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Background: Asthma is characterized by a heterogeneous inflammatory profile and can be subdivided into T(h) 2-high and T(h) 2-low airway inflammation. Profiling of a broader panel of airway cytokines in large unselected patient cohorts is lacking. Methods: Patients (n = 205) were defined as being "cytokine-low/high" if sputum mRNA expression of a particular cytokine was outside the respective 10th/90th percentile range of the control group (n = 80). Unsupervised hierarchical clustering was used to determine clusters based on sputum cytokine profiles. Results: Half of patients (n = 108; 52.6%) had a classical T(h) 2-high ("IL-4-, IL-5-and/or IL-13-high") sputum cytokine profile. Unsupervised cluster analysis revealed 5 clusters. Patients with an "IL-4-and/or IL-13-high"pattern surprisingly did not cluster but were equally distributed among the 5 clusters. Patients with an "IL-5-, IL-17A-/F-and IL-25-high"profile were restricted to cluster 1 (n = 24) with increased sputum eosinophil as well as neutrophil counts and poor lung function parameters at baseline and 2 years later. Four other clusters were identified: "IL-5-high or IL-10-high"(n = 16), "IL-6-high"(n = 8), "IL-22-high"(n = 25). Cluster 5 (n = 132) consists of patients without "cytokine-high"pattern or patients with only high IL-4 and/or IL-13. Conclusion: We identified 5 unique asthma molecular phenotypes by biological clustering. Type 2 cytokines cluster with non-type 2 cytokines in 4 out of 5 clusters. Unsupervised analysis thus not supports a priori type 2 versus non-type 2 molecular phenotypes.

Aluminium (Al) toxicity is a worldwide problem in agricultural practice. Based on evidence that Al resistance may be an inducible process and that rice is one of the most Al-resistant crops, the gene transcriptional responses to Al were investigated in two contrasting rice cultivars (resistant XN1 versus sensitive XX2) using differential display reverse transcription-PCR (DDRT-PCR) in combination with northern blotting analysis. A total of 37 genes were identified as differentially expressed, of which five have been previously known as Al regulated while the others are novel genes. Among the up-regulated genes, four encode ion transporters, two are involved in signal transduction, and five in the synthesis of cysteine and metallothionein. These could be members that are potentially involved in Al adaptation or resistance. On the other hand, the transcription of 17 genes was strongly inhibited under Al stress. These genes are associated with cytoskeletal dynamics and metabolism, and could be possible targets associated with Al toxicity. All of these differentially expressed genes may represent candidates that function in Al responses. The results suggest, at the transcriptional level, that cytoskeletal disruption may be associated with Al toxicity, whereas ion transport and sulphur metabolism could play major roles in Al adaptation or tolerance in rice.

Properly designed alarm systems can benefit operators in conducting routine and emergency tasks. With the digitization of main control rooms, the alarm interface can be designed in various ways that are different from the traditional "alarm tile" style. An innovative alarm bar interface is proposed in this paper. A preliminary lab experiment was conducted to compare the traditional alarm tile and the new alarm bar interfaces. Sixteen university students were recruited to participate in the experiment, in which two emergency scenarios, Loss of Coolant Accident and Steam Generator Tube Rupture, were tested. The experiment task included two parts: alarm detection and identification. The subjective ratings supported the innovative alarm bar design for better parameter trend perception. The objective performance measures showed that the simpler design of the alarm tile interface better aided the alarm detection performance, whereas the alarm bar interface had almost the same alarm identification performance as the alarm tile interface. Relevance to industry: An alarm system is critical for a complex industrial system. The experimental results show that design evaluation is more complex than it may seem. Although it has not been proved to be overwhelmingly superior to the tile design, the alarm bar design shows promise for aiding operators and needs to be further validated. (C) 2014 Elsevier B.V. All rights reserved.

PurposeMore than 25% of US adults experience mental health or substance use conditions annually, yet less than half receive treatment. This study explored how rural participants with behavioral health conditions pursue and receive care, and it examined how these factors differed across American Indian (AI) and geographic subpopulations. MethodsWe undertook a qualitative follow-up study from a statewide survey of unmet mental health and substance use needs in South Dakota. We conducted semistructured phone interviews with a purposive sample of key informants with varying perceptions of need for mental health and substance use treatment. ResultsWe interviewed 33 participants with mental health (n = 18), substance use (n = 9), and co-occurring disorders (n = 6). Twenty participants (61.0%) lived in rural communities that did not overlap with AI tribal land. Twelve participants (34.3%) were AI, 8 of whom lived on a reservation (24.2%). The discrepancy between actual and perceived treatment need was related to how participants defined mental health, alcohol, and drug use problems. Mental health disorders and excessive alcohol consumption were seen as a normal part of life in rural and reservation communities; seeking mental health care or maintaining sobriety was viewed as the result of an individual's willpower and frequently related to a substantial life event (eg, childbirth). Participants recommended treatment gaps be addressed through multicomponent community-level interventions. DiscussionThis study describes how rural populations view mental health, alcohol, and drug use. Enhancing access to care, addressing discordant perceptions, and improving community-based interventions may increase treatment uptake.

Alcohol and substance (drugs and/or alcohol) abuse are major risk factors for traumatic brain injury (TBI); however, it remains unclear whether outcomes differ for those with and without a history of preinjury abuse. A meta-analysis was performed to examine this issue. The PubMed, Embase, and PsycINFO databases were searched for research that compared the neuroradiological, cognitive, or psychological outcomes of adults with and without a documented history of alcohol and/or substance abuse who sustained nonpenetrating TBIs. Data from 22 studies were analyzed using a random-effects model: Hedges's g effect sizes measured the mean difference in outcomes of individuals with/without a history of preinjury abuse, and Bayes factors assessed the probability that the outcomes differed. Patients with a history of alcohol and/or substance abuse had poorer neuroradiological outcomes, including reduced hippocampal (g=-0.82) and gray matter volumes (g=-0.46 to -0.82), and enlarged cerebral ventricles (g=-0.73 to -0.80). There were limited differences in cognitive outcomes: Executive functioning (g=-0.51) and memory (g=-0.39 to -0.43) were moderately affected, but attention and reasoning were not. The findings for fine motor ability, construction, perception, general cognition, and language were inconclusive. Postinjury substance and alcohol use (g=-0.97 to -1.07) and emotional functioning (g=-0.29 to -0.44) were worse in those with a history of alcohol and/or substance abuse (psychological outcomes). This study highlighted the type and extent of post-TBI differences between persons with and without a history of alcohol or substance abuse, many of which may hamper recovery. However, variation in the criteria for premorbid abuse, limited information regarding the history of abuse, and an absence of preinjury baseline data prevented an assessment of whether the differences predated the TBI, occurred as a result of ongoing alcohol/substance abuse, or reflected the cumulative impact of alcohol/substance abuse and TBI.

Pyruvate decarboxylase (Pdc) and alcohol dehydrogenase (Adh) enzymes are responsible for the operation of ethanolic fermentation pathway that appears to correlate to an extent with anoxia tolerance in plants. This study was undertaken with the objective of (a) analysing the rice pdc gene family and (b) altering the efficacy of the ethanolic fermentation process, through production of transgenic rice plants over- and under-expressing pyruvate decarboxylase (employing Ospdc1 gene from rice) as well as over-expressing alcohol dehydrogenase (employing Ghadh2 gene from cotton) proteins. Correlations noted in this study between the pattern of expression of the Pdc alpha-subunit and Ospdc2 transcript as well as between the Pdc beta-subunit and Ospdc1 transcript suggest the possibility that alpha-subunit is encoded by Ospdc2 and that beta-subunit is encoded by Ospdc1. The fact that levels of Pdc beta-subunit were particularly high in pUH-sPdc1 (plasmid construct designed for over-expression of Ospdc1) seedlings while levels of beta-subunit levels were negligible or lower in pUH-asPdc1 (plasmid construct designed for under-expression of Ospdc1) seedlings also support these observations. Transgenics raised for over-expression of Pdc and Adh and under-expression of Pdc were confirmed for the transgene presence and effects by PCR, Southern blotting, Northern blotting, Western blotting and isozyme assays. Pdc and Adh over-expressing rice transgenics at early seedling stage under unstressed control growth conditions showed slight, consistent advantage in root vigour as compared to that of wild-type seedlings. (C) 2007 Elsevier Masson SAS. All rights reserved.

Background: Prior research has repeatedly shown that alcohol dependence is associated with a large range of impairments in psychological processes, which could lead to interpersonal deficits. Specifically, it has been suggested that these interpersonal difficulties are underpinned by reduced recognition and sharing of others' emotional states. However, this pattern of deficits remains to be clarified. This study thus aimed to investigate whether alcohol dependence is associated with impaired abilities in decoding contextual complex emotions and with altered sharing of others' emotions. Methods: Forty-one alcohol-dependent individuals (ADI) and 37 matched healthy individuals completed the Multifaceted Empathy Test, in which they were instructed to identify complex emotional states expressed by individuals in contextual scenes and to state to what extent they shared them. Results: Compared to healthy individuals, ADI were impaired in identifying negative (Cohen's d=0.75) and positive (Cohen's d=0.46) emotional states but, conversely, presented preserved abilities in sharing others' emotional states. Conclusions: This study shows that alcohol dependence is characterized by an impaired ability to decode complex emotional states (both positive and negative), despite the presence of complementary contextual cues, but by preserved emotion-sharing. Therefore, these results extend earlier data describing an impaired ability to decode noncontextualized emotions toward contextualized and ecologically valid emotional states. They also indicate that some essential emotional competences such as emotion-sharing are preserved in alcohol dependence, thereby offering potential therapeutic levers.

Some addicted patients have social cognition deficits that require therapists to have special skills to ensure treatment success. Specific remediation techniques that teach addicted patients to look at the relevant emotional cues when interacting with people should be tested as adjunctive treatment.

Considerable evidence has identified biased cognitive processing of alcohol-related stimuli as an important factor in the maintenance of alcohol-seeking and relapse among individuals suffering from alcohol use-disorders (AUDs). In addition, a large body of research has demonstrated that exposure to alcohol cues can elicit powerful alcohol cravings. Little is known, however, about the possible relationship between attentional bias and cue-induced cravings, and even less is known about these processes in social drinkers without a personal history of AUDs. The goal of this study was to examine the possibility that attentional biases toward alcohol-related stimuli would predict elevated cue-induced alcohol craving in this population. Young adult social drinkers (N = 30, Mean age = 22.8 +/- 1.9, 61% female) recruited from an urban university population completed a visual dot probe task in which they were presented with alcohol and neutral stimulus pictures that were immediately followed by a visual probe replacing one of the pictures. Attentional bias was measured by calculating reaction times to probes that replaced alcohol stimuli vs. neutral stimuli. Participants then completed a classic alcohol cue-exposure task and reported cravings immediately before and after alcohol and neutral cue-exposures. Not surprisingly, exposure to alcohol cues elicited significant cravings. Consistent with the study hypothesis, larger attentional biases toward alcohol stimuli predicted higher levels of alcohol craving. Findings demonstrate that heightened attention to alcohol stimuli can significantly impact motivation to consume in healthy young adults, and suggest a possible pathway linking cognitive processes early in the drinking trajectory to the later development of AUDs. (C) 2017 Elsevier Ltd. All rights reserved.

AimsTo examine the association between a life-time history of insomnia and hypersomnia compared with no sleep disturbance and substance use patterns and amounts before and after a substance use treatment episode. DesignSecondary analysis of data from the Drug Abuse Treatment Outcome Studies conducted from 1991 to 1994. SettingData were collected at 96 substance use treatment programs in 11 United States cities, including short-term in-patient, long-term residential, methadone maintenance and out-patient drug-free treatment modalities. ParticipantsStudy samples included 7168 adults at treatment entry and 2965 at 12months post-treatment entry whose primary substance use at entry was alcohol (14.7%), cocaine (62.7%) or heroin (22.6%). MeasurementsLife-time history of insomnia and hypersomnia was assessed via self-report. Type and frequency of substance use were assessed at treatment entry. Substance use was also assessed 12months following treatment completion. Associations were examined using linear and logistic regression with age, sex, race, education level, depression history, treatment modality and in-treatment substance use as covariates. FindingsLife-time history of insomnia, hypersomnia, both or neither was reported by 26.3, 9.5, 28.0 and 36.2% of participants, respectively. Compared with no sleep disturbance, life-time insomnia and hypersomnia were associated at treatment entry with unique substance use patterns and a higher frequency of any substance use (P<0.001). All types of sleep disturbance were associated with higher rates of cocaine use at 12-month post-entry (odds ratios: 1.30-1.57). ConclusionsThere is evidence of an adverse association between substance use and sleep disturbance including higher frequency of all substance use before substance abuse treatment and higher rates of cocaine use after a treatment episode.

Rationale Social cognition influences social interactions. Alcohol reportedly facilitates social interactions. However, the acute effects of alcohol on social cognition are relatively poorly studied. We investigated the effects of alcoholic or non-alcoholic beer on emotion recognition, empathy, and sexual arousal using the dynamic face emotion recognition task (FERT), Multifaceted Empathy Test (MET), and Sexual Arousal Task (SAT) in a double-blind, random-order, cross-over study in 60 healthy social drinkers. We also assessed subjective effects using visual analog scales (VASs), blood alcohol concentrations, and plasma oxytocin levels. Alcohol increased VAS ratings of stimulated, happy, talkative, open, and want to be with others. The subjective effects of alcohol were greater in participants with higher trait inhibitedness. Alcohol facilitated the recognition of happy faces on the FERT and enhanced emotional empathy for positive stimuli on the MET, particularly in participants with low trait empathy. Pictures of explicit sexual content were rated as less pleasant than neutral pictures after non-alcoholic beer but not after alcoholic beer. Explicit sexual pictures were rated as more pleasant after alcoholic beer compared with non-alcoholic beer, particularly in women. Alcohol did not alter the levels of circulating oxytocin. Alcohol biased emotion recognition toward better decoding of positive emotions and increased emotional concern for positive stimuli. No support was found for a modulatory role of oxytocin. Alcohol also facilitated the viewing of sexual images, consistent with disinhibition, but it did not actually enhance sexual arousal. These effects of alcohol on social cognition likely enhance sociability. www.clinicaltrials.gov/ct2/show/NCT02318823 RefTarget Address="http://www.clinicaltrials.gov/ct2/show/NCT02318823" TargetType="URL"/>

Background and aimsHIV-infected people with substance use disorders are least likely to benefit from advances in HIV treatment. Integration of extended-release naltrexone (XR-NTX) into HIV clinics may increase engagement in the HIV care continuum by decreasing substance use. We aimed to compare (1) XR-NTX treatment initiation, (2) retention and (3) safety of XR-NTX versus treatment as usual (TAU) for treating opioid use disorder (OUD) and/or alcohol use disorder (AUD) in HIV clinics. DesignNon-blinded randomized trial of XR-NTX versus pharmacotherapy TAU. SettingHIV primary care clinics in Vancouver, BC, Canada and Chicago, IL, USA. ParticipantsFifty-one HIV-infected patients seeking treatment for OUD (n=16), AUD (n=27) or both OUD and AUD (n=8). MeasurementsPrimary outcomes were XR-NTX initiation (receipt of first injection within 4weeks of randomization) and retention at 16weeks. Secondary outcomes generated point estimates for change in substance use, HIV viral suppression [HIV RNA polymerase chain reaction (pcr)<200 copies/ml] and safety. FindingsTwo-thirds (68%) of participants assigned to XR-NTX initiated treatment, and 88% of these were retained on XR-NTX at 16weeks. In comparison, 96% of TAU participants initiated treatment, but only 50% were retained on medication at 16weeks. Mean days of opioid use in past 30 days decreased from 17.3 to 4.1 for TAU and from 20.3 to 7.7 for XR-NTX. Mean heavy drinking days decreased from 15.6 to 5.7 for TAU and 12.5 to 2.8 for XR-NTX. Among those with OUD, HIV suppression improved from 67 to 80% for XR-NTX and 58 to 75% for TAU. XR-NTX was well tolerated, with no precipitated withdrawals and one serious injection-site reaction. ConclusionsExtended-release naltrexone (XR-NTX) is feasible and safe for treatment of opioid use disorder and alcohol use disorder in HIV clinics. Treatment initiation appears to be lower and retention greater for XR-NTX compared with treatment as usual ( NCT01908062).

