Gate Keepers Research Articles

PARL and HtrA2: Another Intricate Ischemic Neuronal Apoptotic Process Starting within Mitochondria

Mitochondria integrity is essential for maintaining neuronal viability. Under ischemic stress, neurons undergo apoptosis with death signaling processes originating within mitochondria. The intricate actions of dysfunctional mitochondria in causing ischemic neuronal death were delineated in a recent review in this Journal1 as targets for developing neuroprotective strategies. The featured article by Yoshioka et al2 in this issue reports a novel death signaling process in striatal neurons under ischemic stress, involving presenilin-associated rhomboid-like (PARL) protein and high temperature requirement factor A2 (HtrA2). In elegantly designed experimental paradigms, the authors have established that PARL, an inner mitochondrial membrane protein, has a pivotal role in limiting striatal neuronal apoptosis by binding to HtrA2. Under global ischemia, PARL is degraded to release the processed form of HtrA2 from mitochondria into cytosol to bind to an inhibitor of apoptosis, the X-chromosome-linked inhibitor-of-apoptosis protein (XIAP). This results in striatal neuronal apoptosis. Presenilin-associated rhomboid-like protein is an intramembrane serine protease in the rhomboid subfamily in mitochondria. The complex name containing Presenilin is based on the original findings in yeast two-hybrid studies using a C-terminal region of Presenilin-2 as the bait to identify PARL.3 Presenilin-associated rhomboid-like protein has been shown to interact with a number of other mitochondrial proteins to constrain proapoptotic activities, starting within mitochondria. Presenilin-associated rhomboid-like protein acts in concert with OPA1, another antiapoptotic protein in mitochondria, to serve as ‘a lid on apoptosis',4 or with HtrA2 to act as ‘gate keepers of mitochondrial dynamics and apoptosis'.3 This is the first report linking PARL–HtraA2 interaction inside mitochondria to neuronal apoptosis in a setting of global cerebral ischemia. It adds another death signaling cascade that starts within mitochondria to those described in a comprehensive review of neuroprotective strategies targeting mitochondria.1 The novel findings reported in this featured article raise a number of questions for future exploration. First, is Hax 1, a mitochondrial protein resembling antiapoptotic proteins in the Bcl-2 family carrying BH-1and BH-2 domains, involved in PARL–HtrA2 interaction in ischemic striatal neuronal apoptosis? Hax 1 has been shown to present HtrA2 to PARL to retain the former in the mitochondrial intermembrane space for maintaining cell viability.5 It would be interesting to know if Hax 1 is engaged in this death signaling process in striatal neurons. Second, is this novel apoptotic cascade restricted to striatal neurons only? Does PARL–HtrA2 interaction contribute to cortical neuronal apoptosis under global ischemic stress as well? Presenilin-associated rhomboid-like protein has been linked to Parkinson's disease involving Parkin and PINK1.6 It is not impossible that the antiapoptotic action of PARL is restricted only to striatal neurons. Finally, to what extent can ischemic striatal neuronal apoptosis be ascribed to PARL–HtrA2 interaction, beyond well-established death signaling processes originating within mitochondria? In summary, this featured article reports a novel death signaling cascade in ischemic striatal neurons apoptosis. It broadens our insight into the complex mechanisms of ischemic neuronal death involving mitochondria.

Arginase and Arginine Decarboxylase – Where Do the Putative Gate Keepers of Polyamine Synthesis Reside in Rat Brain?

