Role of Conserved E2 Residue W420 in Receptor Binding and Hepatitis C Virus Infection.

UNLABELLED: Hepatitis C virus (HCV) enters cells via interactions with several host factors, a key one being that between the viral E2 envelope glycoprotein and the CD81 receptor. We previously identified E2 tryptophan residue 420 (W420) as an essential CD81-binding residue. However, the importance of W420 in the context of the native virion is unknown, as those previous studies predate the infectious HCV cell culture (cell culture-derived HCV [HCVcc]) system. Here, we introduced four separate mutations (F, Y, A, or R) at position 420 within the infectious HCVcc JFH-1 genome and characterized their effects on the viral life cycle. While all mutations reduced E2-CD81 binding, only two (W420A and W420R) reduced HCVcc infectivity. Further analyses of mutants with hydrophobic residues (F or Y) found that interactions with the receptors SR-BI and CD81 were modulated, which in turn determined the viral uptake route. Both mutant viruses were significantly less dependent on SR-BI, and its lipid transfer activity, for virus entry. Furthermore, these viruses were resistant to the drug erlotinib, which targets epidermal growth factor receptor (EGFR) (a host cofactor for HCV entry) and also blocks SR-BI-dependent high-density lipoprotein (HDL)-mediated enhancement of virus entry. Together, our data indicate a model where an alteration at position 420 causes a subtle change in the E2 conformation that prevents interaction with SR-BI and increases accessibility to the CD81-binding site, in turn favoring a particular internalization route. These results further show that a hydrophobic residue with a strong preference for tryptophan at position 420 is important, both functionally and structurally, to provide an additional hydrophobic anchor to stabilize the E2-CD81 interaction. IMPORTANCE: Hepatitis C virus (HCV) is a leading cause of liver disease, causing up to 500,000 deaths annually. The first step in the viral life cycle is the entry process. This study investigates the role of a highly conserved residue, tryptophan residue 420, of the viral glycoprotein E2 in this process. We analyzed the effect of changing this residue in the virus and confirmed that this region is important for binding to the CD81 receptor. Furthermore, alteration of this residue modulated interactions with the SR-BI receptor, and changes to these key interactions were found to affect the virus internalization route involving the host cofactor EGFR. Our results also show that the nature of the amino acid at this position is important functionally and structurally to provide an anchor point to stabilize the E2-CD81 interaction.

The 2016 Presidential Election: Reality vs. Myths.

Politics in a democracy requires governance through debate. Nurses are an important part of the voting public and we need to assess our own anger, expectations, and values for this election. Recognizing four myths during this election season can improve the political conversation. This conversation must acknowledge different groups, interests, and opinions and then seek ways to balance or reconcile those interests. Using this as a mental model to define our politics rather than succumbing to divisive rhetoric, we can take a major step toward building a better political system.

Election 2016: Where Are We with the Affordable Care Act?

As this election campaign, like many, has been more about personality than policy, it is important to remember that positions on policy are the real substance of election outcomes. Although health care is ranking lower than other national issues in the minds of voters, it remains a vital topic. Nurses need to stay informed on this important issue, especially regarding the policy proposals from both parties and candidates

The current state of academic centers for interprofessional education.

Team-based interprofessional practice plays a central role in new models of care delivery. However, training health professionals for interprofessional practice remains a challenge. Centers for Interprofessional Education (IPE) exist at many academic institutions but have had limited success. The authors conducted telephone interviews with 12 leaders of academic centers for IPE, identified through a key informant method. Qualitative analysis of interview notes for common themes of barriers, successes, and insights. Most IPE centers in the US are small, underfunded, with no substantial staff and faculty support. Grant funding gives legitimacy, but sustainability is a major concern. Most have had success with limited educational efforts at coordinating classes, single-day events, and learning activities. While IPE centers have support from institutional leadership, they continue to face major challenges in transforming the scope and content of health professional training in their institutions.

Transforming Mental Health Care: Starting with Change Around the Edges.

