bluuebunny/crossref_metadata_2025 huggingface dataset:
A University Wide Model for the Ethical Review of Human Subjects Research
Authors: Williams-Jones Bryn , Holm Søren
Published: January 2012

In the United Kingdom (and elsewhere), there are moves to extend formal ethical review of research involving human subjects beyond the traditional oversight by NHS local or multi-centre research ethics committees of medical or clinical research, to also encompass all ‘non-clinical’ research involving human subjects. This paper describes and analyses the development and implementation of a model for ethical review within the university sector. At Cardiff University, a devolved or two-tiered system of ethics review has been created in which a top-level university research ethics committee provides policy advice to and oversight of school-based research ethics committees that engage in formal ethics review of research conducted in their respective schools. We describe the system and reflect on the challenges and benefits of implementing such a coordinated and comprehensive university-wide system of ethics review.
Categorization of Investigation: Defining the Ethical Questions
Authors: Godfrey Ray
Published: January 2012

This paper draws attention to a simple distinction that, when ignored, considerably distorts discussion of what should be subject to what form of ethical review and by whom. The distinction is between two types of ethical questions that can be asked about any investigation, and indeed about many other types of activity. First, there are questions of the kind: Is it ethical to conduct this investigation at all? Second, there are questions such as: How can this investigation be conducted in an ethical way? Consideration of these questions and of the categorization of research based on study design can lead to a model for triage, however the aim of the paper is not so much to make a real practical suggestion but rather the to highlight the distinction between two types of ethical question. It is clear thinking on the relationship between the two types of question that might lead to some practical suggestions and serve to better define the scope of research ethics review.
Ethical Issues in Research Design: A Commentary
Authors: McGee Paula
Published: January 2012

This case study appeared in full in the last issue of Research Ethics Review (2005); 1(4): 134). It concerned the design of a randomized controlled trial to examine dietary practices among South Asian women during pregnancy.
How Over-Protectionism Can Evidence Unethical Outcomes: Examples from South Africa
Authors: Singh Jerome Amir
Published: January 2012

South Africa has adopted a paternalistic stance on the minimum age of enrolment for HIV vaccine trials, and on the level of compensation for trial participants. Whilst this approach has presumably been taken to protect the interests of research participants an over-protective approach, however well-intended, does not always serve the interests of the particularly vulnerable. It will be argued that an inclusive approach, based on the principles of beneficence and justice, can better guide research in such a way that the necessary data are generated while also furthering the interests of the particularly vulnerable members of a study population.
Guinea Pig Duties: 8. Another Way
Authors: Steiner T.J.
Published: January 2012

This series of articles have explored the need that society has for clinical research to be done and the consequent sets of duties that call on the one hand upon investigators to carry it out and on the other upon patients to be subjects of it. The purpose of the discussions has been to understand what should be the relationship between investigators and patient-subjects in order that both might meet their obligations effectively, efficiently, safely and with mutual respect. Here I reach my conclusions.
Research Ethics Committees and the Law: Indemnity and Independence
Authors: Laurence Desmond R.
Published: January 2012

Members of a National Health Service, or other recognised Research Ethics Committee (REC), in deciding whether or not to withhold their assent for a clinical trial, must obey the law. If they do not do so, then they may become liable to pay personally negligence claims made by injured trials subjects. It could be no defence to say that members had consulted their own lower ethical standards; or merely that they had acted in good faith; or that they had followed Department of Health (DH) guidelines, which do not have the force of law. The law requires that the rights, safety, and well-being of clinical trial subjects shall prevail over other interests. REC favourable opinion is a powerful endorsement of a trial, and prospective subjects are invited to rely upon it. REC members are legally bound to exercise their power to withhold assent to any clinical trial which does not give subjects the protection the law requires.
Indemnity and Liability for Human Volunteers — Ethical Considerations: The Victim's Perspective
Authors: Day Martyn
Published: January 2012

There is much law and many guidelines surrounding the whole issue of the indemnity for human volunteers when it comes to clinical trials. The system that had been put in place to protect individual volunteer drug trialists seems largely to have worked by the fact that there are so few examples of legal cases being issued. However, recent events have shown that when the system fails it fails somewhat spectacularly. The difficulty for groups such as the ethics committee is that lawyers look for targets to try and meet the difference between the claims and the monies available and it might therefore always be possible that the ethics committee becomes centre stage in terms of the pursuit of the action.
The Roles of Research Ethics Committees: Implications for Membership
Authors: Hunter David
Published: January 2012

In this brief paper I intend to make some distinctions between the activities that research ethics committees are required to undertake as part of their role in protecting research participants. These functions are, identifying ethical issues and risks within research projects, providing advice on how to resolve these issues and risks without compromising the validity of the research and finally, when this cannot be achieved, deciding whether the research should still be allowed to go ahead. Distinguishing these distinct functions allows us to determine what an appropriate membership of a Research Ethics Committee is. I will sketch out the implications of these functions for the appropriate membership of NHS and university based ethics committees in the UK.
Ethical Oversight of Multinational Collaborative Research: Lessons from Africa for Building Capacity and for Policy
Authors: Sugarman Jeremy ,   Participants in the Partnership for Enhancing Human Research Protections Durban Workshop1
Published: January 2012