In this paper, a three-stage operational amplifier with low-power consumption for ALD has been designed. Based on TSMC 0.55 mu m CMOS process, using HSPICE 2008 software for circuit simulation, the results showed that the proposed op-amp has more than 100dB open loop gain, meanwhile the static power consumption is less than 900 mu w. The circuit's phase margin is 103degrees, CMRR is 51dB and power supply rejection ratio is 57dB.

One-step aldol condensation of methyl acetate with formaldehyde (or trioxane) for preparing methyl acrylate at 623 K-653 K has stimulated researchers' attention in recent years. Herein, a new methodology for one-step synthesis of methyl acrylate from methyl acetate and trioxane promoted by generated trifluoromethanesulfonate ionic liquid, via aldol condensation, at mild temperature was developed. The kinetic and thermodynamic studies on this new process were also firstly investigated systematically. Experiments were conducted in a batch reactor under the temperatures of 283 K-298 K and reaction times of 10 min - 100 min, wherein the side reactions could be ignored. The proposed mechanism based kinetic model was established and simulated with experimental data. The model showed good agreement with experimental results within the range of acceptable deviation, thereby the pre exponential factor and activation energy of each reaction step were obtained. Moreover, the equilibrium constant and enthalpy change of each reversible reaction were also calculated through Van't Hoff formula. (C) 2017 Elsevier B.V. All rights reserved.

Background: Inflammation is a key feature of aldosterone-induced vascular damage and dysfunction, but molecular mechanisms by which aldosterone triggers inflammation remain unclear. The NLRP3 inflammasome is a pivotal immune sensor that recognizes endogenous danger signals triggering sterile inflammation. Methods: We analyzed vascular function and inflammatory profile of wild-type (WT), NLRP3 knockout (NLRP3(-/-)), caspase-1 knockout (Casp-1(-/-)), and interleukin-1 receptor knockout (IL-1R(-/-)) mice treated with vehicle or aldosterone (600 mu gkg(-1)d(-1) for 14 days through osmotic mini-pump) while receiving 1% saline to drink. Results: Here, we show that NLRP3 inflammasome plays a central role in aldosterone-induced vascular dysfunction. Long-term infusion of aldosterone in mice resulted in elevation of plasma interleukin-1 levels and vascular abnormalities. Mice lacking the IL-1R or the inflammasome components NLRP3 and caspase-1 were protected from aldosterone-induced vascular damage. In vitro, aldosterone stimulated NLRP3-dependent interleukin-1 secretion by bone marrow-derived macrophages by activating nuclear factor-B signaling and reactive oxygen species generation. Moreover, chimeric mice reconstituted with NLRP3-deficient hematopoietic cells showed that NLRP3 in immune cells mediates aldosterone-induced vascular damage. In addition, aldosterone increased the expression of NLRP3, active caspase-1, and mature interleukin-1 in human peripheral blood mononuclear cells. Hypertensive patients with hyperaldosteronism or normal levels of aldosterone exhibited increased activity of NLRP3 inflammasome, suggesting that the effect of hyperaldosteronism on the inflammasome may be mediated through high blood pressure. Conclusions: Together, these data demonstrate that NLRP3 inflammasome, through activation of IL-1R, is critically involved in the deleterious vascular effects of aldosterone, placing NLRP3 as a potential target for therapeutic interventions in conditions with high aldosterone levels.

Aldosterone has been shown to stimulate renal TGF-beta(1) expression. However, the mechanisms for aldosterone-induced TGF-beta(1) expression have not been clearly determined in mesangial cells. We examined the role of extracellular-signal regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) in the aldosterone-induced TGF-beta(1) expression in rat mesangial cells. TGF-beta(1) protein in the conditioned medium released from rat mesangial cells was measured by sandwich ELISA, TGF-beta(1) mRNA expression was analyzed by Northern blotting, AP-1 DNA binding activity was measured by EMSA and the ERK1/2, JNK activity was analyzed by western blotting. Aldosterone significantly stimulated TGF-beta(1) protein production and TGF-beta(1) mRNA expression in mesangial cells in a dose-dependent manner. Aldosterone significantly increased AP-1 DNA binding activity in mesangial cells. Pre-treatment of cells with AP-1 inhibitor, curcumin, blocked aldosterone-induced AP-1 DNA binding activity as well as aldosterone-induced TGF-beta(1) production. Aldosterone increased phosphorylation of ERK1/2 and JNK in mesangial cells. Pre-treatment of cells with ERK1/2 inhibitor, PD98059, or JNK inhibitor, SP600125 significantly inhibited aldosterone-induced ERK1/2 and JNK activity and subsequently TGF-beta(1) production, respectively. We conclude that aldosterone-induced TGF-beta(1) expression in mesangial cells is regulated by the ERK1/2, JNK and AP-1 intracellular signaling pathways.

The objective of this study was to measure the effect of selection for tolerance on the severity of the Aleutian disease (AD) lesions in mink. Sensitivity and specificity of antibody detection in the blood by counter-immunoelectrophoresis (CIEP) relative to the presence of Aleutian mink disease virus (AMDV) in the spleen by PCR in naturally infected farmed mink were also estimated. Carcasses of 680 sero-positive (CIEP-P) black mink from 28 farms in Nova Scotia, Canada, and from 132 sero-negative (CIEP-N) mink from 14 of these farms were collected at pelting time. A total of 116 of the CIEP-P mink were from three farms where animals have been selected for tolerating AD for almost 20 years. The severity of the AD lesions was assessed by histopathological examination of kidneys, lungs, heart, brain and liver on a scale of 0 to 4. Sensitivity and specificity of CIEP relative to PCR were 0.97 and 0.85, respectively, and 16.5% of CIEP-N mink were PCR positive, which could be one of the reasons for the failure of virus eradication by CIEP in Canada. The CIEP-N and tolerant CIEP-P animals had 9.39 and 6.23 greater odds of showing lower lesion severity, respectively, than the CIEP-P animals (P < 0.01). The CIEP-N mink had a slightly higher chance (P = 0.07) of showing lower lesion severity (odds ratio 1.51) compared with tolerant CIEPP mink. The results suggested that tolerant mink had significantly reduced severity of AD lesions despite having anti-viral antibodies and carrying the virus. (C) 2017 The Authors. Published by Elsevier Ltd.

The objective of this study was to assess the sensitivity of the Omni Klentaq-LA DNA polymerase for detecting Aleutian mink disease virus (AMDV) in mink blood and tissues by PCR without DNA extraction. The presence of AMDV DNA was directly tested by Klentaq in the plasma, serum, whole blood, and spleen homogenates of 188 mink 4 and 16 months after inoculation with the virus. Samples from bone marrow, small intestine, liver, lungs, kidneys, and lymph nodes of 20 of the same mink were also tested by Klentaq. DNA was extracted from paired samples of plasma and the aforesaid tissues by a commercial nucleic acid extraction kit (Dynabeads Silane) and tested by PCR. Compared with the extracted DNA, Klentaq detected a significantly greater number of samples in the whole blood, serum, plasma, spleen, and small intestine. It was concluded that Klentaq is a preferred system for directly detecting AMDV DNA in mink blood and tissues. The lower success rate of extracted DNA compared with Klentaq could be the result of DNA losses during the extraction process. This is an important factor in chronically infected mink, which have a low AMDV copy number in the bloodstream. Direct AMDV detection also reduces the cost of PCR amplification and lowers the risk of sample contamination.

Background: Childhood adversities and emotional dysregulation are connected with chronic pain, alexithymia, and depression. Longitudinal studies exploring the impact of their co-occurrence on the pain situation are rare.Aims: The influence of alexithymia, depression, baseline pain situation, and treatment options on the course of chronic pain in a clinical sample was studied.Methods: The baseline data was collected from chronic pain patients (n=154) before their first pain clinic visit, and the follow-up data after 1 year by self-report questionnaires. Study variables consisted of pain intensity, pain disability, alexithymia (TAS-20), depression (BDI-II), and treatment interventions. Statistical analyses were performed to find out differences between baseline and follow-up, as well as between alexithymic and non-alexithymic patients, and to estimate the effect of the treatment provided.Results: At follow-up, the majority of the patients had pain intensity and disability severe enough to disrupt with their daily living. None of treatment interventions was related to better outcome. Alexithymic patients reported more pain disability and depression at both baseline and at follow-up. The effect of alexithymia on pain disability was mediated by depression. The use of opioids was connected to alexithymia and depressiveness. Alexithymia and depression made a substantial contribution to poorer outcome.Conclusions: Severe pain intensity and disability with depression and alexithymia predicted difficulties in achieving improvement. Depression and alexithymia probably impair compliance with treatment and adherence to interventions. Their co-occurrence with a more severe pain situation and with the use of opioids indicates psychological problems underlying the pain experience.

Background and objectives: Alexithymia is a multidimensional personality construct including the components difficulties identifying feelings (DIF), difficulties describing feelings (DDF), and externally oriented thinking (EOT). Different features of alexithymia are thought to reflect specific deficits in the cognitive processing and regulation of emotions. The aim of the present study was to examine for the first time patterns of deployment of attention as a function of alexithymia components in healthy persons by using eye-tracking technology. It was assumed that EOT is linked to avoidance of negative images. Methods: 99 healthy adults viewed freely pictures consisting of anxiety-related, depression-related, positive, and neutral images while gaze behavior was registered. Alexithymia was assessed by the 20 Item Toronto Alexithymia Scale. Measures of anxiety, depression, and (visual-perceptual) intelligence were also administered. Results: A main effect of emotion condition on dwell times was observed. Viewing time was lowest for neutral images, longer for depression-related and happy images, and longest for anxiety-related images. Gender and EOT had significant effects on dwell times. EOT correlated negatively with dwell time on depression-related (but not anxiety-related) images. There were no correlations of dwell times with depression, trait anxiety, intelligence, DIF, or DDF. Limitations: Alexithymia was assessed exclusively by self-report. Conclusions: Our results show that EOT but not DIF or DDF influences attention deployment to simultaneously presented emotional pictures. EOT may reduce attention allocation to dysphoric information. This attentional characteristic of EOT individuals might have mood protecting effects but also detrimental impacts on social relationships and coping competencies. (C) 2016 Elsevier Ltd. All rights reserved.

In legume plants, uricase gene (Nodulin-35) plays a positive role in metabolism of ureide and amide compounds in symbiotic nitrogen-fixing in the nodules. In this study, a pot experiment was performed to examine the effects of ammonium application on the transcription of MsU2 gene and distribution of major nitrogen compounds in alfalfa Medicago sativa. Data showed that alfalfa plant has a significant difference in contents of nitrogen compounds in xylem saps compared with soybean plant, and belongs to typical amide type legume plants with little ureide accumulation, and the accumulation of asparagines and ureide in the tissues of alfalfa is mainly gathered in the nodules. Northern blotting showed that excessive ammonium significantly inhibited the transcription of MsU2 gene in the nodules and roots, and mRNA accumulation of MsU2 gene in the plants exposed to excessive ammonium decreased gradually with culture time extension, indicating that application of ammonium significantly inhibited the transcription of MsU2 gene in the alfalfa plants. Although the application of excessive ammonium increased the contents of amino acids in various tissues of alfalfa, the accumulation of allantoin reflecting the strength of uricase activity is remarkably reduced in the xylem saps, stems and nodules when alfalfa plants exposed to excessive ammonium, suggesting that application of excessive ammonium generated a negative effect on symbiosis fixing-nitrogen system due to inhibition of ammonium ion on uricase activity in the nodules of alfalfa. This result seems to imply that application of excessive ammonium in legume plants should not be proposed to avoid affecting the ability of fixing nitrogen in the nodules of legume plants, and reasonable dose of ammonium should be recommended to effectively utilize the fixed N from atmosphere in legume plant production.

The imminent depletion of fossil fuels and the surging global demand for renewable energy have led to the search for nonconventional energy sources. After a few decades of trial and error, the world is now testing the sources of the third generation of fossil fuels, which contain for most parts microalgae. With more than 80% oil content, being adaptable in growth parameters and highly versatile, microalgae are highly promising sources of biofuels in the present time. The present article makes a sweeping attempt to highlight the various methods employed for cultivation of microalgae, techniques to harvest and extract biomass from huge algal cultures, as well as their downstream production and processing procedures. The advantages, limitations, and challenges faced by each of them have been described to some extent. Major concerns pertaining to biofuels are supposed to be their environmental sustainability and economic viability along with their cost effectiveness. This would require a great deal of empirical data on existing systems and a great deal of optimization to generate a more robust one. We have concluded our article with a SWOT analysis of using algae for biodiesel production in a tabulated form. (C) 2015 International Union of Biochemistry and Molecular Biology, Inc.

The natural variation of environmental factors in freshwater basins determines their biodiversity. Among them, calcium is a key physiological compound for freshwater invertebrates. It is required for shell formation, muscle contraction, it mediates gene expression and allows counteracting acidosis during stress periods, among other functions. Although the distribution of different freshwater species has been suggested to be linked with the environmental calcium concentration, as yet no research studies have confirmed this. Identifying whether environmental calcium concentrations might determine the invasion success of alien species would be critical in developing and implementing effective management strategies to control them. Here, a multidisciplinary approach integrating field surveys, analytical chemistry techniques, molecular biology analyses and a lab-scale experiment was taken to decipher whether the environmental calcium Concentration might hamper the establishment of Corbicula fluminea in northwestern Iberian rivers. A Principal Component Analysis on water chemistry variables from 13 water bodies identified environmental calcium concentration, among others, as one key factor that best characterized the distribution area of C. fluminea. The calcium content in animals' bodies from two representative rivers was dependent on the environmental calcium concentration of freshwater basins; the lower the concentration, the lower the body's content. The expression of stress- and calcium homeostasis-related genes was higher in C fluminea from low calcium concentration environments than in those from calcium-rich freshwater basins. Finally, under experimental conditions, lower water calcium concentrations decreased C fluminea growth rates. The present data suggest, for the first time, that environmental calcium concentration may act as a determinant factor on the invasion success of C. fluminea in freshwater environments. Our results provide new clues for the identification of basins with increased risk of potential invasion by C fluminea based on environmental calcium levels. (C) 2016 Elsevier B.V. All rights reserved.

