Herpesviral replication compartments move and coalesce at nuclear speckles to enhance export of viral late mRNA.
The role of the intranuclear movement of chromatin in gene expression is not well-understood. Herpes simplex virus forms replication compartments (RCs) in infected cell nuclei as sites of viral DNA replication and late gene transcription. These structures develop from small compartments that grow in size, move, and coalesce. Quantitative analysis of RC trajectories, derived from 4D images, shows that most RCs move by directed motion. Directed movement is impaired in the presence of actin and myosin inhibitors as well as a transcription inhibitor. In addition, RCs coalesce at and reorganize nuclear speckles. Lastly, distinct effects of actin and myosin inhibitors on viral gene expression suggest that RC movement is not required for transcription, but rather, movement results in the bridging of transcriptionally active RCs with nuclear speckles to form structures that enhance export of viral late mRNAs.


Studies in polyphenol chemistry and bioactivity. 4.(1) Synthesis of trimeric, tetrameric, pentameric, and higher oligomeric epicatechin-derived procyanidins having all-4beta,8-interflavan connectivity and their inhibition of cancer cell growth through cell cycle arrest.
We report an improved synthesis of bis(5,7,3',4'-tetra-O-benzyl)epicatechin 4beta,8-dimer (3) from 5,7,3',4'-tetra-O-benzylepicatechin (1) and 5,7,3',4'-tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin (2) by replacing the previously employed Lewis acid, titanium tetrachloride, with the clay mineral Bentonite K-10. Under the same conditions, the benzyl-protected all-4beta,8-trimer, -tetramer, and -pentamer were obtained regioselectively from their lower homologues, albeit in rapidly decreasing yields. Reaction of 2 with an organoaluminum thiolate generated from 2-mercaptobenzothiazole and trimethylaluminum followed by acetylation produced 3-O-acetyl-4-[(2-benzothiazolyl)thio]-5,7,3',4'-tetra-O-benzylepicatechin (12). Medium-sized protected oligomers with 4beta,8-interflavan linkages are obtained in improved yields by using this compound as the electrophile and silver tetrafluoroborate as activator and are isolated by reversed-phase HPLC. Their deprotection by ester saponification followed by hydrogenolysis yielded the free procyanidins, which were characterized as their peracetates. The synthetic procyanidins are identical by normal-phase HPLC with fractions isolated from cocoa. The principle of chain extension by two members was demonstrated using a dimeric electrophile obtained by self-condensation of compound 12. Both the synthetic and natural pentamer 32 inhibit the growth of several breast cancer cell lines. Using the MDA MB 231 line, it was established that this outcome is based on the induction of cell cycle arrest in the G0/G1 phase. Subsequent cell death is more likely necrotic rather than apoptotic. Control experiments demonstrate that the polyphenol itself, rather than hydrogen peroxide potentially formed by its autoxidation, is the causative agent.


Pelvic floor involvement in male and female sexual dysfunction and the role of pelvic floor rehabilitation in treatment: a literature review.
The sphincteric and supportive functions of the pelvic floor are fairly well understood, and pelvic floor rehabilitation, a specialized field within the scope and practice of physical therapy, has demonstrated effectiveness in the treatment of urinary and fecal incontinence. The role of the pelvic floor in the promotion of optimal sexual function has not been clearly elucidated. To review the role of the pelvic floor in the promotion of optimal sexual function and examine the role of pelvic floor rehabilitation in treating sexual dysfunction. Review of peer-reviewed literature. It has been proposed that the pelvic floor muscles are active in both male and female genital arousal and orgasm, and that pelvic floor muscle hypotonus may impact negatively on these phases of function. Hypertonus of the pelvic floor is a significant component of sexual pain disorders in women and men. Furthermore, conditions related to pelvic floor dysfunction, such as pelvic pain, pelvic organ prolapse, and lower urinary tract symptoms, are correlated with sexual dysfunction. The involvement of the pelvic floor in sexual function and dysfunction is examined, as well as the potential role of pelvic floor rehabilitation in treatment. Further research validating physical therapy intervention is necessary.


Molecular dynamics simulations of a K+ channel blocker: Tc1 toxin from Tityus cambridgei.
Toxins that block voltage-gated potassium (Kv) channels provide a possible template for improved homology models of the Kv pore. In assessing the interactions of Kv channels and their toxins it is important to determine the dynamic flexibility of the toxins. Multiple 10 ns duration molecular dynamics simulations combined with essential dynamics analysis have been used to explore the flexibility of four different Kv channel-blocking toxins. Three toxins (Tc1, AgTx and ChTx) share a common fold. They also share a common pattern of conformational dynamics, as revealed by essential dynamics analysis of the simulation results. This suggests that some aspects of dynamic behaviour are conserved across a single protein fold class. In each of these three toxins, the residue exhibiting minimum flexibility corresponds to a conserved lysine residue that is suggested to interact with the filter domain of the channel. Thus, comparative simulations reveal functionally important conservation of molecular dynamics as well as protein fold across a family of related toxins.


Clomiphene citrate potentiates the adverse effects of estrogen on rat testis and down-regulates the expression of steroidogenic enzyme genes.
To investigate the antiestrogenic effect of clomiphene citrate (CC) in male rats estrogenized with estradiol-3-benzoate (EB). Prospective experimental study. Laboratory. Adult male albino rats (Holtzman strain). CC was given alone or in combination with EB. Testicular function and steroidogenic enzyme gene expression were evaluated in control versus treated groups. EB after 30 days of treatment induced a rise in TUNEL-positive germ cells adversely affecting spermatogenesis with complete absence of elongated spermatids or sperms. CC alone had only a moderate effect. In contrast, CC+EB synergistically inflicted more adverse effects as apoptotic germ cells per tubule rose further. Significant down-regulation in expression of testicular steroidogenic enzyme genes StAR, p450scc, 3β-HSD, and p450c17 was observed. In the EB-alone group, aromatase gene expression in the testis was up-regulated but reversed in brain and liver tissues. CC alone had little modulatory effect on aromatase expression. On the other hand, CC+EB countered the EB-induced rise of aromatase expression in the testis. The above findings indicate that CC in the presence of estrogen synergistically potentiates more adverse effects in testis, inhibiting expression of upstream steroidogenic enzyme genes and leading to disruption of steroidogenesis.


Risperidone versus typical antipsychotic medication for schizophrenia.
Risperidone is one of the 'new generation' antipsychotics. As well as its reputed tendency to cause fewer movement disorders than the older drugs such as chlorpromazine and haloperidol, it is claimed that risperidone may improve negative symptoms. To evaluate the effects of risperidone for schizophrenia in comparison to 'conventional' neuroleptic drugs. The original electronic searches of Biological Abstracts (1980-1997), Cochrane Schizophrenia Group's Register (1997), The Cochrane Library (1997, Issue 1), EMBASE (1980-1997), MEDLINE (1966-1997), PsycLIT (1974-1997), and SCISEARCH (1997) were updated with a new electronic search of the same databases in 2002. The search term used in the update was identical to that used in 1997. Any new studies or relevant references were added to the review. In addition, references of all identified studies were searched for further trial citations. Pharmaceutical companies and authors of trials were also contacted. All randomised trials comparing risperidone to any 'conventional' neuroleptic treatment for people with schizophrenia or other similar serious mental illnesses. Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were also independently extracted. Where possible, sensitivity analyses on dose of risperidone, haloperidol and duration of illness were undertaken for the primary outcomes of clinical improvement, side effects (movement disorders) and acceptability of treatment. For homogeneous dichotomous data the Relative Risk (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat/harm (NNT/H) were calculated on an intention-to-treat basis. In the short-term, risperidone was more likely to produce an improvement in the Positive and Negative Syndrome Scale (PANSS) when compared with haloperidol (n=2368, 9 RCTs, RR not 20% improved 0.72 CI 0.59 to 0.88 NNT 8). A similar, favourable outcome for risperidone was found in long-term studies (n=859, 2RCTs RR not 20% improved 0.51 CI 0.38 to 0.67 NNT 4;n=675 1RCT, RR not improved 40% 0.75 CI 0.66 to 0.84 NNT 5; n=675, 1 RCT, RR not 60% improved 0.90 CI 0.84 to 0.96, NNT 11). Risperidone was also more likely to reduce relapse at one year follow up, compared with haloperidol (n=367, 1 RCT, RR 0.64 CI 0.41 to 0.99, NNT 7). Less people allocated risperidone left studies before completion, both for short-term (n=3066, 16 RCTs, RR 0.76 CI 0.63 to 0.92, NNT 6) and long-term trials (n=1270, 4RCTs, RR 0.55 CI 0.42 to 0.73 NNT 4). For general movement disorders results favoured risperidone. People given risperidone had significantly fewer general movement disorders (including extrapyramidal side effects) than those receiving older typical antipsychotics (n=2702, 10 RCTs, RR 0.63 CI 0.56 to 0.71, NNT 3). Significantly fewer people given risperidone used antiparkinsonian drugs (n=2524, 11 RCTs, RR 0.66 CI 0.58 to 0.74, NNT 4). As regards body weight, however, four studies (n=1708) found people were more likely to gain weight if allocated risperidone compared to typical antipsychotics (RR 1.55 CI 1.25 to 1.93, NNH 3). Risperidone was no more or less likely than haloperidol to cause sexual problems such as erectile dysfunction (n=106, 2 RCTs, RR 1.55 CI 0.58 to 4.20). Finally, some results found risperidone was more likely to cause rhinitis than conventional antipsychotics (n=656, 3 RCTs, RR1.99 CI 1.24 to 3.19, NNH 3). Risperidone may be more acceptable to those with schizophrenia than older antipsychotics and have marginal benefits in terms of limited clinical improvement. Its adverse effect profile may be better than haloperidol. With the addition of more studies to this review, the publication bias evident in previous versions is no longer a significant issue. Any marginal benefits this drug may have have to be balanced against its greater cost and increased tendency to cause side effects such as weight gain. Recent important longer term data favouring risperidone's effect on relapse needs to be replicated by researchers independently of the manufacturers of the drug.


