the shape and orientation of the stiffness were invariant over subjects and over time. We also investigated the ability of our subjects to produce voluntary and adaptive changes in the stiffness. Our findings indicated that, when a disturbance acting along a fixed and predictable direction was imposed, the magnitude of the stiffness was increased but only minor changes in shape and orientation occurred. Taken together, all of these experiments represent a step toward the understanding of the interactions between geometrical and neural factors involved in maintaining hand posture and its interactions with the environment.


Generation and characterization of a novel candidate gene therapy and vaccination vector based on human species D adenovirus type 56.
The vectorization of rare human adenovirus (HAdV) types will widen our knowledge of this family and their interaction with cells, tissues and organs. In this study we focus on HAdV-56, a member of human Ad species D, and create ease-of-use cloning systems to generate recombinant HAdV-56 vectors carrying foreign genes. We present in vitro transduction profiles for HAdV-56 in direct comparison to the most commonly used HAdV-5-based vector. In vivo characterizations demonstrate that when it is delivered intravenously (i.v.) HAdV-56 mainly targets the spleen and, to a lesser extent, the lungs, whilst largely bypassing liver transduction in mice. HAdV-56 triggered robust inflammatory and cellular immune responses, with higher induction of IFNγ, TNFα, IL5, IL6, IP10, MCP1 and MIG1 compared to HAdV-5 following i.v. administration. We also investigated its potential as a vaccine vector candidate by performing prime immunizations in mice with HAdV-56 encoding luciferase (HAdV-56-Luc). Direct comparisons were made to HAdV-26, a highly potent human vaccine vector currently in phase II clinical trials. HAdV-56-Luc induced luciferase 'antigen'-specific IFNγ-producing cells and anti-HAdV-56 neutralizing antibodies in Balb/c mice, demonstrating a near identical profile to that of HAdV-26. Taken together, the data presented provides further insight into human Ad receptor/co-receptor usage, and the first report on HAdV-56 vectors and their potential for gene therapy and vaccine applications.


Predicting future violence among individuals with psychopathy.
Structured risk assessment aims to help clinicians classify offenders according to likelihood of future violent and criminal behaviour. We investigated how confident clinicians can be using three commonly used instruments (HCR-20, VRAG, OGRS-II) in individuals with different diagnoses. Moderate to good predictive accuracy for future violence was achieved for released prisoners with no mental disorder, low to moderate for clinical syndromes and personality disorder, but accuracy was no better than chance for individuals with psychopathy. Comprehensive diagnostic assessment should precede an assessment of risk. Risk assessment instruments cannot be relied upon when managing public risk from individuals with psychopathy.


NME5 frameshift variant in Alaskan Malamutes with primary ciliary dyskinesia.
Primary ciliary dyskinesia (PCD) is a hereditary defect of motile cilia in humans and several domestic animal species. Typical clinical findings are chronic recurrent infections of the respiratory tract and fertility problems. We analyzed an Alaskan Malamute family, in which two out of six puppies were affected by PCD. The parents were unaffected suggesting autosomal recessive inheritance. Linkage and homozygosity mapping defined critical intervals comprising ~118 Mb. Whole genome sequencing of one case and comparison to 601 control genomes identified a disease associated frameshift variant, c.43delA, in the NME5 gene encoding a sparsely characterized protein associated with ciliary function. Nme5-/- knockout mice exhibit doming of the skull, hydrocephalus and sperm flagellar defects. The genotypes at NME5:c.43delA showed the expected co-segregation with the phenotype in the Alaskan Malamute family. An additional unrelated Alaskan Malamute with PCD and hydrocephalus that became available later in the study was also homozygous mutant at the NME5:c.43delA variant. The mutant allele was not present in more than 1000 control dogs from different breeds. Immunohistochemistry demonstrated absence of the NME5 protein from nasal epithelia of an affected dog. We therefore propose NME5:c.43delA as the most likely candidate causative variant for PCD in Alaskan Malamutes. These findings enable genetic testing to avoid the unintentional breeding of affected dogs in the future. Furthermore, the results of this study identify NME5 as a novel candidate gene for unsolved human PCD and/or hydrocephalus cases.


