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Advances in digital technology enable organisations to engage in two-way, dialogic communication for improved connectivity with stakeholders. However, the willingness of organisations to leverage on such forms of communication is questionable, particularly in relation to communicating about a crisis. In this article, we examine the corporate web communication practices of Tabung Haji, a corporation plagued by allegations of financial mismanagement. Drawing on a framework for assessing effective corporate communication, we examined the corporate web disclosure practices of the organisation as manifested in its website and Facebook page. While there was evidence of opportunities for dialogic communication with stakeholders, the analysis revealed that efficient communication was compromised because the organisation continued to practice strategic silencing and selective disclosure of information. As such, relational connectivity was weak, and there appeared to be a reluctance to leverage on text-external features offered by web communication to mitigate reputational risk.

Sustainability reporting is essential to demonstrate commitment, transparency, and competitive advantage. This study aims to assess the relationship between environmental, social and governance (ESG) factors and firm performance by using firm value (i.e., Tobin's Q) and firm profitability (ROA), and to what extent the practice of continuously and voluntarily disclosures sustainability activities impacts firm performance. This study utilises the dataset of 47 companies that were listed on the FTSE4G Bursa Malaysia from 2014 to 2017. The findings indicate that there is no significant relationship between ESG factors and firm value as well as firm profitability of companies that continuously issued sustainability reports. However, the result reveals that there is a significant and positive relationship between ESG factors and firm value for companies that continuously listed on the FTSE4G Bursa Malaysia. This implies that the companies have gained a good reputation and competitive advantage, regardless of whether they issued sustainability reports annually. The outcomes of this study will be useful for the sustainable reporting of Malaysian companies.

Microglia are implicated as primarily detrimental in pain models; however, they exist across a continuum of states that contribute to homeostasis or pathology depending on timing and context. To clarify the specific contribution of microglia to pain progression, we take advantage of a temporally controlled transgenic approach to transiently deplete microglia. Unexpectedly, we observe complete resolution of pain coinciding with microglial repopulation rather than depletion. We find that repopulated mouse spinal cord microglia are morphologically distinct from control microglia and exhibit a unique transcriptome. Repopulated microglia from males and females express overlapping networks of genes related to phagocytosis and response to stress. We intersect the identified mouse genes with a single-nuclei microglial dataset from human spinal cord to identify human-relevant genes that may ultimately promote pain resolution after injury. This work presents a comprehensive approach to gene discovery in pain and provides datasets for the development of future microglial-targeted therapeutics.

The transition from acute-to-chronic pain is important because underlying mechanisms may reveal targets for the treatment of chronic pain. Spinal cord microglial activation results from persistent neuronal hyperexcitability, and this can trigger feedforward synaptic plasticity that contributes to chronic pain. We used a targeted, inducible genetic microglial depletion strategy in the clinically relevant tibial fracture/casting model of complex regional pain syndrome (CRPS) to interrogate the contribution of microglia to pain progression. When microglia were transiently depleted at the acute-to-chronic phase transition, we observed complete resolution of established mechanical sensitivity which coincided with the timeframe of full repopulation of microglia. These repopulated microglia were morphologically distinct from control microglia, suggesting they may exhibit a unique transcriptome. We studied this transcriptome by RNA-sequencing FACS-isolated microglia and utilizing a combination of Deseq2 and weighted gene co-expression network analysis (WGCNA) to identify networks of genes contributing to the pain resolution. Overall, transcriptome analysis characterized repopulated microglia as highly active, phagocytic cells, that survey and respond to their environment in the context of injury. Microglial targets identified in the mouse pain resolution context were further validated in human dorsal-horn, lumbar spinal cord microglia nuclei. Overlap with the human dataset revealed targets with high translational potential. R35 GM127906. Foundation for Anesthesia Education and Research (FAER) Mentored Research Training Grant. Rita Allen Foundation Award in Pain. Department of Anesthesiology, Perioperative & Pain Medicine at Stanford University.