Researchers and others involved in the research enterprise from 12 African countries met with those working in ethics and oversight in the United States as part of an effort to develop research ethics capacity. Drawing on a wealth of experience among participants, discussions at the meeting revealed five categories of issues that warrant careful attention by those engaged in similar efforts as well as international policymakers and those charged with oversight of research. (1) Principal investigators should build ‘true research teams’ where members of the team are meaningfully involved in decisions regarding the protocol and its implementation. (2)There should be explicit discussion about the ‘standard of care’ at the outset of project planning that includes clarification of the terminology that is being used. (3) While internationally collaborative research may involve populations that have inherent vulnerabilities, it is important to recognize the limitations of host country solutions (such as elaborated consent processes) and look for means to negotiate appropriate protections for those willing to participate. (4) In conducting research involving biological materials it would be prudent to develop material transfer agreements at the outset of the study to clarify expectations and to minimize the likelihood of harm. (5) Those engaged in internationally collaborative research need to be alert to the potential conflicts of interests of host country ethics committees during the approval process and to take measures to manage them if they indeed exist.
Communicating with the Elderly: Decision Making and Informed Consent in Subjects with Frailty or Dementia
Authors: Hugonot-Diener Laurence , Husson Jean-Marc
Published: January 2012

Obtaining a valid informed consent from an elderly person, especially when frail or with possible dementia, will initially involve the practical problem of assessing the ability to communicate. Only then can the assessment of decisionmaking capacities and the obtaining of informed consent for participation in research be progressed. Normal ageing does not impair communication or decision-making, but pathological status does, this may, or may not, be associated with the ageing process. Perceptual impairment may, in particular, interfere with the communication.

Once the subject appreciates and understands that he/she has the right to make a choice then it is important to ensure that he/she fully understands the decision he/she is being asked to make and can communicate and explain in his/her own words why a particular decision was made.

In this paper suggestions, based upon existing guidelines or texts, will be made as to how to improve communication with the elderly and the capabilities that the subject must demonstrate to show his capacity to make a decision will be discussed.
Research Ethics Committees in Europe — Living with Diversity
Authors: Wells Frank
Published: January 2012

This paper presents a review, conducted by the ethics working party of the European Forum for Good Clinical Practice, of the structures and functions of research ethics committees across the member states of the EU. The findings demonstrate widespread differences, and further working groups have been established to develop thinking across Europe, in respect of the training of REC members, ethics committee quality assurance and the involvement of vulnerable subjects in research. In practical terms the differences do not matter, but they should be recognized. The review itself is considered a dynamic document and will be updated every six months.
Protecting or Empowering the Vulnerable? Mental Illness, Communication and the Research Process
Authors: Atkinson Jacqueline M.
Published: January 2012

People with mental illness are treated, in research, as a ‘class’ or category who are vulnerable, without always being clear why they should be treated as such, not why an individual, rather than the class, is vulnerable. The two main reasons given are lack of competence and power imbalance. Competence issues include incapacity and legislation, assessment and the impact of the illness in decisions. Power issues cover the role of mental health legislation, coercion, protectiveness and paternalism, stigma and discrimination and the ‘well’ and ‘ill’ self. These are examined within a framework of risk assessment, both to the patient and to others. Over-concern to protect the vulnerable can lead to gate-keepers preventing their inclusion in studies at various stages of the research. This denies such groups a voice in the research process.

It is suggested that ethical scrutiny of research is not only to prevent harm to the vulnerable, but also to provide a framework to empower such people to take part in research. To do otherwise is to further stigmatize and marginalize them. One way forward is to look at the risk presented by different types of research, from clinical intervention trials to non-therapeutic, qualitative studies and to modify capacity and access requirements in the light of the risks presented.
Ethical Issues in Health Research on Ethnic Minority Populations: Focusing on Inclusion and Exclusion
Authors: Bhopal Raj
Published: January 2012

Used wisely the concepts of race and ethnicity in research have great potential, but used unwisely they can do immense damage. We need to consider the potential issues that might require a change of emphasis or application of ethics in a multi-ethnic society.

Doing no harm (non-maleficence) is the most important ethical pillar in the ethnicity and health field. Ethnic differences can be used in damaging ways. Without the ethic of beneficence in place it is better not to draw attention to ethnic differences.

Respect is the pre-condition for autonomy. Autonomy of ethnic minority populations to live in their own traditional way is not easy to achieve in multi-ethnic societies. There are difficult issues in multi-ethnic societies that require great sensitivity to create a sense of fairness and justice. Justice is the core value that underpins equity. There is a deep paradox – to promote equality, we may need to treat people and groups unequally.

