MEDICAL SCIENCES
Cytoplasmic reverse transcription and macular degeneration
Retina of a person with macular degeneration.
Alu mobile genetic elements propagate via transcription into RNA, which is reverse transcribed into complementary DNA (cDNA) by the L1 reverse transcriptase enzyme and integrated into the genome. Alu RNA accumulation induces death of retinal pigmented epithelium (RPE) in geographic atrophy, a severe form of age-related macular degeneration (AMD). To understand the mechanism of Alu RNA toxicity, Shinichi Fukuda, Akhil Varshney, et al. examined the relationship between the Alu replication cycle and RPE degeneration in mice. RPE degeneration required reverse transcription of Alu RNA by L1, but did not require genomic insertion of Alu cDNA. Reverse transcription occurred in the cytoplasm of cells, whereas it had previously been assumed to occur exclusively in the cell nucleus. Inhibiting cytoplasmic reverse transcription prevented RPE degeneration, but inhibiting nuclear reverse transcription did not. Cytoplasmic Alu cDNA synthesis occurred via self-priming, whereby part of the Alu RNA acts as a primer for its own reverse transcription. Analysis of multiple US health insurance databases containing over 100 million patients’ data revealed that use of nucleoside reverse transcriptase inhibitor (NRTI) drugs was associated with reduced risk of developing atrophic AMD. The results suggest that NRTIs should be explored as potential therapies for geographic atrophy, according to the authors. — B.D.
PNAS e2022751118 (2021)
ECOLOGY
Invasive species and phosphorus in the Great Lakes
Invasive quagga mussels extend their siphons from the sediment of Lake Michigan to feed and breathe.
The ecology of the Great Lakes has been dramatically altered by the invasion of quagga and zebra mussels, with primary production declining by up to 70% following their introduction. However, the role of the mussels in the cycling of phosphorus, the productivity-limiting nutrient in the Great Lakes for which inputs have been regulated, is not well known. Jiying Li et al. constructed a mass balance model to evaluate the impact of the invasive mussels on the phosphorus cycle. As filter feeders on lake floors, these mussels are able to ingest large quantities of particulate phosphorus from the water and redistribute it through physiological processes and decomposition. The results suggest that a single species, the invasive quagga mussel, may now be the primary regulator of phosphorus cycling in the lower four Great Lakes, owing to their enormous biomass. The authors found that the sensitivity of the geochemistry of the Great Lakes to changes in mussel population is increased and sensitivity to external nutrient load management is decreased. According to the authors, the results forewarn similar ecological changes in lakes across Europe and North America which have been invaded by the quagga and zebra mussels. — P.G.
PNAS e2008223118 (2021)
PLANT BIOLOGY
Stable antimicrobial peptides prevent and treat citrus greening
The most destructive citrus disease worldwide is citrus greening, or Huanglongbing (HLB), which is caused by the bacterium Candidatus Liberibacter asiaticus (CLas). Even though the disease is the biggest threat to the global citrus industry, costing billions of dollars in losses each year, there are no effective strategies to prevent infection or treat infected trees. To identify plant immune system molecules that could potentially address this problem, Chien-Yu Huang et al. compared small RNA and mRNA profiles of HLB-sensitive cultivars and HLB-tolerant citrus hybrids and relatives. This analysis revealed that HLB tolerance is associated with a class of molecules named stable antimicrobial peptides (SAMPs). Multiple SAMP injections into three HLB-positive citrus varieties reduced CLas levels, increased tree growth and leaf production, and prevented tree death and disease symptoms such as yellow striping on leaves when compared to injections of a mock solution. Next, the authors sprayed a SAMP solution or buffer as mock treatment onto healthy trees, then exposed the trees to CLas. SAMP application reduced infection rates and CLas levels, increased tree growth, and prevented tree death. According to the authors, SAMP treatments may represent a practical, eco-friendly, nontoxic, long-lasting, and effective strategy to prevent and treat citrus greening. — J.W.
PNAS e2019628118 (2021)
BIOPHYSICS AND COMPUTATIONAL BIOLOGY
Estimating the level of biological complexity that computers can simulate
Computers can simulate complex biological systems, but it is still unclear whether they will ever be able to fully model the molecular complexity of cells. Roland Netz and William Eaton used two approaches to estimate the computation times required to simulate the genetically simplest bacterium, Mycoplasma genitalium, for its two-hour doubling time and the human brain for one hour. Using molecular dynamics calculations, including quantum effects, to simulate a single bacterium would take 109 years using the current fastest super-computer. If computers continue to get faster at the current rate, decreasing this computational time down to one month would take 50 years, whereas bringing the time required to simulate the human brain down to one month using this approach would require 125 years. On the other hand, simulating a single bacterium by solving molecular kinetic equations to get the probability distribution of each type of molecule as a function of time would currently take one month of computation. However, it would take 1015 years to use this approach to simulate the human brain for one hour, and decreasing this computation time to one month could take 80 years. The authors conclude that the simplest bacterial cells could be simulated relatively soon, but modeling the human brain at the molecular level is unlikely to happen for many decades, if ever. — S.R.
