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As the UK's Chartered Institute of Ergonomics and Human Factors (CIEHF) celebrates its 75th anniversary, it is worth reflecting on our discipline's contribution, current state, and critical future endeavours. We present the perspectives of 18 EHF professionals who were asked to respond to five questions regarding the impact of EHF, contemporary challenges, and future directions. Co-authors were in agreement that EHF's impact has been only limited to date and that critical issues require resolution, such as increasing the number of suitably qualified practitioners, resolving the research-practice gap, and increasing awareness of EHF and its benefits. Frequently discussed future directions include advanced emerging technologies such as artificial intelligence, the development of new EHF methods, and enhancing the quality and reach of education and training. The majority felt there will be a need for EHF in 75 years; however, many noted that our methods will need to adapt to meet new needs. Practitioner statement: This article provides the perspectives of 18 Ergonomics and Human Factors (EHF) professionals on the impact of EHF, contemporary challenges and critical future directions, and changes that are necessary to ensure EHF remains relevant in future. As such, it provides important guidance on future EHF research and practice.

Myofibroblast differentiation, essential for driving extracellular matrix synthesis in pulmonary fibrosis, requires increased glycolysis. While glycolytic cells must export lactate, the contributions of lactate transporters to myofibroblast differentiation are unknown. In this study, we investigated how MCT1 and MCT4, key lactate transporters, influence myofibroblast differentiation and experimental pulmonary fibrosis. Our findings reveal that inhibiting MCT1 or MCT4 reduces TGFβ-stimulated pulmonary myofibroblast differentiation in vitro and decreases bleomycin-induced pulmonary fibrosis in vivo . Through comprehensive metabolic analyses, including bioenergetics, stable isotope tracing, metabolomics, and imaging mass spectrometry in both cells and mice, we demonstrate that inhibiting lactate transport enhances oxidative phosphorylation, reduces reactive oxygen species production, and diminishes glucose metabolite incorporation into fibrotic lung regions. Furthermore, we introduce VB253, a novel MCT4 inhibitor, which ameliorates pulmonary fibrosis in both young and aged mice, with comparable efficacy to established antifibrotic therapies. These results underscore the necessity of lactate transport for myofibroblast differentiation, identify MCT1 and MCT4 as promising pharmacologic targets in pulmonary fibrosis, and support further evaluation of lactate transport inhibitors for patients for whom limited therapeutic options currently exist., Competing Interests: W.M.O. has received consulting fees from Nikang Therapeutics outside the scope of this research.J.R. is a consultant and shareholder for Vettore Biosciences.R.S.K. received a Discovery ILD Award from Boehringer Ingelheim and received support through the Partners Drug Development Lab from Bayer Pharmaceuticals, all outside the scope of this research.E.Y.K. received unrelated research funding from Bayer AG, Roche Pharma Research and Early Development, and 10X Genomics. E.Y.K. has a financial interest in Novartis AG unrelated to this work.B.A.M. has received consulting fees from Actelion and Tenax and has performed investigator-initiated research with support from Deerfield, all outside the scope of this research.L.P.H. reports grants from Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) and has received personal consulting fees from BIPI, Pliant Therapeutics, Clario, and Abbvie Pharmaceuticals.The remaining authors declare that they have no competing interests.