Polyamines are important regulators of basal cellular functions but also subserve highly specific tasks in the mammalian brain. With this respect, polyamines and the synthesizing and degrading enzymes are clearly differentially distributed in neurons versus glial cells and also in different brain areas. The synthesis of the diamine putrescine may be driven via two different pathways. In the “classical” pathway urea and carbon dioxide are removed from arginine by arginase and ornithine decarboxylase. The alternative pathway, first removing carbon dioxide by arginine decarboxlyase and then urea by agmatinase, may serve the same purpose. Furthermore, the intermediate product of the alternative pathway, agmatine, is an endogenous ligand for imidazoline receptors and may serve as a neurotransmitter. In order to evaluate and compare the expression patterns of the two gate keeper enzymes arginase and arginine decarboxylase, we generated polyclonal, monospecific antibodies against arginase-1 and arginine decarboxylase. Using these tools, we immunocytochemically screened the rat brain and compared the expression patterns of both enzymes in several brain areas on the regional, cellular and subcellular level. In contrast to other enzymes of the polyamine pathway, arginine decarboxylase and arginase are both constitutively and widely expressed in rat brain neurons. In cerebral cortex and hippocampus, principal neurons and putative interneurons were clearly labeled for both enzymes. Labeling, however, was strikingly different in these neurons with respect to the subcellular localization of the enzymes. While with antibodies against arginine decarboxylase the immunosignal was distributed throughout the cytoplasm, arginase-like immunoreactivity was preferentially localized to Golgi stacks. Given the apparent congruence of arginase and arginine decarboxylase distribution with respect to certain cell populations, it seems likely that the synthesis of agmatine rather than putrescine may be the main purpose of the alternative pathway of polyamine synthesis, while the classical pathway supplies putrescine and spermidine/spermine in these neurons.

UNDERSTANDING FINANCIAL REGULATION

This Article offers an account of financial regulation that is focused on the types of regulatory strategies that financial regulators employ. Noting the lack of prior academic work in this area, the Article presents a taxonomy of strategies, consisting of rulemaking, supervision, certification, and enforcement, and argues that regulators actively choose between versions of strategies that require their direct input and immediate expenditure of regulatory resources (public regulatory strategies) and strategies that delegate the burden of regulation onto private actors (private regulatory strategies). This choice affects the nature and effectiveness of financial regulation, both in terms of the degree to which financial regulation relies on self-regulation, gatekeepers, private rights of action, and other private strategies and the manner in which the interests of private parties involved in private strategies are aligned with those of the public. As the primary difference between public and private regulatory strategies is the immediate cost to the regulator, this Article further argues that the availability of resources is the primary determinant of the types of regulatory strategies selected by financial regulators. This Article then explores two implications of the role of resource constraints on financial regulation. The first is an explanation for the oft- noted “sine curve of regulatory activity,” a cyclical pattern of lighter to heavier regulatory activity before and after a financial crisis or scandal. In the aftermath of any such financial crisis or scandal, regulators face intense pressure to demonstrate they are in control of the financial markets and, therefore, rely more on public strategies—strategies that give the regulator greater visibility and command. Eventually, however, resource constraints force regulators to seek more cost-effective regulatory strategies, driving them to rely more on private strategies. The second is what happens when regulators cannot easily access private strategies, such as in the case of systemic risk regulation. Under resource constraints, regulators resort to “blunter” public strategies that are less costly but are not as fine-tuned, such as proposals to create narrow banks or abandon traditional financial regulatory strategies in favor of extraregulatory solutions, such as bank fees and size limitations on financial institutions.

Fighting spam using social GateKeepers

We introduce LENS (LEveraging social Networking and trust to prevent Spam transmission), a novel spam protection system which leverages the recipient’s social network to allow correspondence within the social network to directly pass to the mailbox of the recipient. To enable new senders to send emails, legitimate and authentic users, called GateKeepers (GKs), are selected from outside the recipient’s social circle and within predefined social distances. Our evaluations show that LENS provides each recipient reliable email delivery from a large fraction (up to 55% of entire userbase) of the social network; it is also effective and lightweight in accepting all the legitimate inbound emails in the real email traces. LENS imposes zero overhead for the common case of frequent and familiar senders, and remains lightweight for the general case. Our prototype implementation of LENS in Postfix/MailAvenger shows that LENS consumes up to 75% less CPU and 9% less memory as traditional solutions like SpamAssassin.

The official discourse of fair access to higher education

Despite significant public investment in the sector, selective universities in the UK have made little if any progress in widening participation over the last ten years. There are also increasing incentives for universities to become more selective in the context of government-driven higher education market competition. At the same time, while some universities may view the pursuit of academic excellence as incompatible with widening participation, key policy documents have consistently included descriptions of a variety of strategies designed to promote wider and fairer access. This paper is concerned with how the idea of fair access has been constructed within official higher education discourse. A method of ‘constructive description’ is employed to analyse the discursive strategies at play within selected governmental texts. The analysis indicates that the primacy of institutional autonomy in the official discourse of fair access operates to exclude descriptions of a ‘common currency’ of merit and potential, which may leave potentially unfair admissions practices unchallenged. The paper proposes a change in ‘mind set’ from universities operating as exclusive ‘gate keepers’ admitting students, to that of the inclusive recognition of applicants’ merit and potential. This may have significant implications for admissions policy, particularly in the light of the shift away from traditional models of funding towards empowering individual or employer ‘buyers’ in the higher education market.:

