In This Issue

doi:10.1073/iti4309106

CHEMISTRY, IMMUNOLOGY

Getting to the heart of hemagglutinin

Influenza's hemagglutinin protein recognizes and binds host cells, with each strain's specific hemagglutinin structure determining the species it can infect. A modified version of the flu virus' primary cell-entry molecule could inspire improved vaccine design, according to a chemical analysis by Cheng-Chi Wang et al. The authors studied how glycans, or sugar chains, attached to hemagglutinin affect binding to host cells. The authors used a microarray of 24 types of synthesized sialic acid-containing saccharides, the molecules that hemagglutinin binds. Dissecting the role of each sugar chain on the viral and host sides, the authors determined that hemagglutinin molecules with fewer sugars showed stronger, but less specific, binding to host molecules. In addition, antibodies raised against these hemagglutinins bound and neutralized a broader spectrum of virus types than the fully glycosylated hemagglutinins typically used in vaccines, according to the authors. — T.H.D.

Removal of nonessential sugars on viral surface glycoproteins.

“Glycans on influenza hemagglutinin affect receptor binding and immune response” by Cheng-Chi Wang, Juine-Ruey Chen, Yung-Chieh Tseng, Che-Hsiung Hsu, Yu-Fu Hung, Shih-Wei Chen, Chin-Mei Chen, Kay-Hooi Khoo, Ting-Jen Cheng, Yih-Shyun E. Cheng, Jia-Tsrong Jan, Chung-Yi Wu, Che Ma, and Chi-Huey Wong (see pages 18137–18142)

BIOCHEMISTRY

Nitric oxide key to hardy bacterium's survival

Known as the world's toughest bacterium, Deinococcus radiodurans can withstand extreme temperatures, severe dehydration, and doses of radiation that would be lethal to larger organisms. Bhumit Patel et al. report that the bacterium's ability to survive radiation poisoning rests on a widespread metabolite, nitric oxide. In animals, this molecule has been shown to play a role in a number of biological processes, including protection from pathogens, regulation of vascular tension, hormone release, and in neuronal signaling. In Deinococcus, UV radiation increased the production of nitric oxide synthase, the enzyme responsible for creating nitric oxide. The authors knocked out the gene for this enzyme in D. radiodurans and found that, although these bacteria survived other stressors, they fared poorly after radiation exposure. The study shows that nitric oxide selectively activated the production of obgE, a gene involved in growth proliferation and stress response, and that overexpression of the enzyme in bacteria lacking nitric oxide synthase alleviated the growth defect after radiation damage. This research may help efforts to exploit the bacteria for bioremediation of toxic waste sites and also improve food safety efforts, as Deinococcus species have been found in some canned food products, according to the authors. — F.A.

Fluorescence detection of Deinococcus radiodurans' nitric oxide production.

“Endogenous nitric oxide regulates the recovery of the radiation-resistant bacterium Deinococcus radiodurans from exposure to UV light” by Bhumit A. Patel, Magali Moreau, Joanne Widom, Huan Chen, Longfei Yin, Yuejin Hua, and Brian R. Crane (see pages 18183–18188)

BIOPHYSICS AND COMPUTATIONAL BIOLOGY

Stretched DNA melts apart

The structure and elastic properties of DNA affect a variety of cellular processes, including cell division, protein-induced DNA bending, and twisting and looping, which are necessary for transcription. To discover how molecules of double-stranded DNA behave when stretched, Joost van Mameren et al. investigated the elasticity of the nucleic acid with single-molecule tools, including fluorescent dyes, microfluidics, optical tweezers, and fluorescence microscopy. With one end of each strand attached to an inflexible microsphere substrate, double-stranded DNA required 65 piconewtons (pN) of force to begin coming apart. At this force, “overstretching” initiated with fraying at the extremities that moved consistently in both directions until the double strand pulled apart to form two single strands. Damaged points in the phosphodiester backbone also acted as nucleation points for strand separation within a molecule. For DNA with both strands fixed to a solid substrate, the force required to separate the strands rose to 110 pN, and overstretching initiated from adenine and thymine-rich regions, similar to thermal melting. These results may provide a basis for the understanding of the thermodynamics of DNA and DNA-protein interactions, according to the authors. — F.A.

Stretched DNA melting.