It is essential for those of us who work in health professions to recognize the good work individuals and organizations are doing to improve the delivery of mental health services in communities across the country. Despite their allure, new practices and radical innovations are hard to come by and resisted by many organizations. Programs like Mental Health First Aid and Make It Ok are examples of how a program can alter a person's understanding of mental illness. Without knowing about successes and new models of care, nurses cannot be as strategic in their efforts to influence meaningful social and systemic change. Changes at the edges of the health care system are happening in the care of mental illness. Changes must continue to be made that will eventually make their way into the center.

Reframing Political Differences: One Conversation at a Time.

The profession of nursing, by it's very nature, is wrought with significantly complex moral and political disagreements. These issues cannot simply be avoided by being relegated to private discussions because their resolution is crucial to the common good. It is important for nurses to develop skills in public discourse if we are to bridge the political divide and influence local, state, and national policy. Failure to do so will leave us with ineffective and dismissed voices.

Dismantle or Improve ObamaCare? Nurses Must Take Action.

Following the 2014 mid-term elections, what will the next 2 years of Republican leadership do to change the structures still being put into place to meet the goals of the Affordable Care Act (ACA)? Nurses need to be visible by creating partnerships with their new state and federal representatives and by demonstrating collaboration through identified shared values. Nurses must hold all congressional leaders accountable for continuing to improve access to quality and affordable health care, while containing costs and strengthening incentives to provide a client-centered approach to care delivery. As health care reform legislation is a highly charged political battleground, nurses must support legislative changes in the ACA that will strengthen our health care system, not weaken it.

ACA implementation: A vulnerable and misunderstood endeavor.

Few policy goals could involve more complexity than designing a new health care system. The debates over the Affordable Care Act (ACA) involve deeply personal values. The health exchange rollout problems provided opponents of the ACA new arguments to disparage the law. It is crucial for nurses to inform themselves about the basics of the ACA and articulate the facts to colleagues, patients, and neighbors. This is the right time and nursing is in the right place to influence the course of health care reform.

Madness in America: holding a rational conversation.

The random, unexpected killing of 20 innocent children in Newtown, CT, touched us all. Targeting people with mental illness who use firearms as the problem in such tragedies is a poor simplification. Delivery of quality care for complex chronic health problems like severe mental illness and substance abuse requires a systematic coordinated effort with resources and expert capacity. We need a health care system that can assess and provide care for the severely mentally ill who may be at risk for becoming violent. Let's challenge the status quo and not simply blame mental illness for these tragedies. As the largest health profession in this country, nurses can make a difference by using the evidence regarding mental illness and violence to hold crucial and rational conversations.

Health insurance exchanges: A call for nursing action.

State health insurance exchanges will provide the opportunity for consumers to have options regarding health insurance coverage. Nurses have a vital role to play in the implementation of exchanges. Knowing the basic facts about how these exchanges will work, what the benefits will be, and access to reliable information sources will enable nurses to provide trusted guidance. The development of this new insurance marketplace is also an opportunity to address the long-standing barriers to advance practice registered nurses (APRN) practice.

The future of the Affordable Care Act: will we abandon health care reform?

With obstacles to the Affordable Care Act (ACA) growing, nurses need to continue to educate themselves about the ACA and the issues it is designed to address. While it has many shortcomings, the ACA invests in creating a new infrastructure that holds the potential to improve care quality and contain costs. Health economist Victor Fuchs suggests three areas must change if we are to have a health care system that is quality focused: information, infrastructure, and incentives. The current health care legislation is noble and lays a basis for future structural cost containment. The health care system continues to unravel as our politicians remain polarized over reform efforts. We must engage or we will never find solutions, never see reform.

The 2012 election: your vote is your voice.

