New pharmaceutical treatment of gastric MALT lymphoma: anti-angiogenesis treatment using VEGF receptor antibodies and celecoxib.
In addition to eradication of Helicobacter pylori, chemotherapy with anticancer agents, and radiation therapy, the treatment with molecular target drugs including rituximab, a CD20 antagonist, is one of the promising new regimens. The mucosa-associated lymphoid tissue (MALT) lymphoma is histologically characterized by rich distribution of the microvascular network consisting of the immature capillaries, lymphatics and venules, and this microvascular network could be the target of the new pharmacotherapy in addition to the direct action on the accumulated B lymphocytes. We have established the animal model of the gastric MALT lymphoma by the Helicobacter heilmannii (H. heilmannii) peroral infection of C57BL/6 mice. The disease induced by this model is very similar to the human counterpart, because of the lymphoepithelial lesion characteristic of the human MALT lymphoma as well as the rich vascularization and localization of vascular endothelial growth factor (VEGF) and its receptors, Flt-1, Flk-1 and Flt-4. By administering VEGF receptor antibodies or celecoxib, one of the cyclooxygenase 2 inhibitors, we were able to induce a significant decrease in the size of the tumor and the apoptotic changes of the endothelial cells of the microvascular network. These antiangiogenic strategies were suggested to be candidates for the new pharmacological treatment of gastric MALT lymphoma, when other treatments are not effective.


2,3,7,8-Tetrachlorodibenzo-p-dioxin alters hippocampal astroglia-neuronal gap junctional communication.
Halogenated aromatic hydrocarbons (HAHs) such as dibenzo-p-dioxins are known to alter cognitive function. However, the cellular basis of this disruption is not well understood. One possible deleterious effect of exposure to HAHs could be on gap junctional intercellular communication (GJIC) between neurons and astroglia in the brain. As such, this study examined the effects of the highly toxic prototypic HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on GJIC in rat hippocampal primary cell culture. Initial measurements of fluorescence recovery after photobleaching (gap-FRAP) showed dye transfer between astroglia and neurons. N-octanol, a lipophilic alcohol known to uncouple cells by decreasing the open probability of gap junctional channels blocked astroglial-neuronal (A-N) communication as well as astroglial-astroglial (A-A) communication. TCDD initially downregulated GJIC between neurons and astroglia of treatment, but had no effect on astroglial cell pairs. These results indicate the presence of GJIC between neurons and astroglia in culture and demonstrate different sensitivities of gap junction responses to TCDD in homologous and heterologous cell pairs. The finding that 2,3,7,8-TCDD disrupts GJIC through A-N but not A-A channels may have important implications for impaired brain function resulting from developmental exposure to TCDD.


When people who inject drugs speak: Qualitative thematic analysis of the perception of a mobile app for needle exchange programs.
Spain is the Western European country with the highest prevalence of Human Immunodeficiency Virus among people who inject drugs. The Hepatitis-C Virus affects over fifty per cent of this population. At the same time, the World Health Organization considers that the average coverage of injection material for drug user per year is low. Harm reduction programs and services have been deployed for over thirty years, and these could now incorporate the advantages of eHealth and mHealth to improve harm reduction. The aim of this qualitative and descriptive study is to analyze how people who inject drugs perceive an application for mobile devices. Fifty-one such drug users participated actively in five focus groups. The main results of the thematic content analysis indicated that the application was welcomed as easy and useful. Participants reported that the application contributed to improving access to injection material, reducing the stigma of drug-dependence and optimizing the organization of the ritual of injection. Excessive preventive information and problems downloading the web app were identified as aspects for improvement. In conclusion, the application was seen as a useful eHealth tool that complements the normal intervention of needle exchange programs.


Effective intracellular delivery of bevacizumab via PEGylated polymeric nanoparticles targeting the CD44v6 receptor in colon cancer cells.
Colorectal cancer (CRC) is one of the most common and deadly cancers in the world, mainly due to its metastatic and metabolic ability. The CD44 receptor isoform containing exon 6 (CD44v6) is a transmembrane protein that plays an important role in the establishment of tumors and metastasis, which make this molecule a potential target for therapy and diagnosis of tumors. Aiming at a targeted therapy, the anti-VEGF monoclonal antibody (mAb) bevacizumab was loaded into poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) nanoparticles (NPs) functionalized with an antibody fragment (Fab) specific for CD44v6-expressing human cancer cells. The sizes of NPs were in the range of 150-250 nm and they had a negative charge between -5 and -10 mV, with an association efficiency (AE) of bevacizumab of 86%. v6 Fab-PLGA-PEG NPs containing bevacizumab specifically bonded to the CD44v6 cell surface receptor and exhibited higher internalization into CD44v6+ epithelial cells than bare and (-) Fab-PLGA-PEG NPs. To understand the biological effect of NP targeting, the intracellular levels of bevacizumab and VEGF were evaluated after the incubation of targeted and untargeted NPs. The intracellular levels of bevacizumab were significantly higher in cells incubated with v6 Fab-PLGA-PEG NPs and these NPs resulted in a significant decrease in the intracellular VEGF compared to untargeted NPs and free bevacizumab. PLGA-PEG NPs, surface-functionalized with a v6-specific Fab, have the potential to intracellularly deliver bevacizumab into CD44v6 expressing cancer cells.


Patient-Reported Symptom Control of Diarrhea and Flushing in Patients with Neuroendocrine Tumors Treated with Lanreotide Depot/Autogel: Results from a Randomized, Placebo-Controlled, Double-Blind and 32-Week Open-Label Study.
In the double-blind (DB) ELECT study, lanreotide depot/autogel significantly reduced versus placebo the need for short-acting octreotide for symptomatic carcinoid syndrome (CS) control in neuroendocrine tumor (NET) patients. Here we present patient-reported symptom data during DB and initial open-label (IOL) treatment. Adults with NETs and CS history, with/without prior somatostatin analog use, were randomized to 16 weeks' DB lanreotide 120 mg subcutaneous or placebo every 4 weeks, followed by 32 weeks' IOL lanreotide. Patients recorded diarrhea and/or flushing frequency and severity daily by Interactive Voice (Web) Response System for 1 month prior to randomization and throughout the study. Of 115 patients randomized (n = 59 lanreotide, n = 56 placebo), 56 lanreotide and 45 placebo patients enrolled in the IOL phase. During DB treatment, least square (LS) mean percentages of days with moderate/severe diarrhea and/or flushing were significantly lower for lanreotide (23.4%) versus placebo (35.8%; LS mean difference [95% confidence interval]: -12.4 [-20.73 to -4.07]; p = .004). For DB lanreotide patients, average daily composite (frequency × severity) diarrhea scores improved significantly between DB and IOL treatment (mean difference: -0.71 [-1.20 to -0.22]; p = .005), and remained stable for diarrhea and/or flushing. For DB placebo patients, composite scores for diarrhea, flushing, and diarrhea and/or flushing improved significantly between DB and IOL treatment (mean differences: -1.07 [-1.65 to -0.49]; -1.06 [-1.93 to -0.19]; and -2.13 [-3.35 to -0.91]; all p ≤ .018). Improved diarrhea and flushing control in CS patients during 16-week lanreotide treatment was sustained during maintenance of lanreotide treatment for the 32-week IOL phase (48 weeks total). This study prospectively collected daily patient-reported data on diarrhea and flushing from the ELECT trial to evaluate the direct impact of lanreotide depot on patients' relief of carcinoid syndrome symptoms. Treatment with lanreotide depot was associated with significant reductions in the percentages of days patients reported symptoms of diarrhea and flushing, as well as reductions in the frequency and severity of daily symptoms compared with placebo during 16 weeks of double-blind treatment. These improvements were sustained for 32 additional weeks of open-label lanreotide treatment (i.e., through week 48 of treatment), resulting in clinically meaningful, long-term symptom reduction.


The role of age at assessment, developmental level, and test in the stability of intelligence scores in young autistic children.
Longitudinal comparisons were made of intelligence and developmental quotient (IQ/DQ) scores for three age groups of 70-72 autistic children aged 2 to 3, 4 to 5, and 6 to 7 years at initial assessment and reassessed at least 2 years later. Stability and predictability over a mean follow-up period of 5 years were related to age, developmental level, and test used at initial assessment. IQ/DQs during preschool years were quite stable and predictive of later IQ scores, except when early scores on the Bayley Scales of Mental Development were compared with later scores on performance or nonverbal tests. As for other populations, predictability for young autistic children was strongest when the same test was used at both assessments, and when children were 4 years or older at initial assessment.


Practice of laparoscopic prolapse surgery in Europe - ESGE Survey.
Sacrocolpopexy is considered as the "gold standard" for management of women with apical prolapse. Numerous technical variants are being practiced. The first aim of this survey was to determine the habits of practice of laparoscopic sacrocolpopexy (LSCP) in Europe. The second aim was to determine whether surgeons who perform laparoscopic pelvic organ prolapse (POP) repair are familiar with the practice of alternative techniques and with mesh-less laparoscopic treatment of prolapse. The questionnaire was designed by the Urogynaecology Special Interest Group of the European Society for Gynaecological Endoscopy (ESGE). All ESGE-members were invited by email to respond to this survey consisting of 54 questions divided in different categories. Following review of ESGE member's responses, we have highlighted the great heterogeneity concerning the practice of LSCP and important variability in performance of concomitant surgeries. Alternative techniques are rarely used in practice. Furthermore, the lack of standardisation of the many surgical steps of a laparoscopic sacrocolpopexy is mainly due to the lack of evidence. There is a need for training and teaching in both standard and newer innovative techniques as well as the reporting of medium and long-term outcomes of both standard laparoscopic sacrocolpopexy and any of its alternatives.


Zebrafish Behavior: Opportunities and Challenges.
A great challenge in neuroscience is understanding how activity in the brain gives rise to behavior. The zebrafish is an ideal vertebrate model to address this challenge, thanks to the capacity, at the larval stage, for precise behavioral measurements, genetic manipulations, and recording and manipulation of neural activity noninvasively and at single-neuron resolution throughout the whole brain. These techniques are being further developed for application in freely moving animals and juvenile stages to study more complex behaviors including learning, decision making, and social interactions. We review some of the approaches that have been used to study the behavior of zebrafish and point to opportunities and challenges that lie ahead.