“Unraveling the structure of DNA during overstretching by using multicolor, single-molecule fluorescence imaging” by Joost van Mameren, Peter Gross, Geraldine Farge, Pleuni Hooijman, Mauro Modesti, Maria Falkenberg, Gijs J. L. Wuite, and Erwin J. G. Peterman (see pages 18231–18236)

NEUROSCIENCE

Peptide may play a critical role in Alzheimer's disease

One of the leading theories of the cause of Alzheimer's disease rests on the prevalence of amyloid-β (Aβ) peptides in the brains of patients. However, research has shown a limited correlation between the number of these peptides in diseased brains and disease progression, and neuroimaging techniques have shown the presence of Aβ plaques in 20–40% of cognitively normal individuals. These peptides form when the presenilin protease complex cleaves amyloid precursor proteins (APP) in a reaction that also generates short APP intracellular domain (AICD) proteins. Kaushik Ghosal et al. overexpressed AICD in mouse brains and report that this peptide produced Alzheimer's-like symptoms in the animals. Although the levels of APP and Aβ peptides remained constant, mice with elevated AICD showed an increase in a protein found in neurofibrillary tangles that are common in Alzheimer's patients. The animals also experienced deficits in working memory and neurodegeneration. Treatment with lithium alleviated the memory-related symptoms in the mice; the drug blocks an enzyme, glycogen synthase kinase-3β, which is elevated in the brains of human Alzheimer's patients and which was also activated in the animals. The authors also observed increased levels of AICD in the brains of human patients. The study may improve researchers' understanding of Alzheimer's disease progression and could aid the development of therapeutics, according to the authors. — F.A.

Sagittal brain sections from mice.

“Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain” by Kaushik Ghosal, Daniel L. Vogt, Man Liang, Yong Shen, Bruce T. Lamb, and Sanjay W. Pimplikar (see pages 18367–18372)

PHARMACOLOGY

Peptide may help prevent cocaine relapse

Blocking the brain's kappa opioid receptors, which are widely believed to be the binding sites for opiate drugs, may elicit antidepressant and antianxiety activity. A kappa opioid receptor (KOR) antagonist developed by Jane Aldrich et al. could prevent stress-induced relapse in cocaine abuse. Most existing KOR-selective antagonists have a long duration of activity, persisting for weeks. To produce antagonists with a shorter duration of activity, the authors looked to peptides, which are quickly degraded by enzymes in the body. The authors added a chemical ring to a KOR-selective peptide and the resulting compound, zyklophin, can cross the blood–brain barrier, bind to KORs, and reduce stress-induced, cocaine-seeking behavior in mice. With an activity lasting less than 12 hours and the ability to be administered by subcutaneous injection, zyklophin shows promise as a potential therapeutic, according to the authors. — T.H.D.

“Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of action” by Jane V. Aldrich, Kshitij A. Patkar, and Jay P. McLaughlin (see pages 18396–18401)

POPULATION BIOLOGY, APPLIED MATHEMATICS

“Roaming” health care workers could trigger hospital outbreaks

A super-spreading event occurs in a hospital when infections appear to spread from one patient to many. Laura Temime et al. used a mathematical model of a hypothetical intensive-care unit to examine whether certain health-care workers (HCWs) play a disproportionate role in spreading common hospital-based pathogens such as antibiotic-resistant Enterococci or Staphylococcus aureus. The authors separated HCWs into three groups: a “nurse-like” group made frequent visits to a small number of patients; a “physician-like” group made infrequent visits to a larger number of patients; and a “peripatetic” group visited all patients daily. Infection outbreaks increased when HCWs failed to follow standard hand-washing procedures. However, infections increased three-fold when peripatetic HCWs failed to wash their hands compared with the nurse cohort. The infection rate when one peripatetic HCW did not hand-wash was equivalent to the infection rate when 23% of all HCWs on the ward failed to do so, making them potential “superspreaders.” Hygiene compliance in hospitals may be more effective if focused on individual workers, rather than the hospital as a whole, according to the authors. — B.A.

“Peripatetic health-care workers as potential superspreaders” by Laura Temime, Lulla Opatowski, Yohan Pannet, Christian Brun-Buisson, Pierre Yves Boëlle, and Didier Guillemot (see pages 18420–18425)