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In the Coast Mountains of western British Columbia, an anomalous seismicity concentration exists near the intersection of the Coast Shear Zone, a major northwest–southeast trending Eocene-age shear zone that accommodated deformation between the Pacific and North America plates, with the Anahim Volcanic Belt, an east-northeast–west-northwest trending zone of volcanic features that decrease in age to the east. To better characterize seismicity in the Coast Mountains, we augment the existing Natural Resources Canada seismicity catalogue by applying an automatic detection and location algorithm to both permanent Canadian National Seismic Network stations and temporary stations from the 2005–2006 BATHOLITHS deployment, resulting in 837 relocated events with at least three paired P- and S-phase picks. Double-difference relocation reveals several small-scale linear strands subparallel to the Coast Shear Zone and within the Anahim Volcanic Belt and three clusters of events striking at a high angle to the Coast Shear Zone that occurred as swarms in 2015 and 2017. First-motion focal mechanisms exhibit extensional and strike-slip faulting. Our observations indicate that most of these events are not associated with surficial processes such as landslides, but rather, we hypothesize that the interaction of the Anahim Volcanic Belt and Coast Shear Zone has weakened the lithosphere in this region, leading to current-day strain localization and high heat flow that manifest seismicity, including swarm-like activity. [ABSTRACT FROM AUTHOR]

Background: To evaluate the effects of a shared decision making (SDM) intervention for older adults with multiple chronic conditions (MCCs). Methods: A pragmatic trial evaluated the effects of the SDMMCC intervention, existing of SDM training for nine geriatricians in two hospitals and a preparatory tool for patients. A prospective pre-intervention post-intervention multi-center clinical study was conducted in which an usual care group of older patients with MCC and their informal caregivers was included before the implementation of the intervention and a new cohort of patients and informal caregivers after the implementation of the intervention. SDM was observed using the OPTIONMCC during video-recorded consultations. Patient- and caregivers reported outcomes regarding their role in SDM, involvement, perceived SDM and decisional conflict were measured. The differences between groups regarding the level of observed SDM (OPTIONMCC) were analyzed with a mixed model analysis. Dichotomous patient-reported outcomes were analyzed with a logistic mixed model. Results: From two outpatient geriatric clinics 216 patients with MCCs participated. The mean age was 77.3 years, and 56.3% of patients were female. No significant difference was found in the overall level of SDM as measured with the OPTIONMCC or in patient-reported outcomes. However, at item level the items discussing 'goals', 'options', and 'decision making' significantly improved after the intervention. The items discussing 'partnership' and 'evaluating the decision-making process' showed a significant decrease. Fifty-two percent of the patients completed the preparatory tool, but the results were only discussed in 12% of the consultations. Conclusion: This study provides scope for improvement of SDM in geriatrics. Engaging older adults with MCCs and informal caregivers in the decision making process should be an essential part of SDM training for geriatricians, beyond the SDM steps of explaining options, benefits and harms. More attention should be paid to the integration of preparatory work in the consultation. [ABSTRACT FROM AUTHOR]

Many individuals with muscular dystrophies remain genetically undiagnosed despite clinical diagnostic testing, including exome sequencing. Some may harbor previously undetected structural variants (SVs) or cryptic splice sites. We enrolled 10 unrelated families: nine had muscular dystrophy but lacked complete genetic diagnoses and one had an asymptomatic DMD duplication. Nanopore genomic long‐read sequencing identified previously undetected pathogenic variants in four individuals: an SV in DMD, an SV in LAMA2, and two single nucleotide variants in DMD that alter splicing. The DMD duplication in the asymptomatic individual was in tandem. Nanopore sequencing may help streamline genetic diagnostic approaches for muscular dystrophy. [ABSTRACT FROM AUTHOR]

Bovine alphaherpesvirus type 1 (BoAHV-1) infections lead to compromised herd health and significantly reduced productivity of affected cattle. While BoAHV-1 may cause rhinotracheitis, conjunctivitis, genital infections, and abortions, respiratory tract infections constitute the predominant clinical disease. Immune suppression induced by BoAHV-1 may contribute to co-infections initiating the bovine respiratory disease complex. In this review, the emphasis is to recapitulate the biology and the vaccine technologies currently in use and in development for BoAHV-1, and to discuss the major limitations. Studies on the life cycle and host interactions of BoAHV-1 have resulted in the identification of virulence factors. While several vaccine types, such as vectored vaccines and subunit vaccines, are under investigation, modified live and inactivated BoAHV-1 vaccines are still most frequently used in most areas of the world, whereas attenuated and inactivated marker vaccines are in use in Europe. The knowledge gained from studies on the biology of BoAHV-1 can form a basis for the rational design of future vaccines. • Modified live and inactivated BoHV-1 vaccines are still most widely used. • Gene-deleted BoHV-1 marker vaccines are in use in Europe. • There is a need for safer live BoHV-1 vaccines, that are not reactivated. • Studies on the biology of BoHV-1 contribute to the rational design of new vaccines. [ABSTRACT FROM AUTHOR]

To explore the relationship between personal characteristics of older adults with multiple chronic conditions (MCCs) and perceived shared decision making (SDM) resp. decisional conflict. In a video-observational study (N = 213) data were collected on personal characteristics. The main outcomes were perceived level of SDM and decisional conflict. The mediating variable was participation in the SDM process. A twostep mixed effect multilinear regression and a mediation analysis were performed to analyze the data. The mean age of the patients was 77.3 years and 56.3% were female. Health literacy (β.01, p <.001) was significantly associated with participation in the SDM process. Education (β = −2.43, p =.05) and anxiety (β = −.26, p =.058) had a marginally significant direct effect on the patients' perceived level of SDM. Education (β = 12.12, p =.002), health literacy (β = −.70, p =.005) and anxiety (β = 1.19, p =.004) had a significant direct effect on decisional conflict. The effect of health literacy on decisional conflict was mediated by participation in SDM. Health literacy, anxiety and education are associated with decisional conflict. Participation in SDM during consultations plays a mediating role in the relationship between health literacy and decisional conflict. Tailoring SDM communication to health literacy levels is important for high quality SDM. • Personal characteristics of older adults may influence their involvement and experience in SDM and decisional conflict. • Health literacy, anxiety and education are associated with decisional conflict. • The effect of health literacy on decisional conflict is mediated by participation in SDM communication during consultation. • Tailoring SDM communication to health literacy levels is important for high quality SDM. [ABSTRACT FROM AUTHOR]

In 1976, a small group of lesbian feminists in Amsterdam named themselves after Jill Johnston's Lesbian Nation: The Feminist Solution (1973) and imagined a separate lesbian society, free from heteropatriarchal oppression. Despite naming themselves after Johnston, Lesbian Nation's main aim was inspired by French feminist theorist Monique Wittig: to subvert the existing symbolic order, and create a new one in its wake. Based on archival research and interviews, this article shows how Lesbian Nation combined both lesbian separatist and cultural feminist tendencies, by experimenting with lesbian identity and creating a women's culture. Discussing the similarities and differences between Lesbian Nation and its predecessor, Paarse September, this article illustrates how lesbian organising evolved in the Netherlands. More broadly, this article adds to lesbian feminist historiography, showing how a small group shaped their own lesbian feminist ideology – and brought this into practice – on a local scale. [ABSTRACT FROM AUTHOR]