Persistence and reactivation of bovine herpesvirus 1 in the tonsils of latently infected calves.
Bovine herpesvirus 1 (BHV-1), like other members of the Alphaherpesvirinae subfamily, establishes latent infection in sensory neurons. Reactivation from latency can occur after natural or corticosteroid-induced stress culminating in recurrent disease and/or virus transmission to uninfected animals. Our previous results concluded that CD4(+) T cells in the tonsil and other adjacent lymph nodes are infected and undergo apoptosis during acute infection (M. T. Winkler, A. Doster, and C. Jones, J. Virol. 73:8657-8668, 1999). To test whether BHV-1 persisted in lymphoreticular tissue, we analyzed tonsils of latently infected calves for the presence of viral DNA and gene expression. BHV-1 DNA was consistently detected in the tonsils of latently infected calves. Detection of the latency-related transcript (LRT) in tonsils of latently infected calves required nested reverse transcription-PCR (RT-PCR) suggesting that only a few cells contained viral DNA or that LRT is not an abundant transcript. bICP0 (immediate-early and early transcripts), ribonucleotide reductase (early transcript), and glycoprotein C (late transcript) were not detected by RT-PCR in latently infected calves. When reactivation was initiated by dexamethasone, bICP0 and ribonucleotide reductase transcripts were detected. Following dexamethasone treatment, viral nucleic acid was detected simultaneously in trigeminal ganglionic neurons and lymphoid follicles of tonsil. LRT was detected at 6 and 24 h after dexamethasone treatment but not at 48 h. Dexamethasone-induced reactivation led to apoptosis that was localized to tonsillar lymphoid follicles. Taken together, these findings suggest that the tonsil is a site for persistence or latency from which virus can be reactivated by dexamethasone. We further hypothesize that the shedding of virus from the tonsil during reactivation plays a role in virus transmission.


Transfusion effects on cardiomyocyte growth and proliferation in fetal sheep after chronic anemia.
Chronic fetal anemia results in significant cardiac remodeling. The capacity to reverse these effects is unknown. We examined the effects of transfusion on cardiomyocyte adaptations after chronic anemia in fetal sheep subjected to daily hemorrhage beginning at 109-d GA (term ∼145 d). After 10 d of anemia, one group was killed for comparison with age-matched controls. A separate group of anemic fetuses was transfused with red blood cells at 119-d GA for comparison with controls at 129-d GA. Anemia significantly increased the heart-to-body weight ratio, an effect partially ameliorated after transfusion. Cardiomyocyte dimensions were similar among all groups, suggesting an absence of hypertrophy. The percentages of mono- and binucleated cardiomyocytes were similar between groups at 119-d GA, although the percentage of binucleated cells was significantly less in transfused fetuses compared with controls at 129-d GA. Protein levels of mitogen-activated protein kinases and protein kinase B were similar between controls and their respective intervention groups, except for a significant increase in phosphorylated c-Jun N-terminal kinase 1/2 in transfused fetuses. Thus, cardiomyocyte proliferation but not hypertrophy contributes to cardiac enlargement during fetal anemia. Transfusion results in slowing but not cessation of cardiac growth after anemia.


Photon beam audits for radiation therapy clinics: a pilot mailed dosemeter study in Turkey.
A thermoluminescent dosemeter (TLD) mailed dose audit programme was performed at five radiotherapy clinics in Turkey. The intercomparison was organised by the University of Wisconsin Radiation Calibration Laboratory (UWRCL), which was responsible for the technical aspects of the study including reference irradiations, distribution, collection and evaluation. The purpose of these audits was to perform an independent dosimetry check of the radiation beams using TLDs sent by mail. Acrylic holders, each with five TLD chips inside and instructions for their irradiation to specified absorbed dose to water of 2 Gy, were mailed to all participating clinics. TLD irradiations were performed with a 6 MV linear accelerator and (60)Co photon beams. The deviations from the TL readings of UWRCL were calculated. Discrepancies inside the limits of ±5 % between the participant-stated dose, and the TLD-measured dose were considered acceptable. One out of 10 beams checked was outside this limit, with a difference of 5.8 %.


[Population interactions in biological system: influenza virus A--wild and domestic animals--human; reasons and consequences of introduction high pathogenic influenza virus A/H5N1 on Russian territory].
Own results and literature data under the analysis of variability of a influenza virus A and population interactions in biological system: influenza virus A--wild and domestic animals--human are presented. Opportunities of virus reassortants appearance between viruses of animals and viruses of human and spreading the new pandemic variants are proved, in particular, at simultaneous infection of pigs with virus H5 and viruses of human influenza H1 and H3, circulating worldwide. Blocks of preparation to a flu pandemic, including on vaccine prophylactic are stated. It is discussed, what vaccines it is necessary to prepare. Inadmissibility the use of alive influenza vaccines is emphasized.


The Effect of Potato Protease Inhibitor II on Gastrointestinal Hormones and Satiety in Humans During Weight Reduction.
It is questioned whether the potato protein protease inhibitor II (PI2) reduces appetite and exerts effects on the satiety hormone cholecystokinin (CCK). To investigate PI2 impact on gastrointestinal hormones and appetite measures during weight reduction. In a randomized, placebo-controlled trial over 20 weeks, fifty-two overweight/obese participants (BMI 25.2-38.0 kg/m2) received a protein-rich diet (30%) adjusted to 500 kcal below their individual daily needs. Subjects ingested a capsule containing either PI2 (150 mg) or placebo twice daily 1 hr before lunch and dinner. At week 0 and week 10 participants joined breakfast test meals to determine CCK, GLP-1, ghrelin, leptin, glucose and insulin concentrations in a time course experimental manner. Appetite sensations were measured on test meal days and in week 4, 9, 14 and 19 using visual analogue scales. Weight loss at week 10 and 20 in the PI2 group was 4.3±3.1 kg and 5.6±4.1 kg, in the control group: 4.7±4.0 kg and 6.8±3.7 kg. A significant effect of PI2 on circulating CCK levels was observed at week 10. The other hormones were unaffected by PI2. At week 10, PI2 group subjects showed higher satiety and decreased desire to eat compared to placebo. During study duration, PI2 showed a significant impact on appetite ratings prior to lunch, one hour before dinner and just before dinner. PI2 increased circulating CCK plasma levels during the diet intervention. Likewise, PI2 modulated appetite sensation from week 4 to 20. The study demonstrated that the PI2 can modulate a key satiety signal.


Different algal symbionts explain the vertical distribution of dominant reef corals in the eastern Pacific.
Symbiotic reef corals occupy the entire photic zone; however, most species have distinct zonation patterns within the light intensity gradient. It is hypothesized that the presence of specific symbionts adapted to different light regimes may determine the vertical distribution of particular hosts. We have tested this hypothesis by genetic and in situ physiological analyses of the algal populations occupying two dominant eastern Pacific corals, over their vertical distribution in the Gulf of California. Our findings indicate that each coral species hosts a distinct algal taxon adapted to a particular light regime. The differential use of light by specific symbiotic dinoflagellates constitutes an important axis for niche diversification and is sufficient to explain the vertical distribution patterns of these two coral species.


Royal Jelly: Beneficial Properties and Synergistic Effects with Chemotherapeutic Drugs with Particular Emphasis in Anticancer Strategies.
Cancer is one of the major causes of death globally. Currently, various methods are used to treat cancer, including radiotherapy, surgery, and chemotherapy, all of which have serious adverse effects. A healthy lifestyle, especially a nutritional diet, plays a critical role in the treatment and prevention of many disorders, including cancer. The above notion, plus the trend in going back to nature, encourages consumers and the food industry to invest more in food products and to find potential candidates that can maintain human health. One of these agents, and a very notable food agent, is royal jelly (RJ), known to be produced by the hypopharyngeal and mandibular salivary glands of young nurse honeybees. RJ contains bioactive substances, such as carbohydrates, protein, lipids, peptides, mineral salts and polyphenols which contribute to the appreciated biological and pharmacological activities. Antioxidant, anticancer, anti-inflammatory, antidiabetic, and antibacterial impacts are among the well-recognized benefits. The combination of RJ or its constituents with anticancer drugs has synergistic effects on cancer disorders, enhancing the drug's effectiveness or reducing its side effects. The purpose of the present review is to emphasize the possible interactions between chemotherapy and RJ, or its components, in treating cancer illnesses.


Cognitive function and quality of life in mild thyroid hormone deficiency.
Subclinical hypothyroidism (sHT) is very common in general population, especially in women and older people. sHT individuals may experience symptoms that resemble those observed in overt hypothyroidism, resulting in impaired quality of life (QOL). Asymptomatic patients may suffer a reduction in perceived health status due to the awareness of disease. Cognitive function represents one of the most important domains of the QOL questionnaires. Given the intrinsic relationship between cognitive status and QOL it is worth to address these topics together, in a systematic review of the literature. Thus, we reviewed the English scientific literature available on National Library of Medicine (www.pubmed.com) sine 1980 regarding hypothyroidism, sHT, elderly, L-thyroxine (LT4) therapy, QOL, cognition, brain. We supplemented the search with records from personal files, textbooks, and relevant articles. The possible link, at molecular level, between cognition and thyroid failure was also assessed. Conflicting results on the association between sHT and cognitive and health related QOL impairment are still present, although the most recent, naturalistic studies did not find any significant relationship. Interestingly, a reduction in health related QOL is frequently reported in patients with thyroid autoimmune diseases regardless of thyroid dysfunction. We also report most significant patents on the topic.


Complementation of P37 (F13L gene) knock-out in vaccinia virus by a cell line expressing the gene constitutively.
Vaccinia virus produces two different infectious forms, intracellular mature virus (IMV) and extracellular enveloped virus (EEV). Acquisition of the EEV envelope occurs by wrapping of IMV with vesicles of the trans-Golgi network (TGN). The most abundant protein in the envelope of EEV, P37, is a 37 kDa palmitylated protein encoded by the F13L gene. P37 is located in the inner side of the EEV envelope and accumulates in the TGN during infection. Deletion of gene F13L results in a severe defect in the wrapping process, although normal levels of IMV are produced. A cell line, derived from RK-13 cells, was obtained that stably expressed P37 (RK(P37)), and the properties of the protein were studied in the absence of other viral polypeptides. P37 produced in RK(P37) cells differed from P37 produced in vaccinia-infected cells in terms of hydrophobicity and intracellular distribution. Despite these differences, RK(P37) cells partially complemented the phenotypic defect of vaccinia virus P37- mutants. EEV production and cell-to-cell virus spread by mutant viruses were increased significantly in RK(P37) cells when compared to normal RK-13 cell cultures. Infection of RK(P37) cells with P37- virus substantially altered the hydrophobicity and the intracellular distribution of P37 in those cells. These results indicate the requirement of the infection context for determination of the normal palmitylation and intracellular localization of P37.