Throughout the coronavirus disease 2019 (COVID-19) pandemic, there have been numerous demands on primary care practices and providers affecting work engagement and burnout, which can affect health-care delivery and patient outcomes. We determined potentially modifiable factors associated with work engagement among employees of federally qualified health centers (FQHCs) throughout Louisiana. Resilient coping, spirituality, and social support were associated with being engaged at work. FQHC employees perceiving a more chaotic work environment and those with depressive or anxiety symptoms were less likely to be engaged at work. Being engaged was associated with confidence in COVID-19 vaccine recommendation for adults., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The Psoriasis Longitudinal Assessment and Registry (PSOLAR) is a global, prospective, longitudinal, disease-based registry. It serves as a post-marketing safety commitment with a focus on patients with moderate to severe plaque psoriasis who are candidates for systemic therapy., Objectives: To describe the baseline disease demographics and clinical characteristics of a Canadian subgroup of participants enrolled in PSOLAR., Methods: Baseline demographic/disease characteristics, medical histories, and previous psoriasis treatments for Canadian patients in PSOLAR were summarized using descriptive statistics., Results: There were 1896 patients analyzed in the Canadian subgroup at 37 clinical sites, accounting for 15.7% of the global PSOLAR population. Baseline disease and clinical characteristics were as expected for a moderate to severe psoriasis population and were generally similar to the global PSOLAR population. Two distinctions were noted in the Canadian subgroup versus those enrolled globally: a higher proportion of patients were overweight/obese (84.7% vs. 80.4%) and male (61.4% vs. 54.7%). In addition, the Canadian subgroup had numerically higher historical peak disease activity (PGA score 3.35 vs. 3.1) and longer disease duration (22.3 years vs. 17.5 years). Canadian PSOLAR patients reported a variety of comorbidities, including psoriatic arthritis (31.5%), hypertension (34.6%), hyperlipidemia (24.3%), mental illness (24.1%), and inflammatory bowel disease (1.6%)., Conclusion: The Canadian subgroup of PSOLAR patients was generally similar to those enrolled globally with respect to baseline disease demographics and clinical characteristics. Multiple comorbidities are noted in the Canadian subgroup, underscoring the need for a holistic approach to the treatment of psoriatic patients., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MJG: Consultant, speaker and/or advisory boards for AbbVie, Akros Pharma, Amgen, Arcutis, Aslan, Aristea, AnaptysBio, Boehringer Ingelheim, BMS, Celgene, Dermira, Dermavant, Eli Lilly and Company, Galderma SA, GSK, Incyte, Janssen, Kyowa Kirin, Leo Pharma, MedImmune, Merck, Moonlake, Meiji, Nimbus, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi Genzyme, and UCB; RB: Advisory Board Member, Consultant, Speaker and/or Investigator for and received honoraria and/or grants from, AbbVie, Alumis, Amgen, AnaptysBio, Bausch Health, Boston, BMS/Celgene, Dermavant, Eli Lilly, Janssen, LEO Pharma, Nimbus, Novartis, Pfizer, Regeneron, UCB, VentyxBio and Xencor. R Bissonnette is also an employee and shareholder of Innovaderm Research; SK: Consultant, speaker or advisory boards for AbbVie, Actelion Pharmaceuticals, Amgen, Boehringer Ingelheim, BMS, Celgene, Eli Lilly and Company, Galderma SA, GSK, Janssen, Leo Pharma, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, UCB, and Valeant Pharmaceutical; KAP: Receive honoraria and/ or clinical research grants as a consultant, speaker, scientific officer, steering committee member, and/or advisory board member for 3M, AbbVie, Akesis, Akros, Alza, Amgen, Astellas, Baxter, Boehringer Ingelheim, Celgene, Centocor, Cipher, Eli Lilly, Forward Pharma, Funxional Therapeutics, Galderma, Glaxo Smith Kline, Isotechnika, Janssen, Janssen Biotech, Kirin, Kyowa, Lypanosys, Merck-Serono, Merck Sharpe Dome, Mitsubishi Pharma, Novartis, Pfizer, Takeda, UCB, Vertex, and/ or Wyeth; LCG: Consultant, speaker, and received grants for clinical research from AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Leo Pharma, Merck, Novartis, Pfizer, and Valeant; speaker and consultant for Aralez; consultant and received grants for clinical research from Bristol-Meyers Squibb, and received grants for clinical research from Boehringer Ingelheim and UCB. WPG: grants/research support from AbbVie, Amgen, Eli Lilly, Novartis, Pfizer; honoraria for ad boards/invited talks/consultation from AbbVie, Actelion, Amgen, Arylide, Bausch Health, Boehringer, Celgene, Cipher, Eli Lilly, Galderma, Janssen, LEO Pharma, Merck, Novartis, PeerVoice, Pfizer, Sanofi-Genzyme, Tribute, UCB, Valeant; and clinical trials (study fees) from AbbVie, Asana Biosciences, Astellas, Boerhinger-Ingleheim, Celgene, Corrona/National Psoriasis Foundation, Devonian, Eli Lilly, Galapagos, Galderma, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron, UCB.>.; VH: Consultant, speaker or advisory boards for Abbvie, Eli Lilly, Janssen, and Novartis; NHS: Consultant for AbbVie, Bausch Medicine, Celgene, Janssen, Leo Pharma, Lilly, Novartis, Sanofi Genzyme; RV: Consultant, speaker and/or advisory boards for AbbVie, Actelion Pharmaceuticals, Amgen, Boehringer Ingelheim, BMS, Celgene, Dermira, Eli Lilly and Company, Galderma SA, GSK, Janssen, Leo Pharma, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, UCB, and Valeant Pharmaceutical; RG: clinical trials for AbbVie, Bausch Health, and Janssen and has received honoraria as consultant and/or speaker from AbbVie, Bausch Health, Eli Lilly, Janssen, Kyowa Kirin, Mallinckrodt, Novartis, Sun Pharma and Sanofi; VHP: Consultant, speaker and/or advisory boards for AbbVie, Actelion, Amgen, AnaptysBio, Aralez, Arcutis, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Eli Lilly, Galderma, GlaxoSmithKline, Homeocan, Incyte, Janssen, LEO Pharma, L’Oreal, Medexus, Novartis, Pediapharm, Pfizer, Sanofi Genzyme, Sun Pharma, Tribute, UCB Pharma, and Valeant; investigator for AbbVie, Amgen, Arcutis, Arena, Asana, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Concert, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Nimbus Lakshmi, Novartis, Pfizer, Regeneron, Reistone, Sanofi Genzyme, UCB Pharma, and Valeant; received educational grants from AbbVie, Bausch Health, Celgene, Janssen, LEO Pharma, Novartis, Sanofi Genzyme, and Valeant; IT: Consultant, speaker or investigator for Abbvie, Amgen, Arcutis, Aristea, Bausch Health, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Kiniksa, LeoPharma, Mallinckrodt, Novartis, Pfizer, Sanofi, SunPharma, UCB; WL, KP, SDS, NA and OL: Employee of either Janssen Research & Development or Janssen Inc. Canada; RA: Consultant, speaker or advisory boards for Abbvie, Amgen, Boehringer Ingelheim, Eli Lilly and Company, Galderma, Janssen, Leo Pharma, Novartis, Pfizer, Sandoz, Sanofi, Sun pharma, and UCB.