Background: Shared decision making (SDM) contributes to personalized decisions that fit the personal preferences of patients when choosing a treatment for a condition. However, older adults frequently face multiple chronic conditions (MCC). Therefore, implementing SDM requires special features. The aim of this paper is to describe the development of an intervention to improve SDM in older adults with MCC.Methods: Following the Medical Research Council framework for developing complex interventions, the SDMMCC intervention was developed step-wise. Based on a literature review and empirical research in a co-creation process with end users, we developed training for geriatricians and a preparatory tool for older patients with MCC and informal caregivers. After assessing feasibility, the intervention was implemented in a pilot study (N = 108) in two outpatient geriatric clinics of an academic and a non-academic teaching hospital in Amsterdam, the Netherlands.Results: Key elements of the training for geriatricians include developing skills to involve older adults with MCC and informal caregivers in SDM and following the six-step 'Dynamic model for SDM with frail older patients', as well as learning how to explore personal goals related to quality of life and how to form a partnership with the patient and the informal caregiver. Key elements of the preparatory tool for patients include an explicit invitation to participate in SDM, nomination that the patient's own knowledge is valuable, invitation to form a partnership with the geriatrician, encouragement to share information about daily and social functioning and exploration of possible goals. Furthermore, the invitation of informal caregivers to share their concerns was also a key element.Conclusions: Through a process of co-creation, both training for geriatricians and a preparatory tool for older adults and their informal caregivers were developed, tailored to the needs of the end users and based on the 'Dynamic model of SDM with frail older patients'. [ABSTRACT FROM AUTHOR]

In shared decision making, the exploration of preferred personal health outcomes is important. Patient-reported outcome measures (PROMs) provide input for discussions between patients and healthcare professionals. The Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS) PROM is a multidimensional questionnaire on the physical and mental health and wellbeing of older adults. This study investigates how the TOPICS-MDS could be used in individual healthcare conversations. We explored views of older adults regarding 1) whether the health domains they want to discuss are included in the TOPICS-MDS and 2) the comprehensibility of the TOPICS-MDS for healthcare conversations with older adults. A three-round Delphi study was conducted. A total of 57 older adults participated in the study, the mean (SD) age was 71.5 (8.5) years, and 78.9% of the participants were female. The participants were divided into four panels based on educational level and cultural background. We used online questionnaires and focus groups. Consensus was pre-defined to be the point when ≥75% of the participants agreed that a domain was important or very important (scored on a 5-point Likert scale). The inter-expert agreement was computed for Round 1 and 3 with Kendall's W. Round 2 was a focus-group. Qualitative data were analyzed by content analysis. Older adults considered 'functional limitations', 'emotional wellbeing', 'social functioning' and 'quality of life' to be important domains of the TOPICS-MDS to discuss in healthcare conversations. The participants added 'coping with stress', 'dealing with health conditions and the effects on life' as extra domains for healthcare conversations. Challenges regarding the comprehensibility of the TOPICS-MDS included difficult words and lengthy or sensitive questions. Questions that included multiple topics were difficult to understand. The TOPICS-MDS covers the domains of life that older adults value as important to discuss with healthcare professionals, and two additional domains were identified. For older adults with a low level of education or a culturally diverse background, the TOPICS-MDS needs to be adjusted for comprehensibility. [ABSTRACT FROM AUTHOR]

Objective: To develop a valid and reliable tool to measure triadic decision making between older adults with multiple chronic conditions (MCC), their informal caregivers and geriatricians.Methods: Video observational study with cross-sectional assessment of interaction during medical consultations between geriatricians (n = 10), patients (n = 108) and informal caregivers (68) by three calibrated raters at the geriatric outpatient department of two Dutch hospitals. The Observer OPTIONMCC instrument was developed, based on the 'Dynamic model of SDM in frail older patients' and the 'Observing Patient Involvement in Decision Making - 5 item scale' (Observer OPTION-5).Results: Factor analysis confirms that it is acceptable to regard the new scale as a single construct. The 7-item single factor solution explained 62.76% of the variability for geriatricians, 61.60% of the variability for patients and 54.32% of the variability for informal caregivers. The inter-rater ICC for the total Observer OPTIONMCC score was .96, .96, and .95 (resp. geriatricians, patients, informal caregivers), with values ranging from .60 to .95 for individual items, showing good levels of agreement.Conclusion and Practice Implications: We conclude that Observer OPTIONMCC is sufficiently valid and reliable to be used for the assessment of triadic SDM in populations of older patients with MCC. [ABSTRACT FROM AUTHOR]

In this study, we explored whether making Eye Movements (EM) during the recall of intrusive images related to alcohol craving reduced the vividness and emotionality of these images and their ability to elicit craving. In a randomized controlled experiment in a treatment facility for substance use disorders in the Netherlands, 50 inpatients with alcohol use disorder were asked to recall mental images related to alcohol craving while simultaneously making EM (n = 29) or keeping a steady gaze (n = 21). Vividness and emotionality of the mental images and craving were measured. Making EM had no significant effect on the vividness and emotionality of images related to alcohol craving, nor on their ability to elicit craving. Our findings do not support the notion that EM reduce alcohol craving. [ABSTRACT FROM AUTHOR]

Tectonic tremor can be used to constrain seismic wave attenuation for use in ground motion prediction equations in regions where moderately sized earthquakes occur infrequently. Here we quantify seismic wave attenuation by inverting tremor ground motion amplitudes in different frequency bands of interest, to determine frequency dependence of and spatial variations in seismic wave attenuation in Cascadia. Due to the density of tremor data, we are able to resolve along‐strike variations in the attenuation parameter. We find that tectonic tremor exhibits the frequency dependence expected for attenuation, as determined from ground motion prediction equations developed from moderate‐to‐large magnitude earthquakes. This implies that attenuation along these paths is independent of the source mechanism. This study demonstrates that tectonic tremor can be used to provide insight into the physical factors responsible for attenuation and to refine estimates of attenuation for ground motion prediction, thus having important implications for hazard assessment and engineering seismology. Plain Language Summary: Earthquake ground motion models use estimates of seismic wave attenuation, that is, the decrease in amplitude of a seismic wave along its path from the earthquake source. Seismic wave attenuation is typically determined by analyzing ground motion from moderate‐to‐large earthquakes. Yet Cascadia also hosts tremor, a group of many small seismic signals accompanying slow sliding of the subducting plate. Because tremor occurs frequently when compared to regular earthquakes in Cascadia, it presents an opportunity to better refine attenuation parameters for use in ground motion models. We quantify seismic wave attenuation using tremor ground motion amplitudes to determine the extent of regional variations and frequency dependence of seismic wave attenuation in Cascadia. Incorporating spatial modifications and allowing for varying frequencies would increase the accuracy of the ground motion model. We are able to resolve spatial variations in the attenuation parameter along strike in Cascadia and observe the frequency dependence expected for attenuation, as seen in ground motion models developed from moderate‐to‐large magnitude earthquakes. Hence, we show that tectonic tremor can be used to provide insight into the physical factors responsible for attenuation and refine estimates of attenuation for ground motion models, thus having important implications for seismic hazard assessment. This is especially helpful in regions where moderate‐to‐large earthquakes are sparse, such as Cascadia. Key Points: Tectonic tremor can be used to constrain physical parameters for use in GMPEs where moderately sized earthquakes occur infrequentlyInversion of tectonic tremor data indicates that seismic wave attenuation varies along strike in CascadiaFrequency‐dependent attenuation from tectonic tremor is observed to be consistent with models developed using moderate‐to‐large earthquakes [ABSTRACT FROM AUTHOR]