Rostral ventrolateral medullary but not medullary lateral tegmental field neurons mediate sympatho-sympathetic reflexes in cats.
This study was designed to build on past work from this laboratory by testing the hypothesis that medullary lateral tegmental field (LTF) neurons play a critical role in mediating sympathoexcitatory responses to activation of sympathetic afferent fibers. We studied the effects of microinjection of N-methyl-d-aspartate (NMDA) or non-NMDA receptor antagonists or muscimol bilaterally into the LTF on the area under the curve of the computer-averaged sympathoexcitatory potential in the right inferior cardiac nerve elicited by short trains of stimuli applied to afferent fibers in the left inferior cardiac or left splanchnic nerve (CN, SN) of baroreceptor-denervated and vagotomized cats anesthetized with a mixture of diallylbarbiturate and urethane. In contrast to our hypothesis, sympathoexcitatory responses to stimulation of CN (n = 5-7) or SN (n = 4-7) afferent fibers were not significantly affected by these procedures. We then determined whether the rostral and caudal ventrolateral medulla (RVLM, CVLM) and nucleus tractus solitarius (NTS) were involved in mediating these reflexes. Blockade of non-NMDA, but not NMDA, receptors in the RVLM significantly reduced the area under the curve of the sympathoexcitatory responses to electrical stimulation of either CN (P = 0.0110; n = 6) or SN (P = 0.0131; n = 5) afferent fibers. Neither blockade of excitatory amino acid receptors nor chemical inactivation of CVLM or NTS significantly affected the responses. These data show that activation of non-NMDA receptors in the RVLM is a critical step in mediating the sympatho-sympathetic reflex.


Chemical sensor based on nonlinearity: principle and application.
Novel chemical sensors based on a time-dependent nonlinear response are reviewed. The strategy is to artificially mimic information transduction in living organisms. In taste and olfaction, information of chemical structure and concentration is transformed into nervous impulses in the nervous cell, i.e., time-dependent multi-dimensional information. Because the excitation and pulse generation in the nervous cell are typically nonlinear phenomena, it may be worthwhile to utilize the nonlinearity as the multi-dimensional information for molecular recognition. The principle of a "nonlinear" sensor is that a sinusoidal modulation is applied to a system, and the output signal is analyzed. The output signal of the sensor is characteristically deformed from the sinusoidal input depending on the chemical structure and concentration of the chemical stimuli. The characteristic nonlinear responses to chemical stimuli are discussed in relation to the kinetics of chemical compounds on the sensor surface. As a practical application, we introduced electrochemical sensors based on the differential capacitance, semiconductor gas sensors under the application of sinusoidal temperature or diffusion change, and a chemical sensor based on the spatio-temporal information. We demonstrated that mutli-dimensional information based on nonlinearity can provide quite useful information for the analysis of chemical species, even in the presence of another analyte or an interference with a single detector.


Does curcumin protect against renal dysfunction following reversible unilateral ureteric obstruction in the rat?
To investigate the effect of curcumin on the alterations in renal functional parameters following reversible unilateral ureteric obstruction in the rat. Wistar rats underwent reversible left ureteric obstruction for 72 h. The group Cm (n = 7) received oral curcumin (200 mg/kg/day), whereas the Vx group (n = 8) had only a vehicle. Ureteric obstruction caused a significant increase in the serum tumour necrosis factor α in both groups. However, the post-obstruction level in the Cm group was significantly lower than in the Vx group. In the Vx group, the glomerular filtration rate, renal blood flow, urine volume and urinary sodium excretion in the left obstructed kidney were significantly lower than those in the right kidney, but the fractional excretion of sodium was comparable in the 2 groups. The left kidney in the Cm group behaved similar to that in the Vx group. Moreover, there was no difference in any variable when comparing the right and left kidneys among the groups. Curcumin appears to have no significant protective effect on the haemodynamic or tubular glomerular functions when measured as early as 3 days following reversible ureteric obstruction despite the amelioration in some of the indicators of renal injury.


Delayed hypersensitivity to Newcastle disease virus in high and low interferon-producing mice.
Since it was previously shown that IFN, under certain conditions, can stimulate sensitization to SRBC, we examined the intensity and duration of DH to NDV in high and low IFN-alpha and -beta producing mice that carried either the h or I allele at the If-1 locus. In C57BL/6 mice (If-1h) DH to NDV is of higher intensity and longer duration than in BALB/c (If-1l). Evidence that this difference is related to the higher IFN-alpha and -beta production induced by NDV in C57BL/6 mice was obtained by comparing DH to NDV in C57BL/6 (If-1h) mice and in mice of three congenic strains, carrying the If-1l allele on a C57BL/6 background (B6.C-H-28c-If-1l). In the latter, DH to NDV was much more of BALB/c than of C57BL/6 type, since after footpad challenge a significant reaction was only observed at 24 hr and no longer at 48 hr. When the low endogenous IFN production of the If-1l congenic mice was compensated for by giving extra IFN-alpha and -beta a few hours after sensitization with NDV, DH was enhanced. If, on the other hand, anti IFN-alpha and -beta globulins were administered to either C57BL/6 or If-1l congenic mice immediately after sensitization with NDV, DH was decreased. These results indicate that, on a C57BL/6 background, the establishment of DH to NDV is influenced by the alleles at If-1, determining the levels of endogenous IFN-alpha and -beta induced by NDV.


Twenty five year mortality and air pollution: results from the French PAARC survey.
Long term effects of air pollution on mortality were studied in 14,284 adults who resided in 24 areas from seven French cities when enrolled in the PAARC survey (air pollution and chronic respiratory diseases) in 1974. Daily measurements of sulphur dioxide, total suspended particles, black smoke, nitrogen dioxide, and nitric oxide were made in 24 areas for three years (1974-76). Cox proportional hazards models controlling for individual confounders (smoking, educational level, body mass index, occupational exposure) were applied, and frailty models used to take into account spatial correlation. Indicators of air pollution were the mean concentration. Models were run before and after exclusion of six area monitors influenced by local traffic (NO/NO2 >3 in ppb). After exclusion of these areas, analyses showed that adjusted risk ratios (95% CI) for TSP, BS, NO2, and NO for non-accidental mortality were 1.05 (1.02 to 1.08), 1.07 (1.03 to 1.10), 1.14 (1.03 to 1.25), and 1.11 (1.05 to 1.17) for 10 microg/m3 respectively. Consistent patterns for lung cancer and cardiopulmonary causes were observed. Urban air pollution assessed in the 1970s was associated with increased mortality over 25 years in France.


Allergenic pollen production across a large city for common ragweed (Ambrosia artemisiifolia).
Predictions of airborne allergenic pollen concentrations at fine spatial scales require information on source plant location and pollen production. Such data are lacking at the urban scale, largely because manually mapping allergenic pollen producing plants across large areas is infeasible. However, modest-sized field surveys paired with allometric equations, remote sensing, and habitat distribution models can predict where these plants occur and how much pollen they produce. In this study, common ragweed (Ambrosia artemisiifolia) was mapped in a field survey in Detroit, MI, USA. The relationship between ragweed presence and habitat-related variables derived from aerial imagery, LiDAR, and municipal data were used to create a habitat distribution model, which was then used to predict ragweed presence across the study area (392 km2). The relationship between inflorescence length and pollen production was used to predict pollen production in the city. Ragweed occurs in 1.7% of Detroit and total pollen production is 312 × 1012 pollen grains annually, but ragweed presence was highly heterogeneous across the city. Ragweed was predominantly found in in vacant lots (75%) and near demolished structures (48%), and had varying associations with land cover types (e.g., sparse vegetation, trees, pavement) detected by remote sensing. These findings also suggest several management strategies that could help reduce levels of allergenic pollen, including appropriate post-demolition management practices. Spatially-resolved predictions for pollen production will allow mechanistic modeling of airborne allergenic pollen and improved exposure estimates for use in epidemiological and other applications.


Design and Characterization of Biosensors for the Screening of Modular Assembled Naringenin Biosynthetic Library in Saccharomyces cerevisiae.
A common challenge in the assembly and optimization of plant natural product biosynthetic pathways in recombinant hosts is the identification of gene orthologues that will result in best production titers. Here, we describe the modular assembly of a naringenin biosynthetic pathway in Saccharomyces cerevisiae that was facilitated by optimized naringenin-inducible prokaryotic transcription activators used as biosensors. The biosensors were designed and developed in S. cerevisiae by a multiparametric engineering strategy, which further was applied for the in vivo, high-throughput screening of the established yeast library. The workflow for assembling naringenin biosynthetic pathways involved Golden gate-directed combinatorial assembly of genes and promoters, resulting in a strain library ideally covering 972 combinations in S. cerevisiae. For improving the performance of our screening biosensor, a series of fundamental components was optimized, affecting the efficiency of the biosensor such as nuclear localization signal (NLS), the detector module and the effector module. One biosensor (pTDH3_NLS_FdeR-N_tPGK1-pGPM1-fdeO_mcherry_tTDH1-MV2) showed better performance, defined as better dynamic range and sensitivity than others established in this study as well as other previously reported naringenin biosensors. Using this biosensor, we were able to identify a recombinant S. cerevisiae strain as the most efficient candidate for the production of naringenin from the established naringenin biosynthetic library. This approach can be exploited for the optimization of other metabolites derived from the flavonoid biosynthetic pathways and more importantly employed in the characterization of putative flavonoid biosynthetic genes.