Munchausen syndrome by proxy (MSBP), also known as fabricated or induced illness in a child by a caretaker, is a form of abuse where a caregiver deliberately produces or feigns illness in a person under his or her care, so that the proxy will receive medical care that gratifies the caregiver. The affected children are often hospitalized for long periods and endure repetitive, painful and expensive diagnostic attempts. We present an analytically confirmed case of MSBP by alimemazine. A 3-year-old boy was brought repetitively to a Pediatric Emergency Department by his mother because he presented limb tremors, dysarthria, obnubilation, and ataxia and generalized tonic-clonic seizures coinciding with intermittent fever. Neither the rest of the physical examination nor the complementary tests showed any significant alterations. MSBP was suspected and a routine systematic toxicological analysis in urine and blood was requested. Alimemazine was detected in all biological samples. The administration of this drug was never mentioned by the mother and the subsequent interview with her corroborated the suspicion of MSBP. Clinically, after separation from the mother, the child's neurological symptoms gradually improved until the complete disappearance of the cerebellar symptoms. Alimemazine was quantified in serum, urine, gastric content and cerebrospinal fluid samples by gas chromatography-mass spectrometry (maximum serum level was 0.42 mu g/ml). Hair quantification of alimemazine was performed by ultra-performance liquid chromatography-tandem mass spectrometry in different segments of hair. The results confirmed regular substance use during the at least eight last months (8.8, 14.7, 19.7 and 4.6 ng/mg hair starting from most proximal segment). This patient represents the first case published with analytical data of alimemazine in blood, urine, gastric content, cerebrospinal fluid and hair, which allowed us to prove an acute and repetitive poisoning with alimemazine as evidence of MSBP. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Immunohistochemistry (IHC) is a widely-tested, low-cost and rapid ancillary technique available in all laboratories of pathology. This method is generally used for diagnostic purposes, but several studies have investigated the sensitivity and specificity of different immunohistochemical anti-bodies as a surrogate test in the determination of predictive biomarkers in non-small cell lung cancer (NSCLC), particularly for Epidermal Growth Factor Receptor (EGFR) gene mutations, Anaplastic Lymphoma Kinase (ALK) gene and ROS1 rearrangements. In this review, a critical examination of the works comparing the consistency of IHC expression and conventional molecular techniques to identify genetic alterations with predictive value in NSCLC is discussed. Summarizing, data on sensitivity and specificity of antibodies against ALK and ROS1 are very consistent and time has come to trust in IHC at least as a cost-effective screening tool to identify patients with rearranged tumors in clinical practice. On the other hand, mutant-specific antibodies against EGFR demonstrate a good specificity but a lowto- fair sensitivity, raising some cautions on their employment as robust predictive biomarkers. A brief comment on preliminary experiences with antibodies against BRAF, RET, HER2 and c-MET is also included.

Allatostatins are important regulatory neuropeptides which are widely distributed in invertebrates and execute their functions through either neural or Immoral routes. However, the regulatory mechanism of the gene expression is unclear. In this paper, we report a naturally occurring amisense transcript, named as asMacro-AST A, of the crustacean FGLamide allatostatin gene (Macro-AST A) from the prawn, Macrobrachium rosenbergii. The asMacro-ASTA contains an 843-bp sequence fully complementary to the 3'end of the Macro-ASTA. To our knowledge, this is the first report of a natural antisense transcript in crustacean and the first endogenous antisense transcript of all identified allatostatin genes. Northern blotting analysis demonstrated that the gene was expressed in the thoracic ganglia where the sense gene was also expressed. Furthermore, we have detected a RNA-RNA duplex between the sense-antisense complementary region by using RNasc protection analysis and RT-PCR. These results suggest that the antisense gene may play a role in the regulation of Macro-AST A gene expression. (c) 2006 Elsevier Inc. All rights reserved.

Traditional digital controls mostly use digital-analog converters to convert input and output voltages into digital coding to achieve control. This paper proposes the use of two digital ramps with two different frequencies to replace a digital-analog converter. This approach can produce seven bit resolution for the DPMW signal. In addition, we use an all-digital DLL phase correction concept to further enhance the resolution of the DPWM signal by an additional three bits, resulting in 10-bit DPWM signal resolution. The proposed circuit uses 0.35 mu m CMOS processes, with a core area of 0.987 mm(2), a system switching frequency of 500 KHz, an input voltage range of 3.3-4.2 V, and an output voltage range of 5 V. Output voltage measurement accuracy reaches 99%, while the system reaches efficiency of 91% with output loads of up to 500 mA. (C) 2015 Elsevier Ltd. All rights reserved.

Background: Knockdown resistance (kdr), caused by alterations in the voltage-gated sodium channel (Na-v), is one of the mechanisms responsible for pyrethroid (PY) resistance. In the Asian tiger mosquito, Aedes albopictus, at least four different mutations were described in the IIIS6 Na-v segment in populations from Asia, North America and Europe. In contrast, in Aedes aegypti at least 12 non-synonymous mutations have been reported at nine different codons, mostly in the IIS6 and IIIS6 Na-v segments. The Phe1534Cys kdr mutation in the IIIS6 Na-v segment is the most prevalent in populations of Ae. aegypti worldwide, also found in Ae. albopictus from Singapore. Herein, we investigated the DNA diversity corresponding to the IIS6 and IIIS6 Na-v segments in natural populations of Ae. albopictus from Brazil. Methods: DNA from eight Brazilian Ae. albopictus natural populations were individually extracted and pooled by states of origin, amplified, cloned and sequenced for the corresponding IIS6 and IIIS6 Na-v segments. Additionally, samples from each location were individually genotyped by an allelic specific PCR (AS-PCR) approach to obtain the genotypic and allelic frequencies for the 1534 Na-v site. Results: No non-synonymous substitutions were observed in the IIS6 sequences. However, the Phe1534Cys kdr mutation was evidenced in the Ae. albopictus Na-v IIIS6 segment sequences from Parana (PR) and Rondonia (RO) states, but not from Mato Grosso (MT) state. The 1534Cys(kdr) allele varied from 3% (Marilena/PR and Porto Velho/RO) to 10% ( Foz do lguacu/ PR). To our knowledge, this paper reports the first occurrence and provides distribution data of a possible kdr mutation in Ae. albopictus in South America. Conclusion: The emergence of a likely kdr mutation in Ae. albopitus natural populations is a signal of alert for vector control measures since PY are the most popular insecticides adopted by residents. Additionally, once the kdr allele is present, its frequency tends to increase faster under exposition to those compounds. Although the Asian tiger mosquito is not incriminated as an important vector of dengue, chikungunya and Zika viruses in South America, its importance in this regard has been extensively discussed since Ae. albopictus is rapidly spreading and can also migrate between sylvatic and urban environments. Therefore, insecticide resistance monitoring initiatives should also be extended to Ae. albopictus in Brazil in order to maintain chemical compounds as an efficient vector control tool when needed.

Introduction: Some glial-neuronal tumors (GNT) (pleomorphic xantho-astrocytoma [PXA], ganglioglioma [GG]) display BRAF-V600E mutation, which represents a diagnostic clue to these entities. Targeted therapies against BRAF-V600 protein have shown promising results in GNT. The aim of this study was to assess the utility of BRAF-V600E immunohistochemistry (IHC, clone VE1) in daily practice in a series of 140 glial, and GNT compared to molecular biology (MB) techniques. Methods: We performed BRAF-V600E IHC on all 140 cases. We used Sanger sequencing and allele-specific quantitative PCR (ASQ-PCR) to detect BRAF-V600E mutation when sufficient amount of materiel was available. Results: BRAF-V600E immunostaining was detected in 29.5% of cases (41/140 cases; 61.5% GG/GC/AGG (32/52), 33% PXA, 6.6% pilocytic astrocytomas). In 47 cases, MB could be performed: Sanger sequencing and ASQ-PCR in 34 cases, ASQ-PCR only in 11 cases, and Sanger sequencing only in two cases. In initial tumors, Sanger sequencing identified BRAF-V600E mutation in 19.5% tumors (seven of 36 tested cases). ASQ-PCR showed mutation in 48.5% tumors (17/35 tested cases). In six cases (5 GG, one PXA), the results were discordant between IHC and MB; the five GG cases were immunopositive for BRAF-V600E but wild type with both MB techniques. In another 7 GG, the percentage of mutated (ganglion) cells was low, and Sanger sequencing failed to detect the mutation, which was detected by IHC and ASQ-PCR. Conclusions: In tumors with few mutated cells (e.g., GG), anti-BRAF-V600E IHC appears more sensitive than Sanger sequencing. The latter, although considered as the gold standard, is not to be used up-front to detect BRAF mutation in GG. The combination of IHC and ASQ-PCR appears more efficient to appraise the indication of targeted therapies in these glioneuronal tumors.

BACKGROUND: It is unclear whether allergen immunotherapy (AIT) can be safely initiated during the pollen season (coseasonal initiation [CSI]) because of a potential increased risk of systemic allergic reactions. OBJECTIVE: To systematically review publications reporting the safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) CSI to validate or invalidate the perception of increased safety risk. METHODS: PubMed, EMBASE, Ovid, Literatura Latino Americana em Ciencias da Saude (LILACS), and Cochrane Library databases were searched without limits for studies of any design reporting SCIT or SLIT CSI for pollen allergen. Congress abstracts were included. RESULTS: Nineteen eligible studies were identified: 8 SCIT (n = 947 subjects total; n[340 double-blind placebo-controlled [DBPC]) and 11 SLIT (n = 2668 subjects total; n = 565 DBPC). Study characteristics and safety reporting were heterogeneous. No epinephrine administrations were reported. Discontinuation frequencies were 6% or less and 10% or less with SCIT and SLIT CSI, respectively. In SCIT studies, systemic allergic reaction frequency was 0% to 7% with "up to peak season" or CSI, 0% to 6% with "after peak season" or out-of-season initiation, and 0% to 7% with placebo. In SCIT studies, serious treatment-related adverse event (AE) frequency with CSI ranged from 0% to 2%; few severe AEs were reported. In SLIT studies, systemic allergic reaction frequency ranged from 0% to 4% with CSI, 0% with out-of-season initiation, and 0% to 2% with placebo. Overall, 2 serious treatment-related AEs with SLIT CSI were reported. Severe AE frequency in SLIT studies ranged from 0% to 8% with CSI, 0% to 12% with out-of-season initiation, and 0% to 8% with placebo. CONCLUSIONS: No increase in AEs of concern was observed with SCIT or SLIT CSI; however, additional data with standardized regimens and doses are needed. (C) 2016 American Academy of Allergy, Asthma & Immunology

Allergic diseases often occur early in life and persist throughout life. This life-course perspective should be considered in allergen immunotherapy. In particular it is essential to understand whether this al treatment may be used in old age adults. The current paper was developed by a working group of AIRWAYS integrated care pathways for airways diseases, the model of chronic respiratory diseases of the European Innovation Partnership on active and healthy ageing (DG CONNECT and DG Sante). It considered (1) the political background, (2) the rationale for allergen immunotherapy across the life cycle, (3) the unmet needs for the treatment, in particular in preschool children and old age adults, (4) the strategic framework and the practical approach to synergize current initiatives in allergen immunotherapy, its mechanisms and the concept of active and healthy ageing.

BackgroundClinical efficacy of pollen allergen immunotherapy (AIT) has been broadly documented in randomized controlled trials. The underlying clinical endpoints are analysed in seasonal time periods predefined based on the background pollen concentration. However, any validated or generally accepted definition from academia or regulatory authorities for this relevant pollen exposure intensity or period of time (season) is currently not available. Therefore, this Task Force initiative of the European Academy of Allergy and Clinical Immunology (EAACI) aimed to propose definitions based on expert consensus. MethodsA Task Force of the Immunotherapy and Aerobiology and Pollution Interest Groups of the EAACI reviewed the literature on pollen exposure in the context of defining relevant time intervals for evaluation of efficacy in AIT trials. Underlying principles in measuring pollen exposure and associated methodological problems and limitations were considered to achieve a consensus. ResultsThe Task Force achieved a comprehensive position in defining pollen exposure times for different pollen types. Definitions are presented for pollen season', high pollen season' (or peak pollen period') and high pollen days'. ConclusionThis EAACI position paper provides definitions of pollen exposures for different pollen types for use in AIT trials. Their validity as standards remains to be tested in future studies.

There is no universally accepted grading system to classify the severity of systemic allergic reactions (SARs), including anaphylaxis. Although a consensus definition for anaphylaxis was established in 2005, the signs and symptoms required to define a reaction as anaphylaxis are inconsistently applied in research and clinical practice. As a result, it is difficult to compare and evaluate safety outcomes in surveys, clinical practice and trials, and pharmacovigilance data. In 2010, the World Allergy Organization (WAO) proposed a uniform grading system to classify allergen immunotherapy SARs. The basis of the grading system is the organ system(s) involved and reaction severity. The final grade is determined by the physician/health care professional after the event is over. Although the 2010 WAO grading system was developed to classify allergen immunotherapy SARs, with appropriate modifications, it can be used to classify SARs from any cause. The purpose of this Rostrum is to present a proposed modification of the 2010 WAO SAR grading system that will make it applicable to all SARs due to any cause. The modified grading system allows for classification of less severe SARs, which may be underreported or overreported in clinical trials and surveillance studies, depending on the criteria specified for adverse event reporting. The universal use of the proposed modified SAR grading system will allow for better safety comparisons across different venues and treatment protocols. (C) 2016 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2017;5:58-62)

Keratinocytes (KCs) play a key role in all phases of skin sensitization. We recently identified interleukin-18 (IL-18) production as useful end point for determination of contact sensitization potential of low molecular weight chemicals. The aim of this study was to identify genes involved in skin sensitizer-induced inflammasome activation and to establish their role in IL-18 production. For gene expression analysis, cells were treated for 6 h with p-phenylenediamine (PPD) as reference contact allergen; total RNA was extracted and examined with a commercially available Inflammasome Polymerase Chain Reaction (PCR) array. Among genes induced, NLRP12 (Nod-like receptor P12) was selected for further investigation. NLRP12 promoter region contains Blimp-1 (B-lymphocyte-induced maturation protein-1)/PRDM1 binding site, and from the literature, it is reported that Blimp-1 reduces NLRP12 activity and expression in monocytes/macrophages. Their expression and role in KCs are currently unknown. To confirm NLRP12 expression and to investigate its relationship with Blimp-1, cells were exposed for different times (3, 6 and 24 h) to the extreme sensitizer 2,4-dinitrochlorobenzene (DNCB) and the strong sensitizer PPD. Allergens were able to induce both genes, however, with different kinetic, with DNCB more rapidly upregulating Blimp-1 and inducing IL-18 production, compared to PPD. NLRP12 and Blimp-1 expression appeared to be inversely correlated: Blimp-1 silencing resulted in increased NLRP12 expression and reduced contact allergen-induced IL-18 production. Overall results indicate that contact allergens of different potency differently modulate Blimp-1/NLRP12 expression, with strong allergen more rapidly downregulating NLRP12, thus more rapidly inducing IL-18 production. Data confirm that also in KCs, NLRP12 has an inhibitory effect on inflammasome activation assessed by IL-18 maturation.

Background There is limited understanding of how maternal diet affects breastmilk food allergen concentrations, and whether exposure to allergens through this route influences the development of infant oral tolerance or sensitization. Objective To investigate how maternal dietary egg ingestion during early lactation influences egg protein (ovalbumin) levels detected in human breastmilk. Methods In a randomized controlled trial, women were allocated to a dietary group for the first six weeks of lactation: high-egg diet (>4 eggs per week), low-egg diet (one-three eggs per week) or an egg-free diet. Breastmilk samples were collected at 2, 4 and 6 weeks of lactation for the measurement of ovalbumin. The permeability of the mammary epithelium was assessed by measuring the breastmilk sodium : potassium ratio. Egg-specific IgE and IgG4 were measured in infant plasma at 6 weeks, and prior to the introduction of egg in solids at 16 weeks. Results Average maternal egg ingestion was associated with breastmilk ovalbumin concentration. Specifically, for each additional egg ingested per week, there was an average 25% increase in ovalbumin concentration (95% CI: 5-48%, P = 0.01). Breastmilk ovalbumin concentrations were significantly higher in the ` high-egg' group (>4 eggs per week) compared with the ` egg-free' group (P = 0.04). However, one-third of women had no breastmilk ovalbumin detected. No detectable associations were found between mammary epithelium permeability and breastmilk ovalbumin concentrations. Infant plasma egg-specific IgG4 levels were also positively associated with maternal egg ingestion, with an average 22% (95% CI: 3-45%) increase in infant egg-specific IgG4 levels per additional egg consumed per week (P = 0.02). Conclusions and Clinical Relevance Increased maternal egg ingestion is associated with increased breastmilk ovalbumin, and markers of immune tolerance in infants. These results highlight the potential for maternal diet to benefit infant oral tolerance development during lactation.