StereoGene: rapid estimation of genome-wide correlation of continuous or interval feature data.
Genomics features with similar genome-wide distributions are generally hypothesized to be functionally related, for example, colocalization of histones and transcription start sites indicate chromatin regulation of transcription factor activity. Therefore, statistical algorithms to perform spatial, genome-wide correlation among genomic features are required. Here, we propose a method, StereoGene, that rapidly estimates genome-wide correlation among pairs of genomic features. These features may represent high-throughput data mapped to reference genome or sets of genomic annotations in that reference genome. StereoGene enables correlation of continuous data directly, avoiding the data binarization and subsequent data loss. Correlations are computed among neighboring genomic positions using kernel correlation. Representing the correlation as a function of the genome position, StereoGene outputs the local correlation track as part of the analysis. StereoGene also accounts for confounders such as input DNA by partial correlation. We apply our method to numerous comparisons of ChIP-Seq datasets from the Human Epigenome Atlas and FANTOM CAGE to demonstrate its wide applicability. We observe the changes in the correlation between epigenomic features across developmental trajectories of several tissue types consistent with known biology and find a novel spatial correlation of CAGE clusters with donor splice sites and with poly(A) sites. These analyses provide examples for the broad applicability of StereoGene for regulatory genomics. The StereoGene C ++ source code, program documentation, Galaxy integration scripts and examples are available from the project homepage http://stereogene.bioinf.fbb.msu.ru/. firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


A picture is worth a thousand lies: using false photographs to create false childhood memories.
Because image-enhancing technology is readily available, people are frequently exposed to doctored images. However, in prior research on how adults can be led to report false childhood memories, subjects have typically been exposed to personalized and detailed narratives describing false events. Instead, we exposed 20 subjects to a false childhood event via a fake photograph and imagery instructions. Over three interviews, subjects thought about a photograph showing them on a hot air balloon ride and tried to recall the event byusing guided-imagery exercises. Fifty percent of the subjects created complete or partial false memories. The results bear on ways in which false memories can be created and also have practical implications for those involved in clinical and legal settings.


Velocity coupling of grid cell modules enables stable embedding of a low dimensional variable in a high dimensional neural attractor.
Grid cells in the medial entorhinal cortex (MEC) encode position using a distributed representation across multiple neural populations (modules), each possessing a distinct spatial scale. The modular structure of the representation confers the grid cell neural code with large capacity. Yet, the modularity poses significant challenges for the neural circuitry that maintains the representation, and updates it based on self motion. Small incompatible drifts in different modules, driven by noise, can rapidly lead to large, abrupt shifts in the represented position, resulting in catastrophic readout errors. Here, we propose a theoretical model of coupled modules. The coupling suppresses incompatible drifts, allowing for a stable embedding of a two-dimensional variable (position) in a higher dimensional neural attractor, while preserving the large capacity. We propose that coupling of this type may be implemented by recurrent synaptic connectivity within the MEC with a relatively simple and biologically plausible structure.


Intestinal Organoids as a Novel Tool to Study Microbes-Epithelium Interactions.
The gut, particularly the colon, is the host of approximately 1000 bacterial species, the so-called gut microbiota. The relationship between the gut microbiota and the host is symbiotic and mutualistic, influencing many aspects of the biology of the host. This homeostatic balance can be disrupted by enteric pathogens, such as Shigella flexneri or Listeria monocytogenes, which are able to invade the epithelial layer and consequently subvert physiological functions. To study the host-microbe interactions in vitro, the crypt culture model, known as intestinal organoids, is a powerful tool. Intestinal organoids provide a model in which to examine the response of the epithelium, particularly the response of intestinal stem cells, to the presence of bacteria. Furthermore, the organoid model enables the study of pathogens during the early steps of enteric pathogen invasion.Here, we describe methods that we have established to study the cellular microbiology of symbiosis between the gut microbiota and host intestinal surface and secondly the disruption of host homeostasis due to an enteric pathogen.