Background Eye movement desensitization and reprocessing (EMDR) is an effective treatment for posttraumatic stress disorder. During EMDR, patients make horizontal eye movements (EMs) while simultaneously recalling a traumatic memory, which renders the memory less vivid and emotional when it is later recalled again. Recalling highly emotional autobiographical memories enhances noradrenergic neurotransmission. Noradrenaline (NA) strengthens memory (re)consolidation. However, memories become less vivid after recall+EMs. Therefore, NA might either play no significant role or serve to strengthen memories that are degraded by EMs. The present study was designed to test the latter hypothesis. We predicted that blocking NA would abolish the memory degrading effects of EMs. Methods Fifty-six healthy participants selected three negative autobiographical memories. One was then recalled while making EMs, one was recalled without EMs, and one was not recalled. Vividness and emotionality of the memories as well as heart rate and skin conductance level during memory retrieval were measured before, directly after, and 24 hours after the EM task. Before the task, participants received a placebo or the noradrenergic β-receptor blocker propranolol (40 mg). Results There were no effects of EMs on memory emotionality or psychophysiological measures in the propranolol and placebo groups. However, in the placebo group, but not in the propranolol group, memory vividness significantly decreased from pretest to posttest and follow-up after recall+EMs relative to the control conditions. Conclusions Blocking NA abolished the effects of EMs on the vividness of emotional memories, indicating that NA is crucial for EMDR effectiveness and possibly strengthens the reconsolidation of the degraded memory. [ABSTRACT FROM AUTHOR]

The sophisticated anti-viral functions of nuclear domain 10 (ND10) are revealed by identifying the role of each component and the countermeasures applied by viruses. Several ND10 proteins suppress herpesviruses at initial and early phases of infection. Herpesviruses need to antagonize these anti-viral proteins to start a productive infection. In this review the recently identified similarities and differences among the strategies adopted by the three subfamilies of herpesviruses are discussed, highlighting that one of the significant purposes of incorporating tegument proteins into the viral particles might be to counteract ND10 proteins immediately after the viral genome enters the host nucleus. Once the infection progresses, a sufficient amount of immediate early proteins is expressed to disperse and hydrolyze ND10 proteins, accelerating the development of infection. [ABSTRACT FROM AUTHOR]

Background: Eye movement desensitization and reprocessing (EMDR) is an effective psychological treatment for posttraumatic stress disorder. Recalling a memory while simultaneously making eye movements (EM) decreases a memory’s vividness and/or emotionality. It has been argued that non-specific factors, such as treatment expectancy and experimental demand, may contribute to the EMDR’s effectiveness. Objective: The present study was designed to test whether expectations about the working mechanism of EMDR would alter the memory attenuating effects of EM. Two experiments were conducted. In Experiment 1, we examined the effects of pre-existing (non-manipulated) knowledge of EMDR in participants with and without prior knowledge. In Experiment 2, we experimentally manipulated prior knowledge by providing participants without prior knowledge with correct or incorrect information about EMDR’s working mechanism. Method: Participants in both experiments recalled two aversive, autobiographical memories during brief sets of EM (Recall+EM) or keeping eyes stationary (Recall Only). Before and after the intervention, participants scored their memories on vividness and emotionality. A Bayesian approach was used to compare two competing hypotheses on the effects of (existing/given) prior knowledge: (1) Prior (correct) knowledge increases the effects of Recall+EM vs. Recall Only, vs. (2) prior knowledge does not affect the effects of Recall+EM. Results: Recall+EM caused greater reductions in memory vividness and emotionality than Recall Only in all groups, including the incorrect information group. In Experiment 1, both hypotheses were supported by the data: prior knowledge boosted the effects of EM, but only modestly. In Experiment 2, the second hypothesis was clearly supported over the first: providing knowledge of the underlying mechanism of EMDR did not alter the effects of EM. Conclusions: Recall+EM appears to be quite robust against the effects of prior expectations. As Recall+EM is the core component of EMDR, expectancy effects probably contribute little to the effectiveness of EMDR treatment. [ABSTRACT FROM AUTHOR]

Herpesviruses are enveloped and have an amorphous protein layer surrounding the capsid, which is termed the tegument. Tegument proteins perform critical functions throughout the viral life cycle. This review provides a comprehensive and comparative analysis of the roles of specific tegument proteins in capsid transport and virion morphogenesis of selected, well-studied prototypes of each of the three subfamilies of Herpesviridae i.e., human herpesvirus-1/herpes simplex virus-1 (Alphaherpesvirinae), human herpesvirus-5/cytomegalovirus (Betaherpesvirinae) and human herpesvirus -8/Kaposi's sarcomavirus (Gammaherpesvirinae). Most of the current knowledge is based on alpha herpesviruses, in particular HSV-1. While some tegument proteins are released into the cytoplasm after virus entry, several tegument proteins remain associated with the capsid and are responsible for transport to and docking at the nucleus. After replication and capsid formation, the capsid is enveloped at the nuclear membrane, which is referred to as primary envelopment, followed by de-envelopment and release into the cytoplasm. This requires involvement of at least three tegument proteins. Subsequently, multiple interactions between tegument proteins and capsid proteins, other tegument proteins and glycoproteins are required for assembly of the virus particles and envelopment at the Golgi, with certain tegument proteins acting as the central hub for these interactions. Some redundancy in these interactions ensures appropriate morphogenesis. [ABSTRACT FROM AUTHOR]

Cockayne syndrome (CS) is a DNA repair disorder primarily associated with pathogenic variants in ERCC6 and ERCC8. As in other Mendelian disorders, there are a number of genetically unsolved CS cases. We ascertained five individuals with monoallelic pathogenic variants in MORC2 , previously associated with three dominantly inherited phenotypes: an axonal form of Charcot-Marie-Tooth disease type 2Z; a syndrome of developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy; and a rare form of spinal muscular atrophy. One of these individuals bore a strong phenotypic resemblance to CS. We then identified monoallelic pathogenic MORC2 variants in three of five genetically unsolved individuals with a clinical diagnosis of CS. In total, we identified eight individuals with MORC2 -related disorder, four of whom had clinical features strongly suggestive of CS. Our findings indicate that some forms of MORC2 -related disorder have phenotypic similarities to CS, including features of accelerated aging. Unlike classic DNA repair disorders, MORC2- related disorder does not appear to be associated with a defect in transcription-coupled nucleotide excision repair and follows a dominant pattern of inheritance with variants typically arising de novo. Such de novo pathogenic variants present particular challenges with regard to both initial gene discovery and diagnostic evaluations. MORC2 should be included in diagnostic genetic test panels targeting the evaluation of microcephaly and/or suspected DNA repair disorders. Future studies of MORC2 and its protein product, coupled with further phenotypic characterization, will help to optimize the diagnosis, understanding, and therapy of the associated disorders. [ABSTRACT FROM AUTHOR]

