New mechanism in the function of a nearly universal biological structure will impact fundamental biology, design of pharmaceuticals

Main Category: Biology / Biochemistry
Also Included In: Pharma Industry / Biotech Industry
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
New mechanism in the function of a nearly universal biological structure will impact fundamental biology, design of pharmaceuticals

Just 12 molecules of water cause the long post-activation recovery period required by potassium ion channels before they can function again. Using molecular simulations that modeled a potassium channel and its immediate cellular environment, atom for atom, University of Chicago scientists have revealed this new mechanism in the function of a nearly universal biological structure, with implications ranging from fundamental biology to the design of pharmaceuticals. Their findings were published online in Nature.

"Our research clarifies the nature of this previously mysterious inactivation state. This gives us better understanding of fundamental biology and should improve the rational design of drugs, which often target the inactivated state of channels" said Benoît Roux, PhD, professor of biochemistry and molecular biology at the University of Chicago.

Potassium channels, present in the cells of virtually living organisms, are core components in bioelectricity generation and cellular communication. Required for functions such as neural firing and muscle contraction, they serve as common targets in pharmaceutical development.

These proteins act as a gated tunnel through the cell membrane, controlling the flow of small ions into and out of cells. After being activated by an external signal, potassium channels open to allow ions through. Soon after, however, they close, entering an inactive state and are unable to respond to stimuli for 10 to up to 20 seconds.

The cause of this long recovery period, which is enormously slow by molecular standards, has remained a mystery, as structural changes in the protein are known to be almost negligible between the active and inactivated states - differing by a distance equivalent to the diameter of a single carbon atom.

To shed light on this phenomenon, Roux and his team used supercomputers to simulate the movement and behavior of every individual atom in the potassium channel and its immediate environment. After computations corresponding to millions of core-hours, the team discovered that just 12 water molecules were responsible for the slow recovery of these channels.

They found that when the potassium channel is open, water molecules quickly bind to tiny cavities within the protein structure, where they block the channel in a state that prevents the passage of ions. The water molecules are released slowly only after the external stimulus has been removed, allowing the channel to be ready for activation again. This computer simulation-based finding was then confirmed through osmolarity experiments in the laboratory.

"Observing this was a complete surprise, but it made a lot of sense in retrospect," Roux said. "Better understanding of this ubiquitous biological system will change how people think about inactivation and recovery of these channels, and has the potential to someday impact human health."

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The work was supported by grants from the National Institutes of Health. Computation resources were provided by Oak Ridge National Laboratory, the National Resource for Biomedical Supercomputing and the Pittsburgh Supercomputing Center.

University of Chicago Medical Center

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New drug targets discovered for aggressive breast cancer

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Research publication: The research findings described in the press release was published in the July 2nd, 2013 issue of PNAS (Proceedings of the National Academy of Sciences, USA) under the title “Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis”.

Authors: Shuet Theng Leea,1, Min Fenga,1, Yong Weib,1, Zhimei Lia, Yuanyuan Qiaoa, Peiyong Guanc, Xia Jianga, Chew Hooi Wonga, Kelly Huynhd, Jinhua Wangd, Juntao Lic, K. Murthy Karuturic, Ern Yu Tane, Dave S. B. Hoond, Yibin Kangb, and Qiang Yua,f,g*

a. Cancer Biology and Pharmacology, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672;

b. Department of Molecular Biology, Princeton University, Princeton, NJ 08544;

c. Information and Mathematical Science, Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore 138672;

d. Department Molecular Oncology, John Wayne Cancer Institute, Santa Monica, CA 90404;

e. Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433;

f. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and

g. Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore

1. These authors contributed equally to this study.

* Correspondance: Qiang Yu, yuq@gis.a-star.edu.sg. Tel: (65)6808-8127

[1] Protein tyrosine phosphatases, are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. These enzymes are key regulatory components in signal transduction pathways and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation. (https://en.wikipedia.org/wiki/Protein_tyrosine_phosphatase)

Agency for Science, Technology and Research (A*STAR), Singapore

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Most ward nurses say time pressures force them to "ration" care, UK

Main Category: Nursing / Midwifery
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
Most ward nurses say time pressures force them to "ration" care, UK

Most ward nurses say they are forced to ration care, and not do or complete certain aspects of it - including adequate monitoring of patients - because they don't have enough time, indicates research published online in BMJ Quality & Safety.