The ocular surface is constantly exposed to environmental irritants, allergens and pathogens, against which it can mount a prompt immune response to preserve its integrity. But to avoid unnecessary inflammation, the ocular surface's mucosal immune system must also discriminate between harmless and potentially dangerous antigens, a seemingly complicated task. Despite its unique features, the ocular surface is a mucosal lining, and as such, it shares some homeostatic and pathophysiological mechanisms with other mucosal surfaces. The purpose of this review is to explore the mucosal homeostatic immune function of the ocular surface in both the healthy and diseased states, with a special focus on mucosal immunology concepts. The information discussed in this review has been retrieved by PubMed searches for literature published from January 1981 to October 2016.

Allergic rhinitis (AR) is a common illness in children and can impair their quality of life. Furthermore, many children remain symptomatic despite maximizing systemic antihistamine and topical therapies. It is at this clinical juncture that immunotherapy may be considered. The efficacy and safety associated with both subcutaneous (SCIT) and sublingual (SLIT) approaches are reviewed and positioned as treatment options for pediatric patients, with specific focus on current literature as it relates to SLIT in children, including those with perennial allergic rhinitis. Although there is more extensive experience with SLIT treatment in Europe, grass and ragweed tablet forms of SLIT are approved in the US. Approaches to the care of pediatric patients with allergic rhinitis are presented. (C) 2016 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2017;5:46-51)

Background: Allergic rhinitis (AR) is the most common chronic disease among children. To characterize the disease, a modified classification of severity (m-ARIA) has recently been validated in AR children. When medical treatment fails, surgery for nasal obstructive disorders (NOD) may be a therapeutic option. Our objective was to assess the prevalence of NOD and their influence in medical treatment response among children with persistent AR (PER). Methods: In a prospective, real-life study, 130 paediatric PER patients (13.1 +/- 2.8years, females 31.5%, severe rhinitis 49%) referred from Allergy to ENT department were assessed for their response (R, responders; NR, non-responders) to medical treatment (intranasal steroids and antihistamines or antileukotrienes) by direct questioning and nasal symptom visual analogue scale, the presence of NOD (septal deformity, turbinate enlargement and adenoidal hyperplasia), comorbidities, nasal symptoms, rhinitis severity (modified ARIA criterion) and asthma control (International Consensus On Pediatric Asthma criterion). Results: After 2months of treatment, the NR group presented a higher prevalence of obstructive septal deformity and severe inferior turbinate enlargement when compared with the R group. Higher septal deformity and turbinate enlargement scores were strongly associated with treatment refractoriness. The prevalence of severe PER was also higher for the NR group. Higher asthma control scores were associated with the probability of treatment-induced improvement. Conclusions: In paediatric PER patients, medical therapy refractoriness was associated with NOD, mainly septal deformity and turbinate enlargement. In those patients, ENT examination will facilitate an early NOD diagnosis in order to indicate potential corrective surgery.

Background Over the past decade, regulatory bodies and scientific societies recommended, as primary efficacy outcome, a score that reflects both symptom severity and use of rescue medication for clinical trials in allergy immunotherapy (AIT). Objective We sought to compare the results obtained with two subject-specific scores, the Combined Score (CS) and the Adjusted Symptom Score (AdSS), for assessment of AIT in seasonal allergic rhinoconjunctivitis due to birch and grass pollen allergens. Methods CS and AdSS were evaluated in subjects receiving a 300IR dose of allergen extract daily, by sublingual route, in four clinical trials with the 5-grass pollen tablet (NCT00367640, NCT00409409, NCT00955825 and NCT00418379) and one with the birch pollen solution (NCT01731249). The CS is derived from the Rhinoconjunctivitis Total Symptom Score (RTSS) and the Rescue Medication Score (RMS) giving equal weight to symptoms and medication use. The AdSS is a symptom score adjusting for rescue medication use. Efficacy end-points were analysed using an analysis of covariance linear model. Results In all trials, despite the different constructs of the two scores, Combined Score or Adjusted Symptom Score were similarly reduced in the 300IR group compared to the placebo group. Treatment effect was consistently demonstrated with both scores, CS and AdSS, used as either daily scores or average of the daily scores over the pollen season. Minor differences with the same statistical conclusions were observed between the results, leading to the same interpretation. Conclusions and Clinical Relevance The two scores, combined and adjusted scores, for evaluation of clinical efficacy of AIT have led to similar results, with similar statistical conclusions and similar interpretation.

Background: Limited accessibility to providers may delay appropriate control of asthma exacerbations. The objective of our study is to estimate the contributors to the hospital/emergency department (ED) visits among adults with asthma focusing on the availability of healthcare providers. Methods: We conducted a pooled cross-sectional analysis using the 2011-2013 Asthma Call-Back Survey linked with 2012-2016 Area Health Resource Files. We employed multivariable logistic regression with dichotomous outcomes of hospitalization and ED visits. Key covariates were the availability of county-level healthcare provider variables per 100,000 persons such as the number of lung disease specialists (including pulmonary care specialists, and allergy and immunology specialists), the number of hospitals, the number of safety-net facilities including rural health centers (RHCs) and federally qualified health centers (FQHCs), and the number of primary care physicians (PCPs). Results: Among 25,621 adults, proportions of hospital visits and ED visits were 3.3% and 13.2%, respectively. An additional RHC reduced by 3% the odds of having an ED visit (odds ratio [OR] = 0.97, p=.004). Patients with cost barriers to seeing a PCP were 60% (OR = 1.60, p=.028) more likely to have a hospital visit than those without. In addition, patients with cost barriers to seeing a specialist were 90% (OR = 1.90, p=.007) and 111% (OR =2.11, p=.001) more likely to have a hospital visit and ED visit, respectively, than those without. Conclusions: Hospital and ED visits among adults with asthma are partially related to the availability of providers, and more related to financial barriers. Therefore, financial support for the vulnerable asthma population might be a target for policy makers interested in reducing hospitalizations and ED visits.

Background: Porphyromonas gingivalis (Pg) capsule enables evasion from phagocytosis, invasion of keratinocytes, and bacterial survival. In mixed infection, the capsule also participates in coaggregation, which may lead to characteristic virulence not present in the monoinfection. The aim of this study is to evaluate the role of Pg capsule as a virulence factor in coaggregated mixed infection with Fusobacterium nucleatum (Fn). Methods: Mixed infections containing Fn and non-capsulated or capsulated strains of Pg were compared with the same infection with lactose as coaggregation inhibitor. Murine experimental periodontitis was used to assess disease severity. Primary polymorphonuclear leukocytes and keratinocytes were used to examine phagocytosis and bacterial invasion, respectively. Results: Mixed infection with capsulated Pg augmented alveolar bone loss compared with that of mixed infection with non-capsulated Pg. Addition of lactose led to attenuation of bone loss in the capsulated mixed infection and to intensification of bone loss in the non-capsulated mixed infection. In the latter mixed infection, Fn evaded phagocytosis, whereas in the capsulated mixed infection Pg displayed a greater capacity for invasion of keratinocytes. Conclusions: Pg capsule was found to serve as a unique virulence factor in mixed infection with Fn. Capsule-dependent coaggregation led to augmented invasion of Pg and may be responsible for the severity of disease after mixed infection with Fn.

Background: Leukotoxin (Ltx) expressed by Aggregatibacter actinomycetemcomitans is a powerful exotoxin, which can cause imbalance in host response. Immunoreactivity to Ltx is a marker for presence of leukotoxic A. actinomycetemcomitans, a presence that may modify the disease pattern of colonized individuals. The aim of the present study is to examine presence of systemic immunoreactivity to A. actionmycetemcomitans Ltx with respect to clinical and inflammatory findings in individuals with or without periodontitis (N = 88). Methods: Periodontal status was examined in patients with severe periodontitis (n = 49) and healthy controls (n = 39), and patients received periodontal treatment. Systemic biomarkers associated with inflammation and infections as well as clinical parameters were analyzed at baseline and 3 and 6 months after treatment. Results: Presence of immunoreactivity against Ltx was associated with impaired remission of disease after periodontal treatment. This immunoreactivity was also significantly associated with increased systemic levels of A. actinomycetemcomitans-specific immunoglobulins and increasing age. Conclusion: Presence and levels of systemic immunoreactivity against A. actinomycetemcomitans Ltx are associated with decreased remission after otherwise successful periodontal treatment.

Among athletes and coaches, there is a common perception that high training loads and competitions, applied chronically, with inadequate nutritional control and/or recovery periods, may reduce the immune resistance, increasing susceptibility to infection episodes, mainly upper respiratory tract infection (URTI). In this sense, this study is focused on reviewing the interactions between immunological parameters with the overtraining syndrome, specifically in team sports, considering its intermittent nature. Thus, a review of national and international journals related to the topic was held. The correlations between exercise, immune system and susceptibility to URTI have been evaluated mainly in individual and endurance sports compared to the team sports. The modulations of leukocytes throughout the season, against the totalization of training loads and competitions, when analyzed specifically for neutrophils and monocytes, are possibly related to tissue repair processes and incidence of URTI. Modulations related to lymphocytes seem to be more directly related to the incidence of URTI. Moreover, an understanding of all the proposed markers, including immunological markers, in association with the performance indicators and control of training, appears to be a more promising avenue for clinical diagnosis of the athlete's immune status and prevention of overtraining syndrome than the search for a unique marker of overtraining.

Background Adrenaline auto-injectors (AAI) should be provided to individuals considered to be at high risk of anaphylaxis. There is some evidence that the rate of AAI prescription is increasing, but the true extent has not been previously quantified. Aim To estimate the trends in annual GP-issued prescriptions for AAI among UK children between 2000 and 2012. Design and setting Retrospective cohort study using data from primary care practices that contributed to The Health Improvement Network (THIN) database. Method Children and young people aged between 0-17 years of age with a prescription for AAIs were identified, and annual AAI device prescription rates were estimated using Stata (version 12). Results A total of 1.06 million UK children were identified, providing 5.1 million person years of follow-up data. Overall, 23 837 children were deemed high risk by their GPs, and were prescribed 98 737 AAI devices. This equates to 4.67 children (95% confidence interval [CI] = 4.66 to 4.69), and 19.4 (95% CI = 19.2 to 19.5) devices per 1000 person years. Between 2000 and 2012, there has been a 355% increase in the number of children prescribed devices, and a 506% increase in the total number of AAI devices prescribed per 1000 person years in the UK. The number of devices issued per high-risk child during this period has also increased by 33%. Conclusion The number of children being prescribed AAI devices and the number of devices being prescribed in UK primary care between 2000 and 2012 has significantly increased. A discussion to promote rational prescribing of AAIs in the NHS is needed.

Background: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines on Allergen Immunotherapy (AIT) for the management of insect venom allergy. To inform this process, we sought to assess the effectiveness, cost-effectiveness and safety of AIT in the management of insect venom allergy. Methods: We undertook a systematic review, which involved searching 15 international biomedical databases for published and unpublished evidence. Studies were independently screened and critically appraised using established instruments. Data were descriptively summarized and, where possible, meta-analysed. Results: Our searches identified a total of 16 950 potentially eligible studies; of which, 17 satisfied our inclusion criteria. The available evidence was limited both in volume and in quality, but suggested that venom immunotherapy (VIT) could substantially reduce the risk of subsequent severe systemic sting reactions (OR = 0.08, 95% CI 0.03-0.26); meta-analysis showed that it also improved disease-specific quality of life (risk difference = 1.41, 95% CI 1.04-1.79). Adverse effects were experienced in both the build-up and maintenance phases, but most were mild with no fatalities being reported. The very limited evidence found on modelling cost-effectiveness suggested that VIT was likely to be cost-effective in those at high risk of repeated systemic sting reactions and/or impaired quality of life. Conclusions: The limited available evidence suggested that VIT is effective in reducing severe subsequent systemic sting reactions and in improving disease-specific quality of life. VIT proved to be safe and no fatalities were recorded in the studies included in this review. The cost-effectiveness of VIT needs to be established.

During the last two decades, hyper-immunoglobulin (Ig) E syndromes have been characterized clinically and molecularly in patients with genetically determined primary immunodeficiencies. However, the detection of low IgE levels, defined here as below detection limit in the routine clinical immunology laboratory, has received little attention. We analysed the association of serum IgA, IgM and IgG levels (including IgG subclasses) with low, normal or high serum IgE levels in patients evaluated in a singlecentre out-patient immunodeficiency and allergy clinic. The correlation of serum IgE levels with IgG subclasses depended on the clinical phenotype. In patients with immunodeficiencies, IgE correlated with IgG2 and IgG4 but not with IgG3. In contrast, in patients referred for signs of allergy, IgE correlated with IgG3 but not with IgG2. A low IgE result was associated with low IgG3 and IgG4 in allergy referrals, while immunodeficiency referrals with a low IgE result had significantly lower IgG1, IgG2 and IgG4 levels. Hierarchical clustering of non-IgE immunoglobulin profiles (IgM, IgA, IgG, IgG1-4) validated that non-IgE immunoglobulin levels predict the clinic referral, i.e. phenotype, of low-IgE patients. These results suggesto guide the clinical management of patients with low serum IgE levels.

Purpose of review Although chronic rhinosinusitis with nasal polyps, asthma, and allergy share common inflammatory mechanisms, there is no evidence of cause-and-effect relationship. In this review, we present new studies investigating the complex immunology that links these diseases. Advances in new therapies as well as evidence regarding indication and timing of surgery, especially of more complex cases, are highlighted. Recent findings New studies have endotyped patients in an effort to describe the exact inflammatory profile of each phenotype, whereas described cytokines seem to play a significant role in amplification of T2 inflammation, directly or via innate lymphoid cells. New mAbs that block specific cytokines of these pathways have been developed and seem to show reduced asthma severity as well as improved sinonasal outcomes. Moreover, it has been shown that operating early in the course of disease leads not only to bigger improvements in SNOT-22 outcomes but also to reduced asthma incidence postoperatively in refractory cases. Summary Applying data from current studies in clinical practice, we could better manage refractory cases with asthma and polyps, both medically and surgically. Treatment has to be patient-centered, and this demands a multidisciplinary-team approach of the airway diseases.