Discrimination between upper versus lower airway components to the rise of total airway resistance measured by Pennock’s method after nasal irritant challenge

Terminals of the trigeminal afferents innervating nasal mucosa are called gate keepers, since these fibres detect substances entering the airways. Trigeminal excitation by irritants initiates airway defensive mechanisms, and it is also attributed to the influence of lower airways resistance in a term of nasobronchial reflex. This phenomenon is frequently under debate, because some investigators were unable to confirm its existence. The aim of our study was to determine, whether pharmacological approach could be useful to reach high accuracy and better interpretation of the data obtained by Pennock’s method. Pennock’s method, which is frequently used to measure airway resistance in vivo (Raw) in fact measures total airway resistance, however, the data are usually interpreted in a terms of bronchomotor response. The upper airway component, which represents approximately 40% of Raw, is commonly not considered as being important in this method. 30 Dunkin Hartley guinea pigs were exposed to nasal stimuli (TRPA1 agonist—irritant allylisothiocyanate (10 mM, AITC), TRPM8 agonist with cooling potential menthol (10-3 M) and saline as a control). Raw was measured pre challenge as baseline, after nasal provocation and further, after nasal inhalation of histamine and methacholine (10-6 M) each. The data showed rise of Raw only after nasal AITC challenge, with further increased responsiveness to histamine and methacholine (5.3 vs 10.18 vs 11.26 vs 17.32 cmH2O.s-1, p 0.05). No significant changes were detected after saline, or menthol respectively. Data obtained in further experiment and its analysis showed that pre-treatment with nasal administration of 1% oxymetazoline but without salbutamol inhalation prevented the rise of Raw after nasal irritant challenges. Raw after nasal irritant challenges rises rather due to nasal response than due to narrowing of the lower airways.

Academic Leadership Scenario in India after Post Globalization

Higher Education in India is beset with a host of problems pertaining to quality when India is aiming to be an important player in the post globalization knowledge economy. Higher Educational Institutions (HEIs) are in a dire need of strengthening individual and institutional effectiveness in imparting higher education that meets the global quality requirements. In such a situation, Academic Leaders who are the gate keepers of the quality standards, imagination and creativity of higher education need to urgently address the maladies and deficiencies of the higher education to make it more professional and global. To do so, training, practice and skill based selection of academic leaders of HEIs is mandatory and relevant for the maintenance of global quality standards. Also there is a need for the Academic Leaders to explore how the concept of globalization, a meaningful integration of local and global forces, can help them inform and enhance their pedagogy and practice.

Use of Human Mucosal Tissue to Study HIV-1 Pathogenesis and Evaluate HIV-1 Prevention Modalities

The use of human mucosal tissue models is an important tool advancing our understanding of the specific mechanisms of sexual HIV transmission. Despite 30 years of study, major gaps remain, including how HIV-1 transverses the epithelium and the identity of the early immune targets (gate keepers). Because defining HIV-1 transmission in vivo is difficult, mucosal tissue is being used ex vivo to identify key steps in HIV-1 entry and early dissemination. Elucidating early events of HIV-1 infection will help us develop more potent and specific HIV-1 preventatives such as microbicides and vaccines. Mucosal tissue has been incorporated into testing regimens for antiretroviral drugs and monoclonal antibodies. The use of mucosal tissue recapitulates the epithelium and immune cells that would be exposed in vivo to virus and drug. This review will discuss the use of mucosal tissue to better understand HIV-1 pathogenesis and prevention modalities.