This article examines rhetorical strategies as well as the linguistic construction of those strategies in press releases put out by Cadbury Malaysia in response to accusations that it has failed to comply with halal certification standards. Drawing on image repair theory and the concept of the ideological square, six press releases were analysed to identify the rhetorical strategies as well as semantic structures that were used to repair the organization’s image and minimize reputational risk. The analysis reveals how the organization moved beyond denial to also employ the rhetorical strategies of attacking one’s accuser and bolstering. Despite early media reports naming government agencies as the accusers, the press releases put out by Cadbury Malaysia determined the source of accusations as unnamed individuals within the agencies, thereby avoiding confrontations with the relevant authorities. The analysis shows how language is used in press releases to construct the positive self and negative other as Cadbury Malaysia promoted a discourse of renewal to reassert its position within a highly lucrative halal market. This article provides novel insights into understanding how language works within rhetorical strategies of image repair.

To review the clinical and biochemical characteristics and clinical outcome of patients presenting with pituitary apoplexy to a tertiary centre.We retrospectively reviewed the clinical features, predisposing factors, biochemistry and clinical outcome of patients presenting with pituitary apoplexy to Imperial College Healthcare NHS Trust between 1991 and 2015.We identified 64 patients with pituitary apoplexy (more complete clinical records were available in 52 patients). The median age at presentation was 46.7 years (IQR 31.5–57.0 years). Pituitary apoplexy was the first presentation of pituitary disease in 38/52 of patients and predisposing factors were identified in 28/52. Pituitary apoplexy predominantly occurred in patients with non-functioning pituitary adenomas (47/52). Headache was most commonly described as sudden onset, severe, lateralising to the frontal or temporal regions. Symptoms of meningeal irritation were reported in 7/18 and visual abnormalities in 22/35. A pre-treatment serum cortisol <100 nmol/L was recorded in 12/31 of patients. All patients with visual disturbance had some resolution of their visual symptoms whether managed surgically (14/14) or conservatively (5/5), although pituitary endocrine function did not fully recover in any patient.In conclusion, these data describe the clinical features of pituitary apoplexy to aid the clinician in diagnosing this rare emergency presentation of pituitary disease. Prospective multicentre studies of the presentation of pituitary apoplexy are required to further characterise presentation and outcomes.

Introduction:BMPR2mutation is the most common genetic cause of pulmonary arterial hypertension (PAH). Loss of BMPR2causes pulmonary arterial (PA) endothelial cell (EC) dysfunction and impairs EC-mediated suppression of smooth muscle cells proliferation. These are characteristic features of PAH vascular cells as is the presence of DNA damage that can be induced by oxidative stress. We previously showed that EC-Bmpr2-/-mice have persistent pulmonary hypertension (PH) with reoxygenation after hypoxia. However, the role of DNA damage in causing persistent PH related to loss of BMPR2 and oxidative stress is unknown.Hypothesis:We hypothesize that loss of BMPR2 causes unrepaired DNA damage and persistent PH by altering the expression of genes that maintain EC homeostasis.Methods and Results:DNA damage assessed by γH2AX foci was observed in PAEC of EC-Bmpr2-/-mice in room air, that was more extensive after reoxygenation (10% hypoxia for 3 weeks followed by recovery in room-air for 4 weeks). Deletion of the DNA damage sensor ataxia-telangiectasia mutated (ATM) in EC of mice (EC-Atm-/-) also resulted in persistent DNA damage and PH. RNA sequencing of PAEC after reoxygenation in EC-Bmpr2-/-and EC-Atm-/-mice vs. controls showed downregulated EC differentiation and development genes enriched in biding motifs for Foxf1, atranscription factor associated with DNA repair and angiogenesis. Foxf1expression was reduced in PAEC with loss of BMPR2 or ATM. Loss of Foxf1decreased angiogenic genes Cldn5and Vegfr2, and DNA damage response genes Atmand p53, and impaired PAEC migration and tube formation. Foxf1overexpression increased these genes in PAEC. Immunohistochemistry showed decreased FOXF1 in PAEC of human pulmonary vascular lesions. Delivery of Foxf1to EC-Bmpr2-/-mice with an AAV2-peptide targeting the PA endothelium attenuated DNA damage in PAEC, restored angiogenesis genes and completely reversed persistent PH returning right ventricular systolic pressure to normal levels.Conclusions:We link loss of BMPR2 and DNA damage sensing in PAEC to persistent DNA damage and PAH and show that both are mediated by reduced FOXF1. In EC-Bmpr2-/-mice, Foxf1gene therapy attenuated DNA damage restored angiogenesis genes, and prevented persistent PH.