Effects of miR-7 on Hcy-induced rat cerebral arterial vascular smooth muscle cell proliferation, migration and inflammatory factor expression by targeting MMP-14 to regulate TLR4/NF-κB signaling pathway.
The current research aimed to investigate the effect of miR-7 targeting matrix metalloproteinase 14 (MMP-14) on homocysteine (Hcy)-induced rat cerebral artery vascular smooth muscle cells (VSMCs) proliferation, migration and inflammatory factor expression and its possible mechanism. The expression of miR-7 and MMP-14 in Hcy-induced VSMCs were detected by real-time fluorescent quantitative PCR (RT-qPCR) and Western blot. Methyl Thiazolyl Tetrazolium (MTT) method, Transwell assays and enzyme-linked immunosorbent assay (ELISA) were performed to detect the effect of miR-7 and MMP-14 expression on the proliferation and migration, as well as interleukin 6 (IL-6) and tumor necrosis factor ɑ (TNF-ɑ) expression of Hcy-induced VSMCs. The interaction between miR-7 and MMP-14 was detected by dual-luciferase reporter gene assay. Western blot was applied to analyse the effects of miR-7 and MMP-14 expression on the Toll-like receptor (TLR4)/nuclear transcription factor-KB (NF-κB) signaling pathway. The results showed that after induced by Hcy, the expression of miR-7 in VSMCs was significantly reduced, the expression of MMP-14 was significantly increased, and the cell viability, the number of migrating cells, IL-6 and TNF-ɑ expression were significantly increased (P<0.05). After overexpression of miR-7, the viability, migration cell numbers, IL-6 and TNF-ɑ expression of Hcy-induced VSMCs were significantly reduced (P<0.05). miR-7 directly binds to MMP-14 and negatively regulates the expression of MMP-14. After overexpression of miR-7, the levels of TLR4 and p-NF-κB p65 in VSMCs were significantly reduced (P<0.05); overexpression of MMP-14 could reduce the effect of miR-7 overexpression on TLR4 and p-NF-κB p65 expression in VSMCs (P<0.05). Overexpression of MMP-14 and/or activation of the TLR4/NF-κB signaling pathway could reverse the effect of miR-7 overexpression on the proliferation, migration and IL-6 and TNF-ɑ expression of Hcy-induced VSMCs (P<0.05). It is concluded that miR-7 can inhibit Hcy-induced rat cerebral artery VSMCs proliferation, migration, and inflammatory factor expression by targeting the regulation of MMP-14 expression and inhibiting the activation of the TLR4/NF-κB signaling pathway.


Binding of immunophilins to the 90 kDa heat shock protein (hsp90) via a tetratricopeptide repeat domain is a conserved protein interaction in plants.
In animal cell lysates, multiprotein complexes containing hsp90, hsp70, p60, p23, and several immunophilins can assemble steroid receptors and oncogenic protein kinases, such as v-Src and v-Raf, into heterocomplexes that contain hsp90 and either immunophilins or, in the case of protein kinases, p50. The complexes with hsp90 are required for the proper functioning of these signal transduction systems. Wheat germ lysate contains a similar protein folding activity that forms functional steroid receptor complexes with hsp90, but not all the components of this system have been identified. The plant chaperone system has conserved interactions with animal chaperones in that wheat hsp70 functions in the rabbit reticulocyte lysate heterocomplex assembly system and human p23 functions in the wheat germ lysate. Here, we ask if wheat germ lysate also contains immunophilins of the FK506-binding class (FKBPs) that bind to the hsp90 component of the chaperone complex via tetratricopeptide repeat (TPR) domains. To demonstrate the plant heterocomplex, we add purified mammalian p23, preadsorbed with the JJ3 antibody to protein A-Sepharose, to wheat germ lysate and allow ATP-dependent formation of an animal p23. plant hsp90 complex. The complex is then washed and incubated with the radiolabeled immunosuppressant drug [3H]FK506, which binds in a specific manner to a coimmunoadsorbed plant FKBP. Binding of the plant FKBP to plant hsp90 is prevented by adding to wheat germ lysate a purified fragment containing the TPR domains of human cyclophilin-40. Geldanamycin, a benzoquinone ansamycin that binds to animal hsp90s and prevents their chaperone activity, binds in a temperature-dependent manner to wheat hsp90 to block formation of the p23.hsp90.FKBP heterocomplex. These data show that immunophilin binding to hsp90 via TPR domains is conserved in the plant kingdom as well as in the animal kingdom and that geldanamycin will be an important tool for the study of hsp90-mediated protein chaperoning in plant cells.


Comparison of the nucleoside sequence of trpA and sequences immediately beyond the trp operon of Klebsiella aerogenes. Salmonella typhimurium and Escherichia coli.
The nucleotide sequence of trpA of Klebsiella aerogenes is presented and compared with the trpA sequences of Salmonella typhimurium and Escherichia coli. The majority of the approximately 200 differences between each pair of trpA's are single nucleotide pair changes that do not alter the amino acid sequence. Codon usage conforms to the general patterns revealed by examination of other prokaryotic gene sequences. However, codon usage in K. aerogenes trpA reflects the high G+C content of the genome of this organism. The DNA sequences just beyond trpA, the presumed transcription termination region, are also compared for the three species. Perusal of these sequences indicates that the secondary structure of the transcript segment just beyond trpA has been preserved, while the primary sequence has diverged appreciably.


Colocalization and interaction of the porcine arterivirus nucleocapsid protein with the small nucleolar RNA-associated protein fibrillarin.
Porcine reproductive and respiratory syndrome virus (PRRSV) replicates in the cytoplasm of infected cells, but its nucleocapsid (N) protein localizes specifically to the nucleus and nucleolus. The mechanism of nuclear translocation and whether N associates with particular nucleolar components are unknown. In the present study, we show by confocal microscopy that the PRRSV N protein colocalizes with the small nucleolar RNA (snoRNA)-associated protein fibrillarin. Direct and specific interaction of N with fibrillarin was demonstrated in vivo by the mammalian two-hybrid assay in cells cotransfected with the N and fibrillarin genes and in vitro by the glutathione S-transferase pull-down assay using the expressed fibrillarin protein. Using a series of deletion mutants, the interactive domain of N with fibrillarin was mapped to a region of amino acids 30 to 37. For fibrillarin, the first 80 amino acids, which contain the glycine-arginine-rich region (the GAR domain), was determined to be the domain interactive with N. The N protein was able to bind to the full-length genomic RNA of PRRSV, and the RNA binding domain was identified as the region overlapping with the nuclear localization signal situated at positions 41 to 47. These results suggest that the N protein nuclear transport may be controlled by the binding of RNA to N. The PRRSV N protein was also able to bind to both 28S and 18S ribosomal RNAs. The protein-protein interaction between N and fibrillarin was RNA dependent but independent of N protein phosphorylation. Taken together, our studies demonstrate a specific interaction of the PRRSV nucleocapsid protein with the host cell protein fibrillarin in the nucleolus, and they imply a potential linkage of viral strategies for the modulation of host cell functions, possibly through rRNA precursor processing and ribosome biogenesis.


EEG arousals and awakenings in relation with periodic leg movements during sleep.
It is known that periodic leg movements are frequently accompanied by full awakenings or by signs of EEG arousals. The time relationship of these EEG arousals with leg movements varies from patient to patient. They may precede or follow leg movements or occur simultaneously. It is not clear whether these arousals trigger leg movements or, alternatively, whether both EEG arousals and leg movements are separate expressions of a common pathophysiological mechanism. We investigated the temporal relationship of five EEG arousals, such as alpha activity, K-complexes, spindles, K-alpha, K-spindle activities and awakenings, with leg movements in 10 periodic leg movement patients. These EEG arousals were considered to be associated with leg movements if they occurred 10 s before/after or simultaneously with the onset of right or left tibialis muscle EMG potentials. It was found that 49.19% of EEG arousals occurred before leg movements, 30.61% occurred simultaneously and 23.18% occurred just after leg movements. The number of EEG arousals was significantly higher in the 10 s preceding leg movement than simultaneously or in the 10 s following. Alpha activity was the phenomenon associated most frequently with leg movements, irrespective of its temporal organization and was significantly higher during the 10 s preceding movement. Spindle and K-spindle activities were significantly higher before leg movement, whereas K-complex activity was significantly more frequent during leg movements. The number of awakenings was significantly higher after leg movements than simultaneously. These results indicated that leg movements are not primary, but rather are a phenomenon associated with an underlying arousal disorder.


Automated sleep stage scoring using hybrid rule- and case-based reasoning.
We propose an automated method for sleep stage scoring using hybrid rule- and case-based reasoning. The system first performs rule-based sleep stage scoring, according to the Rechtschaffen and Kale's sleep-scoring rule (1968), and then supplements the scoring with case-based reasoning. This method comprises signal processing unit, rule-based scoring unit, and case-based scoring unit. We applied this methodology to three recordings of normal sleep and three recordings of obstructive sleep apnea (OSA). Average agreement rate in normal recordings was 87.5% and case-based scoring enhanced the agreement rate by 5.6%. This architecture showed several advantages over the other analytical approaches in sleep scoring: high performance on sleep disordered recordings, the explanation facility, and the learning ability. The results suggest that combination of rule-based reasoning and case-based reasoning is promising for an automated sleep scoring and it is also considered to be a good model of the cognitive scoring process.


Heavy metal accumulation in rosemary leaves and stems exposed to traffic-related pollution near Adana-İskenderun Highway (Hatay, Turkey).
Pollution has become a problem on a global scale and poses a significant risk in terms of human health and natural ecosystems. Generally, the biggest sources of pollution are municipal and industrial facilities. However, traffic-related air pollution cannot be overlooked as a dangerous source either. There have been various methods of interventions to measure and reduce the risk and effects of traffic-related pollution. In the case of measuring, the use of certain plant species that can accumulate pollutants in their tissues is considered a practical solution. In this study, the aim is to find out the metals that are accumulated in rosemary leaves and stems and the rosemary leaves. In other words, the leaves and the stems are to be used as a biomonitors to reveal the rate of metal pollution along the highway. We try to identify the accumulation ability of traffic-related heavy metals (Al, Cd, Cr, Cu, Fe, Mn, Ni, Pb, and Zn) of the Rosmarinus officinalis L. (rosemary) which is used in the refuge and slopes along the highway connecting Adana with İskenderun (Hatay). Our findings concluded that the rosemary could have a decent capacity to accumulate Al, Cd, Cr, Cu, Fe, Mn, Pb, and Zn in both leaves and stem. We therefore believe that R. officinalis is a great tool in determining the amount of traffic-related pollution in urban areas.


Spirillum swimming: theory and observations of propulsion by the flagellar bundle.
The hydrodynamics and energetics of helical swimming by the bacterium Spirillum sp. is analysed using observations from medium speed cine photomicrography and theory. The photographic records show that the swimming organism's flagellar bundles beat in a helical fashion just as other bacterial flagella do. The data are analysed according to the rotational resistive theory of Chwang & Wu (1971) in a simple-to-use parametric form with the viscous coefficients Cs and Cn calculated according to the method of Lighthill (1975). Results of the analysis show that Spirillum dissipated biochemical energy in performing work against fluid resistance to motion at an average rate of about 6 X 10(-8) dyne cm s-1 with some 62-72% of the power dissipation due to the non-contractile body. These relationships yield a relatively low hydromechanical efficiency which is reflected in swimming speeds much smaller than a representative eukaryote. In addition the Cn/Cs ratio for the body is shown to lie in the range 0-86-1-51 and that for the flagellar bundle in the range 1-46-1-63. The implications of the power calculations for the Berg & Anderson (1973) rotating shaft model are discussed and it is shown that a rotational resistive theory analysis predicts a 5-cross bridge M ring for each flagellum of Spirillum.