In this presidential election, as the largest group of health care providers, nurses are witness to the impact of effective and failed health care policies across all health care settings on individuals, communities, agencies, and states. Nurses have a responsibility to not only be informed and participating voters, but we also need to inform those around us on how the current health policies are improving or preventing the delivery of access to quality, cost-effective care. Nurses have the opportunity and responsibility to be key informants regarding the impact of health care reform on the health care delivery system, on the profession, and on health care outcomes. The collective voice of 3.1 million nurses could change the results of this close election.

Quality in life and death: can we have the conversations?

As nurses, we participate in providing social justice through the delivery of health care. While much of what we do supports healthier lifestyles and healing, we must also acknowledge that for an increasing number of our patients, life may have become irreversibly painful and unwanted. Nurses have acute sensitivity to the dilemmas faced by dying patients and their families. Our empathy and know-how in such cases dictates that we make an effort to relieve such suffering. Easing suffering will require assessments of the changing terrain of end-of-life care and the populations receiving that care. Dialogues can bridge the interest of patients, providers, and policymakers and ultimately legislation that reinforces ethical end-of-life care and ensures a voice for those who will be most affected.

Deconstructing health care reform.

As health reform is deconstructed, we need to stop and do some deconstructing of our thinking about it, looking at the context of our assumptions or frames. If we think of health as taking the supreme welfare of the people seriously, we will not allow it to be framed only in terms of for-profit interests and the status quo. Nurses have expertise and knowledge regarding what is needed for a quality health care system. We have to join the conversation with as many good questions as ideas. Working from a different frame, one that reflects more of your values, may give you new insights into holding the conversation.

Sensible compromise: will there be health care reform?

Three significant challenges to the passage of health care legislation bear watching as they have the potential to make sensible compromise between the House and Senate unlikely. The first threat is the continuing exposure of the public to misinformation from media commentary and interest groups. If health care delivery issues weren't complex enough, another growing issue is the misuse of the filibuster, further obscuring change and clarity in legislative discussion. The third threat is a move by opponents of current health care reform to engage the Supreme Court and challenge the constitutionality of the legislation. If substantive health reform legislation fails to pass, nursing will have received a deep wound along with the rest of this country. Our voice as patient advocates must be stronger in these final days.

Expanding scope of practice: inter-professional collaboration or conflict?

With the implementation of the Patient Protection and Affordable Care Act, interdisciplinary fights are becoming more public with more to come. Currently, the most visible fight is over scope of practice (SOP) expansion, state laws that govern advanced practice nursing and vary idiosyncratically by state. Until there is an expansion of SOP, APNs in many states will not be able to provide services to the fullest extent of their training and knowledge, skills, and experience and patients will continue to go without care. For physicians, the values and identity associated with the history of the medical profession being dominant transcend the policy details and budgetary considerations that might be viewed as "interests. For nursing, the values for trust and professional recognition associated with providing high-quality care to all is central to the profession's identity and transcend the interest-based conflict. A mediator can challenge thought leaders from both professions to acknowledge their core values, to facilitate discussions in which each side accepts those aspects of the other's values that it can agree with, and then build on those shared beliefs.

Health care reform: through the lens of change.

Change theory concepts--drivers, vision, current and future states, and social buy-in--provide some analytical leverage in understanding current reform challenges. Various contentious issues in the health care reform battle have long served to polarize stakeholders and differentiate conservative and liberal positions. Successful change efforts are led by the development of a compelling vision, which has certain attributes. Change theory postulates that if there is not strong dissatisfaction with the current state, the future state is less feasible. Social systems change theory is another way to conceptualize and broaden our understanding of health policy as a form of social change, how environmental or external forces influence policy design, and how the ongoing media presentation of a policy influences direction of the outcome.

From Wall Street to Main Street: how will the economic meltdown impact health care reform?

What will happen to health care in the wake of the financial market crisis? Many health policy and economic experts are asking whether it is possible for any of the promises for health care reform to be realized. We could find ourselves in a catastrophic collision between national security priorities and domestic policy goals. Nurses must be vocal regarding the need to reform health care or it may be sidestepped if budgeting continues to prioritize the war abroad and not the crisis at home.