Ethical codes need to be modified to emphasize the importance of including ethnic minority populations in research and not bypassing them, as has been happening. It is correct, for example, that potential research participants' personal details are guarded. If such a person, however, does not read it may be unethical to send written information about a project. It may be more ethical to tele phone or even call at the doorstep of such a person.

The history of racism in research is worrying, not least the fear that it might return. We need a governing code of conduct. Ethical research can help ethnic minority groups to move from the shadows of society and participate in a vibrant, healthy, multi-ethnic society.
Battering Patients?
Authors: Walker Jan
Published: January 2012

This paper reviews some of the ethical issues associated with the administration of long and intrusive questionnaires and interview schedules, particularly to people whose mental health is compromized. The author argues that this approach to research is potentially abusive and challenges its acceptance as the best method of obtaining relevant data. Recommendations focus on collaboration between the National Research Ethics Service, patient representatives and the research community in order to develop more humane approaches to help understand the needs of vulnerable patients.
The Sociology of Bioethics: The ‘is’ and the ‘Ought’
Authors: Humphreys Stephen J.
Published: January 2012

A selection of recent sociological literature dealing with bioethics, concentrating particularly on its interface with research ethics, is reviewed to reveal that the two disciplines of bioethics and sociology have tendencies to approach subject matters from opposed perspectives. These differences in approach have now been generally recognized, accepted and accommodated by proponents of both disciplines. A turning point in the relationship between the two disciplines may have been reached which augers greater mutual respect, appreciation and even learning.
Process Consent and Research with Older Persons Living with Dementia
Authors: Dewing Jan
Published: January 2012

There is always a debate around consent in the context of research. Given the expansion of different approaches to qualitative research within dementia care, there is increasing consideration around consent in this context; particularly in research concerning the experiences of living with dementia and the care of persons with dementia. Specifically there is a drive to directly involve persons with dementia as they offer specific expertise concerning living with dementia. Additionally, capacity legislation strengthens the case for ensuring that persons with dementia are actively enabled to make their own decisions for as long as possible. This paper discusses an approach and method that can enable more persons who are living with dementia to participate in some types of research should they want to. Currently, most researchers rely on an extension of the traditional competency-based informed consent method and/or proxy consent or assent. However, related to the development of so-called person-centred and participatory research in dementia, there are now a number of academic publications on approaches and practical methods of ‘inclusionary’ consent. This paper considers the broader contextual influences on inclusionary consent and outlines the key aspects of such approaches based on the development of one specific method for including persons with dementia in consent processes. The method is based on the premise that, for persons with a dementia, informed consent becomes increasingly redundant and consequently exclusionary to them as persons. And even where capacity is said to no longer exist, persons with dementia are often able to make choices and make known their preferences about participating in research where the consent process is made specifically dementia-sensitive. Ethics committees can facilitate researchers both by supporting them when they need to and want to include persons with dementia in gerontological research and by challenging them to ensure that participation is genuine and starts with process consent.
When to Delete Recorded Qualitative Research Data
Authors: McCrae Niall , Murray Joanna
Published: January 2012

Qualitative data typically contain multiple identifiable characteristics about people, places and events, in the unique voice of each participant. This short report considers sensitivity and security of audio-recordings, drawing attention to a lack of guidelines for researchers on the preservation or destruction of such data. The authors urge debate on this issue, with due consideration to both ethics and scientific rigour.
Ethical Issues in Using the Internet in Research: Commentary
Authors: McGee Paula
Published: January 2012

This study appeared in full in the last issue of Research Ethics Review (2008; 4 (2): 68). MJ's research focuses on those patients with brain damage following trauma such as a road traffic accident. She wants to find out about their experiences of daily life once they have been discharged from hospital. She plans to use a phenomenological approach in which each participant will be asked to take part in a series of in-depth interviews, via email, over a period of about two years. These interviews will allow her to compare participants' experiences in different parts of the UK. MJ has a research partner in Auckland; the two of them are planning a similar series of interviews in New Zealand to allow for comparison between participants' experiences in the two countries.
Statistical Review for NHS Ethics Committees: Personal Experiences and Concerns
Authors: Hart Anna
Published: January 2012

This paper discusses the experiences of a consultant medical statistician who is also a REC member.
The REC Indemnity: ‘Throwing the Kitchen Sink’ at the Committees?
Authors: Roy-Toole Christopher
Published: January 2012

In this article, the author contends that the current indemnity provided to REC members is unfair and is so badly drafted that it cannot be described as an indemnity at all. He contends that the Appointing Authorities should give guidance to clarify the scope of the indemnity or replace it. The author discusses potential legal claims by REC members against their Appointing Authority if this is not provided. The legal liability of REC members for negligence and other claims is also discussed. The author provides a solution in a simpler form of indemnity framed by reference to actual claims that can be made against a REC member.
Antiepileptic drugs in women with epilepsy during pregnancy
Authors: Gedzelman Evan , Meador Kimford J.
Published: January 2012