Removal of S6K1 and S6K2 leads to divergent alterations in learning, memory, and synaptic plasticity.
Protein synthesis is required for the expression of enduring memories and long-lasting synaptic plasticity. During cellular proliferation and growth, S6 kinases (S6Ks) are activated and coordinate the synthesis of de novo proteins. We hypothesized that protein synthesis mediated by S6Ks is critical for the manifestation of learning, memory, and synaptic plasticity. We have tested this hypothesis with genetically engineered mice deficient for either S6K1 or S6K2. We have found that S6K1-deficient mice express an early-onset contextual fear memory deficit within one hour of training, a deficit in conditioned taste aversion (CTA), impaired Morris water maze acquisition, and hypoactive exploratory behavior. In contrast, S6K2-deficient mice exhibit decreased contextual fear memory seven days after training, a reduction in latent inhibition of CTA, and normal spatial learning in the Morris water maze. Surprisingly, neither S6K1- nor S6K2-deficient mice exhibited alterations in protein synthesis-dependent late-phase long-term potentiation (L-LTP). However, removal of S6K1, but not S6K2, compromised early-phase LTP expression. Furthermore, we observed that S6K1-deficient mice have elevated basal levels of Akt phosphorylation, which is further elevated following induction of L-LTP. Taken together, our findings demonstrate that removal of S6K1 leads to a distinct array of behavioral and synaptic plasticity phenotypes that are not mirrored by the removal of S6K2. Our observations suggest that neither gene by itself is required for L-LTP but instead may be required for other types of synaptic plasticity required for cognitive processing.


Mitochondrial DNA as a cancer biomarker.
As part of a national effort to identify biomarkers for the early detection of cancer, we developed a rapid and high-throughput sequencing protocol for the detection of sequence variants in mitochondrial DNA. Here, we describe the development and implementation of this protocol for clinical samples. Heteroplasmic and homoplasmic sequence variants occur in the mitochondrial genome in patient tumors. We identified these changes by sequencing mitochondrial DNA obtained from tumors and blood from the same individual. We confirmed previously identified primary lung tumor changes and extended these findings in a small patient cohort. Eight sequence variants were identified in stage I to stage IV tumor samples. Two of the sequence variants identified (22%) were found in the D-loop region, which accounts for 6.8% of the mitochondrial genome. The other sequence variants were distributed throughout the coding region. In the forensic community, the sequence variations used for identification are localized to the D-loop region because this region appears to have a higher rate of mutation. However, in lung tumors the majority of sequence variation occurred in the coding region. Hence, incomplete mitochondrial genome sequencing, designed to scan discrete portions of the genome, misses potentially important sequence variants associated with cancer or other diseases.


Diverse genetic causes of polymicrogyria with epilepsy.
We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy. We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA. Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus. This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria cohort. Our results suggest possible roles for SCN2A, GRIA3, CACNA1C, and 15q25 deletion in polymicrogyria, each already associated with epilepsy or other neurodevelopmental conditions without brain malformations. The role of these genes in polymicrogyria will be further understood as more patients with polymicrogyria undergo genetic evaluation.