Excessive computer gaming has recently been proposed as a possible pathological illness. However, research on this topic is still in its infancy and underlying neurobiological mechanisms have not yet been identified. The determination of underlying mechanisms of excessive gaming might be useful for the identification of those at risk, a better understanding of the behavior and the development of interventions. Excessive gaming has been often compared with pathological gambling and substance use disorder. Both disorders are characterized by high levels of impulsivity, which incorporates deficits in error processing and response inhibition. The present study aimed to investigate error processing and response inhibition in excessive gamers and controls using a Go/ NoGo paradigm combined with event-related potential recordings. Results indicated that excessive gamers show reduced error-related negativity amplitudes in response to incorrect trials relative to correct trials, implying poor error processing in this population. Furthermore, excessive gamers display higher levels of self-reported impulsivity as well as more impulsive responding as reflected by less behavioral inhibition on the Go/ NoGo task. The present study indicates that excessive gaming partly parallels impulse control and substance use disorders regarding impulsivity measured on the self-reported, behavioral and electrophysiological level. Although the present study does not allow drawing firm conclusions on causality, it might be that trait impulsivity, poor error processing and diminished behavioral response inhibition underlie the excessive gaming patterns observed in certain individuals. They might be less sensitive to negative consequences of gaming and therefore continue their behavior despite adverse consequences. [ABSTRACT FROM AUTHOR]

Abstract: Several studies indicate that individuals with substance use disorders (SUD) exhibit biases in the cognitive processing of substance-related stimuli. These biases facilitate the detection of substance cues and have been argued to play a causal or perpetuating role in addiction. Two electrophysiological indices of cognitive processing, the P300 and Slow Potential (SP) components of the event-related potential (ERP), are associated with the deployment of attentional resources to motivationally relevant stimuli. In the present meta-analysis P300 (300–800ms) and SP (>800ms) amplitudes are used to investigate whether SUD persons show enhanced cognitive processing of substance cues relative to neutral cues as opposed to control participants. Results indicated the P300 and SP amplitude effect sizes were significantly larger in SUD participants than controls. This result is explained by substance users’ motivated attention. Additional stratified moderator analyses revealed that both P300 and SP amplitudes were not moderated by electrode site (Fz vs. Pz), type of substance used (stimulants vs. depressants), substance use status (abstinent vs. non-abstinent), age, gender and task requirements (active vs. passive paradigms). [Copyright &y& Elsevier]

Background: Classical conditioning has been suggested to play an important role in the development, maintenance, and relapse of tobacco smoking. Several studies have shown that initially neutral stimuli that are directly paired with smoking are able to elicit conditioned responses. However, there have been few human studies that demonstrate the contribution of higher-order conditioning to smoking addiction, although it is assumed that higher-order conditioning predominates learning in the outside world. In the present study a higherorder conditioning task was designed in which brain responses of smokers and non-smokers were conditioned by pairing smoking-related and neutral stimuli (CS1smoke and CS1neutral) with two geometrical figures (CS2smoke and CS2neutral). ERPs were recorded to all CSs. Results: Data showed that the geometrical figure that was paired with smoking stimuli elicited significantly larger P2 and P3 waves than the geometrical figure that was paired with neutral stimuli. During the first half of the experiment this effect was only present in smokers whereas non-smokers displayed no significant differences between both stimuli, indicating that neutral cues paired with motivationally relevant smoking-related stimuli gain more motivational significance even though they were never paired directly with smoking. These conclusions are underscored by self-reported evidence of enhanced second-order conditioning in smokers. Conclusions: It can be concluded that smokers show associative learning for higher-order smoking-related stimuli. The present study directly shows the contribution of higher-order conditioning to smoking addiction and is the first to reveal its electrophysiological correlates. Although results are preliminary, they may help in understanding the etiology of smoking addiction and its persistence. [ABSTRACT FROM AUTHOR]

Attentional bias is considered an important concept in addiction since it has been found to correlate with subjective craving and is strongly associated with relapse after periods of abstinence. Hence, investigating in ways to regulate attention for drug cues would be of major clinical relevance. The present study examined deliberate, cognitive modulation of motivated attention for smoking cues in smokers. The effects of three different reappraisal strategies on an electrophysiological measure of attentive processing were investigated. Early and late LPP components in response to passively viewed neutral and smoking pictures were compared with LPPs in response to smoking pictures that were reappraised with three different reappraisal strategies. Results show that when smokers actively imagine how pleasant it would be to smoke (pleasant condition), their early LPP in response to smoking cues increases, but when smokers actively focus on an alternative stimulus (distraction condition) or think of a rational, uninvolved interpretation of the situation (rational condition), smoking-related late LPP amplitude decreases to the processing level of neutral stimuli. Present results are the first to indicate that smoking cue-elicited LPP amplitudes can be modulated by cognitive strategies, suggesting that attentive processing of smoking cues can be intentionally regulated by smokers with various levels of dependence. Although cognitive strategies can lead to enhanced processing of smoking cues, it is not completely clear whether cognitive strategies are also successful in reducing smoking-related motivated attention. Although findings do point in this direction, present study is best considered preliminary and a starting point for other research on this topic. A focus on the distraction strategy is proposed, as there are indications that this strategy is more successful than the rational strategy in decreasing LPP amplitude. [ABSTRACT FROM AUTHOR]

Substance use disorders are characterized by cognitive processing biases, such as automatically detecting and orienting attention towards drug-related stimuli. However, it is unclear how, when and what kind of attention (i.e. implicit, explicit) interacts with the processing of these stimuli. In addition, it is unclear whether smokers are hypersensitive to emotionally significant cues in general or to smoking-related cues in particular. The present event-related potential study aimed to enhance insight in drug-related processing biases by manipulating attention for smoking and other motivationally relevant (emotional) cues in smokers and non-smokers using a visual oddball task. Each of the stimulus categories served as a target (explicit attention; counting) or as a non-target (implicit attention; oddball) category. Compared with non-smokers, smokers’ P300 (350—600 ms) was enhanced to smoking pictures under both attentional conditions. P300 amplitude did not differ between groups in response to positive, negative, and neutral cues. It can be concluded from this study that attention manipulation affects the P300 differently in smokers and non-smokers. Smokers display a specific bias to smoking-related cues, and this bias is present during both explicit and implicit attentional processing. Overall, it can be concluded that both explicit and implicit attentional processes appear to play an important role in drug-related processing bias. [ABSTRACT FROM PUBLISHER]

Introduction: The role of inhibitory control in addictive behaviors is highlighted in several models of addictive behaviors. Although reduced inhibitory control has been observed in addictive behaviors, it is inconclusive whether this is evident in smokers. Furthermore, it has been proposed that drug abuse individuals with poor response inhibition may experience greater difficulties not consuming substances in the presence of drug cues. The major aim of the current study was to provide electrophysiological evidence for reduced inhibitory control in smokers and to investigate whether this is more pronounced during smoking cue exposure. Methods: Participants (19 smokers and 20 non-smoking controls) performed a smoking Go/NoGo task. Behavioral accuracy and amplitudes of the N2 and P3 event-related potential (ERP), both reflecting aspects of response inhibition, were the main variables of interest. Results: Reduced NoGo N2 amplitudes in smokers relative to controls were accompanied by decreased task performance, whereas no differences between groups were found in P3 amplitudes. This was found to represent a general lack of inhibition in smokers, and not dependent on the presence of smoking cues. Conclusions: The current results suggest that smokers have difficulties with response inhibition, which is an important finding that eventually can be implemented in smoking cessation programs. More research is needed to clarify the exact role of cue exposure on response inhibition. [ABSTRACT FROM AUTHOR]