The lower the nurse headcount, the greater the risk, the study shows, prompting the researchers to suggest that hospitals could use episodes of missed care as an early warning sign that nurse staffing levels are too low to provide safe, high quality care.

They base their findings on a survey of almost 3000 registered nurses working in 401 general medical/surgical wards in 46 acute care NHS hospitals across England between January and September 2010.

The questions, which covered five different domains, were designed to gauge the prevalence of missed care - care that nurses deemed necessary, but which they were unable to do or complete because of insufficient time.

Thirteen different aspects of nursing care were included in the survey, ranging from adequate patient monitoring, through to adequate documentation of care, and pain management.

The researchers wanted to find out if there was any association between nurse staffing levels and the number of these episodes, and whether these were linked to overall perceptions of the quality of nursing care and patient safety in a ward.

So they asked nurses to rate the quality of care on their ward, and to indicate how many patients needed assistance with routine activities and frequent monitoring. The researchers also assessed the quality of the working environment using a validated scoring system - the Practice Environment Scale (PES).

The results showed that 86% of the 2917 respondents said that at least one of the 13 care activities on their last shift had been needed, but not done, because of lack of time. On average, nurses were unable to do or complete four activities.

The most commonly rationed of these were comforting and talking to patients, reported by 66% of participating nurses; educating patients (52%); and developing or updating care plans (47%).

Pain management and treatment/procedures were the activities least likely to be missed, reported as not being done by only 7% and 11%, respectively.

Higher numbers of patients requiring assistance with routine daily living or frequent monitoring were linked to higher numbers of missed care activities.

Staffing levels varied considerably across wards, but the average number of patients per nurse was 7.8 on day shifts and 10.9 at night.

The fewer patients a nurse looked after, the less likely was care to be missed or rationed, and the lower was the volume of these episodes. Staffing levels were significantly associated with rationing eight of the 13 care activities.

Nurses looking after the most (in excess of 11) patients were twice as likely to say they rationed patient monitoring as those looking after the fewest (six or fewer). Adequate documentation and comforting/talking with patients also suffered the most.

Staffing levels of healthcare assistants had no bearing on rationing of care. But the quality of the work environment did, with the average number of care activities significantly lower (2.82) in the best than in the worst (5.61).

Around eight care activities were left undone on wards nurses rated as "failing" on patient safety, compared with around 2.5 on wards rated as "excellent."

"Our findings raise difficult questions for hospitals in a climate where many are looking to reduce - not increase - their expenditure on nurse staffing," comment the authors, who go on to say that hospitals would have to reduce the number of patients to seven or fewer per registered nurse to significantly reduce the amount of care left undone.

But they suggest: "Hospitals could use a nurse-rated assessment of "missed care" as an early warning measure to identify wards with inadequate nurse staffing."

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Mathematical biologists study how to best prevent bullet deaths

Main Category: Public Health
Article Date: 30 Jul 2013 - 1:00 PDT Current ratings for:
Mathematical biologists study how to best prevent bullet deaths

Aiming to quell heated national debate about gun control with factual answers, two UC Irvine mathematicians have designed parameters to measure how to best prevent both one-on-one killings and mass shootings in the United States. Their paper appears in the journal PLOS ONE.

"It's time to bring a scientific framework to this problem," said lead author Dominik Wodarz, a mathematical biologist who works on disease and evolutionary dynamics. His co-author and wife, Natalia Komarova, a mathematician who studies biomedical and social trends, added: "Can we design a rational way to argue about guns?"

