Abstract Pandemic H1N1 influenza A (H1N1pdm) elicits stronger pulmonary inflammation than previously circulating seasonal H1N1 influenza A (sH1N1), yet mechanisms of inflammatory activation in ...respiratory epithelial cells during H1N1pdm infection are unclear. We investigated host responses to H1N1pdm/sH1N1 infection and virus entry mechanisms in primary human bronchial epithelial cells in vitro . H1N1pdm infection rapidly initiated a robust inflammatory gene signature (3 h post-infection) not elicited by sH1N1 infection. Protein secretion inhibition had no effect on gene induction. Infection with membrane fusion deficient H1N1pdm failed to induce robust inflammatory gene expression which was rescued with restoration of fusion ability, suggesting H1N1pdm directly triggered the inflammatory signature downstream of membrane fusion. Investigation of intra-virion components revealed H1N1pdm viral RNA (vRNA) triggered a stronger inflammatory phenotype than sH1N1 vRNA. Thus, our study is first to report H1N1pdm induces greater inflammatory gene expression than sH1N1 in vitro due to direct virus–epithelial cell interaction.
The relative roles of the types 1 and 2 iodothyronine deiodinases (D1 and D2) in extrathyroidal 3,5,3'-triiodothyronine (T3) production in humans are unknown. We calculated the rate of thyroxine (T4) ...to T3 conversion by intact cells transiently expressing D1 or D2 at low (2 pM), normal (20 pM), and high (200 pM) free T4 concentrations. Deiodinase activities were then assayed in cell sonicates. The ratio of T3 production in cell sonicates (catalytic efficiency) was multiplied by the tissue activities reported in human liver (D1) and skeletal muscle (D2). From these calculations, we predict that in euthyroid humans, D2-generated T3 is 29 nmol/d, while that of D1-generated T3 is 15 nmol/d, from these major deiodinase-expressing tissues. The total estimated extrathyroidal T3 production, 44 nmol/d, is in close agreement with the 40 nmol T3/d based on previous kinetic studies. D2-generated T3 production accounts for approximately 71% of the peripheral T3 production in hypothyroidism, but D1 for approximately 67% in thyrotoxic patients. We also show that the intracellular D2-generated T3 has a greater effect on T3-dependent gene transcription than that from D1, which indicates that generation of nuclear T3 is an intrinsic property of the D2 protein. We suggest that impairment of D2-generated T3 is the major cause of the reduced T3 production in the euthyroid sick syndrome.
How firms’ doing “good” inspires customers to do “good” is rarely investigated. Drawing upon social exchange, social identity, and signaling theories, this study explores the mechanisms between ...corporate social responsibility (CSR) and customer citizenship behavior (CCB), and examines the mediating effects generated by engagement, identification, and trust. Through convenience and snowball sampling methods, 242 questionnaires were collected from customers of a firm implementing CSR projects. The findings reveal that the most effective path for CSR perception to motivate CCB is to go through a process involving trust, identification, and then customer engagement. Engagement plays the most critical role among these three mediators.
Purpose
Many service firms have adopted creativity reinforcement mechanisms to manage employee-based service creativity so as to pursue their performance growth. However, its impact on firm ...performance has rarely been investigated in the extant research. The purpose of this paper is to satisfy this knowledge gap through an examination of how service creativity reinforcement (SCR) affects a firm’s performance.
Design/methodology/approach
Two samples were used to test the hypotheses. The first sample included a total of 4,381 service firms and was analyzed by using a traditional moderated regression method in relation to sales growth as the outcome variable. Due to a number of missing values, the second sample was reduced to 1,481 service firms. This sample was analyzed by using a moderated fractional regression method and the outcome variable was innovation performance. Furthermore, a multi-valued treatment approach with the augmented inverse-propensity weighted estimator was adopted to assess the performance effect that was associated with each of the SCR mechanisms.