Abstract: Bovine viral diarrhea virus (BVDV) is one of the major pathogens in cattle. In this study, newborn calves with maternal antibodies were vaccinated with a BVDV DNA vaccine, either by conventional intramuscular (IM) injection or with the TriGrid™ Delivery System for IM delivery (TDS-IM). The calves vaccinated with the TDS-IM developed more rapidly and effectively BVDV-specific humoral and cell-mediated immune responses in the presence of maternal antibodies. Overall, the immune responses induced by delivery with the TDS-IM remained stronger than those elicited by conventional IM injection of the BVDV DNA vaccine. Accordingly, electroporation-mediated delivery of the BVDV DNA vaccine resulted in close to complete protection from clinical signs of disease, while conventional IM administration did not fully prevent morbidity and mortality following challenge with BVDV-2. These results demonstrate the TDS-IM to be effective as a delivery system for a BVDV DNA vaccine in newborn calves in the presence of maternal antibodies, which supports the potential of electroporation as a delivery method for prophylactic DNA vaccines. [Copyright &y& Elsevier]

Abstract: CpG oligodeoxynucleotides (ODN) activate the immune system and are promising immunotherapeutic agents against infectious diseases, allergy/asthma and cancer. It has become apparent that while CpG ODN are potent immune activators in mice, their immune stimulatory effects are often less dramatic in humans and large animals. This disparity between rodents and mammals has been attributed to the differences in TLR9 expression in different species. This along with the sometimes transient activity of ODN may limit its potential immunotherapeutic applications. Several approaches to enhance the activity of CpG ODN have been explored including formulation of ODN in depot-forming adjuvants, and more recently, coadministration with polyphosphazenes, inhibitors of cytokines that downregulate TLR9 activation, and simultaneous activation with multiple TLR agonists. We will discuss these approaches and the mechanisms involved, with emphasis on what we have learned from large animal models. [Copyright &y& Elsevier]

Abstract: Toll-like receptors (TLRs), a family of highly conserved germline-encoded pattern-recognition receptors (PRRs), are essential for the host immune response. The cellular localization of TLR proteins determines the access to certain sources of ligands and thus the triggering of downstream cellular signaling. The TLR7/8/9 subfamily proteins are localized intracellularly but the molecular elements determining the cellular localization of these proteins are not fully understood. Here we demonstrated that the bovine TLR8 (bTLR8) protein is localized in the ER cellular compartment of transfected cells before and after cell activation. Using chimeric constructs, we showed that the bTLR8 transmembrane (TM) and cytoplasmic (CP) regions could direct the bovine herpesvirus 1 (BHV-1) glycoprotein D (gD) extracellular domain (ECD) to an intracellular localization. Furthermore, the bTLR8 TM, the linker region between the TM and TIR domains, and the TIR-tail region all partially contributed to the intracellular localization. However, truncation of the bTLR8 with the TM and CP regions removed did not alter its intracellular localization, suggesting that ectodomain (ECD) itself contains intracellular information. Indeed, the bTLR8 ECD also targeted the gD ECD to the intracellular localization. Our results suggest that multiple regions, including ECD, TM, linker and TIR-tail regions of bTLR8, are involved in determining the localization of cellular ER compartment. [Copyright &y& Elsevier]

Aims: To investigate the changes in the electroencephalographic (EEG) spectrum in smokers during exposure to a neutral and a smoking-related cue to determine whether these EEG changes are still present in ex-smokers after prolonged abstinence and to examine the relationship between the power in each spectral bandwidth and subjective craving. Methods: EEG frequencies in response to a smoking-related and a neutral cue were examined in 23 smokers and 21 ex-smokers, who quit smoking for 1.4 years on average. Additionally, self-report measures of cigarette craving and nicotine dependence were obtained. The spectral power of each bandwidth was computed, log-transformed, and analyzed using a within-subject design. Differences between EEG activity under neutral and smoking conditions were correlated with differences between pre- and postexperimental subjective craving. Results: Increases in reward craving (desire and intention to smoke) were associated with reduced theta activity, whereas increases in withdrawal craving (reduction of negative affect and withdrawal symptoms) were correlated with increases in both delta and higher alpha power. Furthermore, in smokers, but not in ex-smokers, a significant beta power increase was observed between the neutral condition and the smoking condition. Conclusion: Since the beta band is associated with arousal, attention, and alertness, it is suggested that the beta increase in response to the smoking cue might reflect an enhanced allocation of resources to smoking-related stimuli, i.e. a processing bias, which is an important feature of substance abuse. Since ex-smokers do not respond to the smoking cue with beta activity enhancement, we preliminarily conclude that smoking cues do not arouse ex-smokers or capture their attention as much as they do in smokers. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Despite the potential of DNA vaccines to induce strong, balanced immune responses in small experimental species, the immune responses to DNA immunization in larger species have generally been moderate and inconsistent. In this study, the TriGrid™ Delivery System (TDS), an electroporation-based DNA delivery platform, was evaluated for administration of DNA vaccines to calves. When compared to conventional intramuscular delivery, TDS-based delivery markedly and consistently enhanced gene expression from a plasmid encoding a reporter gene, secreted alkaline phosphatase, and improved cell-mediated and humoral immune responses to a plasmid encoding a model antigen, hepatitis B surface antigen. Importantly, the TDS-based procedure was well tolerated by the calves, which did not need to be anesthetized or sedated. These results suggest that the TDS is a useful delivery method for DNA vaccines in cattle. [Copyright &y& Elsevier]

Summary: The objective of this study was to evaluate Th1 promoting strategies for vaccination of neonates against bovine herpesvirus-1 (BHV-1). A plasmid encoding a secreted truncated version of glycoprotein D (tgD) and tgD protein formulated with CpG oligodeoxynucleotide (ODN) effectively primed the immune system of newborn lambs, whereas without CpG ODN the tgD protein was less effective. Furthermore, a heterologous DNA prime–protein/CpG boost induced stronger and more balanced immune responses than either the DNA vaccine or a protein/CpG prime–DNA boost. Three of these strategies were compared as an approach to induce protective immunity in newborn calves with BHV-1-specific maternal antibodies. Whereas the DNA vaccine induced minimal protection, the DNA prime–protein boost resulted in reduced temperature response, weight loss and virus shedding in comparison to the placebo group. Close to complete protection against BHV-1 challenge was elicited in the calves immunized with the protein/CpG formulation, as these animals lost very little weight, had only slightly elevated temperatures and shed almost no virus. [Copyright &y& Elsevier]

Processing bias is an important feature of substance abuse. The issue whether processing bias is a more or less permanent feature of nicotine addiction remains to be resolved. The present study addresses the role of smoking status on smoking-related processing bias. We employed Event-Related Brain Potentials (ERPs) as measure of processing bias to investigate this issue. Further, self-report measures of nicotine craving and pleasantness ratings of smoking stimuli were obtained. Three groups, smokers, ex-smokers and never-smokers, were compared on their electrophysiological brain response to smoking-related and neutral pictures. The present study shows that both the P300 and SPW amplitudes in response to smoking-related pictures are significantly more enhanced for smokers than for ex-smokers and never-smokers at frontal and central sites, whereas the magnitude of the P300 and SPW amplitudes in response to neutral pictures does not differ between the three groups. Accordingly, it can be concluded that smokers show more bias for smoking-related pictures than ex-smokers and smokers. Because there is no significant difference between the P300 and SPW amplitudes of ex-smokers and never-smokers, it can also be concluded that ex-smokers display the same (low) level of processing bias as never-smokers. In addition, nicotine-craving ratings and pleasantness ratings of smoking stimuli were higher in smokers compared to ex-smokers. It can be concluded that the smoking-related craving, pleasantness rating, and processing bias decreases after a period of prolonged abstinence. [ABSTRACT FROM AUTHOR]

