Mobility, agriculture, and bone strength
Femoral cross sections from 22,000 years ago (Left) and 1,200 years ago (Right).
Declining bone strength relative to body size since the Pleistocene Epoch has been attributed to increasing sedentism in humans, with associated changes in social structure and health. Christopher Ruff et al. (pp. 7147–7152) measured the strength of the tibia, femur, and humerus from 1,842 people from sites throughout Europe that were as ancient as 33,000 years ago and as recent as the 20th century. The authors found little change in mediolateral, or side-to-side, bending strength in all the bones over time, but a decline in anteroposterior, or front-to-back, bending strength of the tibia and femur beginning in the Neolithic Period, around 7,000 years ago, and continuing through the Iron/Roman Period, about 2,000 years ago. The decline coincides with the onset of food production and reflects the gradual transition to a sedentary lifestyle as agricultural activity intensified. Bone strength changed little over the past 2,000 years, suggesting that mechanization and urbanization had less effect on bone strength than did the adoption of food production. The results suggest that mild changes in activity levels may be insufficient to stimulate changes in bone mass and that vigorous exercise may be required to increase bone strength, according to the authors. — P.G.
Linking hypertension and systemic inflammation
Hypertension increases the pressure load on the heart and is associated with chronic systemic inflammation, but the mechanisms that link hypertension to systemic inflammation are unclear. Using mice with conditional deletions, Wei-Yu Chen et al. (pp. 7249–7254) demonstrated that the heart’s response to high blood pressure is regulated by a signaling pathway in heart muscles that acts through ST2, a receptor for the proinflammatory cytokine IL-33. The authors found that excess pressure on the heart muscles induced IL-33 expression in cardiac endothelial cells, which line the circulatory system. Deletion of either IL-33 in endothelial cells or the ST2 receptor in cardiac muscle cells exacerbated the thickening of heart muscles due to high blood pressure. In addition, endothelial-derived IL-33 mediated local responses in cardiac muscle cells and induced a selective systemic inflammatory response after pressure overload. Further, pressure overload induced systemic circulating IL-33 and IL-13 as well as TGF-beta1, an effect that was abolished by deleting IL-33 in endothelial cells. The study demonstrates that endothelial cells are the major source of systemic IL-33 after the heart is subjected to pressure overload, and thus suggests a mechanistic link between high blood pressure and subsequent inflammatory responses, according to the authors. — S.R.
Gene editing, phage therapy, and antibiotic resistance
CRISPR-Cas system targets resistance plasmids and protects from lytic phages. Image courtesy of iApps Technologies.
Phage therapy, an approach predicated on tailored viruses that target pathogenic bacteria, could help counter the surge of antibiotic resistance, but the strategy suffers from shortfalls, including the difficulty of delivering phages into infected tissues and the frequent transfer of phage-resistance genes between bacteria. Using lambda phage, Ido Yosef et al. (pp. 7267–7272) transferred into the genome of antibiotic-resistant bacteria a clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated (CRISPR-Cas) gene-editing system programmed to seek and disrupt genes encoding β-lactamase enzymes, which confer resistance to last-resort antibiotics. The authors also inserted identical β-lactamase–encoding CRISPR-Cas target sequences into T7 phages, which are lethal to bacteria. When grown on agar dishes coated with the modified T7 phages, bacteria containing the engineered lambda phage were found to be sensitive to the targeted antibiotics, and 20-fold more resistant to the engineered T7 phages, compared with control bacteria, which remained antibiotic-resistant. Together, the phages selectively favored antibiotic-sensitive bacteria, suggesting that an approach that couples bacterial survival and antibiotic sensitivity might be used to treat exposed surfaces and hand sanitizers in hospitals, which are hotbeds of antibiotic resistance. The authors suggest that the use of phage mixtures, including mutant phages that infect many bacterial species, might help expand the narrow host range of phages and override bacterial resistance to phages, potentially surmounting longstanding hurdles to phage therapy. — P.N.
Gene expression profiles of single brain cells
Fetal human neurons (magenta) and astrocytes (cyan) grown in culture.
The human brain contains an enormous variety of cell types that differ in gene expression patterns. Previous approaches to classifying these cell types have been limited to using only a few gene or protein markers and analyzing whole populations of cells. Spyros Darmanis et al. (pp. 7285–7290) used single cell RNA sequencing to analyze the entire transcriptomes of 466 individual cells from human brain tissue. Using the sequence information, the authors could distinguish all of the known major brain cell types: astrocytes, oligodendrocytes, oligodendrocyte precursor cells, neurons, microglia, and vascular cells. Among the neurons, the authors identified seven subcategories consistent with previous classifications. The authors also analyzed the transcriptomes of fetal brain cells and identified gene expression differences between these cells and adult brain cells. Finally, the authors found that some adult neurons express genes of the major histocompatibility complex class I, suggesting that the neurons may be able to elicit an immune response. The results suggest that single cell RNA sequencing can be used to catalog and map the diversity of human brain cells, according to the authors. — B.D.
Potassium transporters in the Venus flytrap
Venus flytrap closing in on prey. Image courtesy of Sönke Scherzer, Jennifer Böhm, and Tanja Bieber.
The Venus flytrap (Dionaea muscipula), a well-characterized carnivorous plant, digests captured insect prey using enzyme-secreting glands that line the inside of an ephemeral, lobed structure that serves as the plant’s stomach. To determine how the plant absorbs prey-derived potassium ions (K+), crucial to growth and movement, Sönke Scherzer et al. (pp. 7309–7314) screened RNA molecules expressed in the gland cells of flytraps stimulated by insects and touch hormones, and identified two putative K+ transporters called DmKT1 and DmHAK5. When RNA molecules encoding each transporter were expressed together with a calcium-dependent kinase enzyme in Xenopus oocytes, an established experimental system for testing gene function, both transporters were found to be functional. Electrode recordings revealed that the transporters had complementary affinities and capacities for K+, suggesting that the two proteins allow the plant to absorb even trace amounts of the cation. As the flytrap digests entrapped insects, the transporters, activated by the calcium-sensing kinase in gland cells, together sequester and absorb K+, leading to rapid uptake of the cation if its concentration is relatively high and resulting in low remnant levels in the plant’s stomach. According to the authors, the findings lend support to previous suggestions of an insect-triggered, dual-affinity K+ uptake system in the flytrap. — P.N.
Sequela of diabetic eye disease
Ischemia and neovascularization in PDR.
Diabetic eye disease is a leading cause of blindness among working-age adults in the developed world. In its most severe form, this disease can restrict blood flow to the retina and trigger the expression of angiogenic factors that promote new blood vessel growth—a condition known as proliferative diabetic retinopathy (PDR). Savalan Babapoor-Farrokhran et al. (pp. E3030–E3039) extended previous studies suggesting that a potent mediator of angiogenesis, VEGF, may collaborate with other unknown angiogenic factors to promote PDR. The authors identified one of the angiogenic factors as angiopoietin-like 4 (ANGPTL4), a potent angiogenic mediator expressed at relatively high levels in the eyes of patients with PDR. Interestingly, ANGPTL4 expression was elevated in the ischemic retina in vivo, independently of VEGF levels. By contrast, aqueous fluid VEGF concentration did not appear to correlate with the potential for new blood vessel formation. Further studies revealed that ANGPTL4 inhibition may reduce the formation of new blood vessels; the effect was more pronounced with concurrent VEGF inhibition. According to the authors, the studies suggest a therapeutic target for the treatment of ocular neovascular disease and may have implications for the treatment of other diseases that stem from the unchecked growth of blood vessels. — A.G.