Activation of platelet-derived growth factor receptor alpha (PDGFRA) by genomic aberrations contributes to tumor progression in several tumor types. In this study, we characterize 16 novel PDGFRA ...mutations identified from different tumor types and identify three previously uncharacterized activating mutations that promote cell survival and proliferation. PDGFRA Y288C, an extracellular domain mutation, is primarily high mannose glycosylated consistent with trapping in the endoplasmic reticulum (ER). Strikingly, PDGFRA Y288C is constitutively dimerized and phosphorylated in the absence of ligand suggesting that trapping in the ER or aberrant glycosylation is sufficient for receptor activation. Importantly, PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors but sensitive to PI3K/mTOR and MEK inhibitors consistent with pathway activation results. Our findings further highlight the importance of characterizing functional consequences of individual mutations for precision medicine.
Deciduous climbing plant canopies strategically integrated to building façades can act as dynamic solar shading devices responsive to the seasonal climatic changes. Maximum shading occurs in the ...summer when the plant is at its peak growth. The shedding of leaves in autumn and winter reduces the shading and allows beneficial solar radiation to be absorbed by the opaque surface of the building façade or penetrated through the windows to the building interior. Although climbing plants have long been used for moderating the microclimate of buildings, there are very few scientific investigations to quantify such effects. This paper reports the findings of a study with specific focus on the shading performance of a vertical deciduous climbing plant canopy. It justifies the selection of Virginia Creeper as an appropriate plant for growth in the UK climate and describes the planting, monitoring and analysis procedures adopted to determine a proposed dynamic Bioshading Coefficient Function – which is used to represent the shading performance of the climbing plant canopy over its annual growing and wilting cycle. A thermal model was developed which identified the key parameters required for establishing the Bioshading Coefficients. Two climbing plant canopies (referred to as Bioshaders) were set up in an existing building in Southeast UK and monitored for 2 years. Measured data were used to calculate a series of daily Bioshading Coefficients which were subsequently applied to establish the Bioshading Coefficient Function. The research also identified issues affecting the indoor environment as a result of the application of Bioshaders.
Considering the marked changes in sleep and circadian rhythms across the lifespan, age may contribute to the heterogeneity in sleep-wake profiles linked to mood disorders. This study aimed to ...investigate the contributions of age and depression severity to sleep-wake disturbances. The Hamilton Depression Rating Scale (HDRS) was administered to assess current symptoms severity in 238 persons with a history of a mood disorder between 12 and 90 years of age (y.o.). Actigraphy was recorded over five to 22 days. Regression analyses and analyses of variance age (12-19 y.o., 20-39 y.o., 40-59 y.o., and ≥ 60 y.o.) by depression severity (HDRS< and ≥ 8) were conducted. The 12-19 y.o. and 20-39 y.o. groups had a delayed sleep schedule and acrophase compared to all other groups. The ≥ 60 y.o. group had a lower rhythmicity and amplitude (p ≤ .006) than the 12-19 y.o. group (p ≤ .046). Participants with a HDRS ≥ 8 spent longer time in bed, had later sleep offset times and had lower circadian rhythmicity than those with a HDRS<8 (p ≤ .036). Younger age and higher HDRS score correlated with later sleep onset and offset times, longer time in bed, higher WASO, lower sleep efficiency and later acrophase (p ≤ .023). Age was a significant predictor of delayed sleep and activity schedules (p ≤ .001). The profile of sleep-wake cycle disturbances associated with mood disorders changes with age, with prominent sleep phase delay during youth and reduced circadian strength in older persons. Conversely, disruptions in sleep consolidation seem more stable across age.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. Large clinical trials have demonstrated the therapeutic efficacy of oseltamivir against influenza. We assessed the indirect effectiveness of oseltamivir in reducing secondary household ...transmission in an incident cohort of influenza index patients and their household members. Methods. We recruited index outpatients whose rapid test results were positive for influenza from February through September 2007 and January through September 2008. Household contacts were followed up for 7–10 days during 3–4 home visits to monitor symptoms. Nose and throat swabs were collected and tested for influenza by reverse-transcription polymerase chain reaction or viral culture. Results. We followed up 384 index patients and their household contacts. Index patients who took oseltamivir within 24 h of symptom onset halved the time to symptom alleviation (adjusted acceleration factor, 0.56; 95% confidence interval CI, 0.42–0.76). Oseltamivir treatment was not associated with statistically significant reduction in the duration of viral shedding. Household contacts of index patients who had taken oseltamivir within 24 h of onset had a nonstatistically significant lower risk of developing laboratory-confirmed infection (adjusted odds ratio, 0.54; 95% CI, 0.11–2.57) and a marginally statistically significant lower risk of clinical illness (adjusted odds ratio, 0.52; 95% CI, 0.25–1.08) compared with contacts of index patients who did not take oseltamivir. Conclusions. Oseltamivir treatment is effective in reducing the duration of symptoms, but evidence of household reduction in transmission of influenza virus was inconclusive.