Abstract: Several characteristics of BHV-1 have contributed to the successful development of both conventional and marker vaccines. BHV-1 is a stable virus, which grows to high titers in vitro, has a limited host range and causes acute viremic infections. Furthermore, the protective antigens, as well as the antigens that are suitable as marker, are present in the predominant virus isolates and induce significant and long-lasting immune responses, both in naïve and in previously vaccinated animals. In many parts of the world including North-America control of BHV-1 is achieved by vaccination with conventional attenuated or inactivated vaccines. With parts of Europe being BHV-1 free, the ability to differentiate infected from vaccinated animals has become critical as a trading tool. Live and killed gE-deleted marker vaccines are now widely used in Europe, in combination with gE-based diagnostic tests to monitor cattle. However, several issues remain to be resolved. BHV-1 causes latency, which creates a need for stringent management practices in case eradication is to be achieved. Since intramuscular delivery with a syringe and needle leads to considerable tissue damage, needle-free delivery methods should be adopted for beef cattle. Furthermore, conventional inactivated and attenuated vaccines are less efficacious in neonates, so alternative vaccine types such as CpG adjuvanted protein vaccines or DNA vaccines are required for effective vaccination of this age group. [Copyright &y& Elsevier]

CpG oligodeoxynucleotides (CpG ODNs) which can induce innate immune responses and promote adaptive immune responses, are powerful tools in defeating diseases. Here, a novel chitosan nanoparticle (CS-NPs) based on host-guest interaction has been designed for encapsulation and delivery of CpG ODNs for the first time. The CS-NPs exhibited high encapsulation efficiency (98.3%) of CpG ODNs and remained stable in storage under room temperature for at least 7 days. CS-NPs can also prevent CpG ODN diffusion at pH 7. The results of confocal laser scanning microscope images and flow cytometry show that CS-NPs can also be efficiently delivered into living cells. Furthermore, CpG@CS-NPs can increase the immunostimulatory activity of CpG ODNs. Raw 264.7 cells treated with CpG@CS-NPs demonstrated upregulation of both TNF-α and IL-6 cytokines by 13% and 40%, respectively. The newly developed CpG@CS-NPs were thus identified as an efficient system to deliver CpG-ODNs to treat various diseases. • Chitosan nanoparticles via host-guest interaction were designed for CpG ODNs delivery. • The nanoparticles exhibited high encapsulation efficiency and stability of CpG ODNs. • The nanoparticles can increase the immunostimulatory activity of CpG ODNs. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis‐like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1. Methods: Two individuals with unsolved juvenile‐onset myopathy were enrolled under approved institutional protocols. Phenotype data were collected and genetic analyses were performed, including whole‐exome sequencing (WES). Results: The two probands (MNOT002‐01 and K1440‐01) showed a similar onset of slowly progressive extremity and facial weakness in early adolescence. K1440‐01 presented with facial weakness, winged scapula, elevated serum creatine kinase (CK) levels, and mild neck weakness. MNOT002‐01 also exhibited elevated CK levels along with facial weakness, cardiomyopathy, respiratory dysfunction, pectus excavatum, a mildly rigid spine, and loss of ambulation. On quadriceps muscle biopsy, K1440‐01 displayed rounded myofibers, mild variation in fiber diameter, and type 2 fiber hypertrophy, while MNOT002‐01 displayed rimmed vacuoles. Monoallelic stop‐loss variants in HNRNPA1 were identified for both probands: c.1119A>C p.*373Tyrext*6 (K1440‐01) and c.1118A>C p.*373Serext*6 (MNOT002‐01) affect the same codon and are both predicted to lead to the addition of six amino acids before termination at an alternative stop codon. Discussion: Both stop‐loss variants in our probands are likely pathogenic. Our findings contribute to the disease characterization of pathogenic variants in HNRNPA1. This gene should be screened in clinical diagnostic testing of unsolved cases of sporadic or dominant juvenile‐onset myopathy. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is highly prevalent. Mechanisms underlying HF remain incompletely understood. Splicing factors (SF), which control pre‐mRNA alternative splicing, regulate cardiac structure and function. This study investigated regulation of the splicing factor heterogeneous nuclear ribonucleoprotein‐L (hnRNPL) in the failing heart. hnRNPL protein increased in left ventricular tissue from mice with transaortic constriction‐induced HF and from HF patients. In left ventricular tissue, hnRNPL was detected predominantly in nuclei. Knockdown of the hnRNPL homolog Smooth in Drosophila induced cardiomyopathy. Computational analysis of predicted mouse and human hnRNPL binding sites suggested hnRNPL‐mediated alternative splicing of tropomyosin, which was confirmed in C2C12 myoblasts. These findings identify hnRNPL as a sensor of cardiac dysfunction and suggest that disturbances of hnRNPL affect alternative splicing in HF. [ABSTRACT FROM AUTHOR]

VP8, the most abundant tegument protein of bovine herpesvirus-1 (BoHV-1), plays an important role in viral replication. According to our previous studies, VP8 localizes to the Golgi apparatus of BoHV-1-infected cells where it can be packaged into the virus; however, Golgi localization of VP8 does not occur outside of the context of infection. The goal of this study was to identify the viral factor(s) involved in the tropism of VP8 towards the Golgi. VP8 was found to interact with glycoprotein M (gM), and the VP8 and gM domains that are essential for this interaction were identified. VP8 and gM colocalized to the Golgi apparatus in BoHV-1-infected cells. In cells co-transfected with VP8- and gM-encoding plasmids, VP8 was also found to be localized to the Golgi, suggesting gM to be sufficient. The localization of VP8 to the Golgi was lost in cells infected with a gM deletion mutant, and the amount of VP8 incorporated into mature virus was significantly reduced. However, with the restoration of gM in a revertant virus, the localization to the Golgi and the amount of VP8 incorporated in the virions were restored. These results indicate that gM plays a critical role in VP8 subcellular localization to the Golgi and packaging into mature virions. [ABSTRACT FROM AUTHOR]

Background and Objectives: Simultaneously making eye movements and recalling a memory leads to competition in working memory (WM), which reduces memory vividness and emotionality. The dose-response relationship between WM taxation and aversive memory degradation is predicted to be either linear (i.e., more cognitively demanding tasks exhibit stronger effects) or follow an inverted U-curve (i.e., there should not be too little, but also not too much taxation).Methods: Participants (N = 44) recalled four aversive autobiographical memories under four conditions that differed in WM taxation: complex, intermediate, simple, or no counting. Before and after each intervention, and at 24 h follow-up, participants recalled the aversive memory and rated it on vividness and unpleasantness. Using a Bayesian approach the linear and inverted U-shape relationships were directly compared.Results: Pretest to posttest drops in vividness and unpleasantness became larger with increased WM taxation of the counting conditions. There was no support for either hypotheses from pretest to follow-up for memory unpleasantness, whereas for memory vividness anecdotal evidence was found for a linear relationship.Limitations: A reaction time (RT) task was used to select counting tasks of varying difficulties. However, the validity of this task appears to be compromised under very strenuous conditions. Higher levels of WM taxation might have been possible with more difficult counting tasks.Conclusions: There is strong evidence for a linear dose-response relationship between WM taxation and memory degradation immediately after the intervention, and some unconvincing evidence for this pattern one day later. There was no evidence for an inverted U-curve. [ABSTRACT FROM AUTHOR]