BACKGROUND: The difference in clinical presentation, causality assessments, and outcomes of patients with delayed antibiotic-associated cutaneous adverse drug reactions (AA-cADR) and nonantibiotic-associated (NA)-cADR is ill defined. OBJECTIVE: We examined the etiology of AA-cADR, with regard to the type of antibiotic exposure, allergy labeling, and patient outcomes, in comparison with NA-cADR. METHODS: A retrospective observational inpatient cohort study of cADR was performed from January 2004 to August 2014. Patients were divided into AA-cADR and NA-cADR groups for analysis. cADR was defined as erythema multiforme, fixed drug eruption, acute generalized erythematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS), drug-associated linear IgA disease, Stevens-Johnson syndrome, and toxic epidermal necrolysis. RESULTS: Of the 84 patients with cADR, 48% were AA-cADR. Male sex (60% vs 32%, P = .004), median length of stay (14.5 vs 11 days, P = .05), median Charlson comorbidity index (3 vs 1, P = .03), and inpatient mortality (20% vs 5%, P = .04) were higher in AA-cADR compared with NA-cADR. The median drug latency was lower in AA-cADR (6 vs 20 days, P = .001). Sulfonamide antibiotics and glycopeptides were implicated in 20% of AA-cADR. DRESS was more frequently reported in AA-cADR. After cADR diagnosis, further antibiotic therapy was administered in 64% of patients, higher in AA-cADR (75%, 30 of 40) compared with NA-cADR (55%, 24 of 44) (P = .06). Fluoroquinolones (53% vs 21%, P = .02), glycopeptides (vancomycin and teicoplanin; 70% vs 38%, P = .05), and carbapenems (33% vs 13%, P = .11) were used more commonly in AA-cADR. CONCLUSIONS: Antibiotics were the cause of cADR requiring hospital admission in 48% of episodes, and were associated with longer length of stay, higher age-adjusted Charlson comorbidity index, shorter drug latency, and mortality. In AA-cADR, glycopeptide and sulfonamide antibiotic exposure predominated. (C) 2016 American Academy of Allergy, Asthma & Immunology

A recreational scuba diver wore a second scuba regulator against his face during a scuba dive, attached by an elastic rubber cord necklace. After surfacing, the diver's left face became swollen. Through a process of elimination all other items of scuba equipment were excluded as potential causes. A dive with the same equipment minus the necklace confirmed the involvement of the necklace in the pathogenesis of the hypersensitive reaction. In vitro ImmunoCap IgE assay was positive to latex (1.30 kUa/L), subsequent patch testing for contact dermatitis provoked a reaction for benzophenone-4, (a UV stabalizer) and Fourier Transform Infra Red spectroscopy identified the elastic as ethylene propylene rubber, containing additional unidentified compounds. Allergy to natural rubber latex occurs in as many as 6% of Americans and Australians. Around three million American residents are thought to scuba dive each year. Recreational divers are, therefore, advised to check such necklaces, which are typically worn around the throat, for frayed ends and exposed rubber filaments.

Allogenic lymphocyte immunotherapy (LIT) as a treatment for unexplained recurrent spontaneous abortion (URSA) is still controversial due to the lack of enough controls to evaluate its effectiveness. Eighteen randomized, placebo-controlled trials with LIT for URSA were included in the meta-analysis. Live birth rates for each group were extracted, and the overall odds ratio (OR) for LIT was calculated. The success rate of treatment group was significantly higher (OR 3.74, 95% CI 3.07 similar to 4.57). LIT performed before and during pregnancy had dramatically improved the live birth rate in women with URSA (OR 4.67, 95% CI 3.70 similar to 5.90). The overall OR was 5.25 (95% CI 4.16 similar to 6.64), which supports a low dose of lymphocytes for treating URSA. Our results indicate that LIT provides a significantly beneficial effect over placebo for URSA. LIT given before and during pregnancy is superior to LIT given only before pregnancy, and the lower doses per treatment (less than 100 x 10(6) lymphocytes or 100 mL peripheral blood) achieved a better outcome.

Objectives. To perform a state of the art about immunological features in renal transplantation, immunosuppressive drugs and their mechanisms of action and immunologically high risk transplantations such as ABO and HLA-incompatible transplantation. Material and methods. An exhaustive systematic review of the scientific literature was performed in the Medline database and Embase using different associations of the following keywords (MESH): "allogenic response; allograft; immunosuppression; ABO incompatible transplantation; donor specific antibodies; HLA incompatible; desensitization; kidney transplantation". Publications obtained were selected based on methodology, language, date of publication (last 10 years) and relevance. Prospective and retrospective studies, in English or French, review articles; meta analysis and guidelines were selected and analyzed. This search found 4717 articles. After reading titles and abstracts, 141 were included in the text, based on their relevance. Results. The considerable step in comprehension and knowledge allogeneic response this last few years allowed a better used of immunosuppression and the discover of news immunosuppressive drugs. In the first part of this article, the allogeneic response will be described. The different classes of immunosuppressive drugs will be presented and the actual management of immunosuppression will be discussed. Eventually, the modalities and results of immunologically high-risk transplantations such as ABO and HLA incompatible transplantations will be reported. Conclusions. The knowledge and the control of allogeneic response to allogeneic graft allowed the development of renal transplantation. (C) 2016 Elsevier Masson SAS. All rights reserved.

Alloparenting, defined as care provided by individuals other than parents, is a universal behavior among humans that has shaped our evolutionary history and remains important in contemporary society. Dysfunctions in alloparenting can have serious and sometimes fatal consequences for vulnerable infants and children. In spite of the importance of alloparenting, they still have much to learn regarding the underlying neurobiological systems governing its expression. Here, they review how a lack of alloparental behavior among traditional laboratory species has led to a blind spot in our understanding of this critical facet of human social behavior and the relevant neurobiology. Based on what is known, they draw from model systems ranging from voles to meerkats to primates to describe a conserved set of neuroendocrine mechanisms supporting the expression of alloparental care. In this review we describe the neurobiological and behavioral prerequisites, ontogeny, and consequences of alloparental care. Lastly, they identified several outstanding topics in the area of alloparental care that deserve further research efforts to better advance human health and wellbeing. (c) 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 214-232, 2017

Objective: Anxiety and mood disorders (AMD) are the most frequent mental disorders in the human population. They have recently shown increasing prevalence, and commonly disrupt personal and working lives. Objective: The aim of our study was to analyze the spectrum of circulating steroids in order to discover differences that could potentially be markers of affective depression or anxiety, and identify which steroids could be a predictive component for these diseases. Methods: We studied the steroid metabolome including 47 analytes in 20 men with depression (group D), 20 men with anxiety (group AN) and 30 healthy controls. OPLS and multivariate regression models were used for statistical analysis. Results: Discrimination of group D from controls by the OPLS method was absolute, as was group AN from controls (sensitivity = 1.000 (0.839, 1.000), specificity = 1.000 (0.887, 1.000)). Relatively good predictivity was also found for discrimination between group D from AN (sensitivity = 0.850 (0.640, 0.948), specificity = 0.900 (0.699, 0.972)). Conclusion: Selected circulating steroids, including those that are neuroactive and neuroprotective, can be useful tools for discriminating between these affective diseases in adult men. (C) 2016 Published by Elsevier Inc.

Neurosteroids are essential for aiding proper fetal neurodevelopment. Pregnancy compromises such as preterm birth, prenatal stress and intrauterine growth restriction are associated with an increased risk of developing behavioural and mood disorders, particularly during adolescence. These pathologies involve the premature loss or alteration of trophic steroid hormones reaching the fetus leading to impaired neurodevelopment. While the specific programming mechanisms are yet to be fully elucidated, in adult life, dysfunctions of allopregnanolone action are prevalent in individuals with depression, post-traumatic stress disorder and anxiety disorders. The objective of this study was to assess if changes in concentrations of the neurosteroid, allopregnanolone, may be a fetal programming factor in priming the brain towards a negative behavioural phenotype during the childhood to adolescent period using a guinea pig model. Pregnant guinea pigs received either vehicle (45% (2-hydroxypropyI)-beta-cyclodextrin) or the 5 alpha-reductase inhibitor, finasteride (25 mg/kg maternal weight) from gestational age 60 until spontaneous delivery (similar to 71 days gestation). Male and female offspring from vehicle and finasteride treated dams were tested at postnatal day 20 (juvenile-equivalence) in an open field arena, and hippocampus and amygdala subsequently assessed for neurological changes in markers of development and GABA production pathways 24 h later. Females with reduced allopregnanolone exposure in utero displayed increased neophobic-like responses to a change in their environment compared to female controls. There were no differences in the neurodevelopmental markers assessed; MAP2, NeuN, MBP, GFAP or GAD67 between intrauterine finasteride or vehicle exposure, in either the hippocampus or amygdala whereas GAT1 staining was decreased. This study indicates that an intrauterine reduction in the supply of allopregnanolone programs vulnerability of female offspring to anxiety-like disorders in juvenility without impacting long term allopregnanolone concentrations. (C) 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

High-temperature requirement A (HtrA; DegP) from Escherichia coli, an important element of the extracytoplasmic protein quality-control system, is a member of the evolutionarily conserved family of serine proteases. The characteristic feature of this protein is its allosteric mode of activation. The regulatory loops, L3, L2, L1 and LD, play a crucial role in the transmission of the allosteric signal. Yet, the role of LD has not been fully elucidated. Therefore, we undertook a study to explain the role of the individual LD residues in inducing and maintaining the proteolytic activity of HtrA. We investigated the influence of amino acid substitutions located within the LD loop on the kinetics of a model substrate cleavage as well as on the dynamics of the oligomeric structure of HtrA. We found that the mutations that were expected to disturb the loop's structure and/or interactions with the remaining regulatory loops severely diminished the proteolytic activity of HtrA. The opposite effect, that is, increased activity, was observed for G174S substitution, which was predicted to strengthen the interactions mediated by LD. HtrAG174S protein had an equilibrium shifted toward the active enzyme and formed preferentially high-order oligomeric forms.

Modern microsurgical techniques have made possible a broad spectrum of novel means for the reconstruction of complex bone and soft tissue defects. These techniques, in combination with developments in transplant immunology, have led to successful hand and facial allotransplantation and achievement of the highest rung in the reconstructive ladder - truly replacing like with like. The utilization of contemporary microsurgical technique in the context of vascularized composite allotransplantation (VCA) (1) permits successful technical execution and feasibility of VCA, (2) facilitates the study of immunologic tolerance in VCA preclinical models, and (3) optimizes functional VCA outcomes.

In this paper, a new Voltage-Mode (VM) first-order All-Pass Filter (APF) topology composed of only a grounded capacitor is proposed. The proposed APF uses a single, minus-type, second-generation, current conveyor (CCII-), which can be constructed by only five MOS transistors. It has low power consumption. The resonance frequency of the proposed APF can be adjusted by changing only a resistor value. However, it needs a single matching condition. As an application, a quadrature oscillator example is given. A non-ideality analysis for the proposed APF is also given. A number of time domain and frequency domain simulation results and an experimental test result are included to confirm the theory. (C) 2015 Sharif University of Technology. All rights reserved.

The transcription factor encoded by the gene Knotted1 is a nuclear homeodomain protein, regulating meristematic cells at the shoot apical meristem. It has been demonstrated that Knotted1 (KN1) expression specifies stem cell fate in adventitious shoot induction in herbaceous plants. This gene may thus potentially identify the initiation of meristem development in adventitious shoot induction in difficult-to-regenerate plants such as Prunoideae. We isolated an almond (Prunus dulcis Mill.) KN1-type gene using degenerate primers targeting the most conserved regions of Knotted1 gene. The 5' and 3' ends of the isolated sequence were obtained by rapid amplification of cDNA ends-polymerase chain reaction (RACE-PCR), and the gene was named P. dulcis Knotted1-like (PdKn1). PdKn1 transcripts were detected by reverse transcription (RT)-PCR mainly in shoot apical and axillary meristems. The RT-PCR and RT-quantitative PCR PdKn1 expression in almond leaf explants was found to anticipate the organization of adventitious shoot meristems. Apricot RNA isolated from induced leaf explants cross-hybridized with the almond probe PdKn1 in Northern blotting. We suggest that almond PdKn1 may be a useful marker to study the adventitious regeneration system by revealing the potential organogenic conditions, not only in almond but also in other Prunoideae.

Laminin (Lm) alpha 4 chain, a constituent of Lm-411 and Lm-421, is mainly localized to mesenchyme-derived tissues, and is suggested to have a role in formation and function of endothelium, transmigration of inflammatory cells through endothelium, and invasion of certain tumors. In this study, we evaluated the distribution of alpha 4 chain Lms in 33 conventional (clear cell) renal cell carcinomas (RCCs) (31 primary tumors, two metastases), two papillary RCCs, and two oncocytomas by immunohistochemistry. In all tumors, immunoreactivity for Lm alpha 4 chain was found in vasculature and stroma. Basement membranes were detected around tumor cell islets in 34/37 tumors. They showed immunoreactivity for Lm alpha 4 chain in 28/34 cases. Northern blotting, inhibition of protein secretion with monensin, and immunoprecipitation combined with Western blotting showed that Caki-2, ACHN, and Caki-1 renal carcinoma cell lines produce alpha 4 chain Lms. In cell adhesion assay, recombinant human Lm-411 did not promote adhesion of renal carcinoma cells but inhibited adhesion to fibronectin (Fn). In cell migration assay, the cells migrated more on Lm-411 than on Fn. The results suggest that alpha 4 chain Lms have a de- adhesive function and could thus play a role in detachment, migration and invasion of renal carcinoma cells in vivo.

The AMPA receptor subunit GluR2 is downregulated in neurons following a wide range of neurological insults. Here we report that suppression of GluR2 gene promoter activity is associated with kainate (KA)-induced downregulation of GluR2 subunit levels in primary cultured cortical neurons. RT-PCR and Northern blotting showed a significant decrease in GluR2 mRNA in cultured neurons after KA exposure. Transfection of cultured neurons with an expression vector pGL3-GluR2(-298/+283), where the reporter gene firefly luciferase was driven by the GluR2 promoter, revealed that KA exposure suppressed the transcriptional activation of the GluR2 promoter. Furthermore, the expression of the RE1-silencing transcription factor (REST) was increased in KA-exposed cortical neurons; enhanced binding of REST to RE1-like silencer element in the proximal promoter of the GluR2 subunit gene was evidenced by electrophoresis mobility shift assay. Chromatin immunoprecipitation showed that suppressed activity of the GluR2 promoter in cultured neurons after KA exposure was related to deacetylation of histone H4. These results indicate that REST as a crucial factor binds to RE1-like silencer element in the GluR2 promoter, suppressing transcription of the GluR2 subunit gene during KA exposure. Our data suggest that transcriptional suppression of the G1uR2 subunit gene may contribute at least in part to downregulation of GluR2 subunit protein in neurons during KA exposure. Because our experiments showed a reduction of glutamate release in KA-exposed cortical neurons, REST may play a latent role in delayed neuronal death or in seizure-induced tolerance. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

alpha-Glucans are present in virtually all domains of life, and these glucose chains linked by alpha-1,4- and alpha-1,6-linked branches form the most important storage carbohydrates in cells. It is likely for this reason that alpha-glucans are not generally considered as bioactive molecules as beta-glucans are. Nevertheless, it is known that depending on their source, many alpha-glucans play important roles as modulators of immune response. Recent efforts have attempted to elucidate the mechanisms through which alpha-glucans exert their immunostimulant effects; however, the main challenge is the accurate identification of the receptors of immune cells involved in their recognition. Here, we review the adjuvant properties reported for some polysaccharides and ultimately focus on alpha-glucans and how their structural characteristics, such as molecular weight, solubility and derivatization, influence their immunostimulatory properties. As a final point, we discuss the potential and associated challenges of using these polysaccharides as adjuvants, particularly in mucosal vaccination. (C) 2017 Elsevier Ltd. All rights reserved.