Molecular Epidemiology of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer mortality with still dismal prognosis (5-year survival <12%) in the U.S.1 Although it is known that advanced liver fibrosis/cirrhosis is the high-risk condition that rationalizes regular HCC surveillance, the extremely high prevalence of cirrhosis (1~2% of population) as well as other factors such as immigration from developing world make it practically difficult to adhere to the surveillance protocol: only 17% of new HCC cases were diagnosed through regular surveillance.2, 3 On the other hand, whereas annual cancer incidence in cirrhotic patients is very high (1~7%), a certain proportion of cirrhotic patients do not develop HCC during their lifetime.4 In addition, there is a huge diversity in the clinical course of HCC tumors. However, our ability to predict these outcomes is still limited or lacking especially in patients with early-stage diseases. There has been a big expectation on molecular biomarkers to fill this unmet need and enable effective, personalized patient management with limited medical resources. Furthermore, such biomarkers will help development of HCC prevention strategies by enriching at-risk patients for clinical trials as well as by predicting or monitoring treatment response. HCC development is a multistep process, involving establishment of chronic liver injury, progressive liver fibrosis that results in cirrhosis, initiation of neoplastic clone, and stepwise malignant transformation and dissemination of the clone (Figure 1). Molecular mechanisms involved in each of the steps have been extensively studied aiming at identifying the key drivers and gate keepers, and now we have many candidates of biomarkers and/or therapeutic targets.5 Figure 1 Multistep process of HCC development in chronic liver diseases.

One way to pathogenesis, many ways to homeostasis

CD4 T cells play central roles in both immune response and regulation. They can either serve as the mediators of adaptive immune response against infections, or act as gate keepers to maintain immune homeostasis. Upon activation by antigens, naive T cells proliferate and differentiate into different T helper (Th) cells with distinct effector functions. Th1 cells, induced by transcription factor T-bet and produce interferon-γ, are crucial for clearing intracellular pathogens. In contrast, IL-4 expressing Th2 cells driven by GATA-3 are responsible for the clearing of extracellular pathogens. Th17 cells, an additional subset of T cells expressing transcription factor RORγt and cytokine IL17, are considered as the main drivers of autoimmune tissue injury. On the contrary, CD4+FoxP3+ regulatory T (Treg) cells, which can be generated either in the thymus or in the peripheral in respond to chronic challenges, are known to play key roles in maintaining immunological homeostasis and the control of autoimmune deviation or diseases. In a recent issue of Nature Immunology, two independent studies from Harvard Medical School described the transcriptional signature of effector Th17 and Treg cells and unveiled very different mechanisms in instructing these two cell types.1,2

Estratégias de inovação de catching-up: as ligações de aprendizagem entre um instituto de P&amp;D e pequenas empresas

Considerando que diferentes estratégias são utilizadas pelas organizações para potencializar seu desempenho por meio da inovação, este estudo teve como objetivo identificar as ligações de aprendizagem entre um instituto de P&amp;D e pequenas empresas da cadeia produtiva da caprinocultura inserida no sistema de inovação local, tendo como base a seguinte questão: os institutos de P&amp;D podem funcionar como porteiro tecnológico (gatekeepers) provendo conhecimento novo às pequenas empresas em estudo? Para isso foi elaborado o marco teórico do estudo baseado nas discussões referentes às estratégias e aos sistemas de inovação, articulando ainda as temáticas sobre pesquisa e desenvolvimento - P&amp;D e os processos de aprendizagem correspondentes. A metodologia está baseada na estratégia do estudo multicaso. Os dados empíricos foram examinados segundo a abordagem qualitativa, sendo coletados através de entrevistas semiestruturadas, durante participações em reuniões e análises documentais. Nas empresas pesquisadas, observou-se que, apesar de essas manterem ligações de aprendizagem ainda incipientes com o instituto de P&amp;D, evidências mostraram que estas estão incidindo na ampliação da base de conhecimento das pequenas empresas. Relevou-se ainda que estas ligações de aprendizagem estejam sendo ampliadas e potencializadas através das fontes externas e abertas entre as empresas e as demais instituições do sistema e que tiveram como base estratégias de inovação do tipo catching-up.

Experience of children attending a specialist CFS/ME service

AimsDescribe the experience of young people accessing a CFS/ME specialist service.MethodsIn-depth qualitative interviews were conducted with 10 adolescents (age 12-18) and their mothers. Purposive sampling ensured that interviews included a...