Ovarian cancer is highly metastatic with a poor prognosis. The serine/threonine kinase, p70 S6 kinase (p70(S6K)), which is a downstream effector of phosphatidylinositol 3-kinase/Akt pathway, is ...frequently activated in ovarian cancer. Here, we show that p70(S6K) is a critical regulator of the actin cytoskeleton in the acquisition of the metastatic phenotype. This regulation is through two important activities: p70(S6K) acts as an actin filament cross-linking protein and as a Rho family GTPase-activating protein. Ectopic expression of constitutively active p70(S6K) in ovarian cancer cells induced a marked reorganization of the actin cytoskeleton and promoted directional cell migration. Using cosedimentation and differential sedimentation assays, p70(S6K) was found to directly bind to and cross-link actin filaments. Immunofluorescence studies showed p70(S6K) colocalized with cytochalasin D-sensitive actin at the leading edge of motile cells. The p70(S6K) did not affect the kinetics of spontaneous actin polymerization, but could stabilize actin filaments by the inhibition of cofilin-induced actin depolymerization. In addition, we showed that p70(S6K) stimulated the rapid activation of both Rac1 and Cdc42, and their downstream effector p21-activated kinase (PAK1), but not RhoA. Depletion of p70(S6K) expression or inhibition of its activity resulted in significant inhibition of actin cytoskeleton reorganization and reduced migration, with a concomitant reduction in Rac1, Cdc42 and PAK1 activation, confirming that the effect was p70(S6K) specific. Similarly, the actin cytoskeleton reorganization/migratory phenotype could be reversed by expression of dominant negative Rac1 and Cdc42, or inhibition of PAK1. These results reveal a new direction for understanding the oncogenic roles of p70(S6K) in tumor progression.
Background. Although the pattern of viral shedding over time has been documented in volunteer challenge studies, understanding of the relationship between clinical symptomatology and viral shedding ...in naturally acquired influenza infections in humans remains limited. Methods. In a community-based study in Hong Kong from 2008 to 2014, we followed up initially healthy individuals and identified 224 secondary cases of natural influenza virus infection in the household setting. We examined the dynamic relationship between patterns of clinical symptomatology and viral shedding as quantified using reverse transcription polymerase chain reaction and viral culture in 127 cases with a clinical picture of acute respiratory infection. Results. Viral shedding in influenza A virus infections peaked on the first 1–2 days of clinical illness, and decreased gradually to undetectable levels by day 6–7, matching closely with the dynamics of clinical illness. Viral shedding in influenza B virus infections rose up to 2 days prior to symptom onset and persisted for 6–7 days after onset with a bimodal pattern. Conclusions. Our results suggest that while clinical illness profiles may serve as a proxy for clinical infectiousness in influenza A virus infections, patients may potentially be infectious even before symptom onset or after clinical improvement in influenza B virus infections.
Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to nonpathogenic microbes is poorly ...understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focusing on cytotoxic necrotizing factor 1 (CNF1), an
Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively, to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential.
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► The bacterial effector CNF1 is sufficient to drive a protective immune response ► CNF1 modification of Rac2 triggers antimicrobial peptide response ► Activation of Rac2 triggers an immune response via the IMD signaling pathway ► Human Rac2 induces immune activation through Rip1 and Rip2
Lipocalin 2 (Lcn2) is a bacteriostatic factor that may also modulate cellular function, however, little is known concerning the expression or role of Lcn2 in CNS inflammation. Therefore, here we ...investigated the regulation and possible function of Lcn2 in the CNS following peripheral lipopolysaccharide (LPS) injection in mice.
A murine model for systemic endotoxemia was used in this study. Wild type or Lcn2 KO mice (both genotypes C57BL/6 strain) were given either a single or dual, staggered intraperitoneal injections of purified E. coli LPS or vehicle alone. The brain was examined for the expression and location of Lcn2 mRNA and protein and various markers for neuroinflammation were analyzed.