Changes in the gastrointestinal microbial community are frequently associated with chronic diseases such as Inflammatory Bowel Diseases. However, understanding the relationship of any individual taxon within the community to host physiology is made complex due to the diversity and individuality of the gut microbiota. Defined microbial communities such as the Altered Schaedler Flora (ASF) help alleviate the challenges of a diverse microbiota by allowing one to interrogate the relationship between individual bacterial species and host responses. An important aspect of studying these relationships with defined microbial communities is the ability to measure the population abundance and dynamics of each member. Herein, we describe the development of an improved ASF species-specific and sensitive real-time quantitative polymerase chain reaction (qPCR) for use with SYBR Green chemistry to accurately assess individual ASF member abundance. This approach targets hypervariable regions V1 through V3 of the 16S rRNA gene of each ASF taxon to enhance assay specificity. We demonstrate the reproducibility, sensitivity and application of this new method by quantifying each ASF bacterium in two inbred mouse lines. We also used it to assess changes in ASF member abundance before and after acute antibiotic perturbation of the community as well as in mice fed two different diets. Additionally, we describe a nested PCR assay for the detection of lowly abundant ASF members. Altogether, this improved qPCR method will facilitate gnotobiotic research involving the ASF community by allowing for reproducible quantification of its members under various physiological conditions. (C) 2017 Elsevier B.V. All rights reserved.

Because of their prominent roles in regulation of gene expression, it is important to understand how levels of Krupple-like transcription factors SP1 and SP3 change in germ cells during spermatogenesis. Using immunological techniques, we found that both factors decreased sharply during meiosis. SP3 declined during the leptotene-to-pachytene transition, whereas SP1 fell somewhat later, as spermatocytes progressed beyond the early pachytene stage. SP3 reappeared for a period in round spermatids. For Sp1, the transition to the pachytene stage is accompanied by loss of the normal, 8.2-kb mRNA and appearance of a prevalent, 8.8-kb variant, which has not been well characterized. We have now shown that this pachytene-specific transcript contains a long, unspliced sequence from the first intron and that this sequence inhibits expression of a reporter, probably because of its many short open-reading frames. A second testis-specific Sp1 transcript in spermatids of 2.4 kb also has been reported previously. Like the 8.8-kb variant, it is compromised translationally. We have confirmed by Northern blotting that the 8.8-, 8.2-, and 2.4-kb variants account for the major testis Sp1 transcripts. Thus, the unexpected decline of SP1 protein in the face of continuing Sp1 transcription is explained, in large part, by poor translation of both novel testis transcripts. As part of this work, we also identified five additional, minor SpI cap sites by 5' rapid amplification of cDNA ends, including a trans-spliced RNA originating from the Glcci1 gene.

Modern drives consist of alternating current electric motors, and the field-oriented control (FOC) of such motors enables fast, precise, and robust regulation of a drive's mechanical variables such as torque, speed, and position. The control algorithm, implemented in a microprocessor, requires feedback from motor currents, and the quality of this feedback is essential to a drive's control properties. Motor phase currents are sampled and processed in order to extract their mean over a digital control interval. Afterwards, the mean phase currents are transformed into a rotating field-oriented reference frame to enable controlling the mechanical variables. The field-oriented frame rotates continuously, but in practice the transformation is carried out using a discrete angular position. This paper investigates how the discretization impacts the computed field-oriented currents in high speed drives, where the rotor displacement during a control interval is substantial. A continuous-time model of field-oriented currents is indicated as a reference to quantify errors. An original approach to normalize variables and to solve the model analytically is proposed in order to investigate how the errors related to rotor position discretization are influenced by drive operating conditions. The analytical solution is validated by computer simulation. The results show that the currently applied methodology of computing field-oriented current components, due to an invalid assumption, introduces errors of a few percent when a drive operates at high speed. These errors can be compensated using the presented solution. (C) 2016 Elsevier Inc. All rights reserved.

This article draws upon recent geographical work on assemblage to reconsider how we understand alternative food economies. In particular it brings attention to the devices upon which these economies relyspecifically plastics. Since the mid-twentieth century, plastics have developed close and complex relations with our agrifood systems; they facilitate commodity valuation and product circulation worldwide but are also recognised as problematic due to their environmental and human health impacts. Despite this paradox and the attention plastics increasingly receive, we know little of their relations with alternative food initiatives (AFIs). How do plastics inhabit alternative food economies? What associations and circulations become performed? What do these markets look like from a device-oriented perspective? To address these questions, the paper draws on fieldwork undertaken in Brisbane (Australia) with two AFIsa weekly organic market and an online box program/wholesaler. Using visualisation and an assemblage approach discloses the presences, flows, functions, and tensions of plastics in AFIs. In this way, plastics are revealed but also act to reveal alternative food economies. This analysis steps away from evaluations of AFIs' (in)effective challenge to neoliberalisation to consider them as complex, processual, sometimes ambivalent efforts that not only distribute good food' but engage in important ways with things like plastics.

Background: We developed and validated a kinetic microplate hemolytic assay (HA) to quantify classical and alternative complement activity in a single dilution of human plasma or serum. Methods: The assay is based on monitoring hemolysis of sensitized sheep (or uncoated rabbit) red blood cells by means of a 96-well microplate reader. The activity of the calibrator was evaluated by reference to 200 healthy adults. The conversion of 50% hemolysis time into a percentage of activity was obtained using a calibration curve plotted daily. Results: The linearity of the assay as well as interference (by hemolysis, bilrubinemia and lipemia) was assessed for classical pathway (CP). The within-day and the between-day precision was satisfactory regarding the performance of commercially available liposome immunoassay (LIA) and ELISA. Patients with hereditary or acquired complement deficiencies were detected (activity was measured <30%). We also provided a reference range obtained from 200 blood donors. The agreement of CP evaluated on samples from 48 patients was 94% with LIA and 87.5% with ELISA. The sensitivity of our assay was better than that of LIA, and the cost was lower than either LIA or ELISA. In addition, this assay was less time consuming than previously reported HAs. Conclusions: This assay allows the simultaneous measurement of 36 samples in duplicate per run of a 96-well plate. The use of a daily calibration curve allows standardization of the method and leads to good reproducibility. The same technique was also adapted for the quantification of alternative pathway (AP) activity.

NO-mediated alternative pathway plays an important role in protecting wheat seedlings against drought stress through dissipating excessive reducing equivalents generated by photosynthesis. Alternative pathway (AP) has been proven to be involved in responses to various stresses. However, the mechanisms of AP in defense response to drought stress are still lacking. The aims of this work are to investigate the role of AP in drought tolerance and how AP is induced under drought stress using two wheat cultivars with different drought tolerance. Our results showed that Longchun22 cultivar is more tolerant to drought than 98SN146 cultivar. Seedlings exposed to drought led to a significant increase in AP, and it increased more in Longchun22. Furthermore, chlorophyll fluorescence parameters (Fv/Fm, I broken vertical bar PSII, qP) decreased significantly in drought-treated seedlings, especially in 98SN146, indicating that photoinhibition occurred under drought stress. Pretreatment with SHAM, the malate-oxaloacetate shuttle activity and photosynthetic efficiency were further inhibited in drought-treated seedlings, resulting in more serious oxidative damage as indicated by higher levels of malondialdehyde and hydrogen peroxide. Moreover, NO modulated AP under drought stress by increasing AOX1a expression and pyruvate content. Taken together, these results indicate that NO-mediated AP is involved in optimizing photosynthesis under drought stress by avoiding the over-reduction of photosynthetic electron transport chain, thus reducing reactive oxygen species production and oxidative damage in wheat leaves.

A hallmark of male germ cell gene expression is the generation by alternative polyadenylation of cell-specific mRNAs, many of which utilize noncanonical A(A/U)UAAA-independent polyadenylation signals. Cleavage factor I (CFlm), a component of the pre-mRNA cleavage and polyadenylation protein complex, can direct A(A/U)UAAA-independent polyadenylation site selection of somatic cell mRNAs. Here we report that the CFlm subunits NUDT21/CPSF5 and CPSF6 are highly enriched in mouse male germ cells relative to somatic cells. Both subunits are expressed from spermatogenic cell mRNAs that are shorter than the corresponding somatic transcripts. Complementary DNA sequencing and Northern blotting revealed that the shorter Nudt21 and Cpsf6 mRNAs are generated by alternative polyadenylation in male germ cells using proximal poly(A) signals. Both sets of transcripts contain CFlm binding sites within their 3 '-untranslated regions, suggesting autoregulation of CFlm subunit formation in male germ cells. CFIm subunit mRNA and protein levels exhibit distinct developmental variation during spermatogenesis, indicating stage-dependent translational and/or posttranslational regulation. CFIm binding sites were identified near the 3 ' ends of numerous male germ cell transcripts utilizing A(A/U)UAAA-independent sites. Together these findings suggest that CFIm complexes participate in alternative polyadenylation directed by noncanonical poly(A) signals during spermatogenesis.

To identify a novel regulatory factor involved in brain development or synaptic plasticity, we applied the differential display PCR method to mRNA samples from NMDA-stimulated and un-stimulated neocortical cultures. Among 64 cDNA clones isolated, eight clones were novel genes and one of them encodes a novel zinc-finger protein, HIT-4, which is 317 amino acid residues (36-38 kDa) in length and contains seven C(2)H(2) zinc-finger motifs. Rat HIT-4 cDNA exhibits strong homology to human ZNF597 (57% amino acid identity and 72% homology) and identity to rat ZNF597 at the carboxyl region. Furthermore, genomic alignment of HIT-4 cDNA indicates that the alternative use of distinct promoters and exons produces HIT-4 and ZNF597 mRNAs. Northern blotting revealed that HIT-4 mRNA (similar to 6 kb) is expressed in various tissues such as the lung, heart, and liver, but enriched in the brain, while ZNF597 mRNA (similar to 1.5kb) is found only in the testis. To evaluate biological roles of HIT-4/ZNF597, targeted mutagenesis of this gene was performed in mice. Homozygous (-/-) mutation was embryonic lethal, ceasing embryonic organization before cardiogenesis at embryonic day 7.5. Heterozygous (+/-) mice were able to survive but showing cell degeneration and vacuolization of the striatum, cingulate cortex, and their surrounding white matter. These results reveal novel biological and pathological roles of HIT-4 in brain development and/or maintenance.

Many basic cellular processes are shared across vast phylogenetic distances, whereas sex-determining mechanisms are highly variable between phyla, although the existence of two sexes is nearly universal in the animal kingdom. However, the evolutionarily conserved DMRT1/dsx/mab3 with a common zinc finger-like DNA-binding motif, DM domain, share both similar structure and function between phyla. Here we report that six transcripts of the chicken DMRT1 were generated in gonads by multiple alternative splicing. By cDNA cloning and genomic structure analysis, we found that there were nine exons of DMRT1, which were involved in alternatively splicing to generate the DMRT1 transcripts. Northern blotting and reverse transcription (RT) PCR analysis revealed that the expression of chicken DMRT1 was testis-specific in adults. Whole-mount in situ hybridizations and RT-PCR indicated that DMRT1 b was specially expressed in embryo gonads and higher in male than female gonads at stage 31. The female gonad had stronger DMRT1 c expression than the male one, whereas DMRT1 f was detectable only in the male gonad at stage 31 of the key time of sex gonadal differentiation. The differential expression of these transcripts during gonadal differentiation provides new insight into roles of alternative splicing of DMRT1 in governing sex differentiation of the chicken.

The pre-mRNA of the fragile X mental retardation 1 gene (FMR1) is subject to exon skipping and alternative splice site selection, which can generate up to 12 isoforms. The expression and function of these variants in vivo has not yet been fully explored. In the present study, we investigated the distribution of Fmr1 exon 12 and exon 15 isoforms. Exon 12 encodes an extension of KH2 domain, one of the RNA binding domains in the FMR1 gene product (FMRP) and we show that exon 12 variant proteins differentially interact with kissing complex RNA. Alternative splicing at exon 15 produces FMRPs differing in RNA binding ability and each is distinguished by unique post-translational modifications. Using semiquantitative RT-PCR and Northern blotting, we found that particular Fmr1 exon 12 and exon 15 isoforms change during neuronal differentiation. Interestingly, Fmr1 exon 12 variants display tissue-specific and developmental differences, while exon 15-containing transcripts vary less. Altogether, the spatio-temporal plasticity of FMR1 mRNA is consistent with complex RNA processing that is mis-regulated in fragile X syndrome. (C) 2009 Elsevier Inc. All rights reserved.

Abcc4 gene codes for a protein (ABCC4) involved in the transportation of different classes of drugs outside the cells. Various important drugs transported by ABCC4 include antiviral and anticancer drugs as well as endogenous molecules such as bile acids, cyclic nucleotides, folates, prostaglandins and steroids. Alternative splicing generates multiple mRNAs that encode protein isoforms having diverse functions. In this study, we have identified a novel transcript of mouse Abcc4 gene using a combination of bioinformatics and molecular biology techniques. This transcript was found to be different from the reported transcript in having a different first exon that was found to be located on previously identified first intron. Newly identified transcript was found to be expressed across different tissues we studied and in different developmental stages. Expression level of novel and reported transcripts was studied using quantitative real-time PCR. After conceptually translating the novel transcript, various post-translational modifications were studied. Translation efficiency and predicted half life of encoded protein isoforms were analysed in silico. Molecular modelling was performed to compare the structural differences in both isoforms. The diversity at N-termini in these protein isoforms explains the diverse function of ABCC4 in mouse. (C) 2016 Elsevier B.V. All rights reserved.

Our aim of the project is to demonstrate all the protections and interlocks available in the critical equipments of power station such as Boiler, Turbine, the Alternator, and how these critical equipments are protected from abnormal conditions and parameters. The failure of any one of these equipments will lead to loss of power generation. The cost of these equipments is huge. Boiler has got protection against abnormal drum level, abnormal live steam pressure, abnormal live steam temperature, abnormal furnace pressure. Turbine has got protection against abnormal condenser vacuum, abnormal lubricating oil pressure, abnormal axial shiftand abnormal turbine speed. Similarly the generator has also got the following protections 1.10.5kv earth fault, 220kv earth fault, differential protection, incomplete phase condition, rotor earth fault, stator inter turn fault, over current protection, stator overvoltage, rotor overvoltage. These protections are classified as class a, class b and class c protections. Distributed digital controls and numerical protections relays play vital role in providing protections to critical equipments to demonstrate these protections in real sense in our project kit. However an effort has been made to demonstrate the functioning of these protections with the aid of a programmable logic controller. Also a few suggestions to improve the existing system are also discussed.

Various types of long-term stable relationships that individuals uphold, including cooperation and competition between group members, define social complexity in vertebrates. Numerous life history, physiological and cognitive traits have been shown to affect, or to be affected by, such social relationships. As such, differences in developmental modes, i.e. the 'altricial-precocial' spectrum, may play an important role in understanding the interspecific variation in occurrence of social interactions, but to what extent this is the case is unclear because the role of the developmental mode has not been studied directly in across-species studies of sociality. In other words, although there are studies on the effects of developmental mode on brain size, on the effects of brain size on cognition, and on the effects of cognition on social complexity, there are no studies directly investigating the link between developmental mode and social complexity. This is surprising because developmental differences play a significant role in the evolution of, for example, brain size, which is in turn considered an essential building block with respect to social complexity. Here, we compiled an overview of studies on various aspects of the complexity of social systems in altricial and precocial mammals and birds. Although systematic studies are scarce and do not allow for a quantitative comparison, we show that several forms of social relationships and cognitive abilities occur in species along the entire developmental spectrum. Based on the existing evidence it seems that differences in developmental modes play a minor role in whether or not individuals or species are able to meet the cognitive capabilities and requirements for maintaining complex social relationships. Given the scarcity of comparative studies and potential subtle differences, however, we suggest that future studies should consider developmental differences to determine whether our finding is general or whether some of the vast variation in social complexity across species can be explained by developmental mode. This would allow a more detailed assessment of the relative importance of developmental mode in the evolution of vertebrate social systems.