Thalassorhabdomicrobium marinisediminis gen. nov., sp. nov., a member of the family Hyphomonadaceae isolated from the Bohai Sea.
A novel Gram-stain-negative bacterium, designated strain BH-SD16T, was isolated from a marine sediment sample collected in the Bohai Sea. Cells of strain BH-SD16T are aerobic, non-flagellated oval-shaped rods, showing oxidase- and catalase-positive activities. Growth occurs between 15-45 °C (optimum, 30 °C), at pH 6.0-9.0 (pH 7.0-7.5) and with 1-10 % (w/v) NaCl (3.0 %). Strain BH-SD16T contains C18 : 1ω7c (49.2 %), C16 : 0 (17.7 %) and C18 : 1ω7c 11-methyl (16.6 %) as the predominant fatty acids and ubiquinone-10 as the major respiratory quinone. The major polar lipids comprise phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, diphosphatidylglycerol and two glycolipids. The size of the draft genome is 3 442 538 bp, including 3213 protein-coding genes, 40 tRNA genes and three rRNA genes, and the DNA G+C content is 63.4 mol%. Strain BH-SD16T shows the highest 16S rRNA gene sequence similarity to Pseudooctadecabacter jejudonensis (95.7 %), strains of the genus Octadecabacter(95.4-95.6 %) and strains of the genus Loktanella(93.8-95.4 %). Phylogenetic trees based on 16S rRNA gene sequences show that strain BH-SD16T forms a distinct lineage within the family Hyphomonadaceae, which is also confirmed in the multigenic phylogenetic tree calculated by RAxML. Based on the results of phenotypic, chemotaxonomic and phylogenetic analysis, strain BH-SD16T is considered to represent a novel genus and species in the family Hyphomonadaceae, for which the name Thalassorhabdomicrobium marinisediminis gen. nov., sp. nov. is proposed. The type strain is BH-SD16T (=CCTCC AB 2017073T=KCTC 62201T).


Cryptococcus gattii VGIII isolates causing infections in HIV/AIDS patients in Southern California: identification of the local environmental source as arboreal.
Ongoing Cryptococcus gattii outbreaks in the Western United States and Canada illustrate the impact of environmental reservoirs and both clonal and recombining propagation in driving emergence and expansion of microbial pathogens. C. gattii comprises four distinct molecular types: VGI, VGII, VGIII, and VGIV, with no evidence of nuclear genetic exchange, indicating these represent distinct species. C. gattii VGII isolates are causing the Pacific Northwest outbreak, whereas VGIII isolates frequently infect HIV/AIDS patients in Southern California. VGI, VGII, and VGIII have been isolated from patients and animals in the Western US, suggesting these molecular types occur in the environment. However, only two environmental isolates of C. gattii have ever been reported from California: CBS7750 (VGII) and WM161 (VGIII). The incongruence of frequent clinical presence and uncommon environmental isolation suggests an unknown C. gattii reservoir in California. Here we report frequent isolation of C. gattii VGIII MATα and MATa isolates and infrequent isolation of VGI MATα from environmental sources in Southern California. VGIII isolates were obtained from soil debris associated with tree species not previously reported as hosts from sites near residences of infected patients. These isolates are fertile under laboratory conditions, produce abundant spores, and are part of both locally and more distantly recombining populations. MLST and whole genome sequence analysis provide compelling evidence that these environmental isolates are the source of human infections. Isolates displayed wide-ranging virulence in macrophage and animal models. When clinical and environmental isolates with indistinguishable MLST profiles were compared, environmental isolates were less virulent. Taken together, our studies reveal an environmental source and risk of C. gattii to HIV/AIDS patients with implications for the >1,000,000 cryptococcal infections occurring annually for which the causative isolate is rarely assigned species status. Thus, the C. gattii global health burden could be more substantial than currently appreciated.


Responses to Financial Loss During the Great Recession: An Examination of Sense of Control in Late Midlife.
The "Great Recession" shocked the primary institutions that help individuals and families meet their needs and plan for the future. This study examines middle-aged adults' experiences of financial loss and considers how socioeconomic and interpersonal resources facilitate or hinder maintaining a sense of control in the face of economic uncertainty. Using the 2006 and 2010 waves of the Health and Retirement Study, change in income and wealth, giving help to and receiving help from others, household complexity, and sense of control were measured among middle-aged adults (n = 3,850; age = 51-60 years). Socioeconomic resources predicted both the level of and change in the engagement of interpersonal resources prior to and during the Great Recession. Experiences of financial loss were associated with increased engagement of interpersonal resources and decreased sense of control. The effect of financial loss was dampened by education. Sense of control increased with giving help and decreased with household complexity. Findings suggest that, across socioeconomic strata, proportional loss in financial resources resulted in a loss in sense of control. However, responses to financial loss differed by socioeconomic status, which differentiated the ability to maintain a sense of control following financial loss.


Human HLA-Ev (147) Expression in Transgenic Animals.
In our previous study, we reported on the development of substituting S147C for HLA-E as a useful gene tool for xenotransplantation. In this study we exchanged the codon of HLA-Ev (147), checked its function, and established a line of transgenic mice. A new construct, a codon exchanging human HLA-Ev (147) + IRES + human beta 2-microgloblin, was established. The construct was subcloned into pCXN2 (the chick beta-actin promoter and cytomegalovirus enhancer) vector. Natural killer cell- and macrophage-mediated cytotoxicities were performed using the established the pig endothelial cell (PEC) line with the new gene. Transgenic mice with it were next produced using a micro-injection method. The expression of the molecule on PECs was confirmed by the transfection of the plasmid. The established molecules on PECs functioned well in regulating natural killer cell-mediated cytotoxicity and macrophage-mediated cytotoxicity. We have also successfully generated several lines of transgenic mice with this plasmid. The expression of HLA-Ev (147) in each mouse organ was confirmed by assessing the mRNA. The chick beta-actin promoter and cytomegalovirus enhancer resulted in a relatively broad expression of the gene in each organ, and a strong expression in the cases of the heart and lung. A synthetic HLA-Ev (147) gene with a codon usage optimized to a mammalian system represents a critical factor in the development of transgenic animals for xenotransplantation.


Effect of dance therapy on blood pressure and exercise capacity of individuals with hypertension: A systematic review and meta-analysis.
Dance therapy is a less conventional modality of physical activity in cardiovascular rehabilitation. We performed a systematic review and meta-analysis to investigate the effects of dance therapy in hypertensive patients. Pubmed, Scopus, LILACS, IBECS, MEDLINE and SciELO via Virtual Health Library (Bireme) (from the earliest data available to February 2016) for controlled trials that investigated the effects of dance therapy on exercise capacity, systolic (SBP) and diastolic (DBP) blood pressure in hypertensive patients. Weighted mean differences (WMD) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed using the I(2) test. Four studies met the eligibility criteria. Dance therapy resulted in a significant reduction in systolic blood pressure (WMD -12.01mmHg; 95% CI: -16.08, -7.94mmHg; P<0.0001) when compared with control subjects. Significant reduction in diastolic blood pressure were also found (WMD -3.38mmHg; 95% CI: -4.81, -1.94mmHg; P<0.0001), compared with control group. Exercise capacity showed a significant improvement (WMD 1.31; 95% CI: 0.16, 2.47; P<0.03). A moderate to high heterogeneity was observed in our analysis: I(2)=92% to SBP, I(2)=55% to DBP, and I(2)=82% to exercise capacity. Our meta-analysis showed a positive effect of dance therapy on exercise capacity and reduction of SBP and DBP in individuals with hypertension. However, the moderate to high heterogeneity found in our analysis limits a pragmatic recommendation of dance therapy in individuals with hypertension.


Rapid cytotoxicity of human B lymphocytes induced by VH4-34 (VH4.21) gene-encoded monoclonal antibodies, II.
We have previously described complement-independent killing of human B lymphocytes by two IgM MoAbs derived from the VH4-34 (VH4.21) gene. Analysis of 17 independently derived VH4-34-encoded MoAbs shows that B cell toxicity is not limited to the two described MoAbs, but is a general property shared by a subset of MoAbs derived from the VH4-34 gene. As observed by two independent microscopy techniques, giant membrane pores were formed on target B cells within 10-15 min of exposure to cytotoxic VH4-34-derived MoAbs. Toxicity by individual MoAb correlated directly to its B cell binding intensity measured by FACS, i.e. stronger the binding greater the killing. Sequence analysis showed that V(H) region in germ-line or in near germ-line configuration was necessary but not sufficient for B cell binding. In addition, a particular sequence motif enriched in basic amino acids in the CDR3 may be required to supplement the reactivity mediated by the V(H) region of the MoAb molecule. VH4-34-encoded antibodies that fulfil the above sequence requirements have cold agglutinin activity towards the i antigen of cord erythrocytes. In vivo, such anti-i/anti-B cell antibodies are rarely detected in healthy adults, but serum levels are dramatically elevated in selective pathological conditions, such as systemic lupus erythematosus and infectious mononucleosis. This strict regulation may be related to the novel and rapid mechanism of human B cell toxicity demonstrated by antibodies encoded by a single human V(H) gene.


Revisiting the Persisting Tension Between Expert and Lay Views About Brain Death and Death Determination: A Proposal Inspired by Pragmatism.
Brain death or determination of death based on the neurological criterion has been an enduring source of controversy in academic and clinical circles. The controversy chiefly concerns how death is defined, and it also bears on the justification of the proposed criteria for death determination and their interpretation. Part of the controversy on brain death and death determination stems from disputed crucial medical facts, but in this paper I formulate another hypothesis about the nature of ongoing controversies. At stake is a misunderstood relationship between, on the one hand, the nature of our lay (or our "manifest image") views about death and, on the other hand, the nature of scientific insights (and related conceptual refinements) into death and its determination (the "scientific image"). The misunderstanding of this relationship has partly anchored the controversy and continues to fuel it. Based on a perspective inspired by pragmatism, which stresses the positive contribution of science to ethical and policy debates but also challenges different forms of scientism in science and philosophy found in foundationalist interpretations, I scrutinize three different stances regarding the relationship between lay and scientific perspectives about the definition of death: (1) foundational lay views, (2) foundational expert views, and (3) co-evolving views. I argue that only the latter is sustainable given recent challenges to foundationalist interpretations.