Teachers’ Enactment of Equity in Alternative Schools: A critical discourse analysis

Purpose: Understanding the needs of at-risk students is thought to be an essential element for educators when they formulate and design alternative educational settings. Yet, it may be difficult for educators to distinguish between responding to the needs of an at-risk student and providing educational equity. The researcher applied equity principles and policy implementation literature to explore how alternative school teachers of at-risk students define, interpret and enact equity. Research Methods: This research was designed as a qualitative cross-case study focusing on five alternative schools in California and Texas. A qualitative thematic analysis was first applied to interviews from fifteen alternative school teachers, followed by a critical discourse analysis of government artifacts, and discursive and social practices. Findings: Teachers’ enactment of equity equated to opportunity; at-risk students were afforded equity by virtue of enrollment in the schools. Implicitly, teachers acted as gate keepers to their classroom and as such only certain students were entitled to attend. Equity arguments emerged when external forces were perceived as creating inequities. Implicit equity arguments emerged by how teachers defined success. Implications: Innovative design and practices used in alternative schools are insufficient for ensuring equity. Enactment of equity through pedagogical choices is reduced by policy procedures. Research is needed in areas: a) that will help teachers reflect on their values and priorities for at-risk students and b) of how efficacy is measured for the alternative school.

The Corporate Parent as Ethical Approver: Issues and Experiences in researching HIV + Children in Jamaica

This paper is written in the context of researching children generally, and in the context of researching vulnerable children, namely children who are HIV +. Research carries with it various notions of power and ethics, often manifested in terms of a researcher’s positionality (ie: Insider/Outsider), the intended use of the research findings and accessing the field of enquiry. In the context of the research experiences being reported in this paper, researcher positionality was of only limited consequence. However, the intended use of the research’s output was crucial to gaining access to the field (namely children who are HIV +), since paramount to ‘gate keepers’ (namely state officials and partners) were such issues as safeguarding children and the protection of their right to privacy and confidentiality.

The Battle for the Next Generation of Mobility

AbstractThe development of the Internet Protocol (IP), which can be used to transport all kinds of content, combined with the digitization of content, the roll-out of high speed broadband networks and the availability of intelligent, multimedia devices have led to “convergence”. “Convergence” refers to the shift from vertical industry silos and from a situation where different services are provided through separate networks - fixed, mobile, cable TV, IP, to a situation in which a variety of electronic communication services are accessed and seamlessly used across various networks and platforms. This convergence has led to the entry of new players into each of the markets and increased competition between players from formerly separate markets (I).It would appear that those playerswho have a dominant position in one of the segments of the electronic communications eco-system are seeking to exploit that position to their advantage to extend their domination to other related segments of the electronics communications ecosystem. Nowhere is this truer than in the area of mobility. This paper will explore three of the major battles in the area of electronic communications mobility and, principally, how three of the major players - Google, Microsoft and Apple - are using (or being subjected to) legal mechanisms to advance or defend their economic interests (I.). The three major battles that are explored are: the battle for spectrum, which is necessary for rolling out next-generation mobile networks (II.) the battle of the “Gate Keepers” (those players with dominant positions in a segment of the market) (III.) and, finally, the battle for the Smartphone market (IV.).

Pediatric liver transplantation – Ethical dilemmas in a disabled patient

Allocation of medical resources, especially resources with absolute scarcity such as organs for transplant, is a difficult task. Medical, surgical, and ethical considerations should be evaluated. In solid organ transplantation, ethics committees are the gate keepers that deal with moral philosophy when moral values are in conflict. Often, no good solution to a dilemma in these medical ethics exists. Our case presents split living liver donation for retransplantation in a mentally disabled girl, with few medical ethics principles at stake.

SMURF and NEDD4: Sharp Shooters Monitor the Gate Keepers and Ion Traffic Controllers of Lead Astray Cell

It is becoming increasingly apparent that a complex bar code underlies the quantitative aspects of extracellular signal regulation. Cell type-specific and context-dependent transcriptional programs are triggered by sophisticated nanomachinery consisting of HECT enzymes which monitor signal generation, transduction and termination. How the HECT enzymes safeguard spatiotemporal organization was a fundamental question towards understanding the process of protein degradation and its functions in diverse biological processes. In this review we will dismantle how HECT E3 enzymes regulate the trafficking of many receptors, channels and transporters as well as how HECT enzymes negatively regulate each other. There is accumulating evidence that suggests an undeniable role of HECT enzymes in regulating mediators of the Wnt signal-transduction cascade. By contrast, little is known about the crosstalk of HECT enzymes with ATM and TRAIL in prostate cancer, but several hints have emerged. This review provides a broader snapshot for studying multiple pathways in parallel, rather than as separate entities.

