Essential but partially redundant roles for POU4F1/Brn-3a and POU4F2/Brn-3b transcription factors in the developing heart

Congenital heart defects contribute to embryonic or neonatal lethality but due to the complexity of cardiac development, the molecular changes associated with such defects are not fully understood. Here, we report that transcription factors (TFs) Brn-3a (POU4F1) and Brn-3b (POU4F2) are important for normal cardiac development. Brn-3a directly represses Brn-3b promoter in cardiomyocytes and consequently Brn-3a knockout (KO) mutant hearts express increased Brn-3b mRNA during mid-gestation, which is linked to hyperplastic growth associated with elevated cyclin D1, a known Brn-3b target gene. However, during late gestation, Brn-3b can cooperate with p53 to enhance transcription of pro-apoptotic genes e.g. Bax, thereby increasing apoptosis and contribute to morphological defects such as non-compaction, ventricular wall/septal thinning and increased crypts/fissures, which may cause lethality of Brn-3a KO mutants soon after birth. Despite this, early embryonic lethality in e9.5 double KO (Brn-3a(-/-) : Brn-3b(-/-)) mutants indicate essential functions with partial redundancy during early embryogenesis. High conservation between mammals and zebrafish (ZF) Brn-3b (87%) or Brn-3a (76%) facilitated use of ZF embryos to study potential roles in developing heart. Double morphant embryos targeted with morpholino oligonucleotides to both TFs develop significant cardiac defects (looping abnormalities and valve defects) suggesting essential roles for Brn-3a and Brn-3b in developing hearts

POU4F2/Brn-3b transcription factor is associated with survival and drug resistance in human ovarian cancer cells

The development of drug resistance following treatment with chemotherapeutic agents such as cisplatin (cis) and paclitaxel (pax) contributes to high morbidity and mortality in ovarian cancers. However, the molecular mechanisms underlying such changes are not well understood. In this study, we demonstrate that the Brn-3b transcription factor was increased in different ovarian cancer cells including SKOV3 and A2780 following treatment with cis and pax. Furthermore, sustained increases in Brn-3b were associated with survival in drug resistant cells and correlated with elevated HSP27 expression. In contrast, targeting Brn-3b for reduction using short interfering RNA (siRNA) also resulted in attenuated HSP27 expression. Importantly, blocking Brn-3b expression with siRNA in SKOV3 cells was associated with reduced cell numbers at baseline but also increased cell death after further treatment, indicating sensitization of cells. Similar results were obtained in the metastatic IP1 cell line derived from ascites of mice bearing SKOV3 tumours. These findings suggest that increased Brn-3b may confer resistance to chemotherapeutic drugs in ovarian cancer cells by regulating key target genes such as HSP27 and that targeting Brn-3b may provide a novel mechanism for treatment of drug resistant ovarian cancers

Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion

Background Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. Methods Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single-blind basis. Follow-up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. Results The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P = 0.008). No significant between- group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. Conclusions Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects.</p

Nitrogen Deposition Reduces Plant Diversity and Alters Ecosystem Functioning: Field-Scale Evidence from a Nationwide Survey of UK Heathlands