Are modern health worries associated with medical conspiracy theories?
This study was concerned with whether Medical Conspiracy Theories (MCTs), along with other variables (demographics, ideology and health perceptions) are associated with Modern Health Worries (MHWs). MCTs were significantly associated with MHWs over and above all other variables. Older individuals, with more religious and right-wing beliefs had higher MHWs. In addition, those who used Complementary and Alternative Medicine (CAM) and individuals who perceived their mental health as worse than their peers were also more likely to display higher MHWs. Implications for helping health professions understand their patients' health-related beliefs and choices were discussed.


Clinical and structural results of arthroscopic repair of isolated subscapularis tear.
Even though the frequency of arthroscopic repair of isolated lesions of the subscapularis tendon has increased, few studies have presented clinical and anatomical outcomes of this treatment. We hypothesized that, after an arthroscopic repair, structural outcomes in the muscle have an influence on functional results. A retrospective study was performed on twenty-two patients who had undergone arthroscopic repair of an isolated tear of the subscapularis tendon and had a mean follow-up of thirty-six months. Patients were evaluated preoperatively and postoperatively with use of the Constant-Murley score, a subjective shoulder value, the lift-off test, the belly-press test, and magnetic resonance imaging or computed tomography arthrography. The results were compared with those of a cohort of thirteen patients who underwent open repair of the subscapularis tendon tear. In the arthroscopic group, the Constant-Murley score improved from a mean of 66 points preoperatively to a mean of 85 points postoperatively (p < 0.05). The subscapularis tendon was healed in 86% of the patients. Three patients (14%) had a partial rupture limited to the superior tendon. Postoperatively, progression of fatty infiltration of the subscapularis muscle was observed in 55% of the patients. Ten patients (45%) had a severe but localized fatty infiltration area of the subscapularis muscle related to the larger tears. Subjective and functional outcomes were not influenced by tendon-healing or postoperative fatty infiltration (p > 0.05). Clinical testing was significantly improved, but incomplete corrections remained frequent. Although open repair resulted in higher subjective shoulder scores and better strength scores, most other clinical parameters, postoperative subscapularis testing results, and structural outcomes were comparable between the arthroscopic repair and the open repair group. Arthroscopic repair of isolated subscapularis tears was associated with improved shoulder function and improved results on clinical testing. The tendon-healing rate was high but resulted in incomplete correction of the results of clinical testing. Progression of fatty infiltration in the subscapularis muscle was observed on magnetic resonance imaging but did not influence the clinical outcomes.


FT-IR- and Raman-based biochemical profiling of the early stage of pulmonary metastasis of breast cancer in mice.
The combination of FT-IR and Raman spectroscopies allowed the biochemical profiling of lungs in the early stage of pulmonary metastasis in the murine model of breast cancer. Histological staining was used as a reference. Raman spectroscopy was especially useful in the detection and semi-quantitative analysis of the vitamin A content in lung lipofibroblasts, whereas the IR technique provided semi-quantitative information on the contents of nucleic acids, carbohydrates including glycogen, and lipids as well as changes in the secondary structures of tissue proteins. Our spectroscopic results suggest that the early phase of metastasis in the lung is characterized by a decrease in the endogenous retinoid content in combination with a decrease in the content of glycogen and lipids.


Integrative Analysis Identifies Candidate Tumor Microenvironment and Intracellular Signaling Pathways that Define Tumor Heterogeneity in NF1.
Neurofibromatosis type 1 (NF1) is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, whereas 40-60% of patients develop plexiform neurofibromas (pNFs), which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions.


Reagent and laboratory contamination can critically impact sequence-based microbiome analyses.
The study of microbial communities has been revolutionised in recent years by the widespread adoption of culture independent analytical techniques such as 16S rRNA gene sequencing and metagenomics. One potential confounder of these sequence-based approaches is the presence of contamination in DNA extraction kits and other laboratory reagents. In this study we demonstrate that contaminating DNA is ubiquitous in commonly used DNA extraction kits and other laboratory reagents, varies greatly in composition between different kits and kit batches, and that this contamination critically impacts results obtained from samples containing a low microbial biomass. Contamination impacts both PCR-based 16S rRNA gene surveys and shotgun metagenomics. We provide an extensive list of potential contaminating genera, and guidelines on how to mitigate the effects of contamination. These results suggest that caution should be advised when applying sequence-based techniques to the study of microbiota present in low biomass environments. Concurrent sequencing of negative control samples is strongly advised.


Temporal Considerations for Stimulating Spiral Ganglion Neurons with Cochlear Implants.
A wealth of knowledge about different types of neural responses to electrical stimulation has been developed over the past 100 years. However, the exact forms of neural response properties can vary across different types of neurons. In this review, we survey four stimulus-response phenomena that in recent years are thought to be relevant for cochlear implant stimulation of spiral ganglion neurons (SGNs): refractoriness, facilitation, accommodation, and spike rate adaptation. Of these four, refractoriness is the most widely known, and many perceptual and physiological studies interpret their data in terms of refractoriness without incorporating facilitation, accommodation, or spike rate adaptation. In reality, several or all of these behaviors are likely involved in shaping neural responses, particularly at higher stimulation rates. A better understanding of the individual and combined effects of these phenomena could assist in developing improved cochlear implant stimulation strategies. We review the published physiological data for electrical stimulation of SGNs that explores these four different phenomena, as well as some of the recent studies that might reveal the biophysical bases of these stimulus-response phenomena.


Binding of DDT to lecithin.
An interaction between DDT and lecithin is indicated by the reciprocal effects of each compound on the proton magnetic resonance spectrum of the other. The phosphoryl choline moiety of the lecithin and the benzylic proton of the DDT seem to be involved. The most pronounced response in the proton magnetic resonance spectrum of the lecithin produced by increasing concentration s of DDT was a change in the chemical shift of the resonance peak due to the protons of the choline methyl groups. Increasing concentrations of lecithin produced changes in the chemical shift of the resonance peaks of the benzylic proton and adjacent ring protons of the DDT. Equilibrium constant of 0.597 +/-0.015 molal(-1) was obtained for this interaction.


[The influence of parental healthy behaviors on healthy lifestyles of early adolescents].
Family behavior models may influence health promoting conducts among adolescents. To determine the association between health promoting behaviors among parents and healthy behaviors of early adolescents. Analysis of the baseline assessment of a longitudinal study of early adolescents in the city of San Felipe, Region of Valparaiso, Chile. Parents and their teenage children, attending 5th to 7th grade, from ten municipal schools, participated in this study. Self-reported questionnaires were used to assess healthy lifestyles, answered separately by parents and their children. Univariable and multivariable ordinal logistic regression analyses with complete data were carried out, using the students' health promoting behaviors as dependent variables and the same behaviors among parents as the main predictors, controlling for other personal and family variables. We contacted 1,035 parents and 682 consented to participate along with 560 students. The mean age of adolescents was 11.5 ± 1.2 years (49% females) The mean age of parents was 39.8 ± 8.8 years and 90% were women. The parental behaviors associated with teenage health promoting behaviors were eating vegetables (odds ratio (OR) = 1.22, p < 0.05), having breakfast (OR = 1.27, p < 0.05), do stretching exercises every day (OR = 1.19, p < 0.05) and take some time for relaxation (OR = 1.24, p < 0.05). These results show an association between healthy behaviors among parents and these behaviors among their adolescent offspring.


Do Children With Developmental Language Disorder Activate Scene Knowledge to Guide Visual Attention? Effect of Object-Scene Inconsistencies on Gaze Allocation.
Our visual environment is highly predictable in terms of where and in which locations objects can be found. Based on visual experience, children extract rules about visual scene configurations, allowing them to generate scene knowledge. Similarly, children extract the linguistic rules from relatively predictable linguistic contexts. It has been proposed that the capacity of extracting rules from both domains might share some underlying cognitive mechanisms. In the present study, we investigated the link between language and scene knowledge development. To do so, we assessed whether preschool children (age range = 5;4-6;6) with Developmental Language Disorder (DLD), who present several difficulties in the linguistic domain, are equally attracted to object-scene inconsistencies in a visual free-viewing task in comparison with age-matched children with Typical Language Development (TLD). All children explored visual scenes containing semantic (e.g., soap on a breakfast table), syntactic (e.g., bread on the chair back), or both inconsistencies (e.g., soap on the chair back). Since scene knowledge interacts with image properties (i.e., saliency) to guide gaze allocation during visual exploration from the early stages of development, we also included the objects' saliency rank in the analysis. The results showed that children with DLD were less attracted to semantic and syntactic inconsistencies than children with TLD. In addition, saliency modulated syntactic effect only in the group of children with TLD. Our findings indicate that children with DLD do not activate scene knowledge to guide visual attention as efficiently as children with TLD, especially at the syntactic level, suggesting a link between scene knowledge and language development.


The genome of tapeworm Taenia multiceps sheds light on understanding parasitic mechanism and control of coenurosis disease.
Coenurosis, caused by the larval coenurus of the tapeworm Taenia multiceps, is a fatal central nervous system disease in both sheep and humans. Though treatment and prevention options are available, the control of coenurosis still faces presents great challenges. Here, we present a high-quality genome sequence of T. multiceps in which 240 Mb (96%) of the genome has been successfully assembled using Pacbio single-molecule real-time (SMRT) and Hi-C data with a N50 length of 44.8 Mb. In total, 49.5 Mb (20.6%) repeat sequences and 13, 013 gene models were identified. We found that Taenia spp. have an expansion of transposable elements and recent small-scale gene duplications following the divergence of Taenia from Echinococcus, but not in Echinococcus genomes, and the genes underlying environmental adaptability and dosage effect tend to be over-retained in the T. multiceps genome. Moreover, we identified several genes encoding proteins involved in proglottid formation and interactions with the host central nervous system, which may contribute to the adaption of T. multiceps to its parasitic life style. Our study not only provides insights into the biology and evolution of T. multiceps, but also identifies a set of species-specific gene targets for developing novel treatment and control tools for coenurosis.