Hybrid nanomaterials: anchoring magnetic molecules on naked gold nanocrystals.
The pairing of molecular magnets and nanomaterials couples top-down and bottom-up approaches to nanotechnology; facilitating a unique methodology to the controlled study of interfacial magnetic properties. Attaching Single-Molecule Magnets (SMMs) to "naked" gold nanoparticles is a novel method of exploring various avenues of magnetic nanotechnology, such as drug delivery, information storage, catalysis, and assembly of magnetic-nanostructural motifs. Herein we report the successful capping of laser ablation synthesized "naked" gold nanoparticles with a dinuclear dysprosium complex, while introducing new information regarding the changes in molecular magnetic properties upon surface attachment. We anticipate that this methodology in producing these magneto-plasmonic nanostructures not only provides answers to fundamental questions but also has the potential to provide new avenues to applications including information storage, multimodal imaging, biomedicine, and optoelectronics.


THC:CBD spray and MS spasticity symptoms: data from latest studies.
New clinical experience with 9-delta-tetrahydocannabinol (THC) and cannabidiol (CBD) oromucosal spray (Sativex®) involving more than an additional 1,000 patients with MS spasticity (approximately 150 in clinical studies and 900 in post-marketing surveillance studies) have become available in 2013 and are reviewed. A randomized, placebo controlled long-term follow-up clinical trial with THC:CBD spray versus placebo demonstrated that it was not associated with cognitive decline, depression or significant mood changes after 12 months of treatment. Furthermore, in a prospective observational pilot study involving 33 patients (60% female) aged 33-68 years and a mean disease duration of 6.6 years, THC:CBD oromucosal spray did not adversely influence standard driving ability in patients with moderate to severe MS spasticity. Other new long term observational data about the use of THC:CBD oromucosal spray in clinical practice are available from patient registries in the UK, Germany and Spain. Findings to date reinforce the efficacy and safety observed in Phase III clinical trials. It is of interest that in practice average dosages used by patients tended to be lower than those reported in clinical studies (5-6.4 vs. >8 sprays/day), and effectiveness was maintained in the majority of patients. Importantly, no additional safety concerns were identified in the registry studies which included findings from patients who have been treated for prolonged periods (in the German/UK registry 45% of patients had >2 years exposure). Thus, these new data support a positive benefit-risk relationship for THC:CBD oromucosal spray during longer-term use.


Glycolipid membrane-binding domain of human erythrocyte acetylcholinesterase.
The membrane-binding domain of human erythrocyte acetylcholinesterase is a small hydrophobic structure at the COOH-terminus of the enzyme subunits. Papain digestion cleaves a COOH-terminal dipeptide linked to the hydrophobic structure with the sequence His-Gly-ethanolamine-Z, where the ethanolamine is in amide linkage to the glycine and Z is a partially characterized glycolipid. This glycolipid includes a second residue of ethanolamine and a residue of glucosamine, both of which have free primary amino groups accessible to radiomethylation. The glycolipid also contains a carbohydrate residue or residues that bind to concanavalin A and nearly stoichiometric amounts of both palmitate and C22 unsaturated fatty acids. Similarities in this membrane-binding structure to those reported for trypanosome variant surface glycoproteins and Thy-1 glycoprotein suggest an important new category of posttranslational modifications involving the attachment of COOH-terminal glycolipid.


Elevated levels of glyoxylate shunt enzymes in Escherichia coli strains constitutive for fatty acid degradation.
Mutants of Escherichia coli K-12 constitutive for the synthesis of the enzymes of fatty acid degradation (fadR) have elevated levels of the glyoxylate shunt enzymes, isocitrate lyase and malate synthase. A temperature-sensitive fadR strain has high levels of glyoxylate shunt enzymes when grown at elevated temperatures but has low, inducible levels of glyoxylate shunt enzymes when grown at low temperatures. The increased activity of glyoxylate shunt enzymes did not appear to be due to the degradation of intracellular fatty acids in fadR strains or differences in allosteric effectors in fadR versus fadR+ strains. These studies suggest that the fadR gene product may be involved in the regulation of the glyoxylate operon.


Storage of iron in bone marrow plasma cells. Ultrastructural characterization, mobilization, and diagnostic significance.
The physiological site of iron storage in the human bone marrow is the macrophage (orthotopic iron store). Iron-storing plasma cells, as bone marrow indicators of iron overload, and/or chronic alcoholism represent a pathological (heterotopic) iron store. They were demonstrated by light and electron microscopy in 23 iron-overloaded patients: transfusional siderosis (n = 8), genetic haemochromatosis (GH; n = 11), iron-loading anaemias (n = 4) and in patients with bone marrow impairment due to chronic alcoholism (n = 6). The pattern of iron storage in bone marrow plasma cells was monitored during iron loading in patients receiving continuous transfusional therapy (n = 7) and also upon reversal of iron overload by repeated phlebotomies in GH (n = 9) and in iron-loading anaemias (n = 4). The first ultrastructural evidence of iron storage in plasma cells was the appearance of free ferritin molecules in the cytosol, thus indicating endogenous ferritin synthesis. Accumulation of iron proceeded with the additional formation of ferritin- and haemosiderin-containing lysosomes (siderosomes) in these cells. Lysosomal ferritin partially showed a paracrystalline array. The siderosomes originated from autophagocytosis of cytoplasmic areas containing free ferritin molecules. In addition, the formation of ferritin-containing vesicles in the proximity of the Golgi apparatus was observed. The heterotopic iron store of bone marrow plasma cells was less readily mobilizable by blood-letting than the orthotopic store of macrophages.


[Effect of parenteral nitrogen feeding on the free amino acid composition of the blood serum and liver tissue in irradiated rats].
A considerable change in the free amino acid composition of blood serum and hepatic tissue was noted on the 7th and 14th days following total-body X-irradiation of rats with a dose of 2.9 Gy. The total free amino acid content of blood serum increased and that of hepatic tissue decreased by 85% (on an average) as compared to the intact controls. Quantitative changes in the content of individual amino acids were analysed. Polyamine injected enterally for 7 days and parenterally for 3 days after irradiation aids the elimination of the postirradiation changes in the amino acid balance.


PRL/PRLR Can Promote Insulin Resistance by Activating the JAK2/STAT5 Signaling Pathway.
Although prolactin (PRL) is known to affect food intake, weight gain, and insulin resistance, its effects on lipid metabolism and underlying mechanisms remain underinvestigated. This study aimed to investigate the effects of PRL and its receptor (PRLR) on fat metabolism in regulating the JAK2/STAT5 signaling pathway. SW872 adipocytes were incubated with oleic acid to establish an insulin resistance (IR) model. Western blot was used to detect the expression of PRLR, JAK2, p-JAK2, STAT5, and p-STAT5. Triglyceride (TG) mass was detected by chemical colorimetry methods. Fat droplets in the high-dose and medium-dose PRL groups were significantly higher than in the IR model group. TG mass in the cells was increased significantly compared with the model group. Compared with the control group, the expression of PRLR, p-JAK2, and p-STAT5 were significantly decreased in the IR model group when PRL was intervened for 24 h and 48 h. The expression of PRLR, p-JAK2, and p-STAT5 in the high-dose PRL intervention group increased significantly compared with the model group. The PRLR overexpressing group had significantly increased TG content and PRLR, and JAK2, p-JAK2, STAT5, and p-STAT5 levels compared with the IR model. PRL and PRLR are related to fat metabolism, and the PRL/PRLR signaling pathway can promote insulin resistance by activating the JAK2/STAT5 signaling pathway and increasing the deposition of TGs.


From poly(3,4-ethylenedioxythiophene) to poly(3,4-phenylenedioxythiophene): impact of the substitution of the ethylene bridge by the phenyl ring on the molecular properties.
The structural and electronic properties of poly(3,4-phenylenedioxythiophene) and poly(3,4-ethylenedioxythiophene) have been studied using quantum mechanical methods. Calculations have been performed considering a series of oligomers up to 12 repeating units in the neutral and cation states, results being used to extrapolate the properties of the two polymers in the undoped and doped states. Moreover, the electronic properties were estimated in the gas phase and acetonitrile solution, the latter solvent being used in the electrogeneration of the two conducting polymers. A detailed analysis of the results indicates that, although the pi-pi* transition energy of poly(3,4-ethylenedioxythiophene) is lower than that of poly(3,4-phenylenedioxythiophene) in the neutral state, the latter behaves as excellent electronic conductor upon p-doping. Accordingly, the oxidized poly(3,4-phenylenedioxythiophene) shows the lowest pi-pi* electron transition energy.


Early Secretory Pathway-Associated Proteins SsEmp24 and SsErv25 Are Involved in Morphogenesis and Pathogenicity in a Filamentous Phytopathogenic Fungus.
Proper protein secretion is critical for fungal development and pathogenesis. However, the potential roles of proteins involved in the early secretory pathway are largely undescribed in filamentous fungi. p24 proteins are cargo receptors that cycle between the endoplasmic reticulum (ER) and Golgi apparatus in the early secretory pathway and recruit cargo proteins to nascent vesicles. This study characterized the function of two p24 family proteins (SsEmp24 and SsErv25) in a phytopathogenic fungus, Sclerotinia sclerotiorum. Both SsEmp24 and SsErv25 were upregulated during the early stages of S. sclerotiorum infection. ΔSsEmp24 mutant and ΔSsErv25 mutant displayed abnormal vegetative growth and sclerotium formation, were defective in infection cushion formation, and showed lower virulence on host plants. ΔSsEmp24 mutant had a more severe abnormal phenotype than ΔSsErv25 mutant, implying that SsEmp24 could play a central role in the early secretory pathway. Similar to their Saccharomyces cerevisiae counterparts, SsEmp24 interacted with SsErv25 and predominantly colocalized in the ER or nuclear envelope. The absence of SsEmp24 or SsErv25 led to defective in protein secretion in S. sclerotiorum, including the pathogenicity-related extracellular hydrolytic enzymes and effectors. It is proposed that SsEmp24 and SsErv25, components in the early secretory pathway, are involved in modulating morphogenesis and pathogenicity in S. sclerotiorum by mediating protein secretion. IMPORTANCE Understanding the reproduction and pathogenesis mechanism of phytopathogens could provide new opinions to effectively control fungal diseases. Although it has been known that effectors and extracellular hydrolytic enzymes secreted by phytopathogenic fungi play important roles in fungus-host interactions, the secretion system for the delivery of virulence factors to the host is still largely undescribed. Although the role of the early secretory pathway-associated p24 proteins in S. cerevisiae has been well characterized, the function of these proteins in filamentous fungi was scarcely known prior to this study. The present research provides evidence that p24 proteins participate in the reproduction and pathogenesis of phytopathogenic fungi through the mediation of protein secretion. This research advances our understanding of p24 proteins in filamentous phytopathogenic fungi. In addition, the candidate cargos of the two p24 proteins, SsEmp24 and SsErv25, were screened out by comparative proteomics, which could aid the identification of novel development and virulence-associated factors in phytopathogenic fungi.