Prescribing antiepileptic drugs (AEDs) in pregnancy is a challenge to the clinician. A multitude of questions arise that must be addressed even prior to conception. In women with proven epilepsy, it may be dangerous to stop or even change the AED regimen during pregnancy. Changes could lead to injury or death in both the mother and the fetus. In the rare cases when discontinuing an AED is plausible, it should be done methodically in consultation with the physician prior to conception. Most women with epilepsy are consigned to continue their AEDs before, during and after pregnancy. The metabolism of AEDs may change drastically during pregnancy. These changes must be addressed by the clinician. Drug levels should be monitored consistently during pregnancy. The risks to the fetus must be delineated in terms of side effects from specific drugs as well as risks from the seizure disorder itself. Many AEDs have well known teratogenic effects, and these must be elucidated to the mother. There are risks (theoretical and evidence based) for obstetrical complications, poor neonatal outcomes, congenital malformations and even cognitive effects on the child later in life. These risks are addressed in this article with respect to individual AEDs. Recommendations include but are not limited to preconception counseling, taking folate pre and post conception, prescribing the most effective AED while minimizing risks, and avoiding polytherapy and valproate if possible.
Regulation of CXCR4 conformation by the small GTPase Rac1: implications for HIV infection
Authors: Zoughlami Younes , Voermans Carlijn , Brussen Kim , van Dort Karel A. , Kootstra Neeltje A. , Maussang David , Smit Martine J. , Hordijk Peter L. , van Hennik Paula B.
Published: January 2012

The chemokine receptor CXCR4 is a critical regulator of cell migration and serves as a coreceptor for HIV-1. The chemokine stromal cell derived factor-1, also known as CXCL12, binds to CXCR4 and exerts its biologic functions partly through the small guanosine triphosphate hydrolase (GTPase) Rac1 (ras-related C3 botulinum toxin substrate 1). We show in different cell types, including CD34+ hematopoietic stem and progenitor cells, that inhibition of Rac1 causes a reversible conformational change in CXCR4, but not in the related receptors CXCR7 or CCR5. Biochemical experiments showed that Rac1 associates with CXCR4. The conformational change of CXCR4 on Rac1 inhibition blocked receptor internalization and impaired CXCL12-induced Gαi protein activation. Importantly, we found that the conformation adopted by CXCR4 after Rac1 inhibition prevents HIV-1 infection of both the U87-CD4-CXCR4 cell line and of primary peripheral blood mononuclear cells. In conclusion, our data show that Rac1 activity is required to maintain CXCR4 in the responsive conformation that allows receptor signaling and facilitates HIV-1 infection; this implies that Rac1 positively regulates CXCR4 function and identifies the Rac1-CXCR4 axis as a new target for preventing HIV-1 infection.
Aurora: a new direction for a new dawn
Authors: Rezvani Katayoun
Published: January 2012

The use of gene transfer techniques to introduce TCR α/β genes that confer specificity for a target antigen offers the opportunity to produce large numbers of cancer-specific T cells for adoptive therapy.1 In this issue of Blood, Nagai and colleagues examine the feasibility of adoptive therapy using lymphocytes genetically engineered to express the T-cell receptor (TCR) for the leukemia-associated antigen Aurora kinase A (AURKA).2
Effect of modeled reduced gravity conditions on bacterial morphology and physiology
Authors: Vukanti Raja , Model Michael A , Leff Laura G
Published: January 2012

Background

Bacterial phenotypes result from responses to environmental conditions under which these organisms grow; reduced gravity has been demonstrated in many studies as an environmental condition that profoundly influences microorganisms. In this study, we focused on low-shear stress, modeled reduced gravity (MRG) conditions and examined, forEscherichia coli and Staphlyococcus aureus, a suite of bacterial responses (including total protein concentrations, biovolume, membrane potential and membrane integrity) in rich and dilute media and at exponential and stationary phases for growth. The parameters selected have not been studied inE. coliandS. aureusunder MRG conditions and provide critical information about bacterial viability and potential for population growth.

Results

With the exception ofS. aureusin dilute Luria Bertani (LB) broth, specific growth rates (based on optical density) of the bacteria were not significantly different between normal gravity (NG) and MRG conditions. However, significantly higher bacterial yields were observed for both bacteria under MRG than NG, irrespective of the medium with the exception ofE. coligrown in LB. Also, enumeration of cells after staining with 4',6-diamidino-2-phenylindole showed that significantly higher numbers were achieved under MRG conditions during stationary phase forE. coliandS. aureusgrown in M9 and dilute LB, respectively. In addition, with the exception of smallerS. aureusvolume under MRG conditions at exponential phase in dilute LB, biovolume and protein concentrations per cell did not significantly differ between MRG and NG treatments. BothE. coliandS. aureushad higher average membrane potential and integrity under MRG than NG conditions; however, these responses varied with growth medium and growth phase.