Amplified fragment length polymorphism markers linked to a major quantitative trait locus controlling scab resistance in wheat.
ABSTRACT Scab is a destructive disease of wheat. To accelerate development of scab-resistant wheat cultivars, molecular markers linked to scab resistance genes have been identified by using recombinant inbred lines (RILs) derived by single-seed descent from a cross between the resistant wheat cultivar Ning 7840 (resistant to spread of scab within the spike) and the susceptible cultivar Clark. In the greenhouse, F(5), F(6), F(7), and F(10) families were evaluated for resistance to spread of scab within a spike by injecting about 1,000 conidiospores of Fusarium graminearum into a central spikelet. Inoculated plants were kept in moist chambers for 3 days to promote initial infection and then transferred to greenhouse benches. Scab symptoms were evaluated four times (3, 9, 15, and 21 days after inoculation). The frequency distribution of scab severity indicated that resistance to spread of scab within a spike was controlled by a few major genes. DNA was isolated from both parents and F(9) plants of the 133 RILs. A total of 300 combinations of amplified fragment length polymorphism (AFLP) primers were screened for polymorphisms using bulked segregant analysis. Twenty pairs of primers revealed at least one polymorphic band between the two contrasting bulks. The segregation of each of these bands was evaluated in the 133 RILs. Eleven AFLP markers showed significant association with scab resistance, and an individual marker explained up to 53% of the total variation (R(2)). The markers with high R(2) values mapped to a single linkage group. By interval analysis, one major quantitative trait locus for scab resistance explaining up to 60% of the genetic variation for scab resistance was identified. Some of the AFLP markers may be useful in marker-assisted breeding to improve resistance to scab in wheat.


Mutations in IRGM are associated with more frequent need for surgery in patients with ileocolonic Crohn's disease.
There are no clear criteria for judging the severity of disease in patients with Crohn's disease. Yet classification of patients into low- and high-risk severity groups would benefit both medical and surgical management. At the time of this study, approximately 80 single-nucleotide polymorphisms within 55 genes had been associated with IBD. The aim of this study was to identify genetic determinants (single-nucleotide polymorphisms) that could be markers of Crohn's disease severity by the use of frequency of ileocolic surgery as a surrogate for disease severity. Sixty-six patients (30 male) with ileocolonic Crohn's disease who previously underwent ileocolectomy were retrospectively studied. The severity of Crohn's disease was quantified by dividing the total number of ileocolectomy procedures by the time between IBD diagnosis and the patient's last clinic visit, the rationale being that more severe disease would be associated with a more frequent need for surgery. Genotyping for the 83 single-nucleotide polymorphisms associated with IBD was done on a customized Illumina Veracode genotyping platform. Three genetic models (general, additive, and dominant) were used to statistically quantify the genetic association of the studied single-nucleotide polymorphisms to the frequency of surgery after adjusting for covariates (age, smoking, family history, disease location, and disease behavior). For the entire group the average number of ileocolectomies per patient was 1.7 (range, 1-5) with an average duration of disease of 14.7 years. Single-nucleotide polymorphism rs4958847 in the IRGM gene (immunity-related GTPase family, M) was the most significant single-nucleotide polymorphism in all 3 models tested (p = 0.007) as being associated with ileocolectomy, and it remained significant even after a Benjamini-Hochberg false-discovery correction for multiple observations. Patients carrying the "at-risk" allele for this single-nucleotide polymorphism (n = 20) had an average of 1 surgery every 6.87 ± 1.33 years in comparison with patients carrying the wild-type genotype (n = 46) who averaged 1 surgery in 11.43 ± 1.21 years (p = 0.007, Mann-Whitney U test). : Single-nucleotide polymorphism rs4958847 in the IRGM gene correlated very significantly with frequency of surgery in patients with ileocolonic Crohn's disease. IRGM is a mediator of innate immune responses and is involved in autophagy. The presence of this IRGM SNP may be a marker for disease severity and/or early recurrence after ileocolectomy and may assist in surgical and medical decision making.


Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the developing male Wistar(Han) rat. II: Chronic dosing causes developmental delay.
We have investigated whether fetal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes defects in the male reproductive system of the rat using chronically exposed rats to ensure continuous exposure of the fetus. Five- to six-week-old rats were exposed to control diet, or diet containing TCDD, to attain an average dose of 2.4, 8, and 46 ng TCDD/kg/day for 12 weeks, whereupon the rats were mated and allowed to litter; rats were switched to control diet after parturition. Male offsprings were allowed to develop until kills on PND70 (25 per group) or PND120 (all remaining animals). Offspring from the high-dose group showed an increase in total litter loss, and the number of animals alive on postnatal day (PND)4 in the high-dose group was approximately 26% less than control. The high and medium dose offsprings showed decreased weights at various ages. Balano-preputial separation (BPS) was significantly delayed in all three dose groups compared to control. There were no significant effects of maternal treatment when the offsprings were subjected to a functional observational battery or learning tests, with the exception that the high-dose group showed a deficit in motor activity. Twenty rats per group were mated to females, and there were no significant effects of maternal treatment on the fertility of these rats or on the F1 or F2 sex ratio. Sperm parameters at PND70 and 120 showed no significant effect of maternal treatment, with the exception that there was an increase in the proportion of abnormal sperm in the high-dose group at PND70; this is associated with the developmental delay in puberty in this dose group. There were no remarkable findings of maternal treatment on organ weights, with the exception that testis weights were reduced by approximately 10% at PND70 (but not PND120), and although the experiment was sufficiently powered to detect small changes, ventral prostate weight was not reduced. There were no significant effects of maternal treatment upon histopathological comparison of high-dose and control group organs. These data confirm that developmental exposure to TCDD shows no potent effect on adult sperm parameters or accessory sexual organs, but show that delay in BPS occurs after exposure to low doses of TCDD, and this is dependent upon whether TCDD is administered acutely or chronically.


Emerging models for mobilizing family support for chronic disease management: a structured review.
We identify recent models for programmes aiming to increase effective family support for chronic illness management and self-care among adult patients without significant physical or cognitive disabilities. We then summarize evidence regarding the efficacy for each model identified. Structured review of studies published in medical and psychology databases from 1990 to the present, reference review, general Web searches and conversations with family intervention experts. Review was limited to studies on conditions that require ongoing self-management, such as diabetes, chronic heart disease and rheumatologic disease. Programmes with three separate foci were identified: (1) Programmes that guide family members in setting goals for supporting patient self-care behaviours have led to improved implementation of family support roles, but have mixed success improving patient outcomes. (2) Programmes that train family in supportive communication techniques, such as prompting patient coping techniques or use of autonomy supportive statements, have successfully improved patient symptom management and health behaviours. (3) Programmes that give families tools and infrastructure to assist in monitoring clinical symptoms and medications are being conducted, with no evidence to date on their impact on patient outcomes. The next generation of programmes to improve family support for chronic disease management incorporate a variety of strategies. Future research can define optimal clinical situations for family support programmes, the most effective combinations of support strategies, and how best to integrate family support programmes into comprehensive models of chronic disease care.


Sensitivity to luminance and chromaticity gradients in a complex scene.
Image gradients--smooth changes in color and luminance--may be caused by intrinsic surface reflectance properties or extrinsic illumination phenomena, including shading, shadowing, and inter-reflections. In turn, image gradients may provide the visual system with information concerning the origin of these factors, such as the orientation of surfaces with respect to the light source. Color gradients induced by mutual illumination (MI) may play a similar role to that of luminance gradients in shape-from-shading algorithms; it has been shown that 3D shape perception modulates the influence of MI on surface color perception (M. G. Bloj, D. Kersten, & A. C. Hurlbert, 1999). In this study, we assess human sensitivity to changes in color and luminance gradients that arise from changes in the light source position, within a complex scene. In Experiment 1, we tested whether observers were able to discriminate between gradients due to different light source positions. We found that observers reliably detected a change in the gradient information when the light source position differed by only 4 deg from the reference scene. This sensitivity was mainly based on the luminance information in the gradient (Experiments 2 and 3). Some observers make use of the spatial distribution of chromaticity and luminance values within gradients when discriminating between them (Experiment 4). The high sensitivity to gradient differences supports the notion that gradients contain information that may assist in the recovery of 3D shape and scene configuration properties.