Findings from nitrogen (N) manipulation studies have provided strong evidence of the detrimental impacts of elevated N deposition on the structure and functioning of heathland ecosystems. Few studies, however, have sought to establish whether experimentally observed responses are also apparent under natural, field conditions. This paper presents the findings of a nationwide field-scale evaluation of British heathlands, across broad geographical, climatic and pollution gradients. Fifty two heathlands were selected across an N deposition gradient of 5.9 to 32.4 kg ha−1 yr−1. The diversity and abundance of higher and lower plants and a suite of biogeochemical measures were evaluated in relation to climate and N deposition indices. Plant species richness declined with increasing temperature and N deposition, and the abundance of nitrophilous species increased with increasing N. Relationships were broadly similar between upland and lowland sites, with the biggest reductions in species number associated with increasing N inputs at the low end of the deposition range. Both oxidised and reduced forms of N were associated with species declines, although reduced N appears to be a stronger driver of species loss at the functional group level. Plant and soil biochemical indices were related to temperature, rainfall and N deposition. Litter C:N ratios and enzyme (phenol-oxidase and phosphomonoesterase) activities had the strongest relationships with site N inputs and appear to represent reliable field indicators of N deposition. This study provides strong, field-scale evidence of links between N deposition - in both oxidised and reduced forms - and widespread changes in the composition, diversity and functioning of British heathlands. The similarity of relationships between upland and lowland environments, across broad spatial and climatic gradients, highlights the ubiquity of relationships with N, and suggests that N deposition is contributing to biodiversity loss and changes in ecosystem functioning across European heathlands

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

RADIUS Authentication in wireless lab environment

The aim of the thesis was to learn and research the development of the Wi-Fi access control methods. This topic will be covered in a chronological order starting from old open-access networks ending to modern methods used today. The practical aim of the study is to implement network access control with an external RADIUS server and to create a RADIUS lab for students. This method has two main advantages. The use of the external server provides a possibility to use one database for many devices like access points and routers. Resources used for this thesis are MB316 classroom access points, hubs, computers and virtual machines of Mikkeli University of Applied Sciences. In the beginning of the study, the theoretical foundation for the study is created with a literature review on authentication, authorization and accounting in Wireless Local Area Networks (WLANs). In the practical part of the study, I implement three different forms of wireless centralized authentication. These forms were autonomous access point RADIUS, Medium business RADIUS setup in Windows server environment and Enterprise RADIUS setup in Windows server environment The findings of the study suggest that autonomous access point solution is no longer a valid method even in small environments because it is not supported in Windows 10 operating system. The server-based solutions either implemented with one or multiple servers are the best for centralized user au-thentication management and access control

The POU4F2/Brn-3b transcription factor is required for the hypertrophic response to angiotensin II in the heart

Adult hearts respond to increased workload such as prolonged stress or injury, by undergoing hypertrophic growth. During this process, the early adaptive responses are important for maintaining cardiac output whereas at later stages, pathological responses such as cardiomyocyte apoptosis and fibrosis cause adverse remodelling, that can progress to heart failure. Yet the factors that control transition from adaptive responses to pathological remodelling in the heart are not well understood. Here we describe the POU4F2/Brn-3b transcription factor (TF) as a novel regulator of adaptive hypertrophic responses in adult hearts since Brn-3b mRNA and protein are increased in angiotensin-II (AngII) treated mouse hearts with concomitant hypertrophic changes [increased heart weight:body weight (HW:BW) ratio]. These effects occur specifically in cardiomyocytes because Brn-3b expression is increased in AngII-treated primary cultures of neonatal rat ventricular myocytes (NRVM) or foetal heart-derived H9c2 cells, which undergo characteristic sarcomeric re-organisation seen in hypertrophic myocytes and express hypertrophic markers, ANP/βMHC. The Brn-3b promoter is activated by known hypertrophic signalling pathways e.g. p42/p44 mitogen-activated protein kinase (MAPK/ERK1/2) or calcineurin (via NFAT). Brn-3b target genes, e.g. cyclin D1, GLUT4 and Bax, are increased at different stages following AngII treatment, supporting distinct roles in cardiac responses to stress. Furthermore, hearts from male Brn-3b KO mutant mice display contractile dysfunction at baseline but also attenuated hypertrophic responses to AngII treatment. Hearts from AngII-treated male Brn-3b KO mice develop further contractile dysfunction linked to extensive fibrosis/remodelling. Moreover, known Brn-3b target genes, e.g. GLUT4, are reduced in AngII-treated Brn-3b KO hearts, suggesting that Brn-3b and its target genes are important in driving adaptive hypertrophic responses in stressed hear