Conclusions

Overall, our data provides novel information aboutE. coliandS. aureusmembrane potential and integrity and suggest that bacteria are physiologically more active and a larger percentage are viable under MRG as compared to NG conditions. In addition, these results demonstrate that bacterial physiological responses to MRG conditions vary with growth medium and growth phase demonstrating that nutrient resources are a modulator of response.
Promoting fit bodies, healthy eating and physical activity among Indigenous Australian men: a study protocol
Authors: Ricciardelli Lina A , Mellor David , McCabe Marita P , Mussap Alexander J , Hallford David J , Tyler Matthew
Published: January 2012

Background

Overall the physical health of Indigenous men is among the worst in Australia. Research has indicated that modifiable lifestyle factors, such as poor nutrition and physical inactivity, appear to contribute strongly to these poor health conditions. To effectively develop and implement strategies to improve the health of Australia's Indigenous peoples, a greater understanding is needed of how Indigenous men perceive health, and how they view and care for their bodies. Further, a more systematic understanding of how sociocultural factors affect their health attitudes and behaviours is needed. This article presents the study protocol of a community-based investigation into the factors surrounding the health and body image of Indigenous Australian men.

Methods and design

The study will be conducted in a collaborative manner with Indigenous Australian men using a participatory action research framework. Men will be recruited from three locations around Australia (metropolitan, regional, and rural) and interviewed to understand their experiences and perspectives on a number of issues related to health and health behaviour. The information that is collected will be analysed using modified grounded theory and thematic analysis. The results will then be used to develop and implement community events in each location to provide feedback on the findings to the community, promote health enhancing strategies, and determine future action and collaboration.

Discussion

This study will explore both risk and protective factors that affect the health of Indigenous Australian men. This knowledge will be disseminated to the wider Indigenous community and can be used to inform future health promotion strategies. The expected outcome of this study is therefore an increased understanding of health and health change in Indigenous Australian men, the development of strategies that promote healthy eating and positive patterns of physical activity and, in the longer term, more effective and culturally-appropriate interventions to improve health.
Extracellular overexpression of recombinant Thermobifida fusca cutinase by alpha-hemolysin secretion system in E. coli BL21(DE3)
Authors: Su Lingqia , Chen Sheng , Yi Li , Woodard Ronald W , Chen Jian , Wu Jing
Published: January 2012

Background

Extracellular expression of proteins has an absolute advantage in a large-scale industrial production. In our previous study, Thermobifida fusca cutinase, an enzyme mainly utilized in textile industry, was expressed via type II secretory system in Escherichia coli BL21(DE3), and it was found that parts of the expressed protein was accumulated in the periplasmic space. Due to the fact that alpha-hemolysin secretion system can export target proteins directly from cytoplasm across both cell membrane of E. coli to the culture medium, thus in the present study we investigated the expression of cutinase using this alpha-hemolysin secretion system.

Results

T. fusca cutinase was fused with the specific signal peptide of alpha-hemolysin scretion system and expressed in E. coli BL21(DE3). In addition, HlyB and HlyD, strain-specific translocation components of alpha-hemolysin secretion system, were coexpressed to facilitate the enzyme expression. The cultivation of this engineered cell showed that cutinase activity in the culture medium reached 334 U/ml, which is 2.5 times that from type II secretion pathway under the same culture condition. The recombinant cutinase was further purified. Biochemical characterization of purified enzyme, which had an α-hemolysin secretion pathway signal peptide attached, had substrate specificity, pH and temperature profile, as well as application capability in bioscouring similar to that of wild-type cutinase.

Conclusions

In the present study, T. fusca cutinase was successfully secreted to the culture media by α-hemolysin secretion system. This is the first report of cutinase being efficiently secreted by this pathway. Due to the limited cases of successful expression of industrial enzyme by E. coli α-hemolysin secretion system, our study further explored the utilization of this pathway in industrial enzymes.
Enhancement of lung tumorigenesis in a Gprc5a Knockout mouse by chronic extrinsic airway inflammation
Authors: Barta Peter , Van Pelt Carolyn , Men Taoyan , Dickey Burton F , Lotan Reuben , Moghaddam Seyed Javad
Published: January 2012

Background

Although cigarette smoking is the principal cause of lung carcinogenesis, chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, has been identified as an independent risk factor for lung cancer. Bacterial colonization, particularly with non-typeable Haemophilus influenzae (NTHi), has been implicated as a cause of airway inflammation in COPD besides cigarette smoke. Accordingly, we hypothesized that lung cancer promotion may occur in a chronic inflammatory environment in the absence of concurrent carcinogen exposure.

Results

Herein, we investigated the effects of bacterial-induced COPD-like inflammation and tobacco carcinogen-enhanced tumorigenesis/inflammation in the retinoic acid inducible G protein coupled receptor knock out mouse model (Gprc5a-/- mouse) characterized by late-onset, low multiplicity tumor formation. Three-month-old Gprc5a-/- mice received 4 intraperitoneal injections of the tobacco-specific carcinogen, NNK, followed by weekly exposure to aerosolized NTHi lysate for 6 months. The numbers of inflammatory cells in the lungs and levels of several inflammatory mediators were increased in Gprc5a-/- mice treated with NTHi alone, and even more so in mice pretreated with NNK followed by NTHi. The incidence of spontaneous lung lesions in the Gprc5a-/- mice was low, but NTHi exposure led to enhanced development of hyperplastic lesions. Gprc5a-/- mice exposed to NNK alone developed multiple lung tumors, while NTHi exposure increased the number of hyperplastic foci 6-fold and the tumor multiplicity 2-fold. This was associated with increased microvessel density and HIF-1α expression.