An increase in glucosylceramide synthase induces Bcl-xL-mediated cell survival in vinorelbine-resistant lung adenocarcinoma cells.
Reversing drug resistance with concurrent treatment confers anticancer benefits. In this study, we investigated the potential mechanism of glucosylceramide synthase (GCS)-mediated vinca alkaloid vinorelbine (VNR) resistance in human lung adenocarcinoma cells. Compared with PC14PE6/AS2 (AS2) and CL1-0 cells, apoptotic analysis showed that both A549 and CL1-5 cells were VNR-resistant, while these cells highly expressed GCS at the protein level. VNR treatment significantly converts ceramide to glucosylceramide in VNR-resistant cells; however, pharmacologically inhibiting GCS with (±)-threo-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol hydrochloride (PDMP) induced ceramide accumulation, accompanied by a decrease in glucosylceramide. Under concurrent treatment with VNR and PDMP, an increase in cell apoptosis could be identified; furthermore, genetically silencing GCS confirmed these effects. In VNR-resistant cells, Bcl-xL expression was aberrantly increased, while pharmacologically inhibiting Bcl-xL with ABT-737 sensitized cells to VNR-induced apoptosis. Conversely, enforced expression of Bcl-xL strengthened the survival response of the VNR-susceptible cells AS2 and CL1-0. Without changes in mRNA expression, Bcl-xL was overexpressed independent of β-catenin-mediated transcriptional regulation in VNR-resistant cells. Simultaneous GCS inhibition and VNR treatment caused a decrease in Bcl-xL expression. According to these findings, an increase in GCS caused Bcl-xL augmentation, facilitating VNR resistance in lung adenocarcinoma cells.


Acute HIV revisited: new opportunities for treatment and prevention.
Inability to recognize incident infection has traditionally limited both scientific and public health approaches to HIV disease. Recently, some laboratories have begun adding HIV nucleic acid amplification testing to HIV diagnostic testing algorithms so that acute (antibody-negative) HIV infections can be routinely detected within the first 1-3 weeks of exposure. In this review article, we will highlight critical opportunities for HIV treatment and prevention that are presented by these diagnostic strategies.


Exploring variation in the use of feedback from national clinical audits: a realist investigation.
National Clinical Audits (NCAs) are a well-established quality improvement strategy used in healthcare settings. Significant resources, including clinicians' time, are invested in participating in NCAs, yet there is variation in the extent to which the resulting feedback stimulates quality improvement. The aim of this study was to explore the reasons behind this variation. We used realist evaluation to interrogate how context shapes the mechanisms through which NCAs work (or not) to stimulate quality improvement. Fifty-four interviews were conducted with doctors, nurses, audit clerks and other staff working with NCAs across five healthcare providers in England. In line with realist principles we scrutinised the data to identify how and why providers responded to NCA feedback (mechanisms), the circumstances that supported or constrained provider responses (context), and what happened as a result of the interactions between mechanisms and context (outcomes). We summarised our findings as Context+Mechanism = Outcome configurations. We identified five mechanisms that explained provider interactions with NCA feedback: reputation, professionalism, competition, incentives, and professional development. Professionalism and incentives underpinned most frequent interaction with feedback, providing opportunities to stimulate quality improvement. Feedback was used routinely in these ways where it was generated from data stored in local databases before upload to NCA suppliers. Local databases enabled staff to access data easily, customise feedback and, importantly, the data were trusted as accurate, due to the skills and experience of staff supporting audit participation. Feedback produced by NCA suppliers, which included national comparator data, was used in a more limited capacity across providers. Challenges accessing supplier data in a timely way and concerns about the quality of data submitted across providers were reported to constrain use of this mode of feedback. The findings suggest that there are a number of mechanisms that underpin healthcare providers' interactions with NCA feedback. However, there is variation in the mode, frequency and impact of these interactions. Feedback was used most routinely, providing opportunities to stimulate quality improvement, within clinical services resourced to collect accurate data and to maintain local databases from which feedback could be customised for the needs of the service.


Metabolism of high density lipoprotein by human fetal adrenal tissue.
The role of lipoproteins as a source of the cholesterol utilized for steroidogenesis by human fetal adrenal (HFA) tissue was investigated previously. It was found that low density lipoprotein (LDL) was the lipoprotein preferred as a source of cholesterol for steroidogenesis by the HFA. [125I]Iodo-LDL was taken up and degraded by HFA tissue in organ culture, and the degradation of [125I]iodo-LDL was stimulated when ACTH (1 microgram X ml-1) was present in the culture medium. Others have shown that high density lipoprotein (HDL) is utilized as a source of cholesterol for steroidogenesis by rat adrenocortical cells in vitro and by the adrenals of the adult rat in vivo. In the present investigation we evaluated the metabolism of [125I]iodo-HDL by HFA tissue. [125I]iodo-HDL uptake by the HFA tissue increased in a linear manner with time and as the concentration of [125I]iodo-HDL in the culture medium was increased. However, there was little degradation of [125I]iodo-HDL by HFA. Moreover, preincubation of HFA tissue in medium containing ACTH (1 microgram X ml-1) or HDL, in various concentrations, did not affect the rate of uptake and degradation of [125I]iodo-HDL. The rate of degradation of [125I]iodo-LDL was found to decrease to low levels as the concentration of nonradiolabeled LDL in the culture medium was increased, whereas nonradiolabeled HDL had little effect on the degradation of [125I]iodo-LDL. HFA tissue fragments were incubated in medium containing ACTH plus lipoprotein-poor serum (LPPS) alone or LPPS plus HDL in various concentrations (50-1000 microgram X ml-1). The medium was changed daily and assayed for dehydroisoandrosterone sulfate and cortisol. In the presence of HDL, steroid secretion rates were no greater than those attained by HFA maintained in medium containing LPPS. It is concluded that the HFA utilizes cholesterol derived from LDL for steroidogenesis and that HDL is not metabolized efficiently by the human fetal adrenal.


Identification of a Novel Autoimmune Peptide Epitope of Prostein in Prostate Cancer.
There is a demand for novel targets and approaches to diagnose and treat prostate cancer (PCA). In this context, serum and plasma samples from a total of 609 individuals from two independent patient cohorts were screened for IgG reactivity against a sum of 3833 human protein fragments. Starting from planar protein arrays with 3786 protein fragments to screen 80 patients with and without PCA diagnosis, 161 fragments (4%) were chosen for further analysis based on their reactivity profiles. Adding 71 antigens from literature, the selection of antigens was corroborated for their reactivity in a set of 550 samples using suspension bead arrays. The antigens prostein (SLC45A3), TATA-box binding protein (TBP), and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) showed higher reactivity in PCA patients with late disease compared with early disease. Because of its prostate tissue specificity, we focused on prostein and continued with mapping epitopes of the 66-mer protein fragment using patient samples. Using bead-based assays and 15-mer peptides, a minimal peptide epitope was identified and refined by alanine scanning to the KPxAPFP. Further sequence alignment of this motif revealed homology to transmembrane protein 79 (TMEM79) and TGF-beta-induced factor 2 (TGIF2), thus providing a reasoning for cross-reactivity found in females. A comprehensive workflow to discover and validate IgG reactivity against prostein and homologous targets in human serum and plasma was applied. This study provides useful information when searching for novel biomarkers or drug targets that are guided by the reactivity of the immune system against autoantigens.


Neonatal manipulations of oxytocin alter expression of oxytocin and vasopressin immunoreactive cells in the paraventricular nucleus of the hypothalamus in a gender-specific manner.
Early postnatal manipulations of oxytocin have long-term behavioral and physiological consequences; the present study examined the hypothesis that oxytocin or its absence influences the subsequent expression of either oxytocin or arginine vasopressin in the CNS. On postnatal day 1 female and male prairie voles (Microtus ochrogaster) received a single i.p. injection of oxytocin (3 microg), oxytocin antagonist (0.3 microg), or 50 microl of isotonic saline or were only handled. On postnatal days 1, 8 and 21, brains were fixed, sectioned and stained for oxytocin or vasopressin immunoreactivity and analyzed as a function of age, treatment and sex. Both oxytocin and vasopressin immunoreactivity were observed on day 1 in the supraoptic and paraventricular nuclei (PVN) of the hypothalamus. Numbers of oxytocin and vasopressin neurons increased with age in both nuclei. Females treated on postnatal day 1 with oxytocin or oxytocin antagonist displayed a significant increase in oxytocin immunoreactivity on day 21 in the PVN. In contrast, males treated with antagonist tended to have decreased vasopressin immunoreactivity in the same region. These results revealed that the effects of neonatal manipulation of oxytocin are age-dependent, site-specific and sexually dimorphic. The long-lasting effects of neonatal exposure to exogenous oxytocin and oxytocin antagonist indicate a role for oxytocin in the development of the CNS during the neonatal period, affecting the development of the oxytocinergic system in females and the vasopressinergic system in males. The developmental effects observed suggest one possible mechanism by which neonatal exposure to oxytocin or neonatal inhibition of endogenous oxytocin produces long-lasting behavioral and physiological alterations and could play a role in the development of male- and female-typical behavior.


Intracellular actin-based transport: how far you go depends on how often you switch.
Intracellular molecular motor-driven transport is essential for such diverse processes as mitosis, neuronal function, and mitochondrial transport. Whereas there have been in vitro studies of how motors function at the single-molecule level, and in vivo studies of the structure of filamentary networks, studies of how the motors effectively use the networks for transportation have been lacking. We investigate how the combined system of myosin-V motors plus actin filaments is used to transport pigment granules in Xenopus melanophores. Experimentally, we characterize both the actin filament network, and how this transport is altered in response to external signals. We then develop a theoretical formalism to explain these changes. We show that cells regulate transport by controlling how often granules switch from one filament to another, rather than by altering individual motor activity at the single-molecule level, or by relying on structural changes in the network.