Hardness cations are ubiquitous and abundant in source water, while the effect of hardness on the performance of coagulation for dissolved organic matter (DOM) removal in water treatment remains unclear due to the limitation of methods that can characterise the subtle interactions between DOM, coagulant and hardness cations. This work quantified the competition between coagulant Al3+ and hardness cations to bind onto DOM using absorbance spectroscopy acquired at different Al3+ concentrations in the absence and presence of Ca2+ or Mg2+. The results indicate that, in the presence of either Mg2+ or Ca2+, an increasing depression of the binding of Al3+-DOM could be observed in the differential spectra of DOM with the increasing of Mg2+ or Ca2+ at a level of 10, 100 and 1000 mu M, with the observation being more significant at higher pH from 6.5 to 8.5. The results of zeta potentials of DOM indicate that the competition of hardness cations results in the negative DOM being less efficiently neutralised by Al3+. This study demonstrates that the removal of DOM by coagulation would significantly deteriorate with the presence of hardness cations, which would compete with coagulant Al3+ to neutralise the unsaturated sites in DOM. (C) 2017 Elsevier Ltd. All rights reserved.

Background and ObjectivePeriodontal disease is a chronic infectious disease that results in bone loss. Many epidemiological studies have reported the progression of periodontal tissue destruction in patients with diabetes; however, the associated mechanism remains unclear. In this study, we comprehensively investigated how diabetes affects the periodontal tissue and alveolar bone loss using a ligature-induced periodontitis model in streptozotocin-induced diabetic (STZ) mice. Material and MethodsDiabetes was induced by intraperitoneal injection with streptozotocin in 6-wk-old C57/BL6J male mice. A silk ligature was tied around the maxillary left second molar in 9-wk-old wild-type (WT) and STZ mice. Bone loss was evaluated at 3 and 7 d after ligation. mRNA expression levels in the gingiva between the two groups were examined by DNA microarray and quantitative polymerase chain reaction at 1, 3 and 7 d post-ligation. Tartrate-resistant acid phosphatase and alkaline phosphatase staining of the periodontal tissue was performed for evaluation of osteoclasts and osteoblasts in histological analysis. ResultsIn the gingiva, hyperglycemia upregulated the osteoprotegerin (Opg) mRNA expression and downregulated Osteocalcin mRNA expression. In the ligated gingiva, tumor necrosis factor- (Tnf-) mRNA expression was upregulated at 1 d post-ligation in STZ mice but not in WT mice. At 3 d post-ligation, alveolar bone loss was observed in STZ mice, but not in WT mice. Significantly severe alveolar bone loss was observed in STZ mice compared to WT mice at 7 d post-ligation. Bone metabolic analysis using DNA microarray showed significant downregulation in the mRNA expression of glioma-associated oncogene homologue 1 (Gli1) and collagen type VI alpha 1 (Col6a1) at the gingiva of the ligated site in STZ mice compared to that in WT mice. Quantitative polymerase chain reaction showed that Gli1 and Col6a1 mRNA expression levels were significantly downregulated in the gingiva of the ligated site in STZ mice compared to WT mice. Histological analysis showed lower alkaline phosphatase activity in STZ mice. In addition, an increased number of tartrate-resistant acid phosphatase-positive multinucleated cells were observed at the ligated sites in STZ mice. ConclusionsThese results suggest that an imbalance of bone metabolism causes osteoclastosis in insulin-deficient diabetes, and that alveolar bone loss could occur at an early phase under this condition.

The lung alveolar epithelium consists of type I and type II pneumocytes. In vivo, the type II cell is the progenitor cell from which the type I cell originates. When freshly-isolated type II cells are cultured under conventional conditions they rapidly lose their phenotypic properties and attain characteristics of type I cells. Taking advantage of this transdifferentiation, we sought to identify genes that are differentially expressed during culture of rat type II cells. Using suppression subtractive hybridization (SSH), a vacuolar-type H+ stop-ATPase (V-ATPase) C2 subunit gene (Atp6v1c2) was found to be enriched in freshly isolated rat type II cells compared to those cultured for 4 days. Northern blotting and reverse-transcription polymerase chain reaction (RT-PCR) confirmed the differential expression of Atp6v1c2 during in vitro culture of isolated type II cells. Expression of Atp6v1c2 was significantly reduced early during in vitro culture: almost 90% reduction was observed after 24 h of incubation as determined by real-time PCR. In situ hybridization showed that Atp6v1c2 is expressed in both bronchiolar and alveolar lung epithelial cells, an expression pattern similar to that of surfactant protein B (SP-B). Multi-tissue Northern blotting revealed a unique tissue distribution with Atp6v1c2 expression limited to lung, kidney and testis. The presence and expression of Atp6v1c2 gene transcript isoforms, resulting from alternative splicing, were also investigated. Elucidation of differential expression of Atp6v1c2 in type II cells and further studies of its regulation may provide information useful in understanding the molecular mechanism underlying phenotypic and functional changes during transdifferentiation of alveolar epithelial cells.

Avian leukosis virus subgroup J (ALV-J) is an oncogenic virus causing hemangiomas and myeloid tumors in chickens. Interleukin-6 (IL-6) is a multifunctional pro-inflammatory interleukin involved in many types of cancer. We previously demonstrated that IL-6 expression was induced following ALV-J infection in chickens. The aim of this study is to characterize the mechanism by which ALV-J induces IL-6 expression, and the role of IL-6 in tumor development. Our results demonstrate that ALV-J infection increases IL-6 expression in chicken splenocytes, peripheral blood lymphocytes, and vascular endothelial cells. IL-6 production is induced by the ALV-J envelope protein gp85 and capsid protein p27 via PI3K- and NF-kappa B-mediated signaling. IL-6 in turn induced expression of vascular endothelial growth factor (VEGF)-A and its receptor, VEGFR-2, in vascular endothelial cells and embryonic vascular tissues. Suppression of IL-6 using siRNA inhibited the ALV-J induced VEGF-A and VEGFR-2 expression in vascular endothelial cells, indicating that the ALV-J-induced VEGF-A/VEGFR-2 expression is mediated by IL-6. As VEGF-A and VEGFR-2 are important factors in oncogenesis, our findings suggest that ALV-J hijacks IL-6 to promote tumorigenesis, and indicate that IL-6 could potentially serve as a therapeutic target in ALV-J infections.

Insulin-degrading enzyme (IDE) is a zinc metalloprotease, known to degrade insulin peptide and amyloid-beta (A beta); the key protein involved in Alzheimer's disease (AD). Considering the important role played by IDE in disease progression of AD and type 2 diabetes mellitus (T2DM), we endeavored to identify the Caenorhabditis elegans (C. elegans) IDE orthologous genes and test them for their role in AD related outcomes. We employed bioinformatics, reverse genetics and molecular biology approaches towards identification and functional characterization of putative IDE candidates in C. elegans. Using in-silico analysis we have identified seven C elegans genes that possess HXXEH motif, an identifying marker of IDE. We further carried out functional analysis of the identified genes in A beta expressing C elegans strain CL4176 [myo-3/A beta 1-42 long 3'-UTR] via studying effect on A beta induced toxicity, cholinergic neuroanatomy, content of acetylcholine/acetylcholine-esterase, extent of reactive oxygen species and expression of FOXO transcription factor DAF-16. Our findings reveal that amongst the identified putative IDE orthologs, a functionally uncharacterized gene C28F5.4 had a profound effect on the tested endpoints. Knocking down C28F5.4 modulated the AD associated conditions by decreasing A beta induced toxicity, severely compromising cholinergic neuroanatomy, reducing expression of acetylcholine-transporter, decreasing acetylcholine content, elevating ROS, with no effect on DAF-16 stress-response protein. These studies provide crucial insight into the structural/functional orthology of IDEs across human and nematode species and further our understanding of the involvement of these proteins and insulin pathway in AD. Further studies could aid in identifying novel drug-targets and in understanding the common modulating factors between AD and T2DM. (C) 2016 Elsevier B.V. All rights reserved.

Alzheimer's disease (AD) has been associated with magnesium ion (Mg2+) deficits and interleukin-1 beta (IL-1 beta) elevations in the serum or brains of AD patients. However, the mechanisms regulating IL-1 beta expression during Mg (2+) dyshomeostasis in AD remain unknown. We herein studied the mechanism of IL-1 beta reduction using a recently developed compound, magnesium-L-threonate (MgT). Using human glioblastoma A172 and mouse brain D1A glial cells as an in vitro model system, we delineated the signaling pathways by which MgT suppressed the expression of IL-1 beta in glial cells. In detail, we found that MgT incubation stimulated the activity of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and peroxisome proliferator-activated receptor gamma (PPAR gamma) signaling pathways by phosphorylation, which resulted in IL-1 beta suppression. Simultaneous inhibition of the phosphorylation of ERK1/2 and PPAR gamma induced IL-1 beta upregulation in MgT-stimulated glial cells. In accordance with our in vitro data, the intracerebroventricular (i.c.v) injection of MgT into the ventricles of APP/PS1 transgenic mice and treatment of Ab precursor protein (APP)/PS1 brain slices suppressed the mRNA and protein expression of IL-1 beta. These in vivo observations were further supported by the oral administration of MgT for 5 months. Importantly, Mg (2+) influx into the ventricles of the mice blocked the effects of IL-1 beta or amyloid beta-protein oligomers in the cerebrospinal fluid. This reduced the stimulation of IL-1 beta expression in the cerebral cortex of APP/PS1 transgenic mice, which potentially contributed to the inhibition of neuroinflammation. Cellular & Molecular Immunology (2017) published online 9 November 2015

The current study determined the ability of a p75(NTR) antagonistic cyclic peptide to rescue cells from beta amyloid (A beta) (1-40)-induced death. p75(NTR)-, p140(trkA)-NIH-3T3 cells or E17 foetal rat cortical neurones were incubated with I-125-NGF or I-125-A beta (1-40) and increasing concentrations of the cyclic peptide (CATDIKGAEC). Peptide ability to displace I-125-NGF or I-125-A beta (1-40) binding was determined. Duplicate cultures were preincubated with CATDIKGAEC (250 nM) or diluent and then stimulated with A beta (1-40). Peptide ability to displace A beta (1-40) binding, interfere with A beta (1-40)-induced signalling and rescue cells from A beta-mediated toxicity was determined by immunoprecipitation and autoradiography, Northern blotting, JNK activation, MTT and trypan blue assays. The peptide inhibited NGF and A beta (1-40) binding to p75(NTR), but not to p140(trkA). A beta (1-40) induced c-jun transcription (57.3% +/- 0.07%) in diluent-treated p75(NTR)-cells, but not in cells preincubated with the cyclic peptide. Also, at 250 nM, the peptide reduced A beta (1-40)-induced phsophorylation of JNK by 71.8% +/- 0.03% and protected neurones against A beta-induced toxicity as determined by: trypan blue exclusion assay (53% +/- 11% trypan blue-positive cells in diluent pretreated cultures vs. 28% +/- 5% in cyclic peptide-pretreated cultures); MTT assay (0.09 +/- 0.03 units in diluent-pretreated cells vs. 0.12 +/- 0.004 units in cyclic peptide-pretreated cells); and visualization of representative microscopic fields. Our data suggest that a cyclic peptide homologous to amino acids 28-36 of NGF known to mediate binding to p75(NTR) can interfere with A beta (1-40) signalling and rescue neurones from A beta (1-40)-induced toxicity.

Although frontal presentations of Alzheimer's disease (fv-AD) have already been described in the literature, we still know little about patients' social cognitive abilities, especially their theory of mind (ToM). We report the case of FT, a 61-year-old woman who was diagnosed with fv-AD. Two assessments of social cognition, using a false-belief task, the Reading the Mind in the Eyes test, and a task probing knowledge of social norms, were performed one year apart. FT exhibited cognitive ToM and social knowledge deficits from the onset. Affective ToM was initially preserved, but deteriorated as the disease progressed.

Alzheimer's disease (AD), since its characterization as a precise form of dementia with its own pathological hallmarks, has captured scientists' attention because of its complexity. The last 30 years have been filled with discoveries regarding the elusive aetiology of this disease and, thanks to advances in molecular biology and live imaging techniques, we now know that an important role is played by calcium (Ca2+). Ca2+, as ubiquitous second messenger, regulates a vast variety of cellular processes, from neuronal excitation and communication, to muscle fibre contraction and hormone secretion, with its action spanning a temporal scale that goes from microseconds to hours. It is therefore very challenging to conceive a single hypothesis that can integrate the numerous findings on this issue with those coming from the classical fields of AD research such as amyloid-beta (A beta) and tau pathology. In this contribution, we will focus our attention on the Ca2+ hypothesis of AD, dissecting it, as much as possible, in its subcellular localization, where the Ca2+ signal meets its specificity. We will also follow the temporal evolution of the Ca2+ hypothesis, providing some of the most updated discoveries. Whenever possible, we will link the findings regarding Ca2+ dysfunction to the other players involved in AD pathogenesis, hoping to provide a crossover body of evidence, useful to amplify the knowledge that will lead towards the discovery of an effective therapy. (C) 2016 Elsevier Ltd. All rights reserved.

AimsTo explore the common effects of the clusterin (CLU) rs11136000 variant on the default mode network (DMN) in amnestic mild cognitive impairment (aMCI) subjects and remitted geriatric depression (RGD) subjects. MethodsFifty-one aMCI subjects, 38 RGD subjects, and 64 cognitively normal elderly subjects underwent resting-state fMRI scans and neuropsychological tests at both baseline and a 35-month follow-up. Posterior cingulate cortex seed-based functional connectivity (FC) analysis was used to obtain the DMN patterns. ResultsA CLU genexdiseasextime interaction for aMCI subjects was mainly detected in the core cortical midline structures of the DMN, and the interaction for RGD subjects was mainly detected in the limbic system. However, they overlapped in two frontal regions, where consistent effects of the CLU gene on FC alterations were found between aMCI and RGD groups. Furthermore, the alterations of FC with frontal, parietal, and limbic regions compensated for episodic memory impairments in CLU-CT/TT carriers, while no such compensation was found in CLU-CC carriers. ConclusionThe CLU gene could consistently affect the DMN FC with frontal regions among individuals at risk for Alzheimer's disease, and the CLU-T allele was associated with more compensatory neural processes in DMN changes.

Young individuals better memorize initially seen faces with emotional rather than neutral expressions. Healthy older participants and Alzheimer's disease (AD) patients show better memory for faces with positive expressions. The socioemotional selectivity theory postulates that this positivity effect in memory reflects a general age-related preference for positive stimuli, subserving emotion regulation. Another explanation might be that older participants use compensatory strategies, often considering happy faces as previously seen. The question about the existence of this effect in tasks not permitting such compensatory strategies is still open. Thus, we compared the performance of healthy participants and AD patients for positive, neutral, and negative faces in such tasks. Healthy older participants and AD patients showed a positivity effect in memory, but there was no difference between emotional and neutral faces in young participants. Our results suggest that the positivity effect in memory is not entirely due to the sense of familiarity for smiling faces.