Conclusion

We conclude that chronic extrinsic lung inflammation induced by bacteria alone or in combination with NNK enhances lung tumorigenesis in Gprc5a-/- mice.
Global gene expression changes in human embryonic lung fibroblasts induced by organic extracts from respirable air particles
Authors: Líbalová Helena , Uhlířová Kateřina , Kléma Jiří , Machala Miroslav , Šrám Radim J , Ciganek Miroslav , Topinka Jan
Published: January 2012

Background

Recently, we used cell-free assays to demonstrate the toxic effects of complex mixtures of organic extracts from urban air particles (PM2.5) collected in four localities of the Czech Republic (Ostrava-Bartovice, Ostrava-Poruba, Karvina and Trebon) which differed in the extent and sources of air pollution. To obtain further insight into the biological mechanisms of action of the extractable organic matter (EOM) from ambient air particles, human embryonic lung fibroblasts (HEL12469) were treated with the same four EOMs to assess changes in the genome-wide expression profiles compared to DMSO treated controls.

Method

For this purpose, HEL cells were incubated with subtoxic EOM concentrations of 10, 30, and 60 μg EOM/ml for 24 hours and global gene expression changes were analyzed using human whole genome microarrays (Illumina). The expression of selected genes was verified by quantitative real-time PCR.

Results

Dose-dependent increases in the number of significantly deregulated transcripts as well as dose-response relationships in the levels of individual transcripts were observed. The transcriptomic data did not differ substantially between the localities, suggesting that the air pollution originating mainly from various sources may have similar biological effects. This was further confirmed by the analysis of deregulated pathways and by identification of the most contributing gene modulations. The number of significantly deregulated KEGG pathways, as identified by Goeman's global test, varied, depending on the locality, between 12 to 29. The Metabolism of xenobiotics by cytochrome P450 exhibited the strongest upregulation in all 4 localities and CYP1B1 had a major contribution to the upregulation of this pathway. Other important deregulated pathways in all 4 localities were ABC transporters (involved in the translocation of exogenous and endogenous metabolites across membranes and DNA repair), the Wnt and TGF-β signaling pathways (associated particularly with tumor promotion and progression), Steroid hormone biosynthesis (involved in the endocrine-disrupting activity of chemicals), and Glycerolipid metabolism (pathways involving the lipids with a glycerol backbone including lipid signaling molecules).

Conclusion

The microarray data suggested a prominent role of activation of aryl hydrocarbon receptor-dependent gene expression.
Xylan oligosaccharides and cellobiohydrolase I (TrCel7A) interaction and effect on activity
Authors: Baumann Martin J , Borch Kim , Westh Peter
Published: January 2012

Background

The well-studied cellulase mixture secreted by Trichoderma reesei (anamorph to Hypocrea jecorina) contains two cellobiohydolases (CBHs), cellobiohydrolase I (TrCel7A) and cellobiohydrolase II (TrCeI6A), that are core enzymes for the solubilisation of cellulose. This has attracted significant research interest because of the role of the CBHs in the conversion of biomass to fermentable sugars. However, the CHBs are notoriously slow and susceptible to inhibition, which presents a challenge for the commercial utilisation of biomass. The xylans and xylan fragments that are also present in the biomass have been suggested repeatedly as one cause of the reduced activity of CHBs. Yet, the extent and mechanisms of this inhibition remain poorly elucidated. Therefore, we studied xylan oligosaccharides (XOSs) of variable lengths with respect to their binding and inhibition of both TrCel7A and an enzyme variant without the cellulose-binding domain (CBM).

Results

We studied the binding of XOSs to TrCel7A by isothermal titration calorimetry. We found that XOSs bind to TrCel7A and that the affinity increases commensurate with XOS length. The CBM, on the other hand, did not affect the affinity significantly, which suggests that XOSs may bind to the active site. Activity assays of TrCel7A clearly demonstrated the negative effect of the presence of XOSs on the turnover number.