Performance Evaluation of a Magnetic Resonance Imager with Evidence-Based Decision Making Tools.
Evidence-based decision-making tools were used to evaluate the performance of a 16-year-old 1.5T Magnetic Resonance Imager (MRI) that has been fully dedicated to clinical service in a public hospital in Mexico. The MRI age highlights the importance of regular performance evaluations to ensure that the equipment is still functioning optimally, even when the system went through an important software and hardware updated. The use of Multiple-Criteria Decision-Making is an effective method to evaluate the performance of complex systems like MR imagers. A technical global indicator was set, revealing that only 50% of available time has been used is interesting and could be further investigated to determine if there are any factors limiting the usage of the system. The good performance indicators in terms of productivity, availability, and technical aspects are encouraging and suggest that the updated software and hardware have had a positive impact on the overall performance of the system.Finally, the use of evidence-based decision-making tools to evaluate the performance of the MR imager was a successful approach and can serve as a model for other healthcare facilities to follow.Clinical Relevance- MRI is a non-invasive diagnostic test that uses a magnetic field and radiofrequency waves to obtain detailed images of internal structures of the body. Unlike X-rays and CT scans, which use ionizing radiation, MRI does not expose patients to harmful radiation, making it a safe option for diagnostic imaging. The use of MRI a valuable tool for characterizing lesions, detecting abnormalities, and monitoring disease progression and it is widely used in several medical fields, including neurology, oncology, and orthopedics, among others. Therefore, ensuring that the MRI system is working optimally is crucial for providing reliable and accurate results, which can lead to timely and appropriate treatment for patients.


Mould Infections of Traumatic Wounds: A Brief Narrative Review.
Mould infections may follow traumatic injuries, with direct fungal inoculum in the site of injury and subsequent angioinvasion, possibly resulting in tissue necrosis and systemic dissemination. The pathogenesis of mould infections following trauma injuries presents unique features compared with classical mould infections occurring in neutropenic or diabetic patients, because a large fraction of post-traumatic mould infections is observed in previously healthy individuals. Most of the published clinical experience and research on mould infections following traumatic injuries regards soldiers and infections after natural disasters. However, following trauma and soil contamination (e.g., agricultural or automotive injuries) other immunocompetent individuals may develop mould infections. In these cases, delays in correct diagnosis and treatment may occur if pertinent signs such as necrosis and absent or reduced response to antibacterial therapy are not promptly recognized. Awareness of mould infections in at-risk populations is needed to rapidly start adequate laboratory workflow and early antifungal therapy in rapidly evolving cases to improve treatment success and reduce mortality.


The Escherichia coli histone-like protein HU affects DNA initiation, chromosome partitioning via MukB, and cell division via MinCDE.
Escherichia coli hupA hupB double mutants, lacking both subunits (HU1 and HU2) of the histone-like protein HU, accumulate secondary mutations. In some genetic backgrounds, these include mutations in the minCDE operon, inactivating this system of septation control and resulting in the formation of minicells. In the course of the characterization of hupA hupB mutants, we observed that the simultaneous absence of the HU2 subunit and the MukB protein, implicated in chromosome partitioning, is lethal for the bacteria; the integrity of either HU or MukB thus seems to be essential for bacterial growth. The HU protein has been shown to be involved in DNA replication in vitro; we show here that its inactivation in the hupA hupB double mutant disturbs the synchrony of replication initiation in vivo, as evaluated by flow cytometry. Our results suggest that global nucleoid structure, determined in part by the histone-like protein HU, plays a role in DNA replication initiation, in proper chromosome partitioning directed by the MukFEB proteins, and in correct septum placement directed by the MinCDE proteins.


Microfilament bundles, LETS protein and growth control in somatic cell hybrids.
Hybrid cell lines between normal rat embryo fibroblasts and TA3B mouse tumour cells, or between TA3B and BI hamster sarcoma cells, have been examined for the expression of the cell surface large external-transformation-sensitive (LETS) protein and the organization of microfilament bundles. LETS protein was detected by lactoperoxidase-catalysed radioiodination and microfilament bundles were visualized by indirect immunofluorescence with antibodies directed against actin or myosin. Hybrids which exhibited normal growth control characteristics had high levels of LETS protein and extensive microfilament bundles. Neoplastic transformation appears to be suppressed in these hybrids. Hybrids which had the growth control characteristics typical of transformed cells had reduced or zero levels of LETS protein and few microfilament bundles. These results confirm previous studies on the expression of the transformed phenotype in these hybrids and demonstrate that there is a good correlation between normal growth control and the presence of LETS protein and microfilament bundles. However, the changes in cell surface LETS protein and in the organization of microfilament bundles often appeared to be quantitative reductions rather than all-or-none effects. The magnitude of the alterations in the levels of LETS protein and in the organization of microfilaments appeared to correlate with the range of transformed characteristics exhibited by the cells. One transformed hybrid in particular, selected for growth in agar, had some surface LETS protein, some microfilament bundles and retained density-dependent inhibition of growth.


A conceptual model exploring the relationship between HIV stigma and implementing HIV clinical trials in rural communities of North Carolina.
HIV/AIDS disproportionately affects minority groups in the United States, especially in the rural southeastern states. Poverty and lack of access to HIV care, including clinical trials, are prevalent in these areas and contribute to HIV stigma. This is the first study to develop a conceptual model exploring the relationship between HIV stigma and the implementation of HIV clinical trials in rural contexts to help improve participation in those trials. We conducted focus groups with HIV service providers and community leaders, and individual interviews with people living with HIV/AIDS in six counties in rural North Carolina. Themes related to stigma were elicited. We classified the themes into theoretical constructs and developed a conceptual model. HIV stigma themes were classified under the existing theoretical constructs of perceived, experienced, vicarious, and felt normative stigma. Two additional constructs emerged: causes of HIV stigma (e.g., low HIV knowledge and denial in the community) and consequences of HIV stigma (e.g., confidentiality concerns in clinical trials). The conceptual model illustrates that the causes of HIV stigma can give rise to perceived, experienced, and vicarious HIV stigma, and these types of stigma could lead to the consequences of HIV stigma that include felt normative stigma. Understanding HIV stigma in rural counties of North Carolina may not be generalizeable to other rural US southeastern states. The conceptual model emphasizes that HIV stigma--in its many forms--is a critical barrier to HIV clinical trial implementation in rural North Carolina.


Probability of detecting nematode infestations for quarantine sampling with imperfect extraction efficacy.
For quarantine sampling, it is of fundamental importance to determine the probability of finding an infestation when a specified number of units are inspected. In general, current sampling procedures assume 100% probability (perfect) of detecting a pest if it is present within a unit. Ideally, a nematode extraction method should remove all stages of all species with 100% efficiency regardless of season, temperature, or other environmental conditions; in practice however, no method approaches these criteria. In this study we determined the probability of detecting nematode infestations for quarantine sampling with imperfect extraction efficacy. Also, the required sample and the risk involved in detecting nematode infestations with imperfect extraction efficacy are presented. Moreover, we developed a computer program to calculate confidence levels for different scenarios with varying proportions of infestation and efficacy of detection. In addition, a case study, presenting the extraction efficacy of the modified Baermann's Funnel method on Aphelenchoides besseyi, is used to exemplify the use of our program to calculate the probability of detecting nematode infestations in quarantine sampling with imperfect extraction efficacy. The result has important implications for quarantine programs and highlights the need for a very large number of samples if perfect extraction efficacy is not achieved in such programs. We believe that the results of the study will be useful for the determination of realistic goals in the implementation of quarantine sampling.


In vitro drug resistance profile of Philadelphia positive acute lymphoblastic leukemia is heterogeneous and related to age: a report of the Dutch and German Leukemia Study Groups.
The t(9;22)(q34;q11) translocation leading to the Philadelphia (Ph) chromosome resulting in BCR-ABL gene fusion is associated with a poor prognosis in acute lymphoblastic leukemia (ALL). We studied the relation between t(9;22), determined by karyotype, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), and in vitro drug resistance, measured by the MTT assay, in precursor B-cell ALL at diagnosis. The findings in twenty-one Ph-positive (Ph+) childhood common/precursorB (c/preB) cases were compared with 254 Ph-negative (Ph-) ALL cases. A large range of LC(50) values was found within the Ph+ patients. Moreover, LC(50) values did not differ significantly between Ph+ and Ph- samples for prednisolone, dexamethasone, L-asparaginase, vincristine, anthracyclines, thiopurines, epipodophyllotoxins, and 4H00-ifosfamide, even after matching for important prognostic features (age, white blood cell count (WBC), and immunophenotype). Adult Ph+ (n = 12) ALL was more resistant to prednisolone (> 270-fold, P = 0.030), and displayed an overall tendency to resistance when compared to matched cases of Ph- (n = 15) adult precursor B-cell ALL. Within Ph+ ALL, in vitro prednisolone resistance increased significantly with age (P = 0.006). The expression of lung resistance protein (LRP), but not P-glycoprotein (P-gp) or multidrug resistance protein (MRP), was significantly higher in all Ph+ patients. Both childhood and adult Ph+ precursor B-cell ALL samples display a heterogeneous in vitro resistance profile, with relatively sensitive and resistant cases. The adult Ph+ samples, however, are generally more resistant compared to matched Ph- controls, reaching significance for prednisolone. The correlation of prednisolone resistance with age within the Ph+ cases might help explain the poorer prognosis of adult Ph+ ALL.