This study examined relations between memories for childhood teasing and symptoms of social anxiety, depression, and eating disorders in 130 Dutch adolescents. Participants completed the Teasing Questionnaire-Revised which measures how much people recall having been teased during childhood, as well as the Social Anxiety Scale for Children, the Child Depression inventory, and the Children's Eating Attitude Test. Analysis yielded significant positive correlations between sell-reported recollections of childhood teasing and various symptoms. Furthermore, some evidence indicated specific domains of teasing were associated with specific types of psychopathological symptoms. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) causes acute respiratory tract infections in infants, the elderly and immunocompromised individuals. No licensed vaccine is available against RSV. We previously reported that intranasal immunization of rodents and lambs with a RSV vaccine candidate (ΔF/TriAdj) induces protective immunity with a good safety profile. ΔF/TriAdj promoted innate immune responses in respiratory mucosal tissues in vivo , by local chemokine and cytokine production, as well as infiltration and activation of immune cells including macrophages. The macrophage is an important cell type in context of both innate and adaptive immune responses against RSV. Therefore, we characterized the effects of ΔF/TriAdj on a murine macrophage cell line, RAW264.7, and bone marrow-derived macrophages (BMMs). A gene expression study of pattern recognition receptors (PRRs) revealed induction of endosomal and cytosolic receptors in RAW264.7 cells and BMMs by ΔF/TriAdj, but no up-regulation by ΔF in PBS. As a secondary response to the PRR gene expression, induction of several chemokines and pro-inflammatory cytokines, as well as up-regulation of MHC-II and co-stimulatory immune markers, was observed. To further investigate the mechanisms involved in ΔF/TriAdj-mediated secondary responses, we used relevant signal transduction pathway inhibitors. Based on inhibition studies at both transcript and protein levels, JNK, ERK1/2, CaMKII, PI3K and JAK pathways were clearly responsible for ΔF/TriAdj-mediated chemokine and pro-inflammatory cytokine responses, while the p38 and NF-κB pathways appeared to be not or minimally involved. ΔF/TriAdj induced IFN-β, which may participate in the JAK-STAT pathway to further amplify CXCL-10 production, which was strongly up-regulated. Blocking this pathway by a JAK inhibitor almost completely abrogated CXCL-10 production and caused a significant reduction in the cell surface expression of MHC-II and co-stimulatory immune markers. These data demonstrate that ΔF/TriAdj induces multiple signaling pathways in macrophages. [ABSTRACT FROM AUTHOR]

Statins are a mainstay intervention for cardiovascular disease prevention, yet their use can cause rare severe myopathy. HMG-CoA reductase, an essential enzyme in the mevalonate pathway, is the target of statins. We identified nine individuals from five unrelated families with unexplained limb-girdle like muscular dystrophy and bi-allelic variants in HMGCR via clinical and research exome sequencing. The clinical features resembled other genetic causes of muscular dystrophy with incidental high CPK levels (>1,000 U/L), proximal muscle weakness, variable age of onset, and progression leading to impaired ambulation. Muscle biopsies in most affected individuals showed non-specific dystrophic changes with non-diagnostic immunohistochemistry. Molecular modeling analyses revealed variants to be destabilizing and affecting protein oligomerization. Protein activity studies using three variants (p.Asp623Asn, p.Tyr792Cys, and p.Arg443Gln) identified in affected individuals confirmed decreased enzymatic activity and reduced protein stability. In summary, we showed that individuals with bi-allelic amorphic (i.e., null and/or hypomorphic) variants in HMGCR display phenotypes that resemble non-genetic causes of myopathy involving this reductase. This study expands our knowledge regarding the mechanisms leading to muscular dystrophy through dysregulation of the mevalonate pathway, autoimmune myopathy, and statin-induced myopathy. [Display omitted] We identified rare bi-allelic variants in HMGCR in nine individuals with muscular dystrophy and no genetic diagnosis. Functional and in silico studies implicate HMGCR dysfunction in muscular dystrophy pathogenesis. [ABSTRACT FROM AUTHOR]

Adjuvants are crucial components of many vaccines. They are used to improve the immunogenicity of vaccines with the aim of conferring long-term protection, to enhance the efficacy of vaccines in newborns, elderly or immunocompromised persons, and to reduce the amount of antigen or the number of doses required to elicit effective immunity. Novel combination adjuvants have been tested in both candidate animals and humans vaccines and have generated encouraging results. Recently, we developed a combination adjuvant platform (TriAdj) comprising of three components, namely a TLR agonist, either polyI:C or CpG oligodeoxynucleotides (ODN), host defense peptide and polyphosphazene. This adjuvant platform is stable and highly effective in a wide range of animal and human vaccines tested in mice, cotton rats, pigs, sheep, and koalas. TriAdj with various vaccines antigens induced effective long-term humoral and cellular immunity. Moreover, the adjuvant platform is suitable for maternal immunization and highly effective in neonates even in the presence of maternal antibodies. This novel vaccine platform, offers excellent opportunity for use in present and future generations of vaccines against multiple infectious agents and targets challenging populations. [ABSTRACT FROM AUTHOR]

This paper compares different low-cost sensors that can measure (5G) RF-EMF exposure. The sensors are either commercially available (off-the-shelf Software Defined Radio (SDR) Adalm Pluto) or constructed by a research institution (i.e., imec-WAVES, Ghent University and Smart Sensor Systems research group (S³R), The Hague University of Applied Sciences). Both in-lab (GTEM cell) and in-situ measurements have been performed for this comparison. The in-lab measurements tested the linearity and sensitivity, which can then be used to calibrate the sensors. The in-situ testing confirmed that the low-cost hardware sensors and SDR can be used to assess the RF-EMF radiation. The variability between the sensors was 1.78 dB on average, with a maximum deviation of 5.26 dB. Values between 0.09 V/m and 2.44 V/m were obtained at a distance of about 50 m from the base station. These devices can be used to provide the general public and governments with temporal and spatial 5G electromagnetic field values. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) causes serious upper and lower respiratory tract infections in newborns and infants. Presently, there is no licensed vaccine against RSV. We previously reported the safety and efficacy of a novel vaccine candidate (ΔF/TriAdj) in rodent and lamb models following intranasal immunization. However, the effects of the vaccine on the innate immune system in the upper and lower respiratory tracts, when delivered intranasally, have not been characterized. In the present study, we found that ΔF/TriAdj triggered transient production of chemokines, cytokines and interferons in the nasal tissues and lungs of BALB/c mice. The types of chemokines produced were consistent with the populations of immune cells recruited, i.e. dendritic cells, macrophages and neutrophils, in the nose-associated lymphoid tissue (NALT), lung and their draining lymph nodes of the ΔF/TriAdj-immunized group. In addition, ΔF/TriAdj stimulated cellular activation with generation of mucosal and systemic antibody responses, and conferred complete protection from viral infection in the lungs upon RSV challenge. The effect of ΔF/TriAdj was short-lived in the nasal tissues and more prolonged in the lungs. In addition, both innate and adaptive immune responses were lower when mice were immunized with ΔF alone. These results suggest that ΔF/TriAdj modulates the innate mucosal environment in both upper and lower respiratory tracts, which contributes to robust adaptive immune responses and long-term protective efficacy of this novel vaccine formulation. [ABSTRACT FROM AUTHOR]