Conclusions

On the basis of these binding data and a comparison of XOS inhibition of the activity of the two enzyme variants towards, respectively, soluble and insoluble substrates, we propose a competitive mechanism for XOS inhibition of TrCel7A with phosphoric swollen cellulose as a substrate.
Knockdown of menin affects pre-mRNA processing and promoter fidelity at the interferon-gamma inducible IRF1 gene
Authors: Auriemma Lauren B , Shah Shaili , Linden Lara M , Henriksen Melissa A
Published: January 2012

Background

The tumor suppressor menin (MEN1) is mutated in the inherited disease multiple endocrine neoplasia type I, and has several documented cellular roles, including the activation and repression of transcription effected by several transcription factors. As an activator, MEN1 is a component of the Set1-like mixed lineage leukemia (MLL) MLL1/MLL2 methyltransferase complex that methylates histone H3 lysine 4 (H3K4). MEN1 is localized to the signal transducer and activator of transcription 1 (STAT1)-dependent gene, interferon regulatory factor 1 (IRF1), and is further recruited when IRF1 transcription is triggered by interferon-γ signaling.

Results

RNAi-mediated knockdown of MEN1 alters the H3K4 dimethylation and H3 acetylation profiles, and the localization of histone deacetylase 3, at IRF1. While MEN1 knockdown does not impact the rate of transcription, IRF1 heteronuclear transcripts become enriched in MEN1-depleted cells. The processed mRNA and translated protein product are concomitantly reduced, and the antiviral state is attenuated. Additionally, the transcription start site at the IRF1 promoter is disrupted in the MEN1-depleted cells. The H3K4 demethylase, lysine specific demethylase 1, is also associated with IRF1, and its inhibition alters H3K4 methylation and disrupts the transcription start site as well.

Conclusions

Taken together, the data indicate that MEN1 contributes to STAT1-activated gene expression in a novel manner that includes defining the transcription start site and RNA processing.
The correlation between locomotor performance and hindlimb kinematics during burst locomotion in the Florida scrub lizard,Sceloporus woodi
Authors: McElroy Eric J. , Archambeau Kristen L. , McBrayer Lance D.
Published: January 2012

Burst locomotion is thought to be closely linked to an organism's ability to survive and reproduce. During the burst, animals start from a standstill and then rapidly accelerate to near-maximum running speeds. Many previous studies have described the functional predictors of maximum running speed; however, only recently has work emerged that describes the morphological, functional and biomechanical underpinnings of acceleration capacity. Herein we present data on the three-dimensional hindlimb kinematics during burst locomotion, and the relationship between burst locomotor kinematics and locomotor performance in a small terrestrial lizard (Sceloporus woodi). We focus only on stance phase joint angular kinematics. Sceloporus woodi exhibited considerable variation in hindlimb kinematics and performance across the first three strides of burst locomotion. Stride 1 was defined by larger joint angular excursions at the knee and ankle; by stride 3, the knee and ankle showed smaller joint angular excursions. The hip swept through similar arcs across all strides, with most of the motion caused by femoral retraction and rotation. Metatarsophalangeal (MTP) kinematics exhibited smaller maximum angles in stride 1 compared with strides 2 and 3. The significant correlations between angular kinematics and locomotor performance were different across the first three strides. For stride 1, MTP kinematics predicted final maximum running speed; this correlation is likely explained by a correlation between stride 1 MTP kinematics and stride 2 acceleration performance. For stride 3, several aspects of joint kinematics at each joint predicted maximum running speed. Overall, S. woodi exhibits markedly different kinematics, performance and kinematics-performance correlations across the first three strides. This finding suggests that future studies of burst locomotion and acceleration performance should perform analyses on a stride-by-stride basis and avoid combining data from different strides across the burst locomotor event. Finally, the kinematics-performance correlations observed in S. woodi were quite different from those described for other species, suggesting that there is not a single kinematic pattern that is optimal for high burst performance.
Flexural stiffness of feather shafts: geometry rules over material properties
Authors: Bachmann Thomas , Emmerlich Jens , Baumgartner Werner , Schneider Jochen M. , Wagner Hermann
Published: January 2012

Flight feathers of birds interact with the flow field during flight. They bend and twist under aerodynamic loads. Two parameters are mainly responsible for flexibility in feathers: the elastic modulus (Young's modulus, E) of the material (keratin) and the geometry of the rachises, more precisely the second moment of area (I). Two independent methods were employed to determine Young's modulus of feather rachis keratin. Moreover, the second moment of area and the bending stiffness of feather shafts from fifth primaries of barn owls (Tyto alba) and pigeons (Columba livia) were calculated. These species of birds are of comparable body mass but differ in wing size and flight style. Whether their feather material (keratin) underwent an adaptation in stiffness was previously unknown. This study shows that no significant variation in Young's modulus between the two species exists. However, differences in Young's modulus between proximal and distal feather regions were found in both species. Cross-sections of pigeon rachises were particularly well developed and rich in structural elements, exemplified by dorsal ridges and a well-pronounced transversal septum. In contrast, cross-sections of barn owl rachises were less profiled but had a higher second moment of area. Consequently, the calculated bending stiffness (EI) was higher in barn owls as well. The results show that flexural stiffness is predominantly influenced by the geometry of the feathers rather than by local material properties.
The polarization compass dominates over idiothetic cues in path integration of desert ants
Authors: Lebhardt Fleur , Koch Julja , Ronacher Bernhard
Published: January 2012