Both were appalled not just by the December shooting deaths of 20 youngsters and eight adults in Newtown, Conn., but also by the bitterly emotional dispute over weapons that erupted anew. They decided to put their professional expertise to work.

"This debate cannot be settled satisfactorily by verbal arguments alone, since these are often driven by opinion and lack a solid scientific backing," the authors write. "What is under debate is essentially an epidemiological problem: How do different gun control strategies affect the rate at which people become killed by attackers, and how can this rate be minimized?"

The duo reviewed available data stretching as far back as World War I, then drew up equations to compute whether policies ranging from a total firearm ban to "arm everyone" increase or decrease homicides. After running the numbers, they found that in more common domestic and one-on-one crimes, reduced legal gun availability - if properly enforced - is likelier to lower deaths. But in rare mass shootings, armed citizens might save lives if sufficiently trained to avoid accidentally shooting fleeing bystanders.

They note that data is missing that could strengthen their results. For instance, homeowners who used a weapon to stop a robbery might not make a report to police. "Stand your ground" laws being widely discussed in the wake of Trayvon Martin's killing could influence the parameters too. "Whether such laws better protect the public or increase deaths needs to be determined statistically," Wodarz said. "Do you have a greater chance of dying if you run or if you face your attacker with a weapon?"

The authors say key parts of their equations should be studied more closely: the fraction of offenders who illegally possess a gun, the statistical degree of protection provided by legal gun ownership, and the number of people who are legally carrying a gun when attacked. Comprehensive data in those areas, they say, could further aid the development and implementation of effective policies.

Federal funding for gun control research was essentially nonexistent for nearly two decades, but President Barack Obama in January labeled firearm deaths a public health crisis and ended the longstanding freeze. About 11,000 Americans die each year from gunshot homicides.

A large number of peer reviews - 11 in total - were solicited by journal editors; two or three are the norm. A wide array of opinions were expressed, ranging from enthusiastically positive and constructive to a critic who stated that scientific methods would never be useful in this area.

The authors were warned to be prepared for heated responses to their paper but believe it's critical to bring the best tools of research to the issue.

"If the current discussion could be steered toward science, rather than having a heated debate without much of a logical foundation, a big step forward toward saving lives would be achieved," they said.

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Materialism may not entirely deserve its bad reputation

Main Category: Psychology / Psychiatry
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
Materialism may not entirely deserve its bad reputation

Despite being much-maligned, materialism is not always bad for consumers.

Loneliness may cause materialism, but the opposite is not necessarily true, according to a new study in the Journal of Consumer Research.

"It is widely believed that there is a vicious cycle in which loneliness leads to materialism and materialism in turn contributes to loneliness. But, contrary to popular beliefs about the universal perils of materialism, the pursuit of material possessions as part of a lifestyle of 'happy hedonism' may not actually be detrimental to consumer well-being when kept within certain limits," writes author Rik Pieters (Tilburg University).

The author studied more than 2,500 consumers over a period of six years and found that loneliness was likely to lead to materialism. However, while materialism sometimes caused loneliness, it could also decrease loneliness. Loneliness increased over time for consumers who valued material possessions as a measure of success or a type of "happiness medicine," but decreased for those who sought possessions just for the sheer joy and fun of consumption.

The study also found that singles were lonelier than other consumers. Singles pursued material possessions less for the pleasure of acquiring and owning them and more as a type of "material medicine." In addition, men were more likely to view possessions as a measure of success in life and as a material medicine, whereas women viewed possessions more as a source of "material mirth."

Materialism does not necessarily lead to a vicious cycle in which shopping makes consumers lonelier. While materialism can be bad for consumers who seek meaning or status through their possessions, it can actually benefit consumers who acquire possessions solely for pleasure and comfort. In other words, materialism may not entirely deserve its bad reputation.