Phytochemical analysis and a study on the antiestrogenic antifertility effect of leaves of Piper betel in female albino rat.
To study the effect of graded doses of the aqueous and methanolic extract of the leaves of Piper betel (PB) Linn (PBL) on the estrous cycle of female albino rats. Both the extracts were tested for their effect on the estrous cycle at three dose levels of 500, 1000 and 1500 mg/kg/day and the vaginal smears were examined daily microscopically for the different phases of the estrous cycle for a period of 30 days. The estrous cycle was irregular and prolonged in the treated groups indicating anestrus condition, which would result in infertility. Both types of the extract showed a significant decrease in the duration of proestrus and estrus with a prolonged diestrus at 1000 mg/kg/day and 1500 mg/kg/day doses as compared with control. However, no change was seen in the metestrus phase. The rats treated with PB showed a significant (P < 0.05), dose-dependent decrease in the estrus phase, in comparison to the control group, the effect was more with the methanolic extract. Large, cornified cells appeared after proestrus phase with decreased number of cornified cells. There was a significant reduction in the number of the estrous cycle, in the PBL treated group. Anestrus phase appeared in all the rats treated with the aqueous and methanolic PB extract, which was not observed in the control group. However, the aqueous extract at a dose of 500 mg/kg/day had no effect either on the estrous cycle or on its different phases. The observed effect of PB leaves could be due to the flavonoids and saponin contents, which also contributes to its antiestrogenic mechanism of action. Both the aqueous and methanolic extract of PBL possesses antifertility effect in female albino rats.


Weight status, energy-balance behaviours and intentions in 9-12-year-old inner-city children.
Dutch youth health care promotes four so-called energy-balance behaviours for the prevention of obesity: increasing physical activity, reducing sedentary behaviour and sugar-containing drinks, and eating breakfast. However, data on the prevalence of these behaviours and intentions to engage in them among primary schoolchildren is limited, especially for multi-ethnic, inner-city populations. The present study aimed to provide these data and explore differences according to socio-demographic characteristics and weight status. Data on behaviours and accompanying intentions were collected using classroom questionnaires. Stature and body weight were measured by trained staff. Twenty primary schools in Rotterdam participated. Data on 1095 9-12 year olds (81.7% response rate) were available for analysis. Multiple logistic regression analyses were conducted to determine associations between behaviours (favourable or unfavourable), intentions (positive or not), gender, age, ethnicity, neighbourhood income level and weight status. The prevalence of being overweight was 30.4%, including 9.0% obesity. Engagement in energy-balance behaviours varied from 58.6% for outdoor play (>1 h previous day) to 85.9% for active transportation to school (day of survey). The highest positive intentions were reported for taking part in sports (83.9%), and lowest for reducing computer time (41.3%). Small differences in behaviours and intentions according to socio-demographic characteristics were found, most notably a lower engagement in physical activity by girls. Skipping breakfast and total number of energy-balance behaviours were associated with being overweight. The prevalence of being overweight among Dutch inner-city schoolchildren is high. A general rather than a differentiated approach is needed to improve engagement in energy-balance behaviours among inner-city schoolchildren.


Neck/shoulder and back pain in new graduate nurses: A growth mixture modeling analysis.
Although it is well known that musculoskeletal disorders are common among registered nurses, little longitudinal research has been conducted to examine this problem from nursing education to working life. The aim was to investigate the prevalence and incidence of neck/shoulder and back pain in nursing students in their final semester, and one and two years after graduation. Furthermore, to identify common trajectories of neck/shoulder and back pain, and explore sociodemographic and lifestyle-related factors, contextual factors and health outcome that might be characteristic of individuals in the various trajectories. Longitudinal study following nursing students from their final year of studies, with follow-ups one and two years after graduation. Nursing students who graduated from the 26 universities providing undergraduate nursing education in Sweden 2002 were invited to participate (N=1700). Of those asked, 1153 gave their informed consent. The participants answered postal surveys at yearly intervals. Descriptive statistics were used to analyze prevalence and incidence of pain, and growth mixture modeling was applied to identify different homogeneous clusters of individuals following similar trajectories in pain development across time. The prevalence of neck/shoulder and back pain remained constant over time (around 50% for neck/shoulder pain and just over 40% for back pain). Six different development trajectories for each symptom were found, reflecting patterns of stable pain levels or variation in levels over time: one symptom-free group, two decreasing pain groups, two increasing pain groups, and one chronic pain group. With few exceptions, the same factors (sex, children, chronic disease, working overtime, work absence, sickness presence, physical load, depression, self-rated health, sleep quality and muscular tension) were associated with neck/shoulder and back pain trajectories. Different types of physical load characterized new nurses with neck/shoulder pain and back pain respectively. The high prevalence of pain among nursing students and among new graduate nurses, suggests that it would be effective to implement preventive strategies already during nursing education, but they should also preferably continue after graduation. Many factors associated with pain in the neck/shoulder and back seem to be modifiable, and thereby constitute targets for preventive strategies.


Body composition analysis, anthropometric indices and lipid profile markers as predictors for prediabetes.
To compare different anthropometric indices, Body composition analysis and lipid profile markers in terms of their ability to predict prediabetes (PD). We enrolled 83 subjects with PD and 84 normoglycemic subjects who were matched for age and gender. The diagnosis of prediabetes was done according to the American Diabetes Association (ADA) criteria. All subjects were aged between 30-55 years of age and visited the outpatient department of tertiary care hospital. Anthropometric and lipid profile measurements were obtained. Analysis of body composition was done using Bodystat 1500MDD Instrument. Backward logistic regression was performed for detecting the predictors of PD. A receiver operator characteristic curve (ROC) with area under curve (AUC) was utilized for the accuracy of the predictors of PD. Comparison of anthropometric measurement and body composition analysis parameters between the two groups showed that Waist circumference (WC), Body mass index, Body Fat% were significantly higher whereas Extracellular water and Dry lean weight in percentage (ECW% and DLW%) were found to be lower in PD (p< 0.05). Higher triglyceride (TG) levels and lower high-density cholesterol (HDL-C) with high TG/HDL-C were seen in subjects with PD. Backward logistic regression analysis found the combination of Body Fat % with WC, TG, ECW% and DLW% as strong predictors of PD. In ROC analysis, ECW% (AUC = 0.703) was the most predictive measure, followed by WC (AUC = 0.702). This study demonstrated that estimation of Body Fat % combined with waist circumference, Extracellular water and Dry lean weight in percentage are valuable in screening and diagnosis of prediabetes. Plasma levels of TG in lipid profile measurements can also serve as an additional marker for prediction of prediabetes.


A fitness programme for patients with chronic low back pain: 2-year follow-up of a randomised controlled trial.
The aim of this study was to assess the long-term effect of a supervised fitness programme on patients with chronic low back pain. The design of the study was a single blind randomised controlled trial with follow-up, by postal questionnaire, 2 years after intervention. The Oswestry Low Back Pain Disability Index was used as the outcome measure to assess daily activity affected by back pain. Eighty-one patients with chronic low back pain, who were referred to the physiotherapy department of a National Health Service orthopaedic hospital, were randomised to either a supervised fitness programme or a control group. Patients in the intervention group and control group were taught specific exercises to be continued at home and referred to a backschool for back care education. In addition, the intervention group attended eight sessions of a supervised fitness programme. Sixty-two patients (76%) with a mean age of 37 years, returned the Oswestry Low Back Pain Disability Index questionnaire. Of these, 29 were in the intervention group and 31 in the control group. Patients in the intervention group demonstrated a mean reduction of 7.7% in the Oswestry Low Back Pain Disability Index score (95% confidence interval of mean paired difference 3.9, 11.6 P < 0.001), compared with only 2.4% in the control group (95% confidence interval of mean paired difference -2.0, 6.9 P > 0.05). Between group comparisons demonstrated a statistically significant difference in disability scores between the treatment and control group (mean difference 5.8, 95% confidence interval 0.3, 11.4 P < 0.04). This study supports the current trend towards a more active treatment approach to low back pain. We have demonstrated clinical effectiveness of a fitness programme 2 years after treatment but this needs to be replicated in a larger study which should include a cost effectiveness analysis, further analysis of objective functional status and a placebo intervention group.


A characteristic occipital epileptiform EEG pattern in ADCK3-related mitochondrial disease.
ADCK3-related disease is a mitochondrial disorder associated with an abnormality of coenzyme Q10 metabolism. Ataxia and epilepsy are common, and the phenotype overlaps with other mitochondrial encephalopathies, particularly POLG-related disease. CoQ10 supplementation may be beneficial. We have noted a remarkable epileptiform pattern in ADCK3-related encephalopathy, and since EEG studies in this rare condition are limited, we wished to assess the evolution of EEG characteristics in patients with this disorder. All EEG recordings of the four known patients from Mid-Norway were systematically reviewed. EEG graphoelements were classified according to the standardized computer-based organized reporting of EEG (SCORE) and international glossary terms. The evolution of EEG features was assessed. A total of 96 recordings spanning over 15-32 years were available, with a mean of 24 per patient (range: 17-28). Altogether, 50 digital recordings were reviewed, including four long-term and 46 selected paper segments. In three patients, EEG showed prominent bilateral asynchronous and synchronous epileptiform discharges in occipital and posterior-temporal regions. This intense activity included multiple epileptiform graphoelements, which occurred continuously, nearly continuously or in prolonged runs. The findings remained stable over many years. Although the number of patients is small, we suggest that interictal EEG findings of continuous/nearly continuous bi-occipital spike-waves may serve as a biomarker for this potentially treatable condition. This peculiar EEG pattern might help to differentiate ADCK3-related disease from the more common POLG-related disease, which is usually characterized by lateralized or focal slowing with more sporadic epileptiform elements of similar topography.