Desert ants, Cataglyphis, use the sky's pattern of polarized light as a compass reference for navigation. However, they do not fully exploit the complexity of this pattern, rather – as proposed previously – they assess their walking direction by means of an approximate solution based on a simplified internal template. Approximate rules are error-prone. We therefore asked whether the ants use additional cues to improve the accuracy of directional decisions, and focused on ‘idiothetic’ cues, i.e. cues based on information from proprioceptors. We trained ants in a channel system that was covered with a polarization filter, providing only a single e-vector direction as a directional ‘celestial’ cue. Then we observed their homebound runs on a test field, allowing full view of the sky. In crucial experiments, the ants were exposed to a cue conflict, in which sky compass and idiothetic information disagreed, by training them in a straight channel that provided a change in e-vector direction. The results indicated that the polarization information completely dominates over idiothetic cues. Two path segments with different e-vector orientations are combined linearly to a summed home vector. Our data provide additional evidence that Cataglyphis uses a simplified internal template to derive directional information from the sky's polarization pattern.
Origin and mechanism of thermal insensitivity in mole hemoglobins: a test of the ‘additional’ chloride binding site hypothesis
Authors: Signore Anthony V. , Stetefeld Jörg , Weber Roy E. , Campbell Kevin L.
Published: January 2012

The structural and evolutionary origins underlying the effect of temperature on the O2 binding properties of mammalian hemoglobins (Hbs) are poorly understood, despite their potential physiological importance. Previous work has shown that the O2 affinities of the blood of the coast mole (Scapanus orarius) and the eastern mole (Scalopus aquaticus) are significantly less sensitive to temperature changes than that of the star-nosed mole (Condylura cristata). It was suggested that this difference may arise from the binding of ‘additional’ chloride ions within a cationic pocket between residues 8His, 76Lys and 77Asn on the β-like δ-globin chains of coast and eastern mole Hbs. To test this hypothesis, we deduced the primary sequences of star-nosed mole and American shrew mole (Neurotrichus gibbsii) Hb, measured the sensitivity of these respiratory proteins to allosteric effector molecules and temperature, and calculated their overall oxygenation enthalpies (ΔH′). Here we show that the variability in ΔH′ seen among mole Hbs cannot be attributed to differential Cl– binding at δ8, δ76 and δ77, as the Cl– sensitivity of mole Hbs is unaffected by amino acid changes at this site (i.e. the proposed ‘additional’ Cl– binding site is not operational in mole Hbs). Rather, we demonstrate that the numerically low ΔH′ of coast and eastern mole Hbs results from heightened proton binding relative to other mole Hbs. Comparative sequence analysis and molecular modelling moreover suggest that this attribute evolved in a common ancestor of these two fossorial lineages and arises from the development of a salt bridge between a pair of amino acid residues (δ125His and α34Glu/Asp) that are not present in other mole Hbs.
Premedication with meloxicam exacerbates intracranial haemorrhage in an immature swine model of non-impact inertial head injury
Authors: Friess S H , Naim M Y , Kilbaugh T J , Ralston J , Margulies S S
Published: January 2012

Meloxicam is a cyclo-oxygenase-2 (COX-2) preferential non-steroidal anti-inflammatory drug with very effective analgesic and anti-inflammatory effects in swine. Previous reports in piglets have demonstrated that meloxicam also inhibits COX-1 and reduces production of thromboxane significantly. We use preinjury analgesia in our immature swine (3–5-day-old piglets) model of brain injury using rapid head rotations without impact. In 23 consecutive subjects we found that premedication with meloxicam ( n = 6) produced a significantly higher mortality rate (5/6 or 83%) than buprenorphine ( n = 17, 1/17 or 6%, P < 0.02). On gross neuropathological examination of the meloxicam-treated swine, we observed massive subdural and subarachnoid bleeding which were not present in buprenorphine-premedicated animals. To our knowledge there are no previous reports in swine of increased bleeding or platelet inhibition associated with meloxicam administration and further research is needed to define mechanisms of action in piglets. We caution the use of meloxicam in swine when inhibition of platelet aggregation might adversely affect refinement of experimental research protocols, such as in stroke, trauma and cardiac arrest models.
Prelude: The ISME Commission on community music activity and its Oslo seminar
Authors: Drummond John
Published: January 2012

This short introduction to the proceedings of the 1990 Commission of Community Music Activity spells out a prevailing spirit of those involved. Describing community music as the cutting edge in music education, this prelude suggests that community music activity should play a vital
role in the future of music education training.
So what's new? A survey of the educational policies of orchestras and opera companies
Authors: Winterson Julia
Published: January 2012

The creative music workshop involving professional players was intended to give direct support to school teachers and to enhance music in the classroom. However, today's large-scale, high-profile projects mounted by orchestras and opera companies appear to be developing into a full-scale
industry on their own, their role in partnership with schools and colleges requiring clarification. Through research into orchestral education policies, this paper reveals some of the confusion and suggests that music companies could profit from the experience of museums and art galleries.