Normal stem cells from a variety of tissues display unique metabolic properties compared to their more differentiated progeny. However, relatively little is known about metabolic properties of cancer stem cells, also called tumor initiating cells (TICs). In this study we show that, analogous to some normal stem cells, breast TICs have distinct metabolic properties compared to nontumorigenic cancer cells (NTCs). Transcriptome profiling using RNA‐Seq revealed TICs underexpress genes involved in mitochondrial biology and mitochondrial oxidative phosphorylation, and metabolic analyses revealed TICs preferentially perform glycolysis over oxidative phosphorylation compared to NTCs. Mechanistic analyses demonstrated that decreased expression and activity of pyruvate dehydrogenase (Pdh), a key regulator of oxidative phosphorylation, plays a critical role in promoting the proglycolytic phenotype of TICs. Metabolic reprogramming via forced activation of Pdh preferentially eliminated TICs both in vitro and in vivo. Our findings reveal unique metabolic properties of TICs and demonstrate that metabolic reprogramming represents a potential therapeutic strategy for targeting these cells. StemCells2014;32:1734–1745

Follicular lymphoma (FL) is currently incurable using conventional chemotherapy or immunotherapy regimes, compelling new strategies. Advances in high-throughput sequencing technologies that can reveal oncogenic pathways have stimulated interest in tailoring therapies toward actionable somatic mutations. However, for mutation-directed therapies to be most effective, the mutations must be uniformly present in evolved tumor cells as well as in the self-renewing tumor-cell precursors. Here, we show striking intratumoral clonal diversity within FL tumors in the representation of mutations in the majority of genes as revealed by whole exome sequencing of subpopulations. This diversity captures a clonal hierarchy, resolved using immunoglobulin somatic mutations and IGH-BCL2 translocations as a frame of reference and by comparing diagnosis and relapse tumor pairs, allowing us to distinguish early versus late genetic eventsduring lymphomagenesis. We provide evidence that IGH-BCL2 translocations and CREBBP mutations are early events, whereas MLL2 and TNFRSF14 mutations probably represent late events during disease evolution. These observations provide insight into which of the genetic lesions represent suitable candidates for targeted therapies.

Policy‐makers have described the many potential benefits that biofuels can provide, but there are numerous challenges in realizing this potential. The technical hurdles to producing biofuels economically and on a scale to replace a significant fraction of petroleum‐based transportation fuels have been well described, along with the potential environmental concerns. The use of biotechnology can potentially address many of these technical challenges and environmental concerns, but brings significant regulatory obstacles that have not been discussed extensively in the scientific community. This review will give an overview of some of the approaches being developed to produce transgenic biofuel feedstocks, particularly cellulosic ethanol, and the regulatory process in the United States that oversees the introduction of new transgenic plants. We hope to illustrate that the level of regulation for transgenic organisms is not proportional to their potential risk to human health or to the environment, and that while revisions to the regulatory system in the USA are currently under consideration, further modifications are necessary to reflect the risk level of transgenic crops and realize their benefits. © 2009 Society of Chemical Industry and John Wiley & Sons, Ltd

Nedd4-2 has been proposed to play a critical role in regulating epithelial Na+channel (ENaC) activity. Biochemical and overexpression experiments suggest that Nedd4-2 binds to the PY motifs of ENaC subunits via its WW domains, ubiquitinates them, and decreases their expression on the apical membrane. Phosphorylation of Nedd4-2 (for example by Sgk1) may regulate its binding to ENaC, and thus ENaC ubiquitination. These results suggest that the interaction between Nedd4-2 and ENaC may play a crucial role in Na+homeostasis and blood pressure (BP) regulation. To test these predictions in vivo, we generated Nedd4-2null mice. The knockout mice had higher BP on a normal diet and a further increase in BP when on a high-salt diet. The hypertension was probably mediated by ENaC overactivity because 1) Nedd4-2null mice had higher expression levels of all three ENaC subunits in kidney, but not of other Na+transporters; 2) the downregulation of ENaC function in colon was impaired; and 3) NaCl-sensitive hypertension was substantially reduced in the presence of amiloride, a specific inhibitor of ENaC. Nedd4-2null mice on a chronic high-salt diet showed cardiac hypertrophy and markedly depressed cardiac function. Overall, our results demonstrate that in vivo Nedd4-2 is a critical regulator of ENaC activity and BP. The absence of this gene is sufficient to produce salt-sensitive hypertension. This model provides an opportunity to further investigate mechanisms and consequences of this common disorder.