Vanadyl sulfate prevents fructose-induced hyperinsulinemia and hypertension in rats.
To determine whether insulin resistance and hyperinsulinemia are causally related to fructose-induced hypertension, we used vanadyl sulfate, a drug that improves insulin sensitivity in rats. Chronic oral vanadyl treatment was initiated in 6-week-old male Sprague-Dawley rats. One week after vanadyl was started, rats were fed either normal rat chow or a fructose-enriched diet. Plasma glucose and insulin levels and systolic blood pressure were measured weekly for 4 weeks. Fructose feeding induced hyperinsulinemia (fructose-fed, 366.6 +/- 8.4 versus control, 276 +/- 10.8 pmol/L, P < .001) and increased blood pressure (fructose-fed, 160 +/- 3.0 versus control, 124 +/- 3.0 mm Hg, P < .001). Vanadyl (0.4 to 0.6 mmol/kg per day) prevented the rise in plasma insulin (treated, 211.2 +/- 6.0 pmol/L, P < .001) and blood pressure (treated, 127 +/- 3.0 mm Hg, P < .001) in the fructose-fed rats without a change in plasma glucose. No change in blood pressure was seen in the control group. After 4 weeks, euglycemic clamps were performed on 20-hour fasted, conscious, mobile rats. Low-dose porcine insulin infusion (14 pmol/kg per minute) with concomitant somatostatin infusion resulted in similar steady-state plasma glucose and insulin levels in the various groups. Hepatic glucose production was suppressed and similar among various groups under clamp conditions. Insulin sensitivity index (micromoles of glucose per kilogram per hour per picomole per liter of insulin) was reduced in the fructose-fed rats compared with controls (fructose-fed, 0.9 +/- 0.4 versus control, 5.4 +/- 1.2, P < .002).(ABSTRACT TRUNCATED AT 250 WORDS)


Introduction to B-Cell disorders.
Healthcare professionals have a good understanding of B cells in normal immunity. Although the role of lymphocytes and the lymphoid system in lymphoma is understood, the role of B cells is less clear in several autoimmune diseases, such as rheumatoid arthritis, idiopathic thrombocytopenic purpura, and autoimmune hemolytic anemia. This article will present an overview of malignant and nonmalignant B-cell disorders. Experts hypothesize that some monoclonal antibodies can deplete the B-cell population and prevent B- and T-cell responses in autoimmune diseases. Nurses should understand the data surrounding monoclonal therapy, which are not always presented clearly. Nurses' ability to interpret data is important to their patients and colleagues.


A regulatory circuit that involves HR23B and HDAC6 governs the biological response to HDAC inhibitors.
Histone deacetylase (HDAC) is an emergent anticancer target, and HR23B is a biomarker for response to HDAC inhibitors. We show here that HR23B has impacts on two documented effects of HDAC inhibitors; HDAC inhibitors cause apoptosis in cells expressing high levels of HR23B, whereas in cells with low level expression, HDAC inhibitor treatment is frequently associated with autophagy. The mechanism responsible involves the interaction of HDAC6 with HR23B, which downregulates HR23B and thereby reduces the level of ubiquitinated substrates targeted to the proteasome, ultimately desensitising cells to apoptosis. Significantly, the ability of HDAC6 to downregulate HR23B occurs independently of its deacetylase activity. An analysis of the HDAC6 interactome identified HSP90 as a key effector of HDAC6 on HR23B levels. Our results define a regulatory mechanism that involves the interplay between HR23B and HDAC6 that influences the biological outcome of HDAC inhibitor treatment.


Effect of Ions on the Optical Absorption Spectra of Aqueously Solvated Chromophores.
In the condensed phase, ions often create heterogeneous local environments around a solute, which may impart chemical reactivity or perturbations to physicochemical properties. Although the former has been the subject of some study, the latter-particularly as is pertains to optical absorption spectroscopy-is much less understood. In this work, the computed UV-vis absorption spectrum is examined for the aqueously solvated chromophore anion of green fluorescent protein for different local ion configurations. The strong ability of water to screen the ions from the chromophore results in little change in excitation energy compared to a purely aqueous environment. However, upon forming a contact ion pair with a sodium ion at either of the two electronegative oxygen sites of the chromophore, there is a spectral shift to either higher or lower energies. Surprisingly, our analysis suggests that the cause of the spectral shift is dominated not by the electrostatic presence of the ion but instead by ion disruption of the hydrogen bond network at the oxygen contact ion pair site.


Brain Reactivity and Selective Attention to Sleep-Related Words in Patients With Chronic Insomnia.
Sleep-related attentional bias has been suggested to represent an important factor for the maintenance of chronic insomnia. However, little is known about potentially underlying psychological mechanisms such as threat or craving. As these are associated with distinguishable brain activation patterns, we performed a functional neuroimaging study. Functional magnetic resonance imaging was used to investigate brain reactivity to sleep-related words in 20 patients with primary insomnia according to DSM-IV criteria and 35 good sleeper controls according to Research Diagnostic Criteria. In addition, an emotional Stroop task was performed in all participants outside the scanner to investigate sleep-related attentional bias. Contrary to the hypotheses, patients with chronic insomnia did not differ from good sleeper controls in terms of threat- or craving-related brain reactivity to sleep-related words. In addition, the emotional Stroop task did not reveal any significant group difference in sleep-related attentional bias. Exploratory analyses did not show any significant correlations between brain reactivity/selective attention to sleep-related words and questionnaire scores/PSG parameters. The results from the present study call into question that attentional bias to sleep-related stimuli is a core feature of chronic insomnia. Future studies may use pictorial stimuli and larger sample sizes for investigating sleep-related information processing in insomnia.


Functional features of crossmodal mismatch responses.
Research on brain mechanisms of deviance detection and sensory memory trace formation, best indexed by the mismatch negativity, mainly relied on the investigation of responses elicited by auditory stimuli. However, comparable less research reported the mismatch negativity elicited by somatosensory stimuli. More importantly, little is known on the functional features of mismatch deviant and standard responses across different sensory modalities. To directly compare different sensory modalities, we adopted a crossmodal roving paradigm and collected event-related potentials elicited by auditory, non-nociceptive somatosensory, and nociceptive trains of stimuli, during Active and Passive attentional conditions. We applied a topographical segmentation analysis to cluster successive scalp topographies with quasi-stable landscape of significant differences to extract crossmodal mismatch responses. We obtained three main findings. First, across different sensory modalities and attentional conditions, the formation of a standard sensory trace became robust mainly after the second stimulus repetition. Second, the neural representation of a modality deviant stimulus was influenced by the preceding sensory modality. Third, the mismatch negativity significantly covaried between Active and Passive attentional conditions within the same sensory modality, but not between different sensory modalities. These findings provide robust evidence that, while different modalities share a similar process of standard trace formation, the process of deviance detection is largely modality dependent.


Inhibition of thiamin diphosphate dependent enzymes by 3-deazathiamin diphosphate.
3-Deazathiamin diphosphate (deazaTPP) and a second thiamin diphosphate (TPP) analogue having a benzene ring in place of the thiazolium ring have been synthesised. These compounds are both extremely potent inhibitors of pyruvate decarboxylase from Zymomonas mobilis; binding is competitive with TPP and is essentially irreversible even though no covalent linkage is formed. DeazaTPP binds approximately seven-fold faster than TPP and at least 25,000-fold more tightly (K(i) less than 14 pM). DeazaTPP is also a potent inhibitor of the E1 subunit of alpha-ketoglutarate dehydrogenase from E. coli and binds more than 70-fold faster than TPP. In this case slow reversal of the inhibition could be observed and a K(i) value of about 5 nM was calculated (ca. 500-fold tighter binding than TPP).


Outcomes of renal transplantation in recipients with peak panel reactive antibody >30% under tacrolimus-based immunosuppression.
Renal transplant recipients with high panel reactive antibodies (PRA) have worse outcomes than those with lower PRA. High PRA re-transplant recipients are thought to have worse outcomes than high PRA first transplant recipients. In this study, we examined outcomes of renal transplantation recipients with a peak PRA >30% and compared the outcomes of first and re-transplanted recipients. Survival outcomes between recipients of first transplants (n=68) and re-transplants (n=155) operated between June 1990 and August 2000 were compared. Sub-group analysis was done based on patient's gender, race and first/re-transplant. All patients received tacrolimus-based immunosuppression. No difference in graft survival was noted between first and re-transplanted patients. Ten-year patient survival was better in the re-transplanted group (p<0.004). Factors affecting patient survival on univariate analysis were age >55 years (p=0.015), deceased donor transplant (p=0.009), first transplant patient (p=0.004) and diabetes mellitus (DM) as the cause of End Stage Renal Disease (ESRD) (p=0.005). On multivariable analysis, factors affecting patient survival were number of the transplant (re-transplant versus first transplant, Relative risk [RR]=0.54, p=0.009) and cause of ESRD (DM versus no DM, RR=1.91, p=0.012).Diabetes as a cause for ESRD was the only factor affecting graft survival on univariate(p=0.015) and multivariable analysis (DM versus no DM, RR=1.63, p=0.017). High PRA recipients of first transplants had poorer patient survival than high PRA re-transplants. On multivariable analysis, diabetes etiology of ESRD and first transplantation were found to be independent risk factors for poorer patient survival.


Risk management analysis of air ambulance blood product administration in combat operations.
Between June-October 2012, 61 flight-medic-directed transfusions took place aboard U.S. Army Medical Evacuation (medevac) helicopters in Afghanistan. This represents the initial experience for pre-hospital blood product transfusion by U.S. Army flight medics. We performed a retrospective review of clinical records, operating guidelines, after-action reviews, decision and information briefs, bimonthly medical conferences, and medevac-related medical records. A successful program was administered at 10 locations across Afghanistan. Adherence to protocol transfusion indications was 97%. There were 61 casualties who were transfused without any known instance of adverse reaction or local blood product wastage. Shock index (heart rate/systolic blood pressure) improved significantly en route, with a median shock index of 1.6 (IQR 1.2-2.0) pre-transfusion and 1.1 (IQR 1.0-1.5) post-transfusion (P < 0.0001). Blood resupply, training, and clinical procedures were standardized across each of the 10 areas of medevac operations. Potential risks of medical complications, reverse propaganda, adherence to protocol, and diversion and/or wastage of limited resources were important considerations in the development of the pilot program. Aviation-specific risk mitigation strategies were important to ensure mission success in terms of wastage prevention, standardized operations at multiple locations, and prevention of adverse clinical outcomes. Consideration of aviation risk mitigation strategies may help enable other helicopter emergency medical systems to develop remote pre-hospital transfusion capability. This pilot program provides preliminary evidence that blood product administration by medevac is safe.