Chronic neuroinflammation is thought to potentiate medial temporal lobe (MTL) atrophy and memory decline in Alzheimer's disease (AD). It has become increasingly important to find novel immunological biomarkers of neuroinflammation or other processes that can track AD development and progression. Our study explored which pro- or anti-inflammatory cerebrospinal fluid (CSF) biomarkers best predicted AD neuropathology over 24 months. Using Alzheimer's Disease Neuroimaging Initiative data (N = 285), CSF inflammatory biomarkers from mass spectrometry and multiplex panels were screened using step-wise regression, followed up with 50%/50% model retests for validation. Neuronal Pentraxin 2 (NPTX2) and Chitinase-3-like-protein-1 (C3LP1), biomarkers of glutamatergic synaptic plasticity and microglial activation respectively, were the only consistently significant biomarkers selected. Once these biomarlcers were selected, linear mixed models were used to analyze their baseline and longitudinal associations with bilateral MTL volume, memory decline, global cognition, and established AD biomarkers including CSF amyloid and tau. Higher baseline NPTX2 levels corresponded to less MTL atrophy [R-2 = 0.287, p < 0.001] and substantially less memory decline [R-2 = 0.560, p < 0.001] by month 24. Conversely, higher C3LP1 modestly predicted more MTL atrophy [R-2 = 0.083, p < 0.001], yet did not significantly track memory decline over time. In conclusion, NPTX2 is a novel pro -inflammatory cytokine that predicts AD-related outcomes better than any immunological biomarker to date, substantially accounting for brain atrophy and especially memory decline. C3LP1 as the microglial biomarker, by contrast, performed modestly and did not predict longitudinal memory decline. This research may advance the current understanding of AD etiopathogenesis, while expanding early diagnostic techniques through the use of novel pro -inflammatory biomarkers, such as NPTX2. Future studies should also see if NPTX2 causally affects MTL morphometry and memory performance. (C) 2016 Elsevier Inc. All rights reserved.

Alzheimer's disease patients display neuropathological lesions, including the accumulation of amyloid-beta (A beta) peptide and neurofibrillary tangles. Although the mechanisms causing the neurodegenerative process are largely unknown, increasing evidence highlights a critical role of immunity in the pathogenesis of Alzheimer's disease. In the present study, we investigated the role of regulatory T cells (Tregs) on Alzheimer's disease progression. First, we explored the effect of Tregs (CD4(+)CD25(+) T cells) and Teffs (CD4(+)CD25(-) T cells) in an adoptive transfer model. Systemic transplantation of purified Tregs into 3xTg-AD mice improved cognitive function and reduced deposition of A beta plaques. In contrast, adoptive transfer of Teffs diminished behavioral function and cytokine production. Next, we transiently depleted Treg population using an anti-CD25 antibody (PC61). Depletion of Tregs for four months resulted in a marked aggravation of the spatial learning deficits of six-month-old 3xTg-AD mice. Additionally, it resulted in decreasing glucose metabolism, as assessed by positron emission tomography (PET) with F-18-2 fluoro-2-deoxy-D-glucose ([F-18] FDG) neuroimaging. Importantly, the deposition of A beta plaques and microglia/macrophage was increased in the hippocampal CA1 and CA3 regions of the Treg depleted 3xTg-AD compared to the vehicle-treated 3xTg-AD group. Our finding suggested that systemic Treg administration ameliorates disease progression and could be an effective Alzheimer's disease treatment.

Introduction: Subjective cognitive decline (SCD) could indicate preclinical Alzheimer's disease, but the existing literature is confounded by heterogeneous approaches to studying SCD. We assessed the differential cognitive, affective, and neuroimaging correlates of two aspects of SCD: reporting high cognitive difficulties on a self-rated questionnaire versus consulting at a memory clinic. Methods: We compared 28 patients from a memory clinic with isolated SCD, 35 community-recruited elders with similarly high levels of self-reported cognitive difficulties, and 35 community-recruited controls with low self-reported cognitive difficulties. Results: Increased anxiety and amyloid beta deposition were observed in both groups with high self-reported difficulties, whereas subclinical depression and (hippocampal) atrophy were specifically associated with medical help seeking. Cognitive tests showed no group differences. Discussion: These results further validate the concept of SCD in both community-and clinic-based groups. Yet, recruitment methods influence associated biomarkers and affective symptomatology, highlighting the heterogeneous nature of SCD depending on study characteristics. (C) 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

this paper presents an amplitude modulation transmitter for 50 MHz application with low power consumption. The transmitter consists of Gilbert cell mixer, cross coupled with symmetric load voltage controlled oscillator, two stage operational amplifier and a high pass filter implemented in TSMC CMOS 0.18 mu m process. A 200 mV RF input of 50 MHz and 500 mV LO output of 1.5 GHz are applied at both RF and LO ports of the mixer with conversion gain of 14.25 dB results to a 300 mV IF output of 1.2 GHz. The reference voltage V-dd = 1.8 V, the tuning range of oscillator is 0 to 2 GHz and the amplifier has a gain of 42.1 dB, phase margin of 56 degrees, unity gain bandwidth of 1.43 GHz and slew rate of 291 V/mu s. The overall power consumption is 74.3 mW and a chip size of 9.68 nm(2). The chip is connected to an I/O pad with rectangular pad frame of size 0.46 mu m(2).

Using a field-programmable gate array (FPGA) development board, a digital signal processor (DSP) builder, and the phase-to-amplitude conversion principle, a low-cost system for measuring the amplitude-to-amplitude (AM/AM) and amplitude-to-phase (AM/PM) distortion curves of radio frequency (RF) power amplifiers (PAs) is presented. The state of the art based on the measurements and preliminary studies of AM/AM and AM/PM distortion curves is discussed. A full digital control of the test bed simulated/emulated in Matlab/Simulink is introduced to recalculate the known AM/AM and AM/PM measurements stored as look-up table (LUT). Finally, the low-cost system comprises the memory polynomial model (MPM) that involves the nonlinearity order and memory effects of real PAs. (C) 2015 Elsevier B.V. All rights reserved.

Considerable interest in the relationship between biodiversity and disease has recently captured the attention of the research community, with important public policy implications. In particular, malaria in the Amazon region is often cited as an example of how forest conservation can improve public health outcomes. However, despite a growing body of literature and an increased understanding of the relationship between malaria and land use/land cover change (LULC) in Amazonia, contradictions have emerged. While some studies report that deforestation increases malaria risk, others claim the opposite. Assessing malaria risk requires examination of dynamic processes among three main components: (i) the environment (i.e. LULC and landscape transformations), (ii) vector biology (e.g. mosquito species distributions, vector activity and life cycle, plasmodium infection rates), and (iii) human populations (e.g. forest-related activity, host susceptibility, movement patterns). In this paper, we conduct a systematic literature review on malaria risk and deforestation in the Amazon focusing on these three components. We explore key features that are likely to generate these contrasting results using the reviewed articles and our own data from Brazil and Peru, and conclude with suggestions for productive avenues in future research. This article is part of the themed issue 'Conservation, biodiversity and infectious disease: scientific evidence and policy implications'.

How can a firm develop, distribute, and use knowledge more effectively and efficiently in ways that increase its ability to pursue an ambidextrous orientation? Synthesizing insights from social cognition and upper-echelons perspectives, we offer a new theoretical vantage point that brings the role of top management teams' cognitive structure to the fore and, in particular, the enabling influence of transactive memory systems. We argue that transactive memory provides a top management team with a system for generating, distributing, and integrating knowledge based on members' specific areas of expertise in ways that increase its ability to both differentiate and integrate strategic agendas for ambidexterity. From a multisource study of top management teams in a sample of technology-based small-to-medium-sized firms, we find that while top management teams with well-developed transactive memory systems are able to pursue an ambidextrous orientation, the impact of transactive memory is also shaped by diverse organizational experience and functional expertise within these teams. We discuss the scope and significance of these findings for theory, future research, and managerial practice.

Electrical arcs emit extremely high intensity light across a wide spectrum that can damage the eye's delicate structures, such as the cornea or the retina. Developing industry safety standards to mitigate light hazards is a critical component of arc flash safety. Accurate measurement of light intensity is the first step in understanding the level of eye protection needed. Traditionally, light measurement devices are an assembly of light-detecting resistors made from cadmium sulfide (CdS) or silicon (Si) cells. However, their response times are inadequate for capturing the peak light intensity or the dynamic changes during the initial arc flash. In addition, the brightness of an arc flash is greater than the measurable light levels from traditional light measurement devices. Furthermore, the light sensitivity of traditional sensors does not match the Commission Internationale de l'Eclairage luminosity function V (lambda) curve, which defines the human eye's sensitivity to bright light as a function of wavelength under typical ambient light conditions. This paper discusses a novel light measurement technique to overcome the limitations of traditional approaches. This design is capable of measuring the light intensity of the arc flash as perceived by the human eyes. These results can be used to evaluate the potential of an arc flash to harm the eyes.

Background: Evidence for extreme ambient temperature effects on the risk of mental disorders (MDs) is limited. In this study, we evaluated the short-term effects of daily mean temperature on hospital admissions of MDs in Shanghai, China. Methods: We obtained daily hospital admission data for MDs, daily meteorological and ambient pollution data in Shanghai from January 2008 to December 2015. Adjusted for time trend, air pollution, relative humidity and other confounders, a quasi-Poisson generalized additive model (GAM) combined with a distributed lag non-linear model (DLNM) was used to analyze the lag-exposure-response relationship between daily mean temperature and hospital admissions for MDs. Results: Total daily hospital admissions for MDs during the study period were 93,971. With a reference of median temperature (18.3 degrees C), there was a significant positive association between the temperature above threshold (24.6 degrees C) and MD hospital admission visits at a lag of 0-1 days. The relative risks of extreme hot temperatures (33.1 degrees C, 99% percentile) over the lag 0-1 days compared to median temperature were 1.266 (95% confidence intervals: 1.074-1.493). No effect of cold weather on the hospital admissions for MDs was observed. Conclusions: This study suggests that extreme hot temperature poses significant risks on MD; health counseling and cooling measures should be considered for the susceptible population. (C) 2017 Elsevier B.V. All rights reserved.

Beyond the universality of the symmetry concept, there are different emphases on its application in different branches of science. Chemistry, being between particle physics and astrophysics, represents a bridge in, and a utilitarian approach to, the application of the symmetry concept, which has proved immensely fruitful in twentieth-century science. Some pivotal discoveries, especially in structural chemistry, molecular biology, and materials science, emerged by relaxing some of the stipulations of the classical teachings about symmetry. This highly personal presentation relies on ideas expressed by a number of notable individuals in recent science, among them J. Desmond Bernal, Francis Crick, Ronald J. Gillespie, Aleksandr I. Kitaigorodskii, Alan L. Mackay, George A. Olah, Linus Pauling, Roger Penrose, Dan Shechtman, James D. Watson, Steven Weinberg, and Eugene P. Wigner.

Recently, most of sonokembang, Pterocarpus indicus trees are dying in Malang. In 2012, the death rate of trees reached ca. 11%. In addition, death of trees spread to other regencies in East Java. Euplatypus parallelus is a specific species of ambrosia beetles that were the causal agents to the dying and wilting of sonokembang trees in Malang. Wilting is caused mainly by the pathogenic fungi carried by ambrosia beetles. To confirm the microbial communities related to E. parallelus that attack sonokembang, E. parallelus and some attacked trees were collected in Malang city. Isolation and identification of these species were conducted at the Laboratory of Mycology, Faculty of Agriculture, University of Brawijaya and Laboratory of Molecular Biology, Islamic State University, Malang. Results showed that there were nine microbes including five genera of fungi, two genera of yeasts and one genus of bacterium were identified. The microbial communities that were found namely Aspergillus spp., Penicilium spp., Trichoderma spp., Fusarium spp., Acremonium spp., Gliocladium spp. (fungi), Streptomyces spp. (bacteria), Saccharomyces spp., and Candida spp. (yeast).

The modifiable areal unit problem and the ecological fallacy are known problems that occur when modelling multiscale spatial processes. We investigate how these forms of spatial aggregation error can guide a regionalization over a spatial domain of interest. By regionalization' we mean a specification of geographies that define the spatial support for areal data. This topic has been studied vigorously by geographers but has been given less attention by spatial statisticians. Thus, we propose a criterion for spatial aggregation error, which we minimize to obtain an optimal regionalization. To define the criterion we draw a connection between spatial aggregation error and a new multiscale representation of the Karhunen-Loeve expansion. This relationship between the criterion for spatial aggregation error and the multiscale Karhunen-Loeve expansion leads to illuminating theoretical developments including connections between spatial aggregation error, squared prediction error, spatial variance and a novel extension of Obled-Creutin eigenfunctions. The effectiveness of our approach is demonstrated through an analysis of two data sets: one using the American Community Survey and one related to environmental ocean winds.

ObjectiveWe examined the relationship between American Indian men's attitudes toward pregnancy prevention, STI/HIV prevention, and sexual risk behavior. Attention was given to: (1) attitudes and intentions to use condoms and sexual risk behavior; (2) STI/HIV prevention characteristics and sexual risk behavior; (3) attitudes toward abstinence and monogamy and sexual risk behavior; and (4) decision-making in relationships and sexual risk behavior. Study DesignOur sample included 120 heterosexual American Indian men aged 18 to 24 living on a reservation. Data were collected during in-depth interviews. A community-based participatory research framework was used to ensure the relevancy and acceptability of the study given the sensitivity of the topic. Principal FindingsResults demonstrated that attitudinal factors were associated with sexual risk behavior, particularly inconsistent condom use. Attitudes associated with consistent condom use suggested greater levels of positive dispositions toward prevention and intention to use condoms. Consistent condom use was associated with more cautious attitudes toward sex with multiple sex partners. Study results suggested that American Indian men who reported sex with multiple partners exhibited a set of attitudes and beliefs toward pregnancy prevention and STI/HIV prevention that corresponded with a disposition resulting from their behaviors, in that engaging in sexual risk behavior elevated their levels of risk perception. ConclusionsOur findings suggest that heterosexual American Indian men living in rural environments need sexual and reproductive health programs and clinical services that address differing attitudes toward condom use within the context of multiple sex partners and sexual risk behavior.

Nitrile-converting enzymes, including nitrilase and nitrile hydratase (NHase), have received increasing attention from researchers of industrial biocatalysis because of their critical role as a tool in organic synthesis of carboxylic acids and amides from nitriles. To date, these bioconversion approaches are considered as one of the most potential industrial processes using resting cells or purified enzymes as catalysts for production of food additives, pharmaceutical, and agrochemical precursors. This review focuses on the distribution and catalytic mechanism research of nitrile-converting enzymes in recent years. Molecular biology aspects to improve the biocatalytic performance of microbial nitrilase and NHase are demonstrated. The process developments of microbial nitrilase and NHase for organic synthesis are also discussed.

Aminoacylase 1 (ACY1) is important for regulating the proliferation of numerous types of cancer. However, the expression and mechanisms underlying the function of ACY1 in colorectal cancer remain unclear. In order to investigate the expression and function of ACY1 in colorectal cancer, tumor tissue and blood samples were collected for analysis from 132 patients diagnosed with colorectal cancer. Reverse transcription-quantitative polymerase chain reaction analysis and western blotting identified significantly increased expression of ACY1 mRNA in colorectal tumor tissue (P<0.05 vs. adjacent normal tissue) and notably increased ACY1 protein levels. This ACY1 mRNA expression was found to be positively correlated with tumor stage. In addition, plasma ACY1 concentration was increased in patients with colorectal cancer compared with healthy controls. Furthermore, in vitro knockdown of ACY1 in human colorectal cancer HT-29 cells was shown to inhibit proliferation and increase apoptosis. This effect was found to be associated with the activation of ERK1 and TGF-beta 1 signaling. In conclusion, the results of the present study suggest that ACY1 promotes tumor progression, and thus may be a potential target for the diagnosis and treatment of colorectal cancer.