[Ultrastructure of the polysome-lamella complexes in ovarian cancers].
Electron-microscopy was used to study the intraoperative material in 37 patients with serous (24), mucinous (8) and endometroid (5) ovarian neoplasms of benign, boundary and malignant forms. It was shown that the polysome-lamellae complexes are characteristic only of the carcinoma epithelium and practically are observed neither in benign nor in boundary analogs. This may serve an additional criterion of a malignant nature of neoplasms at the ultrastructural level. Taking into account the architectonics 3 variants of the polysome-lamellae complexes should be distinguished: polysome-lamellae, lamellae and lattice structures. All these variants may be encountered in one and the same tumor.


Oridonin inhibits tumor angiogenesis and induces vessel normalization in experimental colon cancer.
Purpose: Tumor blood vessels exhibit morphological and functional aberrancies. Its maturity and functionality are closely associated with colon cancer progression and therapeutic efficacy. The direct evidence proving whether oridonin (ORI) has vascular normalization promoting effect from which combination therapies will benefit is still lacking. Methods: We established a subcutaneous xenograft model of human colon cancer. The animals were divided into the Control and ORI-treated groups. Immunohistochemical analysis and TUNEL staining was applied to evaluate the proliferation, apoptosis and angiogenesis. Western blot analysis was employed to characterize the angiogenesis-related factors and JAK2/STAT3 signaling. Then, vascular normalization and macrophage reprogramming were assessed by immunofluorescence analysis. Results: The results showed that ORI obviously reduced tumor growth, diminished the numbers of Ki67+ cells and CD31+ microvessel density, while increased the numbers of TUNEL+ cells. The expression levels of VEGF and bFGF proteins were dramatically down-regulated while the angiostatin and endostatin levels were increased in the ORI-treated group. Moreover, ORI therapy remarkably promoted the pericyte coverage of tumor vessels from days 5 to 10, with the highest pericyte coverage rate occurred at day 7. In the time window of vascular normalization, hypoxia of the tumor microenvironment was improved by ORI, the expression of HIF-1a was downregulated. Moreover, CD206+ macrophage cells were diminished in the ORI-treated group. These anticancer effects of ORI maybe partly mediated by suppressing JAK2/STAT3 signaling pathway. Conclusions: These results highlight the potential effect of ORI on anti-angiogenesis and inducing vessel normalization roles of ORI, and probably provide optimum time point for the ORI therapy in conjunction with the chemoradiotherapy or immunotherapy.


Insight into the hybrid luminescence showed by carbon dots and molecular fluorophores in solution.
Carbon dots have attracted great attention from the research community given their very attractive luminescent properties. However, the recent discovery that some of these properties may result from fluorescent impurities originating from the synthesis process, and not from the carbon dots themselves, constitute a significant setback to our knowledge of these materials. Herein, we proceeded to the study of carbon dots generated from citric acid and urea via a microwave-assisted synthesis, focusing on their analysis by AFM, HR-TEM, XPS, FT-IR, ESI-MS, UV-Vis and fluorescence spectroscopy. We have found that this synthesis process does generate molecular fluorophores that can mask the luminescence of the carbon dots. More importantly, our data demonstrates that when present in the same solution, the carbon dots and these fluorophores do not behave as separated species with individual emission. Instead, they interact to produce a hybrid luminescence, which excited state properties and reactivity are different from the properties of the individual species. These results indicate the possibility for the development of hybrid materials composed by carbon dots and related molecular fluorophores with new and improved properties.


Diagnosis of influenza: only a problem of coding?
To evaluate the characteristics of hospital discharge diagnoses of influenza measured by using specific International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9 CM) codes. The study was conducted for the 3 years 2007, 2008 and 2011. The database included (1) administrative and clinical data on Sicilian patients admitted to acute care hospitals and (2) data from the influenza virological surveillance of 10 European countries (FluNet database). All Sicilian patients diagnosed with at least 1 ICD-9 CM code for influenza (487.0, 487.1 and 487.9) were considered influenza cases. Overall, 2,880 patients with an ICD-9 CM code attributable to influenza were hospitalized in Sicily: 2,119 (73.6%) were admitted from November to April, whereas 761 (26.4%) were admitted from May to October. In the 3 years studied, the analyzed European influenza surveillance systems recorded a peak of laboratory-confirmed influenza activity from November to April with 36,753 (99.7%) influenza cases, whereas only 124 cases (0.3%) were observed from May to October. In Sicily, more than one quarter of all hospital admissions with an ICD-9 CM code for influenza were observed in the months with a negligible circulation of influenza viruses. Our findings show that several hospital discharge records included ICD-9 CM codes for influenza with low levels of sensitivity, specificity and/or appropriateness for clinical information and support the need for improving medical education on the epidemiology and hospital management of influenza cases.


Characteristics of visitors to traditional healers in central Sudan.
Traditional healing is widespread in Sudan and traditional healers are well respected by the community. This study aimed to assess the characteristics of visitors attending traditional healers, the reasons for visits, the frequency of visits, satisfaction with visits and advantages and disadvantages of visits. The results showed that children under ten years did not take part in visits; most of the visitors were between 21 and 40 years (61%) and were women (62%). Visitors were less educated compared to the general population in the area. The main reasons given for attending traditional healers were treatment (60%) and blessing (26%). Visitors did not mention any disadvantages to visiting traditional healers.


Restoration of KMT2C/MLL3 in human colorectal cancer cells reinforces genome-wide H3K4me1 profiles and influences cell growth and gene expression.
The histone 3 lysine 4 (H3K4) monomethylase KMT2C is mutated across several cancer types; however, the effects of mutations on epigenome organization, gene expression, and cell growth are not clear. A frequently recurring mutation in colorectal cancer (CRC) with microsatellite instability is a single nucleotide deletion within the exon 38 poly-A(9) repeat (c.8390delA) which results in frameshift preceding the functional carboxy-terminal SET domain. To study effects of KMT2C expression in CRC cells, we restored one allele to wild type KMT2C in the two CRC cell lines RKO and HCT116, which both are homozygous c.8390delA mutant. Gene editing resulted in increased KMT2C expression, increased H3K4me1 levels, altered gene expression profiles, and subtle negative effects on cell growth, where higher dependence and stronger effects of KMT2C expression were observed in RKO compared to HCT116 cells. Surprisingly, we found that the two RKO and HCT116 CRC cell lines have distinct baseline H3K4me1 epigenomic profiles. In RKO cells, a flatter genome-wide H3K4me1 profile was associated with more increased H3K4me1 deposition at enhancers, reduced cell growth, and more differential gene expression relative to HCT116 cells when KMT2C was restored. Profiling of H3K4me1 did not indicate a highly specific regulation of gene expression as KMT2C-induced H3K4me1 deposition was found globally and not at a specific enhancer sub-set in the engineered cells. Although we observed variation in differentially regulated gene sets between cell lines and individual clones, differentially expressed genes in both cell lines included genes linked to known cancer signaling pathways, estrogen response, hypoxia response, and aspects of immune system regulation. Here, KMT2C restoration reduced CRC cell growth and reinforced genome-wide H3K4me1 deposition at enhancers; however, the effects varied depending upon the H3K4me1 status of KMT2C deficient cells. Results indicate that KMT2C inactivation may promote colorectal cancer development through transcriptional dysregulation in several pathways with known cancer relevance.


Metastability in pixelation patterns of coexisting fluid lipid bilayer phases imposed by e-beam patterned substrates.
We study the dynamic evolution of pixilation patterns of the liquid-ordered (Lo) phase in coexistence with the liquid-disordered phase in lipid multibilayers. The pixilation patterns were formed by imposing lattice patterns of localized high curvature on phase-separating multibilayers using curvature-patterned regions of an underlying support. The projected radius of underlying hemisphere-like features, that provided the local curvature, was varied from 60 nm to 100 nm and the square lattice spacing between the features was varied between 200 nm and 400 nm using standard electron (e) -beam lithography. Over time, the area fraction of the Lo phase on the patterned regions of the substrate decreased toward zero at room temperature. This apparent metastability of the pattern derives from the high line energy of a pixelation pattern where a Boltzmann distribution shows near zero equilibrium partitioning of the Lo phase in the patterned regions. Kinetic rate analysis identifies two pattern-dependent mechanisms that dominate the transition to zero Lo area fraction; diffusion limited dissolution of the Lo phase driven by an Ostwald ripening-type process or the cooperative formation of vesicles containing Lo phase lipids. Interestingly, we observed the spontaneous formation of tubules in the corners of the array due to the high local curvature applied to the membrane. Furthermore we show that it is possible to regenerate pixilation patterns on the curvature-patterned regions by cooling below room temperature. Regenerated area fractions are in agreement with a room-temperature composition of primarily Ld phase and the high degree of overlap with the original patterns is suggestive of fixed nucleation sites.


How Modulator Binding at the Amyloidβ-γ-Secretase Interface Enhances Substrate Binding and Attenuates Membrane Distortion.
Inhibition of γ-secretase, an intramembrane protease, to reduce secretion of Amyloid-β (Aβ) peptides has been considered for treating Alzheimer's disease. However, γ-secretase inhibitors suffer from severe side effects. As an alternative, γ-secretase modulators (GSM) reduce the generation of toxic peptides by enhancing the cleavage processivity without diminishing the enzyme activity. Starting from a known γ-secretase structure without substrate but in complex with an E2012 GSM, we generated a structural model that included a bound Aβ43 peptide and studied interactions among enzyme, substrate, GSM, and lipids. Our result suggests that E2012 binding at the enzyme-substrate-membrane interface attenuates the membrane distortion by shielding the substrate-membrane interaction. The model predicts that the E2012 modulation is charge-dependent and explains the preserved hydrogen acceptor and the aromatic ring observed in many imidazole-based GSM. Predicted effects of γ-secretase mutations on E2012 modulation were confirmed experimentally. We anticipate that the study will facilitate the future development of effective GSMs.


Clinical and experimental studies of the congenital constriction band syndrome, with an emphasis on its etiology.
The findings in fifty-nine patients with congenital constriction band syndrome and in experiments in which limb malformations resembling those of the human constriction band syndrome were successfully reproduced in rat fetuses by amniocentesis indicated that these malformations arise from excessive contraction of the uterine muscle during pregnancy, with resulting hemorrhages from the marginal blood sinuses of the digital rays. Such malformations in humans may arise during the fifth and sixth weeks counted from ovulation. It therefore was concluded that this syndrome is not hereditary but is produced by prenatal environmental factors.