A human factors subsystems approach to trauma care.
A physician-centered approach to systems design is fundamental to ameliorating the causes of many errors, inefficiencies, and reliability problems. To use human factors engineering to redesign the trauma process based on previously identified impediments to care related to coordination problems, communication failures, and equipment issues. This study used an interrupted time series design to collect historically controlled data via prospective direct observation by trained observers. We studied patients from a level I trauma center from August 1 through October 31, 2011, and August 1 through October 31, 2012. A range of potential solutions based on previous observations, trauma team engagement, and iterative cycles identified the most promising subsystem interventions (headsets, equipment storage, medication packs, whiteboard, prebriefing, and teamwork training). Five of the 6 subsystem interventions were successfully deployed. Communication headsets were found to be unsuitable in simulation. The primary outcome measure was flow disruptions, with treatment time and length of stay as secondary outcome measures. A total of 86 patients were observed before the intervention and 120 after the intervention. Flow disruptions increased if the patient had undergone computed tomography (CT) (F1200 = 20.0, P < .001) and had been to the operating room (F1200 = 63.1, P < .001), with an interaction among the intervention, trauma level, and CT (F1200 = 6.50, P = .01). For total treatment time, there was an effect of the intervention (F1200 = 21.7, P < .001), whether the patient had undergone CT (F1200 = 43.0, P < .001), and whether the patient had been to the operating room (F1200 = 85.8, P < .001), with an interaction among the intervention, trauma level, and CT (F1200 = 15.1, P < .001), reflecting a 20- to 30-minute reduction in time in the emergency department. Length of stay was reduced significantly for patients with major mortality risk (P = .01) from a median of 8 to 5 days. Deployment of complex subsystem interventions based on detailed human factors engineering and a systems analysis of the provision of trauma care resulted in reduced flow disruptions, treatment time, and length of stay.


Serosurveillance of eastern equine encephalitis virus in amphibians and reptiles from Alabama, USA.
Eastern equine encephalitis virus (EEEV) is among the most medically important arboviruses in North America, and studies suggest a role for amphibians and reptiles in its transmission cycle. Serum samples collected from 351 amphibians and reptiles (27 species) from Alabama, USA, were tested for the presence of antibodies against EEEV. Frogs, turtles, and lizards showed little or no seropositivity, and snakes had high seropositivity rates. Most seropositive species were preferred or abundant hosts of Culex spp. mosquitoes at Tuskegee National Forest, that target ectothermic hosts. The cottonmouth, the most abundant ectotherm sampled, displayed a high prevalence of seropositivity, indicating its possible role as an amplification and/or over-wintering reservoir for EEEV.


Lyme arthritis: a new clinical entity.
Named for the Connecticut town where the first identified cases occurred in 1972, this disorder has since been found elsewhere and may be caused by a virus transmitted by ticks. Attacks are often preceded by erythema chronicum migrans and are seldom prolonged, though they may recur. Symptomatic treatment only is advised, except in the rare instances of severe neurologic complications or myocardial conduction abnormality.


dbOGAP - an integrated bioinformatics resource for protein O-GlcNAcylation.
Protein O-GlcNAcylation (or O-GlcNAc-ylation) is an O-linked glycosylation involving the transfer of β-N-acetylglucosamine to the hydroxyl group of serine or threonine residues of proteins. Growing evidences suggest that protein O-GlcNAcylation is common and is analogous to phosphorylation in modulating broad ranges of biological processes. However, compared to phosphorylation, the amount of protein O-GlcNAcylation data is relatively limited and its annotation in databases is scarce. Furthermore, a bioinformatics resource for O-GlcNAcylation is lacking, and an O-GlcNAcylation site prediction tool is much needed. We developed a database of O-GlcNAcylated proteins and sites, dbOGAP, primarily based on literature published since O-GlcNAcylation was first described in 1984. The database currently contains ~800 proteins with experimental O-GlcNAcylation information, of which ~61% are of humans, and 172 proteins have a total of ~400 O-GlcNAcylation sites identified. The O-GlcNAcylated proteins are primarily nucleocytoplasmic, including membrane- and non-membrane bounded organelle-associated proteins. The known O-GlcNAcylated proteins exert a broad range of functions including transcriptional regulation, macromolecular complex assembly, intracellular transport, translation, and regulation of cell growth or death. The database also contains ~365 potential O-GlcNAcylated proteins inferred from known O-GlcNAcylated orthologs. Additional annotations, including other protein posttranslational modifications, biological pathways and disease information are integrated into the database. We developed an O-GlcNAcylation site prediction system, OGlcNAcScan, based on Support Vector Machine and trained using protein sequences with known O-GlcNAcylation sites from dbOGAP. The site prediction system achieved an area under ROC curve of 74.3% in five-fold cross-validation. The dbOGAP website was developed to allow for performing search and query on O-GlcNAcylated proteins and associated literature, as well as for browsing by gene names, organisms or pathways, and downloading of the database. Also available from the website, the OGlcNAcScan tool presents a list of predicted O-GlcNAcylation sites for given protein sequences. dbOGAP is the first public bioinformatics resource to allow systematic access to the O-GlcNAcylated proteins, and related functional information and bibliography, as well as to an O-GlcNAcylation site prediction tool. The resource will facilitate research on O-GlcNAcylation and its proteomic identification.


A loss-of-function screen for phosphatases that regulate neurite outgrowth identifies PTPN12 as a negative regulator of TrkB tyrosine phosphorylation.
Alterations in function of the neurotrophin BDNF are associated with neurodegeneration, cognitive decline, and psychiatric disorders. BDNF promotes axonal outgrowth and branching, regulates dendritic tree morphology and is important for axonal regeneration after injury, responses that largely result from activation of its tyrosine kinase receptor TrkB. Although intracellular neurotrophin (NT) signaling presumably reflects the combined action of kinases and phosphatases, little is known about the contributions of the latter to TrkB regulation. The issue is complicated by the fact that phosphatases belong to multiple independently evolved families, which are rarely studied together. We undertook a loss-of-function RNA-interference-based screen of virtually all known (254) human phosphatases to understand their function in BDNF/TrkB-mediated neurite outgrowth in differentiated SH-SY5Y cells. This approach identified phosphatases from diverse families, which either positively or negatively modulate BDNF-TrkB-mediated neurite outgrowth, and most of which have little or no previously established function related to NT signaling. "Classical" protein tyrosine phosphatases (PTPs) accounted for 13% of the candidate regulatory phosphatases. The top classical PTP identified as a negative regulator of BDNF-TrkB-mediated neurite outgrowth was PTPN12 (also called PTP-PEST). Validation and follow-up studies showed that endogenous PTPN12 antagonizes tyrosine phosphorylation of TrkB itself, and the downstream activation of ERK1/2. We also found PTPN12 to negatively regulate phosphorylation of p130cas and FAK, proteins with previously described functions related to cell motility and growth cone behavior. Our data provide the first comprehensive survey of phosphatase function in NT signaling and neurite outgrowth. They reveal the complexity of phosphatase control, with several evolutionarily unrelated phosphatase families cooperating to affect this biological response, and hence the relevance of considering all phosphatase families when mining for potentially druggable targets.


Enhanced photoluminescence from single nitrogen-vacancy defects in nanodiamonds coated with phenol-ionic complexes.
Fluorescent nanodiamonds are attracting major attention in the field of bio-sensing and bio-labeling. In this work we demonstrate a robust approach to achieve an encapsulation of individual nanodiamonds with phenol-ionic complexes that enhance the photoluminescence from single nitrogen vacancy (NV) centers. We show that single NV centres in the coated nanodiamonds also exhibit shorter lifetimes, opening another channel for high resolution sensing. We propose that the nanodiamond encapsulation reduces the non-radiative decay pathways of the NV color centers. Our results provide a versatile and assessable way to enhance photoluminescence from nanodiamond defects that can be used in a variety of sensing and imaging applications.


Peanut oral immunotherapy modifies IgE and IgG4 responses to major peanut allergens.
Patients with peanut allergy have highly stable pathologic antibody repertoires to the immunodominant B-cell epitopes of the major peanut allergens Ara h 1 to 3. We used a peptide microarray technique to analyze the effect of treatment with peanut oral immunotherapy (OIT) on such repertoires. Measurements of total peanut-specific IgE (psIgE) and peanut-specific IgG(4) (psIgG(4)) were made with CAP-FEIA. We analyzed sera from 22 patients with OIT and 6 control subjects and measured serum specific IgE and IgG(4) binding to epitopes of Ara h 1 to 3 using a high-throughput peptide microarray technique. Antibody affinity was measured by using a competitive peptide microarray, as previously described. At baseline, psIgE and psIgG(4) diversity was similar between patients and control subjects, and there was broad variation in epitope recognition. After a median of 41 months of OIT, polyclonal psIgG(4) levels increased from a median of 0.3 μg/mL (interquartile range [25% to 75%], 0.1-0.43 μg/mL) at baseline to 10.5 μg/mL (interquartile range [25% to 75%], 3.95-45.48 μg/mL; P < .0001) and included de novo specificities. psIgE levels were reduced from a median baseline of 85.45 kU(A)/L (23.05-101.0 kU(A)/L) to 7.75 kU(A)/L (2.58-30.55 kU(A)/L, P < .0001). Affinity was unaffected. Although the psIgE repertoire contracted in most OIT-treated patients, several subjects generated new IgE specificities, even as the total psIgE level decreased. Global epitope-specific shifts from IgE to IgG(4) binding occurred, including at an informative epitope of Ara h 2. OIT differentially alters Ara h 1 to 3 binding patterns. These changes are variable between patients, are not observed in control subjects, and include a progressive polyclonal increase in IgG(4) levels, with concurrent reduction in IgE amount and diversity.


Observation of intensity dependent phase-separation in photoreactive monomer-nanoparticle formulations under non-uniform visible light irradiation.
We report observations of photopolymerization driven phase-separation in a mixture of a photo-reactive monomer and inorganic nanoparticles. The mixture is irradiated with visible light possessing a periodic intensity profile that elicits photopolymerization along the depth of the mixture, establishing a competition between photo-crosslinking and thermodynamically favorable phase-separating behavior inherent to the system. In situ Raman spectroscopy was used to monitor the polymerization reaction and morphology evolution, and reveals a key correlation between irradiation intensity and composite morphology extending the entire depth of the mixture, i.e. unhindered phase-separation at low irradiation intensity and arrested phase-separation at high irradiation intensity. 3D Raman volume mapping and energy dispersive X-ray mapping confirm that the intensity-dependent irradiation process dictates the extent of phase separation, enabling single-parameter control over phase evolution and subsequent composite morphology. These observations can potentially enable a single-step route to develop polymer-inorganic composite materials with tunable morphologies.