Engine damage as a consequence of foreign object debris (FOD) during flight is frequently caused by birds. One approach to minimising disruption caused by this damage is to provide flight crew with accurate information relating to the continuing operational status of the aircraft's engines. Before designing such avionic systems however, understanding of current procedures is needed. Hierarchical Task Analysis (HTA) and Systematic Human Error Reduction and Prediction Approach (SHERPA) were used to identify potential failures that flight crew may make when managing an engine bird strike. Workshops with commercial pilots generated insights into current practice and a commercial pilot SME reviewed outputs for accuracy. Over 200 potential failures were identified, most commonly related to communication. Remedial measures, considering future avionic systems, are proposed to mitigate identified failures. This analysis provides a starting point for future design concepts for assisting flight crew in dealing with engine malfunction due to FOD strikes. Practitioner summary: Hierarchical Task Analysis was conducted to show all tasks involved in dealing with an in-flight aircraft engine bird strike. Systematic Human Error Reduction and Prediction Approach analysis was performed and over 200 possible failures were identified when managing this event. Remedial measures are proposed to help mitigate possible failures.

There have been recent calls for Human Factors and Ergonomics (HFE) to expand its reach and focus to address larger scale societal and global issues. An area of growing awareness is the issue of the gender data gap, whereby women are under-represented in research data, leading to inequitable outcomes when research findings are used to design real world technologies, products, environments, processes, and policies. The aim of this paper is to showcase how structured HFE methods can be used to address the gender data gap. We applied the Sociotechnical Systems Design Toolkit which involved using causal loop diagrams and abstraction hierarchy modelling from Cognitive Work Analysis to understand the system in which the issue occurs and key pain points, followed by the application of the Design with Intent Toolkit to generate design ideas. A total of 43 ideas were developed that could be implemented by universities to address the research data gap. The application demonstrates the utility of HFE methods in tackling complex issues and offers an opportunity for the HFE community to reflect upon the importance of gender sensitive research practices and gender equity more broadly., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Telemedicine has been shown to improve patient access to medical care while potentially improving overall healthcare efficiency. It has not been consistently explored on an acute care surgery service as a method of increasing clinic availability and efficiency within a safety-net hospital system. Socioeconomic hardships associated with an in-person clinic visit can deter patients with limited resources. A virtual clinic for post-operative laparoscopic cholecystectomy patients was developed. We hypothesized that a virtual follow-up increases clinic efficiency and availability for new patients without compromising patient safety., Methods: A retrospective review of patient and clinic outcomes before and after implementing virtual post-op visits for uncomplicated laparoscopic cholecystectomy patients on an acute care surgery service was performed. Providers called post-operative patients using a standardized questionnaire. Data included outpatient clinic composition (new vs. post-operative patients), elective operations scheduled, emergency department visits, and loss to follow-up rates., Results: February to March 2017 was the baseline pre-intervention period, while February to March 2019 was post-intervention. Pre-intervention clinics consisted of 17% new and 50% post-op visits, in comparison to 31% new and 27% post-op visits in the post-intervention group (p < 0.01). Elective operations scheduled increased slightly from 8.4 to 11.5 per 100 patient visits, but was not statistically significant (p = 0.09). There was no change in the number of post-operative patients returning to the emergency department (p = 0.91) or loss to follow-up (p = 0.30) rates., Conclusions: Through the implementation of virtual post-operative visits for laparoscopic cholecystectomy patients, clinic efficiency improved by increasing new patient encounters, decreasing post-operative volume, and trending towards increased operations scheduled. This change did not compromise patient safety. Further implementation of telemedicine on an acute care surgery service is a promising method to expand services offered to an at-risk population and increase efficiency in a resource-limited environment., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that typically causes asymptomatic infection but can promote B lymphoid tumors in the immune suppressed. In vitro, EBV infection of primary B cells stimulates glycolysis during immortalization into lymphoblastoid cell lines (LCLs). Lactate export during glycolysis is crucial for continued proliferation of many cancer cells-part of a phenomenon known as the "Warburg effect"- and is mediated by monocarboxylate transporters (MCTs). However, the role of MCTs has yet to be studied in EBV-associated malignancies, which display Warburg-like metabolism in vitro. Here, we show that EBV infection of B lymphocytes directly promotes temporal induction of MCT1 and MCT4 through the viral proteins EBNA2 and LMP1, respectively. Functionally, MCT1 was required for early B cell proliferation, and MCT4 up-regulation promoted acquired resistance to MCT1 antagonism in LCLs. However, dual MCT1/4 inhibition led to LCL growth arrest and lactate buildup. Metabolic profiling in LCLs revealed significantly reduced oxygen consumption rates (OCRs) and NAD+/NADH ratios, contrary to previous observations of increased OCR and unaltered NAD+/NADH ratios in MCT1/4-inhibited cancer cells. Furthermore, U- 13 C 6 -glucose labeling of MCT1/4-inhibited LCLs revealed depleted glutathione pools that correlated with elevated reactive oxygen species. Finally, we found that dual MCT1/4 inhibition also sensitized LCLs to killing by the electron transport chain complex I inhibitors phenformin and metformin. These findings were extended to viral lymphomas associated with EBV and the related gammaherpesvirus KSHV, pointing at a therapeutic approach for targeting both viral lymphomas., Competing Interests: The authors declare no competing interest.