Vertical instability in spondylolisthesis: a traction radiographic assessment technique and the principle of management.
Lateral radiographs of the lumbar spine were taken of 40 patients with lumbar spondylolisthesis. These radiographs were taken in the neutral, flexion, and extension positions for both erect and recumbent postures, and also in the prone and supine positions with traction applied via a traction table. To define and demonstrate the presence of "vertical instability" in spondylolisthesis, and to determine the most useful radiographic views for clinical purposes and analysis of the surgical principle. Lateral radiographs of patients in flexion and extension are widely used to obtain quantitative and qualitative data on lumbar spondylolisthesis. Changes in lumbar disc height and segmental translation in a group of patients with spondylolisthesis have been demonstrated with the addition of traction and compression. Lateral and flexion extension radiographs of the lumbosacral spine in 37 patients with spondylolisthesis taken in standing and recumbent positions and under pelvic traction in the prone or supine positions were suitable for analysis. The changes in disc area, intervertebral kyphotic slip angle, and amount of anteroposterior shift (olisthesis) were measured from the radiographs using a computer digitizer. The disc area was normalized against the area of the superior vertebra, and the amount of anteroposterior shift was normalized against the anteroposterior width of the superior vertebra. Inter- and intraobserver error was found to be negligible, and results were analyzed by paired t test. Maximum slip angle, maximum olisthesis, and minimum normalized disc area were found with the subject under erect flexion. Conversely, prone traction and recumbent extension produced minimum slip angle, whereas the lowest anteroposterior shifts were seen with the subject under prone and supine traction. Prone traction also resulted in a significantly larger normalized disc area than any other posture. The change in kyphotic slip angle between erect flexion and prone traction is correlated with the change in normalized olisthesis and disc area. Erect flexion and prone traction radiographs represent the extremes of subluxation and reduction of the olisthesis, respectively, and the change in olisthesis seen between these extremes is correlated with the change in disc area and the intervertebral slip angle. Vertical laxity of the affected functional spinal unit resulting from disc degeneration produces laxity in the ligaments and disc anulus, allowing olisthetic motion. Restoration of disc height in turn restores tension to the soft tissues around the disc and results in a spontaneous reduction of the subluxation. Restoration and maintenance of disc height with a spacer or interbody fusion therefore is recommended as a goal in the treatment of spondylolisthesis. When spondylolytic spondylolisthesis involves a posterior column deficiency, additional reconstruction of this column with posterior instrumentation is recommended. Application of the traction radiographic technique in planning for spondylolisthesis reduction is discussed along with the technique of stabilization.


Preservation of passive constructions in a patient with primary progressive aphasia.
Research into agrammatic comprehension in English has described a pattern of impaired understanding of passives and retained ability on active constructions. Some accounts of this dissociation predict that patients who are unable to comprehend actives will also be impaired in the comprehension of passives. We report the case of a man with primary progressive aphasia (PPA) (WR), whose comprehension was at chance on active sentences, but at ceiling on passives. In a series of reversible sentence comprehension tests WR displayed difficulties with active transitives and truncated actives with an auxiliary. In passive sentences, he displayed sensitivity to the agent marker by, as well as the passive morphology of the verb. This pattern of dissociation challenges current theories of agrammatic comprehension. We explore explanations based on the distinction between morphological and configurational cues, as well as on the semantic and discourse related differences between active and passive constructions.


The current status and the future of JAK2 inhibitors for the treatment of myeloproliferative diseases.
Janus kinases (JAKs) are critical components of cytokine signaling pathways which regulate immunity, inflammation, hematopoiesis, growth, and development. The recent discovery of JAK2-activating mutations as a causal event in the majority of patients with Philadelphia chromosome negative (Ph-) myeloproliferative disorders (MPDs) prompted many pharmaceutical companies to develop JAK2-selective inhibitors for the treatment of MPDs. JAK2 inhibitors effectively reduce JAK2-driven phosphorylation of signal transducer and activator of transcription 5, and cell proliferation and cell survival in JAK2-activated cells in vitro and in vivo. Most inhibitors are currently being evaluated in patients with one form of MPD, myelofibrosis. Patients treated with these inhibitors experienced a rapid reduction of splenomegaly, significant improvement of constitutional symptoms, and increased daily activity with few adverse events. A partial reduction of JAK2V617F disease burden during the treatment with JAK2 inhibitors was also observed. The inhibitors appear to have a therapeutic benefit in the treatment of these disorders. The results of ongoing clinical trials will allow further evaluation of clinical benefits and safety of these compounds. In this review, the authors summarize the status of JAK2 inhibitors in development and discuss their benefits and challenges.