Using the hospital as a venue for reproductive health interventions: a survey of hospitalized adolescents.
Less than one-half of sexually active adolescents have received counseling regarding contraception and sexually transmitted disease (STD) from their health care provider. We hypothesized that hospitalized adolescents would be interested in receiving reproductive health education and/or STD testing. In addition, we assessed the opinion of female adolescents on initiation of contraception during hospitalization. A convenience sample of 13- to 18-year-old male and female adolescent patients hospitalized at a tertiary pediatric hospital were approached for inclusion. Consenting patients completed a self-administered anonymous questionnaire. Questionnaires from 49 female adolescents and from 51 male adolescents were collected. Based on their answers, 37% of female adolescents and 44% of male adolescents want to learn more about contraception and/or abstinence in the hospital independent of sexual activity. Thirty percent of respondents reported a desire for STD testing in the hospital. Fifty-seven percent of female subjects answered that adolescents should be offered contraception while in the hospital. Among hospitalized adolescents in this study, there was an interest in reproductive health education and contraception even among those with a primary care provider and without sexual experience. Thus, hospital-based pediatricians can play a pivotal role in expanding critical sexual health services by discussing and offering sexual health care to hospitalized adolescents. We recommend that hospitals make a brochure available to all admitted adolescents, with opportunity for follow-up discussions with their hospitalist.


Dysregulation of IFN system can lead to poor response to pegylated interferon and ribavirin therapy in chronic hepatitis C.
Despite being expensive, the standard combination of pegylated interferon (Peg-IFN)-α and ribavirin used to treat chronic hepatitis C (CH) results in a moderate clearance rate and a plethora of side effects. This makes it necessary to predict patient outcome so as to improve the accuracy of treatment. Although the antiviral mechanism of genetically altered IL28B is unknown, IL28B polymorphism is considered a good predictor of IFN combination treatment outcome. Using microarray, we quantified the expression profile of 237 IFN related genes in 87 CH liver biopsy specimens to clarify the relationship between IFN pathway and viral elimination, and to predict patients' clinical outcome. In 72 out of 87 patients we also analyzed IL28B polymorphism (rs8099917). Five IFN related-genes (IFI27, IFI 44, ISG15, MX1, and OAS1) had expression levels significantly higher in nonresponders (NR) than in normal liver (NL) and sustained virological responders (SVR); this high expression was also frequently seen in cases with the minor (TG or GG) IL28B genotype. The expression pattern of 31 IFN related-genes also differed significantly between NR and NL. We predicted drug response in NR with 86.1% accuracy by diagonal linear discriminant analysis (DLDA). IFN system dysregulation before treatment was associated with poor IFN therapy response. Determining IFN related-gene expression pattern based on patients' response to combination therapy, allowed us to predict drug response with high accuracy. This method can be applied to establishing novel antiviral therapies and strategies for patients using a more individual approach.


Phytophthora morindae, a new species causing black flag disease on noni (Morinda citrifolia L) in Hawaii.
A homothallic, papillate Phytophthora species causing foliar and fruit blight of noni (Morinda citrifolia var. citrifolia) in Hawaii was identified. The asexual phase of this species is characterized by the production of umbellate sporangiophores and papillate sporangia that are ellipsoid and obpyriform with conspicuously tapered bases and possess caducous, medium to long pedicels. The sexual phase is characterized by the production of oogonia with tapered bases, small amphigynous antheridia and thick-walled, plerotic oospores. The morphology of the taxon does not match any of the valid 95 Phytophthora species described to date. Phylogenetic analysis based on sequences of the internal transcribed spacer rDNA region (ITS) and the translation elongation factor 1 alpha (EF-1 alpha) of this taxon and those from other Phytophthora species from GenBank and the Phytophthora database indicates that the new taxon is most closely related to species in ITS clade 10, including P. kernoviae, P. boehmeriae and the recently described P. gallica. The most closely related species is P. kernoviae, an invasive plant pathogen causing bleeding stem lesions on forest trees (beech, Fagus sylvatica) and foliar necrosis of ornamentals (rhododendron, pieris and magnolia) in the UK, and isolated in New Zealand from necrotic cherimoya shoots and fruits and soil. Although the morphological characters of the sexual phase of P. morindae and P. kernoviae are similar, the umbellate sporangiophores produced by the new taxon marks the main morphological distinction. In this paper we describe the morphological characteristics, the phylogenetic relationships and pathogenicity characteristics that support the description of this taxon as a new species with the proposed name Phytophthora morindae sp. nov.


The cortical hem regulates the size and patterning of neocortex.
The cortical hem, a source of Wingless-related (WNT) and bone morphogenetic protein (BMP) signaling in the dorsomedial telencephalon, is the embryonic organizer for the hippocampus. Whether the hem is a major regulator of cortical patterning outside the hippocampus has not been investigated. We examined regional organization across the entire cerebral cortex in mice genetically engineered to lack the hem. Indicating that the hem regulates dorsoventral patterning in the cortical hemisphere, the neocortex, particularly dorsomedial neocortex, was reduced in size in late-stage hem-ablated embryos, whereas cortex ventrolateral to the neocortex expanded dorsally. Unexpectedly, hem ablation also perturbed regional patterning along the rostrocaudal axis of neocortex. Rostral neocortical domains identified by characteristic gene expression were expanded, and caudal domains diminished. A similar shift occurs when fibroblast growth factor (FGF) 8 is increased at the rostral telencephalic organizer, yet the FGF8 source was unchanged in hem-ablated brains. Rather we found that hem WNT or BMP signals, or both, have opposite effects to those of FGF8 in regulating transcription factors that control the size and position of neocortical areas. When the hem is ablated a necessary balance is perturbed, and cerebral cortex is rostralized. Our findings reveal a much broader role for the hem in cortical development than previously recognized, and emphasize that two major signaling centers interact antagonistically to pattern cerebral cortex.


Syndrome of megalencephaly, mega corpus callosum, and complete lack of motor development: an unusual case and a literature review.
The syndrome of megalencephaly, mega corpus callosum (MEG-MegaCC) accompanied by complete lack of motor development is a rare condition with only few sporadic cases having been reported in the literature. In this paper, we describe a child from non-consanguineous parents presenting with MegaCC, psychomotor retardation, and language impairment linked to MEG-MegaCC syndrome. Genetic analysis, radiological findings, and detailed neurological phenotype of MEG-MegaCC syndrome with its overlapping syndromes would allow for a better classification of the disease spectrum.


Next generation sequencing and analysis of a conserved transcriptome of New Zealand's kiwi.
Kiwi is a highly distinctive, flightless and endangered ratite bird endemic to New Zealand. To understand the patterns of molecular evolution of the nuclear protein-coding genes in brown kiwi (Apteryx australis mantelli) and to determine the timescale of avian history we sequenced a transcriptome obtained from a kiwi embryo using next generation sequencing methods. We then assembled the conserved protein-coding regions using the chicken proteome as a scaffold. Using 1,543 conserved protein coding genes we estimated the neutral evolutionary divergence between the kiwi and chicken to be ~45%, which is approximately equal to the divergence computed for the human-mouse pair using the same set of genes. A large fraction of genes was found to be under high selective constraint, as most of the expressed genes appeared to be involved in developmental gene regulation. Our study suggests a significant relationship between gene expression levels and protein evolution. Using sequences from over 700 nuclear genes we estimated the divergence between the two basal avian groups, Palaeognathae and Neognathae to be 132 million years, which is consistent with previous studies using mitochondrial genes. The results of this investigation revealed patterns of mutation and purifying selection in conserved protein coding regions in birds. Furthermore this study suggests a relatively cost-effective way of obtaining a glimpse into the fundamental molecular evolutionary attributes of a genome, particularly when no closely related genomic sequence is available.


An assessment of the magnitude of intra-fraction movement of head-and-neck IMRT cases and its implication on the action-level of the imaging protocol.
A planning margin ⩽3 mm is employed in some head-and-neck IMRT cases due to the proximity of critical structures. This study aims to explore the need to redefine the action-level in the head-and-neck imaging protocol in consideration of the intra-fraction movement. This is a local study of 18 patients treated using the same immobilisation system and setup protocol. Post-treatment orthogonal pair of kilovoltage X-ray images was acquired on the first three days of treatment. 106 sets of pre- and post-treatment kV X-ray images acquired over 53 fractions were analysed against the treatment planning DRR for calculation of intra-fraction movement. Individual mean intra-fraction movement in all directions ranged from -1.8 to 1.1 mm. Population mean (median) intra-fraction movement in the x-, y-, and z-planes were -0.1 mm (0 mm), -0.3 mm (-0.3 mm) and -0.2 mm (-0.2 mm) respectively. Intra-fraction movement in all three dimensions, x-, y- and z-planes were considered statistically significant (p<0.05). 7 out of 53 fractions (13.2%) were highlighted as the combined magnitude of the intra-fraction motion with the uncorrected pre-treatment setup errors had exceeded the boundaries of given margins. 3 mm-AL was not adequate to account for intra-fraction movement when the CTV-PTV margin was ⩽3 mm and should be excluded from the routine imaging protocol and daily image-guided radiotherapy should be employed. Adjusting the action-level to 2 mm would allow a more confident approach in delivery of the prescribed dose in head-and-neck IMRT cases.


Lp Quasi-norm Minimization: Algorithm and Applications.
Sparsity finds applications in diverse areas such as statistics, machine learning, and signal processing. Computations over sparse structures are less complex compared to their dense counterparts and need less storage. This paper proposes a heuristic method for retrieving sparse approximate solutions of optimization problems via minimizing the [[EQUATION]] quasi-norm, where $0<p<1$. An iterative two-block algorithm for minimizing the [[EQUATION]] quasi-norm subject to convex constraints is proposed. The proposed algorithm requires solving for the roots of a scalar degree polynomial as opposed to applying a soft thresholding operator in the case of $\ell_{1}$ norm minimization. The algorithm's merit relies on its ability to solve the [[EQUATION]] quasi-norm minimization subject to any convex constraints set. For the specific case of constraints defined by differentiable functions with Lipschitz continuous gradient, a second, faster algorithm is proposed. Using a proximal gradient step, we mitigate the convex projection step and hence enhance the algorithm's speed while proving its convergence. We present various applications where the proposed algorithm excels, namely, sparse signal reconstruction, system identification, and matrix completion. The results demonstrate the significant gains obtained by the proposed algorithm compared to other [[EQUATION]] quasi-norm based methods presented in previous literature.