Development and delivery of a physiotherapy intervention for the early management of whiplash injuries: the Managing Injuries of Neck Trial (MINT) Intervention.
This paper describes the development and implementation of a physiotherapy intervention for a large multicentred randomised controlled trial of the early management of whiplash injuries in a National Health Service setting. Participants were eligible if they were classified as having whiplash-associated disorder grades I to III and self-referred for treatment within 6 weeks of injury. The intervention development was informed through a variety of methods including the current evidence base, published guidelines, clinician opinion, a pilot study and expert opinion. The intervention was targeted at known, potentially modifiable risk factors for poor recovery, and utilised manual therapy, exercises and psychological strategies. The treatment was individually tailored, with a maximum of six treatments allowed within the trial protocol over an 8-week period. The intervention was delivered to 300 participants. The amount and types of treatments delivered are described.


Short-term synaptic dynamics control the activity phase of neurons in an oscillatory network.
In oscillatory systems, neuronal activity phase is often independent of network frequency. Such phase maintenance requires adjustment of synaptic input with network frequency, a relationship that we explored using the crab, Cancer borealis, pyloric network. The burst phase of pyloric neurons is relatively constant despite a > two fold variation in network frequency. We used noise input to characterize how input shape influences burst delay of a pyloric neuron, and then used dynamic clamp to examine how burst phase depends on the period, amplitude, duration, and shape of rhythmic synaptic input. Phase constancy across a range of periods required a proportional increase of synaptic duration with period. However, phase maintenance was also promoted by an increase of amplitude and peak phase of synaptic input with period. Mathematical analysis shows how short-term synaptic plasticity can coordinately change amplitude and peak phase to maximize the range of periods over which phase constancy is achieved.


The Antimicrobial and Antiviral Activity of Polyphenols from Almond (Prunus dulcis L.) Skin.
Due to their antimicrobial and antiviral activity potential in vitro, polyphenols are gaining a lot of attention from the pharmaceutical and healthcare industries. A novel antiviral and antimicrobial approach could be based on the use of polyphenols obtained from natural sources. Here, we tested the antibacterial and antiviral effect of a mix of polyphenols present in natural almond skin (NS MIX). The antimicrobial potential was evaluated against the standard American Type Culture Collection (ATCC) and clinical strains of Staphylococcus aureus, including methicillin-resistant (MRSA) strains, by minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Herpes simplex virus type I was used for the antiviral assessment of NS MIX by plaque assay. Furthermore, we evaluated the expression of viral cascade antigens. NS MIX exhibited antimicrobial (MIC values of 0.31-1.25 mg/ml) and antiviral activity (decrease in the viral titer ** p < 0.01, and viral DNA accumulation * p < 0.05) against Staphylococcus aureus and HSV-1, respectively. Amongst the isolated compounds, the aglycones epicatechin and catechin showed the greatest activity against S. aureus ATCC 6538P (MIC values of 0.078-0.15 and 0.15 mg/ml, respectively), but were not active against all the other strains. These results could be used to develop novel products for topical use.


Glucose transporter 4 promotes head and neck squamous cell carcinoma metastasis through the TRIM24-DDX58 axis.
Head and neck squamous cell carcinoma (HNSCC) represents a unique and major health concern worldwide. Significant increases in glucose uptake and aerobic glycolysis have been observed in HNSCC cells. Glucose transporters (GLUTs) represent a major hub in the glycolysis pathway, with GLUT4 having the highest glucose affinity. However, GLUT4's role in HNSCC has not been fully appreciated. An in silico analysis was performed in HNSCC cohorts to identify the most significant glucose transporter associated with HNSCC patient prognosis. An immunohistochemical analysis of a tissue microarray with samples from 90 HNSCC patients was used to determine the association of GLUT4 with prognosis. Complementary functional expression and knockdown studies of GLUT4 were performed to investigate whether GLUT4 plays a role in HNSCC cell migration and invasion in vitro and in vivo. The detailed molecular mechanism of the function of GLUT4 in inducing HNSCC cell metastasis was determined. Our clinicopathologic analysis showed that increased GLUT4 expression in oral squamous cell carcinoma patients was significantly associated with a poor overall survival (OS, P = 0.035) and recurrence-free survival (RFS, P = 0.001). Furthermore, the ectopic overexpression of GLUT4 in cell lines with low endogenous GLUT4 expression resulted in a significant increase in migratory ability both in vitro and in vivo, whereas the reverse phenotype was observed in GLUT4-silenced cells. Utilizing a GLUT4 overexpression model, we performed gene expression microarray and Ingenuity Pathway Analysis (IPA) to determine that the transcription factor tripartite motif-containing 24 (TRIM24) was the main downstream regulator of GLUT4. In addition, DDX58 was confirmed to be the downstream target of TRIM24, whose downregulation is essential for the migratory phenotype induced by GLUT4-TRIM24 activation in HNSCC cells. Here, we identified altered glucose metabolism in the progression of HNSCC and showed that it could be partially attributed to the novel link between GLUT4 and TRIM24. This novel signaling axis may be used for the prognosis and therapeutic treatment of HNSCC in the future.


Maryland power plant cooling-water intake regulations and their application in evaluation of adverse environmental impact.
Maryland's cooling-water intake and discharge regulations, the Code of Maryland Regulations (COMAR) 26.08.03, stem from Sections 316(a) and (b) of the Clean Water Act (CWA). COMAR 26.08.03.05 and litigative and administrative rulings stipulate that the location, design, construction, and capability of cooling-water intake structures must reflect the best technology available (BTA) for minimizing adverse environmental impacts (AEIs), providing that the costs of implementing the BTA are not wholly disproportionate to the expected environmental benefits. Maryland law exempts facilities that withdraw less than 10 million gallons/day (MGD) and less than 20% of stream or net flow by the intake. If not exempt, BTA must be installed if the cost of doing so is less than five times the value of fish impinged annually. Through site-specific studies and the use of a Spawning and Nursery Area of Consequence (SNAC) model applied to Representative Important Species, several power plants were evaluated to determine if they have had an adverse effect on spawning and nursery areas of consequence. Examples of application of the Maryland law to a number of power plants in the state are presented, together with the outcome of their evaluation.


Fish Intake in Pregnancy and Child Growth: A Pooled Analysis of 15 European and US Birth Cohorts.
Maternal fish intake in pregnancy has been shown to influence fetal growth. The extent to which fish intake affects childhood growth and obesity remains unclear. To examine whether fish intake in pregnancy is associated with offspring growth and the risk of childhood overweight and obesity. Multicenter, population-based birth cohort study of singleton deliveries from 1996 to 2011 in Belgium, France, Greece, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Spain, and Massachusetts. A total of 26,184 pregnant women and their children were followed up at 2-year intervals until the age of 6 years. Consumption of fish during pregnancy. We estimated offspring body mass index percentile trajectories from 3 months after birth to 6 years of age. We defined rapid infant growth as a weight gain z score greater than 0.67 from birth to 2 years and childhood overweight/obesity at 4 and 6 years as body mass index in the 85th percentile or higher for age and sex. We calculated cohort-specific effect estimates and combined them by random-effects meta-analysis. This multicenter, population-based birth cohort study included the 26,184 pregnant women and their children. The median fish intake during pregnancy ranged from 0.5 times/week in Belgium to 4.45 times/week in Spain. Women who ate fish more than 3 times/week during pregnancy gave birth to offspring with higher body mass index values from infancy through middle childhood compared with women with lower fish intake (3 times/week or less). High fish intake during pregnancy (>3 times/week) was associated with increased risk of rapid infant growth, with an adjusted odds ratio (aOR) of 1.22 (95% CI, 1.05-1.42) and increased risk of offspring overweight/obesity at 4 years (aOR, 1.14 [95% CI, 0.99-1.32]) and 6 years (aOR, 1.22 [95% CI, 1.01-1.47]) compared with an intake of once per week or less. Interaction analysis showed that the effect of high fish intake during pregnancy on rapid infant growth was greater among girls (aOR, 1.31 [95% CI, 1.08-1.59]) than among boys (aOR, 1.11 [95% CI, 0.92-1.34]; P = .02 for interaction). High maternal fish intake during pregnancy was associated with increased risk of rapid growth in infancy and childhood obesity. Our findings are in line with the fish intake limit proposed by the US Food and Drug Administration and Environmental Protection Agency.


A role for cortical crosstalk in the binding problem: stimulus-driven correlations that link color, form, and motion.
The putative independence of cortical mechanisms for color, form, and motion raises the binding problem-how is neural activity coordinated to create unified and correctly segmented percepts? Binding could be guided by stimulus-driven correlations between mechanisms, but the nature of these correlations is largely unexplored and no one has (intentionally) studied effects on binding if this joint information is compromised. Here, we develop a theoretical framework which: (1) describes crosstalk-generated correlations between cortical mechanisms for color, achromatic form, and motion, which arise from retinogeniculate encoding; (2) shows how these correlations can facilitate synchronization, segmentation, and binding; (3) provides a basis for understanding perceptual oddities and binding failures that occur for equiluminant and stabilized images. These ideas can be tested by measuring both perceptual events and neural activity while achromatic border contrast or stabilized image velocity is manipulated.


Free carrier induced spectral shift for GaAs filled metallic hole arrays.
For a GaAs filled metallic hole array on a pre-epi GaAs substrate, the free carriers, generated by three-photon absorption (3PA) assisted by strongly enhanced local fields, reduce the refractive index of GaAs in ~200-nm thick active area through band filling and free carrier absorption. Therefore, the surface plasma wave (SPW) resonance, and the related second harmonic (SH) spectrum blue shifts with increasing fluence; For the plasmonic structure on a substrate with surface defects, free carrier recombination dominates. The band gap emission spectral peak wavelength decreases 10-nm with increasing fluence, showing the transition from nonradiative-, at low excitation, to bimolecular-recombination at high carrier concentrations.