Modeling reveals the strength of weak interactions in stacked-ring assembly.

Cells employ many large macromolecular machines for the execution and regulation of processes that are vital for cell and organismal viability. Interestingly, cells cannot synthesize these machines as functioning units. Instead, cells synthesize the molecular parts that must then assemble into the functional complex. Many important machines, including chaperones such as GroEL and proteases such as the proteasome, comprise protein rings that are stacked on top of one another. While there is some experimental data regarding how stacked-ring complexes such as the proteasome self-assemble, a comprehensive understanding of the dynamics of stacked-ring assembly is currently lacking. Here, we developed a mathematical model of stacked-trimer assembly and performed an analysis of the assembly of the stacked homomeric trimer, which is the simplest stacked-ring architecture. We found that stacked rings are particularly susceptible to a form of kinetic trapping that we term deadlock, in which the system gets stuck in a state where there are many large intermediates that are not the fully assembled structure but that cannot productively react. When interaction affinities are uniformly strong, deadlock severely limits assembly yield. We thus predicted that stacked rings would avoid situations where all interfaces in the structure have high affinity. Analysis of available crystal structures indicated that indeed the majority-if not all-of stacked trimers do not contain uniformly strong interactions. Finally, to better understand the origins of deadlock, we developed a formal pathway analysis and showed that, when all the binding affinities are strong, many of the possible pathways are utilized. In contrast, optimal assembly strategies utilize only a small number of pathways. Our work suggests that deadlock is a critical factor influencing the evolution of macromolecular machines and provides general principles for understanding the self-assembly efficiency of existing machines

Src-like Adaptor Protein (Slap) Is a Negative Regulator of T Cell Receptor Signaling

Initiation of T cell antigen receptor (TCR) signaling is dependent on Lck, a Src family kinase. The Src-like adaptor protein (SLAP) contains Src homology (SH)3 and SH2 domains, which are highly homologous to those of Lck and other Src family members. Because of the structural similarity between Lck and SLAP, we studied its potential role in TCR signaling. Here, we show that SLAP is expressed in T cells, and that when expressed in Jurkat T cells it can specifically inhibit TCR signaling leading to nuclear factor of activated T cells (NFAT)-, activator protein 1 (AP-1)–, and interleukin 2–dependent transcription. The SH3 and SH2 domains of SLAP are required for maximal attenuation of TCR signaling. This inhibitory activity can be bypassed by the combination of phorbol myristate acetate (PMA) and ionomycin, suggesting that SLAP acts proximally in the TCR signaling pathway. SLAP colocalizes with endosomes in Jurkat and in HeLa cells, and is insoluble in mild detergents. In stimulated Jurkat cells, SLAP associates with a molecular signaling complex containing CD3ζ, ZAP-70, SH2 domain–containing leukocyte protein of 76 kD (SLP-76), Vav, and possibly linker for activation of T cells (LAT). These results suggest that SLAP is a negative regulator of TCR signaling

Development and implementation of worksite health and wellness programs: a focus on non-communicable disease

The development and implementation of worksite health and wellness programs (WHWPs) in the United States (US) hold promise as a means to improve population health and reverse current trends in non-communicable disease incidence and prevalence. However, WHWPs face organizational, economic, systematic, legal, and logistical challenges which have combined to impact program availability and expansion. Even so, there is a burgeoning body of evidence indicating WHWPs can significantly improve the health profile of participating employees in a cost effective manner. This foundation of scientific knowledge justifies further research inquiry to elucidate optimal WHWP models. It is clear that the development, implementation and operation of WHWPs require a strong commitment from organizational leadership, a pervasive culture of health and availability of necessary resources and infrastructure. Since organizations vary significantly, there is a need to have flexibility in creating a customized, effective health and wellness program. Furthermore, several key legal issues must be addressed to facilitate employer and employee needs and responsibilities; the US Affordable Care Act will play a major role moving forward. The purposes of this review are to: 1) examine currently available health and wellness program models and considerations for the future; 2) highlight key legal issues associated with WHWP development and implementation; and 3) identify challenges and solutions for the development and implementation of as well as adherence to WHWPs

Il meticciato nell'Italia contemporanea. Storia, memorie e cultura di massa.

L'idea diffusa degli "italiani brava gente" e della diversit\ue0 della nostra storia rispetto alla storia USA, segnata da razzismo istituzionale, si fonda sul silenziamento del passato coloniale e razzista italiano. Il ripudio della categoria di razza da parte dell'Italia repubblicana e la smentita scientifica dell'esistenza biologica della categoria non hanno cancellato la presenza della razza, formazione storico-culturale che paradossalmente esiste e non esiste. Priva di referenti oggettivi nella realt\ue0, la razza produce in essa effetti significativi, opera sia come categoria sociale e strumento di esclusione, sia come costruzione simbolica e istanza identitaria. A fronte del silenziamento del meticciato storico nell'uso pubblico della storia e nella memoria nazionali del secondo dopoguerra, il saggio sottolinea la presenza diffusa del meticciato nei prodotti della cultura di massa italiani contemporanei e ne indaga i significati con gli strumenti degli studi critici sulla razza e in prospettiva comparata tra Italia e Stati Uniti

Who will deliver comprehensive healthy lifestyle interventions to combat non-communicable disease? Introducing the healthy lifestyle practitioner discipline

Unhealthy lifestyle characteristics (i.e., physical inactivity, excess body mass, poor diet, and smoking) as well as associated poor health metrics (i.e., dyslipidemia, hyperglycemia, and hypertension) are the primary reasons for the current non-communicable disease crisis. Compared to those with the poorest of lifestyles and associated health metrics, any movement toward improving lifestyle and associated health metrics improves health outcomes. To address the non-communicable disease crisis we must: 1) acknowledge that healthy lifestyle (HL) interventions are a potent medicine; and 2) move toward a healthcare system that embraces primordial as much as, if not more than, secondary prevention with a heavy focus on HL medicine. This article introduces the Healthy Lifestyle Practitioner, focused on training health professionals to deliver HL medicine

Current trends in reducing cardiovascular risk factors in the United States: Focus on worksite health and wellness

Health care in the United States (US) is changing with a broad provision of health care services to every American due to the Affordable Care Act (ACA) slated to begin in January of 2014. An important aspect of the ACA is that US companies may begin to offer health insurance incentives to employees for participating in health and wellness initiatives. Moreover, since US employers directly absorb many of the financial costs associated with the high degree of cardiovascular (CV) risk factors present in their personnel, employers may be financially vested in improving employee health. However, employers must also consider the costs of developing and maintaining programs to improve employee health and their return on investment (ROI). This review will identify key risk factors to address in a worksite health and wellness program and to examine the performance of such programs in improving CV risk factors and their ROI. © 2014 Elsevier Inc

The affordable care act: New opportunities for cardiac rehabilitation in the workplace?

Many people affected by cardiovascular disease (CVD) are working age. Employers bear a large percentage of the costs associated with CVD. Employers pay 80 times more in diagnosis and treatment than in prevention, although there is evidence that 50% to 70% of all diseases are associated with preventable health risks. As a result, the worksite is an appealing location to deliver health care.Cardiac rehabilitation has developed a track record of delivering improved outcomes for patients with CVD. Partnerships between cardiac rehabilitation providers and worksite health programs have the potential to improve referral and participation rates of employees with CVD. The current era of health reform in the United States that has been stimulated by the Affordable Care Act provides an ideal opportunity to reconsider worksite health programs as an essential partner in the health care team. Copyright © 2014 by American College of Occupational and Environmental Medicine