The metabolic rewiring of cardiomyocytes is a widely accepted hallmark of heart failure (HF). These metabolic changes include a decrease in mitochondrial pyruvate oxidation and an increased export of lactate. We identify the mitochondrial pyruvate carrier (MPC) and the cellular lactate exporter monocarboxylate transporter 4 (MCT4) as pivotal nodes in this metabolic axis. We observed that cardiac assist device-induced myocardial recovery in chronic HF patients was coincident with increased myocardial expression of the MPC. Moreover, the genetic ablation of the MPC in cultured cardiomyocytes and in adult murine hearts was sufficient to induce hypertrophy and HF. Conversely, MPC overexpression attenuated drug-induced hypertrophy in a cell-autonomous manner. We also introduced a novel, highly potent MCT4 inhibitor that mitigated hypertrophy in cultured cardiomyocytes and in mice. Together, we find that alteration of the pyruvate-lactate axis is a fundamental and early feature of cardiac hypertrophy and failure., Competing Interests: Declaration of interests The University of Utah has filed a patent related to the mitochondrial pyruvate carrier, of which J.R. is listed as co-inventor. J.R. is a founder of Vettore Biosciences and a member of its scientific advisory board. K.M.P. is an employee and shareholder of Vettore Biosciences. S.M. was an employee of Vettore Biosciences. S.G.D. is a consultant to Abbott (Steering Committee member of the INTELLECT-2 multicenter trial of LVAD and CardioMEMS). J.R. and S.G.D. are the recipients of a grant from Merck related to mechanisms of HF and myocardial recovery. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Hyperactivation of sterol regulatory element binding protein 1c (SREBP-1c), which transcriptionally induces expression of enzymes responsible for de novo lipogenesis and triglyceride (TG) formation, is implicated in nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) pathogenesis. Posttranslational SREBP-1c maturation and activation is stimulated by the protein per-arnt-sim kinase (PASK). PASK- knockout mice are phenotypically normal on a conventional diet but exhibit decreased hypertriglyceridemia, insulin resistance, and hepatic steatosis on a high-fat diet. We investigated the effects of pharmacologic PASK inhibition using BioE-1115, a selective and potent oral PASK inhibitor, in Zucker fatty ( fa ) /fa) rats, a genetic model of obesity, dyslipidemia, and insulin resistance, and in a dietary murine model of NAFLD/NASH. Female Zucker ( fa/fa ) rats and lean littermate ( fa /+) controls received BioE-1115 (3-100 mg/kg/day) and/or omega-3 fatty acids, and blood glucose, hemoglobin A1c, glucose tolerance, insulin, and serum TG were measured. C57BL/6J mice fed a high-fat/high-fructose diet (HF-HFrD) were treated with BioE-1115 (100 mg/kg/day) or vehicle. Body weight and fasting glucose were measured regularly; serum TG, body and organ weights, and liver TG and histology were assessed at sacrifice. Messenger RNA (mRNA) abundance of SREBP-1c target genes was measured in both models. In Zucker rats, BioE-1115 treatment produced significant dose-dependent reductions in blood glucose, insulin, and TG (all greater than omega-3 fatty acids) and dose dependently restored insulin sensitivity assessed by glucose tolerance testing. In HF-HFrD mice, BioE-1115 reduced body weight, liver weight, fasting blood glucose, serum TGs, hepatic TG, hepatic fibrosis, hepatocyte vacuolization, and bile duct hyperplasia. BioE-1115 reduced SREBP-1c target mRNA transcripts in both models. Conclusion: PASK inhibition mitigates many adverse metabolic consequences associated with an HF-HFrD and reduces hepatic fat content and fibrosis. This suggests that inhibition of PASK is an attractive therapeutic strategy for NAFLD/NASH treatment., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.)