Background:Renal abnormalities discovered in the elderly have often been considered the result of aging, hypertensive changes, and so on. Recently, we noted an increase in renal biopsies among patients 80 years and older. This is a demographic subset with little or no previously reported clinicopathologic correlation between renal biopsy findings and clinical syndromes. Methods:We examined our files for all biopsies performed in patients 80 years and older and report 100 patients of a total of 3,227 biopsies (3.1%) from multiple referral centers. Results:Significant differences in the disease spectrum were found in the very elderly, not only compared with studies of adults and children, but also compared with studies of renal biopsies in the elderly. Crescentic glomerulonephritis was the most common diagnosis in patients aged 80 years and older. Although membranous glomerulopathy is the most common cause of idiopathic nephrotic syndrome in studies of the elderly (23% to 38%) and adults (35% to 40%), only 15% of our patients aged 80 years and older with idiopathic nephrotic syndrome had membranous nephropathy. Overall, at least 40 of 100 biopsies performed on the very elderly showed a renal condition that would benefit from therapeutic intervention, and the remaining biopsies provided at least prognostic information and/or ruled out a more severe condition, preventing potentially harmful empiric therapy. Conclusion:As the population ages, more elderly patients are undergoing diagnostic renal biopsies. This study emphasizes the variance between clinical presentation and expected diagnosis compared with actual biopsy findings in patients aged 80 years and older.

Background/Aims:We examined the correlations between renal biopsy findings in Wegener’s granulomatosis and renal function at baseline and 1 year in 22 patients who presented between 1988 and 1999. Methods:Renal histology was independently reviewed by 2 pathologists who were masked to the clinical data. The primary outcome was the relationship of the percentage of normal glomeruli to reciprocal serum creatinine at baseline and 1 year. Other histologic data were collected using a series of ordinal rating scales. Acute and chronic sum scores were calculated. Results:The median serum creatinine (SCr) at baseline was 3.9 mg/dl (0.8–14 mg/dl). Seven patients initially required hemodialysis, of whom 4 subsequently regained independent renal function. By 1 year of follow-up, the median (SCr) for patients with independent renal function was 1.9 mg/dl (0.9–6.8 mg/dl). Reciprocal SCr at baseline correlated with the percentage of normal glomeruli (r = 0.584, p = 0.005), crescent score (r = –0.595, p = 0.003), interstitial fibrosis as a percentage of cortical surface area (r = –0.669, p = 0.002), interstitial inflammation (r = –0.439, p = 0.041), eosinophil (r = –0.495, p = 0.019), neutrophil score (r = –0.557, p = 0.005), and acute sum score (r = –0.499, p = 0.018). However, only the percentage of normal glomeruli (r = 0.493, p = 0.023), the crescent score (r = –0.452, p = 0.035), and interstitial fibrosis as a percentage of cortical surface area (r = –0.466, p = 0.052) correlated with reciprocal SCr at 1 year of follow-up. Conclusion:In this relatively small data set, the percentage of normal glomeruli, the crescent score, and interstitial fibrosis as a percentage of cortical surface area correlated with renal function at both baseline and 1 year of follow-up.