Signatures of a quantum diffusion limited hydrogen atom tunneling reaction.
We are studying the details of hydrogen atom (H atom) quantum diffusion in highly enriched parahydrogen (pH2) quantum solids doped with chemical species in an effort to better understand H atom transport and reactivity under these conditions. In this work we present kinetic studies of the 193 nm photo-induced chemistry of methanol (CH3OH) isolated in solid pH2. Short-term irradiation of CH3OH at 1.8 K readily produces CH2O and CO which we detect using FTIR spectroscopy. The in situ photochemistry also produces CH3O and H atoms which we can infer from the post-photolysis reaction kinetics that display significant CH2OH growth. The CH2OH growth kinetics indicate at least three separate tunneling reactions contribute; (i) reactions of photoproduced CH3O with the pH2 host, (ii) H atom reactions with the CH2O photofragment, and (iii) long-range migration of H atoms and reaction with CH3OH. We assign the rapid CH2OH growth to the following CH3O + H2 → CH3OH + H → CH2OH + H2 two-step sequential tunneling mechanism by conducting analogous kinetic measurements using deuterated methanol (CD3OD). By performing photolysis experiments at 1.8 and 4.3 K, we show the post-photolysis reaction kinetics change qualitatively over this small temperature range. We use this qualitative change in the reaction kinetics with temperature to identify reactions that are quantum diffusion limited. While these results are specific to the conditions that exist in pH2 quantum solids, they have direct implications on the analogous low temperature H atom tunneling reactions that occur on metal surfaces and on interstellar grains.


The Magnaporthe oryzae nitrooxidative stress response suppresses rice innate immunity during blast disease.
Understanding how microorganisms manipulate plant innate immunity and colonize host cells is a major goal of plant pathology. Here, we report that the fungal nitrooxidative stress response suppresses host defences to facilitate the growth and development of the important rice pathogen Magnaporthe oryzae in leaf cells. Nitronate monooxygenases encoded by NMO genes catalyse the oxidative denitrification of nitroalkanes. We show that the M. oryzae NMO2 gene is required for mitigating damaging lipid nitration under nitrooxidative stress conditions and, consequently, for using nitrate and nitrite as nitrogen sources. On plants, the Δnmo2 mutant strain penetrated host cuticles like wild type, but invasive hyphal growth in rice cells was restricted and elicited plant immune responses that included the formation of cellular deposits and a host reactive oxygen species burst. Development of the M. oryzae effector-secreting biotrophic interfacial complex (BIC) was misregulated in the Δnmo2 mutant. Inhibiting or quenching host reactive oxygen species suppressed rice innate immune responses and allowed the Δnmo2 mutant to grow and develop normally in infected cells. NMO2 is thus essential for mitigating nitrooxidative cellular damage and, in rice cells, maintaining redox balance to avoid triggering plant defences that impact M. oryzae growth and BIC development.


Production of podophyllotoxin from Podophyllum hexandrum: a potential natural product for clinically useful anticancer drugs.
Podophyllum hexandrum Royle of family Berberidaceae is an endangered medicinal plant. Rhizome ofP.hexandrum contains several lignans which posses antitumor activity. Podphyllotoxin is the most active cytotoxic natural product. It is used as starting compound for the synthesis of anticancer drug etoposide and teniposide. Podophyllotoxin acts as an inhibitor of microtubule assembly. These drugs are used for lung cancer, testicular cancer, neuroblastoma, hepatoma and other tumors. Besides this, it also shows antiviral activities by interfering with some critical viral processes. Availabilityof podophyllotoxin from plants has its limitations because of its intense collection from nature and lack of organized cultivation. The chemical synthesis of podophyllotoxin is considered to be very complicated as yet. The use of biotechnological approaches for the production of podophyllotoxin using cell cultures, organ cultures, and biotransformation route or by manipulating biosynthetic pathway proves to be an attractive alternative for production of podophyllotoxin. The present paper discusses the current status of research, limitations and future prospects for theproduction of podophyllotoxinin vitro.