We analyse the impact of ship traffic in the vicinity of navigation channels in a wide shallow waterbody. The crucial hydrodynamic driver in this situation is the depression (Bernoulli) wake that may be transferred into a long-living solitary wave of depression over the shoals. The analysis considers navigation channels in the Venice Lagoon using a new large dataset of approximately 600 measured wake events associated to specific ships whose data are provided by the AIS system. Since the development of the modern industrial port and the opening of the Malamocco-Marghera channel in the late 1960s, growing pressure on the lagoon caused by ship traffic has raised concerns about its physical integrity and habitat survival. The transit of large vessels has been shown to have serious impacts on the shallow water areas adjacent to waterways. Depression wakes created by such vessels can reach significant dimensions (water level dropdown of up to 2.45 m at the channel margin), causing unusually large retreat rates of several sections of the shoreline and which may adversely affect the lagoon morphology. The wakes are analysed in relation to ship and morphological parameters. A formulation is proposed to predict wake amplitude on the basis of ship characteristics and motion.

A 72-year-old woman presented to outpatient clinic with fatigue, light-headedness, dyspnoea and dark stool suggestive of lower gastrointestinal bleeding. She was previously diagnosed with multiple myeloma and completed 9 cycles of chemotherapy with bortezomib, lenalidomide and dexamethasone. She had very good partial response. A CT scan of the abdomen revealed a 9 cm mass at the hepatic flexure of the large intestine with an apple core deformity causing a marked narrowing of the lumen. Colonoscopy confirmed a large, nearly obstructing ulcerative mass in the distal right colon. The patient underwent a right hemicolectomy, distal ileal resection and lymph node dissection. Histopathology confirmed the mass as a plasmacytoma. Postoperatively, the patient was started with bortezomib and liposomal doxorubicin followed by carfilzomib. She showed excellent response to the chemotherapy., (2015 BMJ Publishing Group Ltd.)

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

Objective: Altered microbiota composition, changes in immune responses and impaired intestinal barrier functions are observed in IBD. Most of these features are controlled by proteases and their inhibitors to maintain gut homeostasis. Unrestrained or excessive proteolysis can lead to pathological gastrointestinal conditions. The aim was to validate the identified protease IBD candidates from a previously performed systematic review through a genetic association study and functional follow-up., Design: We performed a genetic association study in a large multicentre cohort of patients with Crohn's disease (CD) and UC from five European IBD referral centres in a total of 2320 CD patients, 2112 UC patients and 1796 healthy controls. Subsequently, we did an extensive functional assessment of the candidate genes to explore their causality in IBD pathogenesis., Results: Ten single nucleotide polymorphisms (SNPs) in four genes were significantly associated with CD: CYLD, USP40, APEH and USP3. CYLD was the most significant gene with the intronically located rs12324931 the strongest associated SNP (p(FDR)=1.74e-17, OR=2.24 (1.83 to 2.74)). Five SNPs in four genes were significantly associated with UC: USP40, APEH, DAG1 and USP3. CYLD, as well as some of the other associated genes, is part of the ubiquitin proteasome system (UPS). We therefore determined if the IBD-associated adherent-invasive Escherichia coli (AIEC) can modulate the UPS functioning. Infection of intestinal epithelial cells with the AIEC LF82 reference strain modulated the UPS turnover by reducing poly-ubiquitin conjugate accumulation, increasing 26S proteasome activities and decreasing protein levels of the NF-κB regulator CYLD. This resulted in IκB-α degradation and NF-κB activation. This activity was very important for the pathogenicity of AIEC since decreased CYLD resulted in increased ability of AIEC LF82 to replicate intracellularly., Conclusions: Our results reveal the UPS, and CYLD specifically, as an important contributor to IBD pathogenesis, which is favoured by both genetic and microbial factors., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Activators of the pyruvate kinase M2 (PKM2) are currently attracting significant interest as potential anticancer therapies. They may achieve a novel antiproliferation response in cancer cells through modulation of the classic 'Warburg effect' characteristic of aberrant metabolism. In this Letter, we describe the optimization of a weakly active screening hit to a structurally novel series of small molecule 3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as potent PKM2 activators., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Inactivation of the M2 form of pyruvate kinase (PKM2) in cancer cells is associated with increased tumorigenicity. To test the hypothesis that tumor growth may be inhibited through the PKM2 pathway, we generated a series of small-molecule PKM2 activators. The compounds exhibited low nanomolar activity in both biochemical and cell-based PKM2 activity assays. These compounds did not affect the growth of cancer cell lines under normal conditions in vitro, but strongly inhibited the proliferation of multiple lung cancer cell lines when serine was absent from the cell culture media. In addition, PKM2 activators inhibited the growth of an aggressive lung adenocarcinoma xenograft. These findings show that PKM2 activation by small molecules influences the growth of cancer cells in vitro and in vivo, and suggest that such compounds may augment cancer therapies.