The general phenylpropanoid pathways generate a wide array of aromatic secondary metabolites that range from monolignols, which are ubiquitous in all plants, to sinapine, which is confined to crucifer seeds. The biosynthesis of these compounds involves hydroxylated and methoxylated cinnamyl acid, aldehyde, or alcohol intermediates. Of the three enzymes originally proposed to hydroxylate the 4-, 3-, and 5-positions of the aromatic ring, cinnamate 4-hydroxylase (C4H), which converts trans-cinnamic acid to p-coumaric acid, is the best characterized and is also the archetypal plant P450 monooxygenase. Ferulic acid 5-hydroxylase (F5H), a P450 that catalyzes 5-hydroxylation, has also been studied, but the presumptive 3-hydroxylase converting p-coumarate to caffeate has been elusive. We have found that Arabidopsis CYP98A3, also a P450, could hydroxylate p-coumaric acid to caffeic acid in vivo when expressed in yeast (Saccharomyces cerevisiae) cells, albeit very slowly. CYP98A3 transcript was found in Arabidopsis stem and silique, resembling both C4H and F5H in this respect. CYP98A3 showed further resemblance to C4H in being highly active in root, but differed from F5H in this regard. In transgenic Arabidopsis, the promoters of CYP98A3 and C4H showed wound inducibility and a comparable developmental regulation throughout the life cycle, except in seeds, where the CYP98A3 promoter construct was inactive while remaining active in silique walls. Within stem and root tissue, the gene product and the promoter activity of CYP98A3 were most abundant in lignifying cells. Collectively, these studies show involvement of CYP98A3 in the general phenylpropanoid metabolism, and suggest a downstream function for CYP98A3 relative to the broader and upstream role of C4H.

Successful therapeutic targeting of genetic lesions in cancer generally requires that such lesions be clonally dominant and uniformly represented. The commonest indolent non-Hodgkin's lymphoma (NHL) subtype, Follicular lymphoma (FL), is currently incurable with conventional regimes and is therefore an attractive candidate for targeted therapies. Our prior studies[1] and studies by others[2],[3] have shown that clinically significant variation in patient outcomes can be captured by differences in expression of CD20 both between tumor B-cells and between patients with NHL treated with or without rituximab. We hypothesized that a hierarchy of somatic mutations might exist in FL, and could impact the opportunity for future mutation-directed therapies in this disease.Here, we examined clonal diversity in human Follicular Lymphoma (FL) using tumor subpopulations at diagnosis and at disease progression, through a genetic analysis of coding genomes and gene expression. We profiled whole-exomes and transcriptomes of 26 tumor-derived subpopulations sorted based on expression of CD20 in 10 lymphomas derived from 8 patients, including pairs at diagnosis and first disease relapse (mean exome coverage per patient >200x). We used phylogenies derived from ongoing somatic hypermutation of cloned immunoglobulin VH genes at diagnosis and relapse as a framework for comparing mutational hierarchies across the coding genome. We employed qPCR of invariant BCL2 and VDJ recombination to quantitate tumor purity in subpopulations.We identified 882 somatic nucleotide variants (SNVs) encoding missense and nonsense mutations in 572 unique genes, with an average of 103 mutations/case, with 95% of mutations seen in only 1 case. Mutated genes were significantly enriched for those involved in chromosome and chromatin organization (FDR=4.07×10-4 and FDR=6.40×10-4, respectively). We identified mutations in many of the genes previously implicated in lymphomas, including MLL2 and CREBBP, and in several genes not previously implicated in lymphomas including IKZF2, CD40, CALR, NBPF14, ROS1 and ERBB2.We observed 11–343 nonsynonymous coding mutations per tumor, with a striking tendency for most of these to be subclonal based on their low allelic variant frequencies (Figure 1). Many of these mutations were differentially distributed between tumor subpopulations which were evident both at diagnosis and at relapse. In addition, mutations in these populations were associated with distinct gene expression profiles. Surprisingly, subclonal distribution of mutations occurred in several genes which are known to be highly recurrently mutated in FL and thought to be drivers of pathogenesis. With rare exception, the frequency of mutation within a given gene across 375 patients with NHL studied by high throughput sequencing (FL=24, DLBCL=158, CLL=193) correlated poorly with clonal dominance within individual FL tumors in this study. By using immunoglobulin somatic mutations and BCL2 translocations as a frame of reference and by comparing diagnosis and relapse tumor pairs, we could distinguish early versus late somatic events during tumor evolution. We observed two contrasting patterns of clonal evolution, reflecting either maintenance or loss of most mutations at relapse. These two patterns were also mirrored by maintenance or loss of DNA copy number alterations in the respective cases.These observations allow construction of genetic evolution models for FL. This framework provides important insight into lymphomagenesis and is a key step in prioritization of candidates for gene mutation-directed therapies.No relevant conflicts of interest to declare.