Perception of suprathreshold naturalistic changes in colored natural images.
Simple everyday tasks, such as visual search, require a visual system that is sensitive to differences. Here we report how observers perceive changes in natural image stimuli, and what happens if objects change color, position, or identity-i.e., when the external scene changes in a naturalistic manner. We investigated whether a V1-based difference-prediction model can predict the magnitude ratings given by observers to suprathreshold differences in numerous pairs of natural images. The model incorporated contrast normalization and surround suppression, and elongated receptive-fields. Observers' ratings were better predicted when the model included phase invariance, and even more so when the stimuli were inverted and negated to lessen their semantic impact. Some feature changes were better predicted than others: the model systematically underpredicted observers' perception of the magnitude of blur, but over-predicted their ability to report changes in textures.


Identifying barriers to culture change: A qualitative analysis of the obstacles to delivering resident-centered care.
A growing number of healthcare organizations have moved from traditional, institutional nursing home models to ones that emphasize culture change, or resident-centered care (RCC). In 2006, the Department of Veterans Affairs (VA) began implementing a number of changes to VA nursing homes, now called Community Living Centers (CLCs), to provide veterans with a more resident-centered and homelike environment. This study aimed to understand the barriers CLC staff face when delivering RCC. Ten CLCs were included on the basis of their performance levels on RCC and quality of care. Semistructured interviews that focused on facility efforts in RCC and quality were conducted with all levels of staff. Interviews were systematically content coded. We found similarities and differences in barriers reported at high- and low-performing sites. Staff across all performance levels cited 5 main categories of barriers to delivering RCC: staffing, resources, acuity of residents, RCC and quality of care conflicts, and regulations. Staff in high-performing sites reported fewer barriers to RCC, although 1 barrier cited was difficulty coordinating RCC across departments. Staff in low-performing sites reported additional categories of barriers related to administrator turnover/lack of guidance, CLC culture/staff morale, and difficulty working with residents and families. As RCC continues to spread, it is important to anticipate the barriers to implementing these practices. Particular focus on regulatory, leadership, organizational, workforce, and process factors may help organizations avoid or reduce barriers to RCC. Given their training and skill set, mental health providers may be uniquely situated to assist staff in overcoming these barriers. (PsycINFO Database Record


Defining Core Competencies for Epidemiologists in Academic Settings to Tackle Tomorrow's Health Research Challenges: A Structured, Multinational Effort.
Only a few efforts have been made to define core competencies for epidemiologists working in academic settings. Here we describe a multinational effort to define competencies for epidemiologists, who are increasingly facing emerging and potentially disruptive technological and societal health trends in academic research. During a 1.5-year period (2017-2019), we followed an iterative process that aimed to be inclusive and multinational to reflect the various perspectives of a diverse group of epidemiologists. Competencies were developed by a consortium in a consensus-oriented process that spanned 3 main activities: 2 in-person interactive meetings held in Amsterdam, the Netherlands, and Zurich, Switzerland, and an online survey. In total, 93 meeting participants from 16 countries and 173 respondents from 19 countries contributed to the development of 31 competencies. These 31 competencies included 14 on "developing a scientific question" and "study planning," 12 on "study conduct and analysis," 3 on "overarching competencies," and 2 on "communication and translation." The process described here provides a consensus-based framework for defining and adapting the field. It should initiate a continuous process of thinking about competencies and the implications for teaching epidemiology to ensure that epidemiologists working in academic settings are well prepared for today's and tomorrow's health research.