2-Arylamino-4-aryl-pyrimidines were found to be potent inhibitors of PAK1 kinase. The synthesis and SAR are described. The incorporation of a bromide at the 5-position of the pyrimidine core and in combination with a 1,2-dimethylpiperazine pendant domain yielded a lead compound with potent PAK1 inhibition and anti-proliferative activity in various colon cancer cell lines., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A series of compounds based on a 4-phenyl-2-phenylaminopyridine scaffold that are potent and selective inhibitors of Traf2- and Nck-interacting kinase (TNIK) activity are described. These compounds were used as tools to test the importance of TNIK kinase activity in signaling and proliferation in Wnt-activated colorectal cancer cells. The results indicate that pharmacological inhibition of TNIK kinase activity has minimal effects on either Wnt/TCF4/β-catenin-driven transcription or viability. The findings suggest that the kinase activity of TNIK may be less important to Wnt signaling than other aspects of TNIK function, such as its putative role in stabilizing the TCF4/β-catenin transcriptional complex., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Fatty acid modifying enzyme (FAME) has been shown to modify free fatty acids to alleviate their bactericidal effect by esterifying fatty acids to cholesterol or alcohols. Although it has been shown in previous studies that FAME is required for Staphylococcus aureus survival in skin abscesses, FAME is poorly studied compared to other virulence factors. FAME activity had also been detected in coagulase-negative staphylococci (CNS). However, FAME activity was only surveyed after a bacterial culture was grown for 24 h. Therefore if FAME activity was earlier in the growth phase, it would not have been detected by the assay and those strains would have been labeled as FAME negative., Results: Fifty CNS bovine mastitis isolates and several S. aureus, Escherichia coli, and Streptococcus uberis strains were assayed for FAME activity over 24 h. FAME activity was detected in 54% of CNS and 80% S. aureus strains surveyed but none in E. coli or S. uberis. While some CNS strains produced FAME activity comparable to the lab strain of S. aureus, the pattern of FAME activity varied among strains and across species of staphylococci. All CNS that produced FAME activity also exhibited lipase activity. Lipase activity relative to colony forming units of these CNS decreased over the 24 h growth period. No relationship was observed between somatic cell count in the milk and FAME activity in CNS., Conclusions: Some staphylococcal species surveyed produced FAME activity, but E. coli and S. uberis strains did not. All FAME producing CNS exhibited lipase activity which may indicate that both these enzymes work in concert to alter fatty acids in the bacterial environment.

Epigenetic modification of DNA leads to changes in gene expression. DNA methyltransferases (DNMTs) comprise a family of nuclear enzymes that catalyze the methylation of CpG dinucleotides, resulting in an epigenetic methylome distinguished between normal cells and those in disease states such as cancer. Disrupting gene expression patterns through promoter methylation has been implicated in many malignancies and supports DNMTs as attractive therapeutic targets. This review focuses on the rationale of targeting DNMTs in cancer, the historical approach to DNMT inhibition, and current marketed hypomethylating therapeutics azacytidine and decitabine. In addition, we address novel DNMT inhibitory agents emerging in development, including CP-4200 and SGI-110, analogs of azacytidine and decitabine, respectively; the oligonucleotides MG98 and miR29a; and a number of reversible inhibitors, some of which appear to be selective against particular DNMT isoforms. Finally, we discuss future opportunities and challenges for next-generation therapeutics.

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17)), 16q22 (CDH1 and CDH3; P = 2.8 x 10(-8)) and 7q31 (LAMB1; P = 3.0 x 10(-8)). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.