Findings
Statistical analyses suggested that SCR positively affected both the firm’s performance and its innovation performance. Specifically, the stronger performance effects of SCR were associated with firms that had high innovation intensity, were small service firms and were part of the knowledge-intensive business service (KIBS) sector. The results also found that brainstorming sessions, a multi-disciplinary team approach, task rotation and non-financial incentives had greater performance effects than other mechanisms, especially for firms in the KIBS sector that had high innovation intensity. In addition, the results indicated that team-level mechanisms were more effective in developing highly innovative services than were individual-level mechanisms.
Originality/value
This study has contributed to the service literature by developing a contingency framework for SCR. This study has also advanced service research through the presentation of contextual effects associated with each mechanism of SCR.
Customer participation of mandatory (ensuring the completion of a service delivery) and voluntary behaviours (achieving the optimal results of the service) influence the outcomes of service ...organizations. This study examines how service firms transform from coproduction to cocreation in sharing economy by enhancing customer voluntary behaviour through encouraging customer mandatory behaviour. This study explores the mediating effect of perceived value on the mandatory-voluntary relationship, and the driving effect of customer readiness on mandatory behaviour. A total of 181 valid questionnaires were collected from the Taiwanese bed and breakfast sector and analysed by structural equation analysis. The results reveal: (1) the strong impact of customer mandatory behaviour on voluntary behaviour, (2) the partial mediating effect of perceived value on the mandatory-voluntary relationship, and (3) the distinct effects that cooperation has on helping others and word-of-mouth. The findings support the influential roles of customer readiness factors, especially ability, on triggering mandatory behaviour.
Mutations in the transcription factor, KLF1, are common within certain populations of the world. Heterozygous missense mutations in KLF1 mostly lead to benign phenotypes, but a heterozygous mutation ...in a DNA-binding residue (E325K in human) results in severe Congenital Dyserythropoietic Anemia type IV (CDA IV); i.e. an autosomal-dominant disorder characterized by neonatal hemolysis.
To investigate the biochemical and genetic mechanism of CDA IV, we generated murine erythroid cell lines that harbor tamoxifen-inducible (ER™) versions of wild type and mutant KLF1 on a Klf1
genetic background. Nuclear translocation of wild type KLF1 results in terminal erythroid differentiation, whereas mutant KLF1 results in hemolysis without differentiation. The E to K variant binds poorly to the canonical 9 bp recognition motif (NGG-GYG-KGG) genome-wide but binds at high affinity to a corrupted motif (NGG-GRG-KGG). We confirmed altered DNA-binding specificity by quantitative in vitro binding assays of recombinant zinc-finger domains. Our results are consistent with previously reported structural data of KLF-DNA interactions. We employed 4sU-RNA-seq to show that a corrupted transcriptome is a direct consequence of aberrant DNA binding.
Since all KLF/SP family proteins bind DNA in an identical fashion, these results are likely to be generally applicable to mutations in all family members. Importantly, they explain how certain mutations in the DNA-binding domain of transcription factors can generate neomorphic functions that result in autosomal dominant disease.
Abstract The role of Group X secreted phospholipase A2 (GX-sPLA2 ) during influenza infection has not been previously investigated. We examined the role of GX-sPLA2 during H1N1 pandemic influenza ...infection in a GX-sPLA2 gene targeted mouse (GX−/− ) model and found that survival after infection was significantly greater in GX−/− mice than in GX+/+ mice. Downstream products of GX-sPLA2 activity, PGD2 , PGE2 , LTB4 , cysteinyl leukotrienes and Lipoxin A4 were significantly lower in GX−/− mice BAL fluid. Lung microarray analysis identified an earlier and more robust induction of T and B cell associated genes in GX−/− mice. Based on the central role of sPLA2 enzymes as key initiators of inflammatory processes, we propose that activation of GX-sPLA2 during H1N1pdm infection is an early step of pulmonary inflammation and its inhibition increases adaptive immunity and improves survival. Our findings suggest that GX-sPLA2 may be a potential therapeutic target during influenza.