Although undetectable under physiological conditions, both Lcn2 mRNA and protein were induced to high levels in the brain after LPS injection. By contrast, RNA corresponding to the putative Lcn2 (termed 24p3R) receptor was present at high levels in the normal brain and remained unaltered by LPS injection. Differences between Lcn2 and 24p3R mRNA expression were found at the anatomic and cellular level. Endothelial cells, microglia and the choroid plexus but not neurons were identified as the main cellular sources for Lcn2 mRNA in the CNS. By contrast, 24p3R mRNA was detected in neurons and the choroid plexus only. Lcn2 protein was found to have a similar cellular localization as the corresponding RNA transcripts with the exception that subsets of neurons were also strongly positive. Various inflammatory, glial, and iron handling markers were analyzed and found to have similar alterations between WT and Lcn2 KO animals.
1) Lcn2 production is strongly induced in the CNS by systemic LPS injection, 2) in addition to Lcn2 production at key gateways of bacterial entry to the CNS, neurons may be a target for the actions of Lcn2, which is apparently taken up by these cells, and 3) the cellular functions of Lcn2 in the CNS remain enigmatic.
•Vaccination intention explained over 60% of actual vaccination uptake among healthcare personnel.•Attitude towards influenza vaccination was the strongest predictor of vaccination intention.•Norms ...could shape one’s attitude and thereby influenced his/her intention to vaccinate.
Although annual seasonal influenza vaccination is recommended for healthcare personnel (HCPs), their vaccination uptake has been suboptimal. This study aimed to examine the psychosocial determinants of influenza vaccination among HCPs in Hong Kong using a longitudinal study design based on behavioral change theories.
Participants were invited to complete a baseline survey before the 2017/18 influenza vaccination campaign to measure their baseline perceptions and vaccination intention, and followed up for 9 months to measure actual vaccination uptake. The survey used a theoretical framework combining the Health Belief Model and Theory of Planned Behaviour with extended psychosocial factors for predicting HCPs’ vaccination uptake. Structural equation modelling was used to test the theoretical model and estimate path coefficients (β) to infer associations of psychosocial factors with HCPs’ influenza vaccination uptake.
Of the 845 participants who completed follow-up, 43.0% indicated intending to take vaccination and 30.8% reported actual receipt of the vaccination. The structural equation modeling analysis showed that positive attitude towards influenza vaccination (β = 0.69), greater perceived susceptibility to influenza virus infection (β = 0.34), greater anticipated regret for not vaccinating (β = 0.31), and more cues to action (β = 0.29) were significantly associated with higher vaccination intention which directly predicted greater vaccination uptake (β = 0.82). Norms were found to have an indirect association with vaccination intention through the mediation of attitude towards influenza vaccination (β = 0.63). Self-efficacy was significantly associated with actual receipt of influenza vaccination (β = 0.13) but not vaccination intention. The structural equation model explained 84.7% and 69.6% of the variance, respectively, in HCPs’ intention to receive and actual receipt of influenza vaccination.
Attitude towards influenza vaccination was the strongest predictor of HCPs’ intention and actual receipt of influenza vaccination. Social norm approach may be an intervention strategy to shape HCPs’ attitude towards influenza vaccination and their subsequent decision-making for influenza vaccination.
Summary
Cardiac events remain the leading cause of peri‐operative morbidity and mortality, and patients undergoing major surgery are exposed to significant risks which may be preventable and ...modifiable. Proper assessment and management of various cardiac conditions in the peri‐operative period by anaesthetists can markedly improve patient safety, especially in high‐risk patient populations. This involves understanding and applying current evidence‐based practice and international guidelines on the main aspects of cardiac optimisation, including management of patients with hypertension, chronic heart failure, valvular heart diseases and cardiac implantable electronic devices. Peri‐operative management of antihypertensive drugs in keeping with the current best evidence is discussed. Pre‐operative cardiac risk assessment and cardiac biomarkers can be used to help predict and quantify peri‐operative adverse cardiac events. There is an increasing need for anaesthetist‐led services, including focused transthoracic echocardiography and management of implantable cardiac electronic devices. Anaesthetists should be encouraged to play a proactive role in pre‐operative risk stratification and make timely multidisciplinary referrals if necessary. A personalised approach to pre‐operative cardiac optimisation enables a safer peri‐operative journey for at‐risk patients undergoing major surgery.
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