The biogenesis of the large (60S) ribosomal subunit in eukaryotes involves nucleolar, nucleoplasmic, and cytoplasmic steps. The cytoplasmic protein Rei1, found in all eukaryotes, was previously shown to be necessary for the nuclear reimport of 60S subunit export factor Arx1. In this study we investigate the function of Reh1, a protein with high sequence similarity to Rei1. We demonstrate an overlapping function for Reh1 and Rei1 in the cytoplasmic maturation of the 60S subunit that is independent of Arx1 recycling. We observe that strains lacking both Reh1 and Rei1 accumulate salt-labile 60S subunits, suggesting that Reh1/Rei1 is necessary for the cytoplasmic 60S subunit to adopt its mature, stable form.

Aims: Common polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are strongly associated with Type 2 diabetes. Many studies include a large proportion of cases enriched for family history or young age of diagnosis and may therefore provide an overestimation of the general population risk. We aimed to compare the impact of TCF7L2 in UK community-based Type 2 diabetic subjects with that in subjects ascertained for genetic studies., Methods: We genotyped the TCF7L2 polymorphism rs7903146 in 1068 cases from two sources: 487 from 10 GP practices and 601 ascertained for genetic studies, and 2099 control subjects from two sources: 1099 parents from a birth cohort (population control subjects) and 300 subjects with normal fasting glucose aged > or = 45 years (community control subjects)., Results: When compared with Type 2 diabetes cases ascertained for genetic studies, the risk allele frequency in community-based cases was lower (40 vs. 36%, P = 0.04), but there was no difference in risk allele frequency between community-based control and population-based control subjects (31 vs. 30%, P = 0.61). The T allele of rs7903146 increased Type 2 diabetes risk with an odds ratio (OR) of 1.32 (95% CI: 1.13-1.52; P = 0.0002) in community-based cases, but this OR was lower than the OR of cases enriched for genetic studies [1.58 (95% CI: 1.38-1.80), P = 1.4 x 10(-11)] and the combined OR of meta-analysis of 10 studies to date on rs7903146 [1.48 (95% CI: 1.41-1.54), P < 10(-20)]., Conclusion: Common variation in the TCF7L2 gene contributes to Type 2 diabetes risk in UK patients recruited in general practice, but the risk allele frequency may be lower than that in subjects enriched for genetic effects.

Aim: The rapid evolvement of beta-lactamases in Enterobacteriaceae is an important concern and the clinical microbiology laboratory is required to detect them, where possible, using a rapid, reliable, simple and low cost methodology., Materials and Methods: A disc diffusion method using NCCLS breakpoints, Jarlier's principle and cefoxitin test for AmpC was carried out. It incorporated seven antimicrobial discs in one agar plate: cefotaxime, aztreonam, amoxicillin-clavulanate, ceftazidime, cefpodoxime, cefepime and cefoxitin. NCCLS disc confirmation test for extended-spectrum beta-lactamase (ESBL) was carried out simultaneously., Results: AmpC, ESBL, CTX-M, and K1 were detected using these tests. The prevalence of ESBL was <1% in the hospital., Conclusion: The method is recommended for the phenotypic detection of beta-lactamases in Enterobacteriaceae or for confirmation after the results are obtained by conventional automated systems.

The ribosome accelerates the rate of peptide bond formation by at least 10(7)-fold, but the catalytic mechanism remains controversial. Here we report evidence that a functional group on one of the tRNA substrates plays an essential catalytic role in the reaction. Substitution of the P-site tRNA A76 2' OH with 2' H or 2' F results in at least a 10(6)-fold reduction in the rate of peptide bond formation, but does not affect binding of the modified substrates. Such substrate-assisted catalysis is relatively uncommon among modern protein enzymes, but it is a property predicted to be essential for the evolution of enzymatic function. These results suggest that substrate assistance has been retained as a catalytic strategy during the evolution of the prebiotic peptidyl transferase center into the modern ribosome.

The peptidyl transferase center of the ribosome is literally the mother of all protein enzymes, yet it was only recently that the content of its active site was found to be RNA and not protein. This review focuses on how this RNA enzyme orients its substrates and promotes the chemical reaction that is center stage in protein synthesis.

The crystal structure of the ribosomal 50S subunit from Haloarcula marismortui in complex with the transition state analog CCdA-phosphate-puromycin (CCdApPmn) led to a mechanistic proposal wherein the universally conversed A2451 in the ribosomal active site acts as an "oxyanion hole" to promote the peptidyl transferase reaction [Nissen, P., Hansen, J., Ban, N., Moore, P.B., and Steitz, T.A. (2000) Science 289, 920-929]. In the model, close proximity (3 A) between the A2451 N3 and the nonbridging phosphoramidate oxygen of CCdApPmn suggested that the carbonyl oxyanion formed during the tetrahedral transition state is stabilized by hydrogen bonding to the protonated A2451 N3, the pKa of which must be perturbed substantially. We characterize the contribution of the putative hydrogen bond between the N3 of A2451 and the nonbridging phosphoramidate oxygen by using chemical protection and peptidyl transfer inhibition assays. If this putative hydrogen bond makes a significant thermodynamic contribution, then CCdApPmn-binding affinity to the 50S ribosomal subunit should be strongly pH-dependent, with affinity increasing as the pH is lowered. We report that CCdApPmn binds 50S ribosomes with essentially equal affinity at all pH values between 5.0 and 8.5. These data argue against a mechanism for peptidyl transfer in which a residue with near neutral pKa stabilizes the transition-state oxyanion, at least to the extent that CCdApPmn accurately mimics the transition state.