Abstract Background/Purpose Thyroidectomy is the primary therapy for thyroid cancer and an established treatment of hyperthyroidism. Because of the relative rarity of these conditions in childhood, ...few single-institution series exist in the pediatric literature. Here we analyze our institution's experience to assess patient demographics, operative risks, and the role of preoperative testing. Methods This is a retrospective chart review of 175 consecutive patients not older than 18 years who underwent thyroid surgery at Children's Hospital Boston from 1970 to 2004. Results The most common indication for thyroidectomy was thyroid nodules (83%), followed by hyperthyroidism (7%) and goiter (7%). For children referred for nodules, we observed a peak incidence in adolescence and a female to male ratio of 3.7:1. Cancer was found in 36%, with papillary thyroid cancer the most common subtype (85%). Operative complications were rare, with permanent hypocalcemia in 2 (4.7%) of 43 patients who underwent bilateral resection for thyroid nodules (no cases of permanent hypocalcemia in other procedures). Permanent unilateral vocal cord paralysis was documented in 2 children after the resection of malignant nodules. Conclusions Pediatric thyroidectomy can be performed with low operative risk. Because permanent hypocalcemia remains an obligate risk of bilateral thyroidectomy, we recommend the routine use of preoperative fine-needle aspiration to guide the extent of initial surgical resection, reserving near-total thyroidectomy for those cases where cytology is positive for malignancy.
Background
Right ventricular (RV) function is tightly coupled to afterload, yet echocardiographic indices of RV function are frequently assessed in isolation. Normalizing RV function for afterload ...(RV-PA coupling) using a simplified ratio of tricuspid annular plane systolic excursion (TAPSE)/ tricuspid regurgitant velocity (TRV) could help to identify RV decompensation and improve risk stratification in critically ill patients. This is the first study to explore the distribution of TAPSE/TRV ratio and its prognostic relevance in a large general critical care cohort.
Methods
We undertook retrospective analysis of echocardiographic, clinical, and mortality data of intensive care unit (ICU) patients between January 2012 and May 2017. A total of 1077 patients were included and stratified into tertile groups based on TAPSE/TRV ratio: low (< 5.9 mm.(m/s)
−1
), middle (≥ 5.9–8.02 mm.(m/s)
−1
), and high (≥ 8.03 mm.(m/s)
−1
). The distribution of the TAPSE/TRV ratio across ventricular function subtypes of normal, isolated left ventricular (LV), isolated RV, and biventricular dysfunction was explored. The overall prognostic relevance of the TAPSE/TRV ratio was tested, including distribution across septic, cardiovascular, respiratory, and neurological subgroups.
Results
Higher proportions of ventricular dysfunctions were seen in low TAPSE/TRV tertiles. TAPSE/TRV ratio is impacted by LV systolic function but to a lesser extent than RV dysfunction or biventricular dysfunction. There was a strong inverse relationship between TAPSE/TRV ratio and survival. After multivariate analysis, higher TAPSE/TRV ratios (indicating better RV-PA coupling) were independently associated with lower risk of death in ICU (HR 0.927 0.872–0.985,
p
< 0.05). Kaplan–Meier analysis demonstrated higher overall survival in middle and high tertiles compared to low tertiles (log rank
p
< 0.0001). The prognostic relevance of TAPSE/TRV ratio was strongest in respiratory and sepsis subgroups. Patients with TAPSE/TRV < 5.9 mm (m/s)
−1
had a significantly worse prognosis than those with higher TAPSE/TRV ratios.
Conclusion
The TAPSE/TRV ratio has prognostic relevance in critically ill patients. The prognostic power may be stronger in respiratory and septic subgroups. Larger prospective studies are needed to investigate the role of TAPSE/TRV in pre-specified subgroups including its role in clinical decision-making.
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