"While materialism can increase loneliness, it may actually reduce loneliness for some consumers. Increasing opportunities for social interaction and improving social skills may be more effective at reducing loneliness than the usual appeals to turn off the television or stop shopping," the author concludes.

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Rik Pieters. "Bidirectional Dynamics of Materialism and Loneliness: Not Just a Vicious Cycle." Journal of Consumer Research: December 2013. For more information, visit http://ejcr.org/.

University of Chicago Press Journals

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MAPS technology may generate vaccines conferring strong immunity at reduced cost and risk

Main Category: Immune System / Vaccines
Article Date: 30 Jul 2013 - 2:00 PDT Current ratings for:
MAPS technology may generate vaccines conferring strong immunity at reduced cost and risk

A new method of vaccine design, called the Multiple Antigen Presentation System (MAPS), may result in vaccines that bring together the benefits of whole-cell and acellular or defined subunit vaccination. The method, pioneered by researchers at Boston Children's Hospital, permits rapid construction of new vaccines that activate mulitple arms of the immune system simultaneously against one or more pathogens, generating robust immune protection with a lower risk of adverse effects.

As reported by Fan Zhang, PhD, Ying-Jie Lu, PhD, and Richard Malley, MD, from Boston Children's Division of Infectious Disease, in the Proceedings of the National Academy of Sciences on July 29, the method could speed development of new vaccines for a range of globally serious pathogens, or infectious agents.

Broadly speaking, the vaccines available today fall into two categories: whole-cell vaccines, which rely on weakened or killed bacteria or viruses; and acellular or subunit vaccines, which include a limited number of antigens - portions of a pathogen that trigger an immune response. Both approaches have advantages and disadvantages.

"Whole-cell vaccines elicit a broad range of immune responses, often just as an infection would, but can cause side effects and are hard to standardize," said Malley. "Acellular vaccines can provide good early immunity with less risk of side effects, but the immune responses they induce wane with time."

The MAPS method may allow vaccine developers to take a middle ground, where they can link multiple protein and polysaccharide (sugar) antigens from one or more pathogens together in a modular fashion, much as one would connect Lego blocks.

The resulting complex - which resembles a scaffold of polysaccharides studded with proteins - can stimulate both antibody and T-cell responses simultaneously much like whole-cell vaccines, resulting in stronger immunity to the source pathogen(s). However, because the composition of a MAPS vaccine is well defined and based on the use of isolated antigens (as one would find with an acellular vaccine) the risk of side effects should be greatly reduced.

For instance, mice injected with a MAPS vaccine combining proteins from tuberculosis (TB) and polysaccharides from Streptococcus pneumoniae (pneumococcus) mounted vigorous antibody and T-cell responses against TB, whereas those vaccinated with TB protein antigens alone mounted only an antibody response.

Similarly, 90 percent of mice given a MAPS-based vaccine containing multiple pneumococcal polysaccharide and protein antigens were protected from a lethal pneumococcus infection, mounting strong antibody and T-cell responses against the bacteria. By contrast, 30 percent of mice vaccinated with the same antigens in an unbound state survived the same challenge.

"The MAPS technology gives you the advantages of: whole-cell vaccines while being much more deliberate about which antigens you include; doing it in a quantitative and precise way; and including a number of antigens so as to try to replicate the effectiveness of whole-cell vaccination," Malley explained. "The immunogenicity of these constructs is greater than the sum of their parts, somewhat because they are presented to the host as particles."

The system relies on the interactions of two compounds, biotin and rhizavidin, rather than covalent binding as is used in most of the current conjugate vaccines. To build a MAPS vaccine, biotin is bound to the polysaccharide(s) of choice and rhizavidin to the protein(s). The biotin and rhizavidin then bind together through an affinity interaction analogous to Velcro. The construction process is highly efficient, significantly reducing the time and cost of vaccine development and production.