Among the clinically used nucleoside analogue inhibitors that target human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), there is little detailed mechanistic information on the interactions of 2',3'-didehydro-2', 3'-dideoxythymidine-5'-triphosphate (d4TTP) with the enzyme. primer-template complex and how these interactions compare with those of the natural substrate, dTTP. Using a pre-steady-state kinetic analysis, we found that d4TTP was incorporated by HIV-1 RT just as efficiently as dTTP during both DNA- and RNA-dependent DNA synthesis. To our knowledge, these results represent the first observation of a 3'-modified nucleoside triphosphate analogue that has an incorporation efficiency comparable to that observed for the natural substrate during DNA synthesis by HIV-1 RT. This information provides a mechanistic basis for understanding the inhibition of HIV-1 RT by d4TTP as well as insight into the clinically observed lack of d4T resistance mutations in HIV-1 RT isolated from AIDS patients.

Improved understanding of the pathophysiologic course of heart failure has led to many advances in pharmacologic therapy. Angiotensin-converting enzyme inhibitors represent the first effort at targeting neurohormonal activation in chronic heart failure. More recently, beta-adrenergic receptor antagonists have been shown effective in blocking chronic sympathetic nervous system activation. The roles of digoxin and the newer, vasoselective calcium channel blockers in heart failure have been better defined. Other agents targeting the neurohormonal system are under investigation. These include angiotensin-receptor antagonists, aldosterone inhibitors, and endothelin antagonists. Experience with phosphodiesterase inhibitors and adrenergic agents has confirmed the importance of neurohormonal activation in progression of heart failure. Despite angiotensin-converting enzyme inhibitor, diuretic, and digoxin therapy, mortality in heart failure remains high. Careful manipulation of the neurohormonal response to heart failure holds promise for altering the course of the disease.

Diffuse subcortical MRI signal abnormalities were seen during a subacute exacerbation in a patient with Hashimoto's encephalopathy. The patient had an excellent clinical response to corticosteroids. Clinical recovery paralleled normalization of MRI abnormalities and lowering of thyroid microsomal antibody titer.

A stratified, random sample of 344 White and Black adolescent females participated in a survey of ideal body size beliefs, which included responses to a questionnaire and a series of nine female and male body size drawings. Using SES and race as independent variables and BMI (kg/m2) as a covariate. Black females preferred a significantly heavier ideal female body size than Whites. They also perceived their parents and both male and female friends would select as ideal a significantly heavier female body size than White subjects. Black subjects' body size preferences were significantly more influenced by family members than were White subjects, who were significantly more influenced by their peer group. These findings suggest a greater social approval of increasing weight and body size for Black adolescent females, a desire for a smaller size by White adolescent females, and cultural differences in the influencing factors that help to communicate these body size preferences.

Cells of the oral bacterium Streptococcus oralis CN3410 produce lateral tufts of cell-surface fibrils of two lengths. Treatment of cells with trypsin resulted in loss of the tufts and release of longer fibrils intact. SDS-PAGE analysis of trypsin extracts containing fibrils revealed two groups of high molecular mass polypeptides which were denoted group A (molecular mass 227-246 kDa) and group B (molecular mass 175-208 kDa). Antibodies were raised to these two groups of trypsin-extracted polypeptides (TEPs) and to purified fibrils, and the reactivities of the three different antisera were found to be similar both on nitrocellulose blots of cell-surface polypeptides and in ELISA with whole cells. Similar patterns of TEPs were obtained from cells of a spontaneously derived mutant strain, KP34V, which lacked the short fibril components of tufts. Cells of strain KP34V had similar cell-surface hydrophobicity to strain CN3410 cells, and adhered to the same extent to parotid salivary pellicle or human buccal epithelial cells (BECs) as the wild-type cells. Trypsin treatment of strain CN3410 cells abolished their surface hydrophobicity and ability to adhere to BECs, but did not affect streptococcal cell binding to experimental salivary pellicle. Antibodies to TEPs or fibrils had no effect on cell adhesion to BECs or salivary pellicle. The results imply that the short fibril components of tufts are not involved in the cell adhesion properties tested. It is suggested that the TEPs are components of long fibrils, but they are not determinants of streptococcal cell adhesion to pellicle or to epithelial cells.