Clinical Comparisons of Split Septum, Positive and Negative Mechanical Valve Intravenous Connectors to an Intraluminal Protection Connector on Infection Rates

Intravenous connectors differ on design features of the septum, intraluminal fluid pathway and function. As the gate keepers of the intraluminal fluid pathway the connector's design may potentially affect the outcome of infection.

Probiotics: The Potential for a Live Microbicide to Prevent HIV

After early microbicide candidates failed in clinical trials to prevent HIV, recent news from the South African CAPRISA-004 study suggest that the new generation of vaginal microbicide gels using antiretroviral drugs like tenofovir could be effective and reduce HIV and herpes simplex virus (HSV)-2 acquisition.1 This landmark study greatly energized the field and revived enthusiasm for the development of female-controlled products to prevent HIV acquisition in women, and if ongoing trials confirm the CAPRISA-004 results lead to a licensed product by 2014. 2,3 While the field is getting closer to identifying an effective compound against vaginal HIV transmission, significant challenges remain, such as a sustained coitally-independent release of an effective drug, and a product formulation and administration that suits life circumstances of women in developing countries. Stigma continues to limit women’s access to HIV prevention strategies, and many women underestimate their own risk of HIV infection4. Thus, a microbicide product perceived to improve overall vaginal health may decrease possible acceptability barriers that a single purpose product associated with HIV prevention may face. In late May, the bi-annual global conference Microbicides 2010 held in Pittsburgh (USA) was attended by 1000 scientists and advocates, including more than 300 from Africa. The UCSF Bixby Center for Global Reproductive Health and the Consortium to Advance Multipurpose Innovations (CAMI) organized a Satellite Symposium titled ‘Probiotics: the Potential for a Live Microbicide’. The event provided a platform for researchers working in related fields to educate the conference audience and to initiate a discussion with other scientists, donors, advocates, members of federal agencies and world bodies, and regulatory experts in order to accelerate the development of probiotics for HIV prevention. A handful of small biotechnology companies and academic groups are working to develop a new generation of genetically enhanced probiotics by inserting genes which code for potent antiviral compounds into bacteria that naturally colonize the vagina. Once administered to the vagina, these next generation probiotics have the potential to serve as a sustained, self-replicating delivery system for antimicrobial compounds to combat reproductive tract infections, including HIV. The potential advantages of a probiotic microbicide continuously producing anti- HIV protein compounds in situ over conventional microbicide delivery systems such as gels and films include: i) periodic, possibly weekly or monthly replenishment vs. coitally dependent or daily dosing; ii) minimal disposal concerns, e.g. applicators; and iii) low-risk of developing HIV resistance in comparison to antiretroviral therapy commonly used in treatment, such as tenofovir. However, the field to date has been hampered by a relative lack of interest among donors due to competing HIV prevention technologies under development, lack of clarity regarding the regulatory pathway for licensure and general sensitivity surrounding genetically modified organisms (GMO), and financial fall-out from the recent worldwide recession.

Implementation of a competency assessment tool for agency nurses working in an acute paediatric setting

This paper reports on the implementation of a competency assessment tool for registered general agency nurses working in an acute paediatric setting, using a change management framework. The increased number of registered general agency nurses working in an acute children's hospital alerted concerns around their competency in working with children. These concerns were initially raised via informal complaints about 'near misses', parental dissatisfaction, perceived competency weaknesses and rising cost associated with their use. [Young's (2009) Journal of Organisational Change, 22, 524-548] nine-stage change framework was used to guide the implementation of the competency assessment tool within a paediatric acute care setting. The ongoing success of the initiative, from a nurse manager's perspective, relies on structured communication with the agency provider before employing competent agency nurses. Sustainability of the change will depend on nurse managers' persistence in attending the concerns of those resisting the change while simultaneously supporting those championing the change. These key communication and supporting roles highlight the pivotal role held by nurse managers, as gate keepers, in safe-guarding children while in hospital. Leadership qualities of nurse managers will also be challenged in continuing to manage and drive the change where resistance might prevail.