The pneumonia virus of mice (PVM) model is used to study respiratory syncytial virus (RSV) pathogenesis. The outcome of PVM infection varies in different inbred mouse strains, BALB/c being highly susceptible and C57BL/6 more resistant. As the disease symptoms induced by RSV infection can become more severe as people age, we examined the primary and secondary immune responses to infection with PVM in aged BALB/c and C57BL/6 mice. Based on clinical parameters, aged C57BL/6 mice displayed less severe disease than young adult mice when infected with 3000 pfu of PVM-15, while BALB/c mice were equally susceptible at both ages showing significant weight loss and high levels of virus replication. Furthermore, after primary infection the CD4 + T cell numbers in the lungs were higher in young adult mice, while the CD8 + T cell numbers were comparable in both age groups and strains. When either C57BL/6 or BALB/c mice were infected with PVM as young adults and then re-infected as aged mice, they were protected from clinical disease, while virus replication was reduced. In contrast to mice with a primary PVM-infection, re-infected mice did not have infiltration of neutrophils or inflammatory mediators in the lung. BALB/c mice had higher virus neutralizing antibody levels in the serum and lung than C57BL/6 mice upon re-infection. Re-infection with PVM led to significant influx of effector CD4 + T cells into the lungs when compared to aged mice with a primary infection, while this cell population was decreased in the lung draining lymph nodes in both mouse strains. After re-infection the effector CD8 + T cell population was also decreased in the lung draining lymph nodes in both mouse strain when compared to aged mice after primary infection. However, the central memory CD4 + and CD8 + T cells were significantly enhanced in numbers in the lungs and draining lymph nodes of both mouse strains after re-infection, and these numbers were higher for C57BL/6 mice. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate endocrinological and immunological effects of early postnatal immunisation against gonadotrophin-releasing hormone (GnRH) in heifer calves, as similar treatment in sheep provokes long-term immunocastration. Heifer calves were injected with either a construct of GnRH - bovine herpes virus 1 glycoprotein D (BHV1 gD; n = 9) or saline (n = 9) at 2, 6 and 13.5 weeks of age. Antibody (GnRH and carrier) and endocrine responses to immunisation were measured twice monthly (FSH and progesterone) or during intensive sampling regimes (LH). Early postnatal immunisation against GnRH induced a high, but variable, antibody response against both GnRH and carrier. Based on antibody responses, animals were divided into high-titre (HT, n = 5) and low-titre (LT, n = 4). Occurring mainly in HT, a further peak in anti-GnRH antibodies, stimulated independently of the carrier, was observed at 23 weeks of age, with antibody titres ⩾10% binding for ∼9 weeks post-peak. Conversely immunisation had only temporary, reversible effects on reproductive function, not affecting age at puberty. We hypothesise that the newly generated antibody measured 10 weeks after the final immunisation resulted from antigenic stimulation and immunological memory cell activation to an endogenous GnRH release. This outcome offers an opportunity for further manipulation of reproductive function based on modulation of GnRH secretion and activity where long-term immunological memory may contribute to durable endocrine effects. [ABSTRACT FROM AUTHOR]

Abstract: The development of vaccines for infants and young children requires the use of animal models at various stages of preclinical development. Animal models are being used to assess the quantity and quality of the immune response, onset and duration of the response, induction of systemic versus local immunity, protection against challenge infection for the assessment of vaccine efficacy, as well as safety and toxicity of the vaccine formulation itself. A variety of animal models are available, each with its own specific advantages and disadvantages. Here, we review the most common animal models for preclinical vaccine development for human infants. [Copyright &y& Elsevier]

Abstract: Dendritic cells (DCs) play a crucial role in the initiation of an immune response. As maturation is critical for effective antigen presentation, different methods have been used to generate mature DCs (mDCs) ex vivo. The use of a maturation cocktail (MC) consisting of IL-1β, IL-6, TNF-α, and prostaglandin E2 (PGE2) initially showed promising results, but then was challenged because of low production of IL-12p70 and the potential for induction of Th2-type immune responses. To investigate this contention, we compared two of the most commonly used maturation factors, TNF-α and LPS, with MC. Maturation cocktail was superior to TNF-α and LPS with respect to enhancement of mDC-specific surface marker expression (CD83, CD86, and HLA-DR), induction of T cell proliferation by mDCs, and directional motility of mDCs toward CCL19. These results were supported by increased expression of a significant number of additional maturation-related genes by MC in comparison to TNF-α and LPS. In addition, we did not observe a Th2-biased shift in the gene expression profile of mDCs generated by MC. Conversely, MC induced more Th1-promoting transcriptional changes than LPS or TNF-α, including increased transcript levels of Th1-type cytokines such as IL-15, IL-12β, and EBI3 (IL-27β) and MHC class I molecules, Th1-promoting changes in the transcripts of CXCL16, CCL13, and CCL18, and reduced transcript levels of MHC class II molecules. More interestingly, the Th1-promoting characteristics of MC-mDCs were confirmed by their potential to produce large amounts of IL-12p70 after effective stimulation simulating in vivo events. [Copyright &y& Elsevier]

Abstract: The intracellular trafficking of different VP22-enhanced yellow fluorescent protein (EYFP) fusion proteins expressed by bovine herpesvirus-1 (BHV-1) recombinants was examined by live-cell imaging. Our results demonstrate that (i) the fusion of EYFP to the C terminus of VP22 does not alter the trafficking of the protein in infected cells, (ii) VP22 expressed during BHV-1 infection translocates to the nucleus through three different pathways, namely early mitosis-dependent nuclear translocation, late massive nuclear translocation that follows a prolonged cytoplasmic stage of the protein in non-mitotic cells, and accumulation of a small subset of VP22 in discrete dot-like nuclear domains during its early cytoplasmic stage, (iii) the addition of the SV40 large-T-antigen nuclear localization signal (NLS) to VP22-EYFP abrogates its early cytoplasmic stage, and (iv) the VP22 131PRPR134 NLS is not required for the late massive nuclear translocation of the protein, but this motif is essential for the targeting of VP22 to discrete dot-like nuclear domains during the early cytoplasmic stage. These results show that the amount of VP22 in the nucleus is precisely regulated at different stages of BHV-1 infection and suggest that the early pathways of VP22 nuclear accumulation may be more relevant to the infection process as the late massive nuclear influx starts when most of the viral progeny has already emerged from the cell. [Copyright &y& Elsevier]

The prevention of infectious diseases of animals by vaccination has been routinely practiced for decades and has proved to be one of the most cost-effective methods of disease control. However, since the pioneering work of Pasteur in the 1880s, the composition of veterinary vaccines has changed very little from a conceptual perspective and this has, in turn, limited their application in areas such as the control of chronic infectious diseases. New technologies in the areas of vaccine formulation and delivery as well as our increased knowledge of disease pathogenesis and the host responses associated with protection from disease offer promising alternatives for vaccine formulation as well as targets for the prevention of bacterial disease. These new vaccines have the potential to lessen our reliance on antibiotics for disease control, but will only reach their full potential when used in combination with other intervention strategies. [ABSTRACT FROM AUTHOR]