While his team's initial work has focused on bacterial pathogens, Malley believes the technology could impact vaccine development for a broad range of pathogens, in particular those of importance in the developing world. "Technically, one could construct MAPS vaccines for viruses, parasites, even cancer antigens," he said. "And the modularity is such that one could include antigens from multiple pathogens into the same vaccine, allowing the development of combinatorial vaccines much more efficiently."

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Fan Zhang, Ying-Jie Lu, and Richard Malley "Multiple antigen-presenting system (MAPS) to induce comprehensive B- and T-cell immunity" Published online before print July 29, 2013, doi: 10.1073/pnas.1307228110

The study was supported by the National Institute for Allergy and Infectious Diseases (grant R01AI067737) and the Translational Research Program at Boston Children's Hospital.

Boston Children's Hospital

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No improvement seen in HIV-associated lymphoma survival during the antiretroviral therapy era

Main Category: Lymphoma / Leukemia / Myeloma
Also Included In: HIV / AIDS
Article Date: 30 Jul 2013 - 0:00 PDT Current ratings for:
No improvement seen in HIV-associated lymphoma survival during the antiretroviral therapy era

Stable survival rates were observed for HIV-associated lymphoma patients during the antiretroviral therapy (ART) era in the US, according to a new study published in the Journal of the National Cancer Institute.

Studies have shown that HIV infection increases the risk of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) and that incidence for many lymphoma types has not decreased in the ART era. Furthermore, lymphoma is the most frequent cancer-related cause of death among HIV-infected persons. However, trends in presentation and survival have not been investigated among HIV-associated lymphoma patients in routine care since the beginning of the ART era.

Satish Gopal, M.D., M.P.H., from the Program in Global Oncology at the Lineberger Comprehensive Cancer Center of the University of North Carolina, and colleagues compared differences in presentation and survival, across histologic subtypes and diagnosis years, among HIV-infected lymphoma patients. They also examined predictors of death in this population. Data from 476 HIV-associated lymphoma patients living in the US who were diagnosed with various types of lymphoma including HL, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), primary central nervous system lymphoma (PCNSL), and other types of NHL, between 1996 and 2010 were analyzed using various statistical methods.

Their results demonstrate that HIV-associated lymphoma is heterogeneous and changing since the ART era began. Clinical presentations across the different lymphoma subtypes was highly variable during the study period (79 HL, 201 DLBCL, 56 BL, 54 PCNSL, and 86 with other NHL). Histologic shifts in the proportion of BL vs other NHL subtypes is increasing consistent with other reports. Data showed that more recently diagnosed patients were older and more likely to be male, of nonwhite/nonblack ethnicity (primarily Latino patients), to be men who have sex with men, and to have prior AIDS-related illness. They were also more likely to be on ART at lymphoma diagnosis with higher CD4 counts and better HIV control. The authors also report that more recent diagnosis year was not associated with decreased mortality and that 61.6% of patients with HIV-associated HL were alive 5 years after lymphoma diagnosis, compared with 50.0% for BL, 44.1% for DLBCL, 43.3% for other NHL, and 22.8% for PCNSL. Of note, lymphomas occurring on ART were associated with a doubling of mortality, which may suggest important biologic differences between tumors developing on and off ART, although these results require confirmation.

Gopal and colleagues conclude, "These results highlight an ongoing need to elucidate lymphoma biology and optimize treatments for this challenging population to reduce deaths from one of the leading causes of mortality in the modern ART era."

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In an accompanying editorial, Kieron Dunleavy, M.D., and Wyndham H. Wilson, M.D., Ph.D., from the Metabolism Branch of the Center for Cancer Research at the National Cancer Institute, state the findings reflect the shifting demographics of the HIV epidemic in the US. However, the shift towards more biologically favorable and curable types of lymphoma has not resulted in improved survival over the study period. They assert, "In conclusion, because HIV-associated lymphomas are potentially as curable as those arising in HIV-negative patients, it is critical that they be approached with the same care as HIV negative cases."

Journal of the National Cancer Institute

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