PNAS e2022753118 (2021)
MEDICAL SCIENCES
Arsenic trioxide and chemotherapy deescalation in acute promyelocytic leukemia
Combining ATRA and ATO provides a mechanism to target PML-RARA and treat acute promyelocytic leukemia.
All-trans retinoic acid (ATRA) and anthracycline-based chemotherapy has proven effective for treating acute promyelocytic leukemia (APL). First used as an ATRA-chemotherapy relapse therapy, arsenic trioxide (ATO) has more recently gained acceptance as a highly curative and less toxic treatment for newly diagnosed APL. Li Chen et al. present results from the APL2012 trial evaluating whether ATO can replace or reduce chemotherapy in individuals with APL at different risks and thus reduce toxicity without negatively affecting clinical outcomes. Starting with a cohort of 855 patients, brought into complete remission via ATRA-ATO therapy, participants were placed into randomized risk-based groups and given different treatments: ATRA-ATO versus ATRA–anthracycline for low- and intermediate-risk patients; and ATRA-ATO–anthracycline versus ATRA–anthracycline–cytarabine for those at high risk. The authors reveal that both the 3-year and estimated 7-year disease-free survival rates for both the ATO and non-ATO groups were similar enough to confirm the statistical noninferiority of ATO, versus intensive chemotherapy, during the consolidation treatment. Furthermore, the ATO group exhibited significantly fewer hematological side effects compared with the non-ATO group. According to the authors, the findings suggest that the APL2012 ATO regimen represents an effective chemotherapy-deescalating strategy. — T.J.
PNAS e2020382118 (2021)
GENETICS
Human dispersal and dog domestication
Dogs are considered the first species domesticated by humans. However, the timing of dog domestication and when dogs first accompanied people to the Americas are unclear. To better understand the dynamics of early dog domestication, Angela Perri et al. compared population genetic results derived from the ancient DNA of human and dog remains excavated from Siberia, Beringia, and North America. Analyses of ancient dog DNA suggest that dogs were likely domesticated from Eurasian wolves by approximately 23,000 years ago, possibly in Siberia, where both humans and wolves were isolated together during the harshest period of the last ice age. From Siberia, domesticated dogs crossed the Bering Land Bridge with the first people to reach the Americas and traveled with them as humans rapidly dispersed throughout the continent, beginning around 15,000 years ago; further DNA analysis supports this theory in revealing late Pleistocene gene flow from ancient humans in northern Siberia to ancient Native Americans. The findings suggest that all ancient dogs belonged to a single haplogroup lineage, A2b, which is no longer found in the Americas. According to the authors, overlapping migration histories and population divergences of dogs and humans suggests that early domesticated dogs may have followed humans as they dispersed across the globe. — M.S.
PNAS e2010083118 (2021)
PSYCHOLOGICAL AND COGNITIVE SCIENCES
Increasing political tolerance
Rising political intolerance can ruin personal relationships and undermine open discussion. Emily Kubin et al. report that sharing personal experiences may help build respect between those with opposing political or moral beliefs. The authors investigated whether increasing perceptions of rationality in opponents could foster mutual respect and increase political tolerance. Across 15 studies, the authors examined two strategies for increasing the perceived rationality of political opponents: supporting one’s moral beliefs with facts versus supporting one’s moral beliefs with personal experiences. These studies, with varied methodologies, samples, and issues—including analyses of 300,978 comments for 194 YouTube videos expressing opinions about abortion, in-person conversations about guns, and 137 Fox News and CNN transcripts—reveal that people are more likely to respect moral stances of political adversaries that are based on personal experience rather than facts. The personal experiences most likely to build respect are issue relevant and those that involve suffering or vulnerability. According to the authors, the study, which leaves the question of persuasion aside, provides a concrete demonstration of how to create mutual respect and decrease political intolerance and also suggests that, in today’s “fake news” world, facts are seen as less true than anecdotes of personal vulnerability. — T.H.D.
PNAS e2008389118 (2021)
MICROBIOLOGY
Different types of bacteria cooperate to defend against a common predator
Bacteria naturally produce molecules to defend themselves against parasites, pathogens, and competitors. But studying isolated strains in the laboratory could miss bioactive compounds that are only produced when phylogenetically distinct bacteria interact in communities. Shuaibing Zhang, Ruchira Mukherji, et al. investigated whether different types of bacteria use natural products for cooperative defense against a common enemy, the amoeba Dictyostelium discoideum. The authors found that 28 of 58 bacterial strains isolated from forest soil were individually vulnerable to D. discoideum. Among 378 pairs of the vulnerable strains, only 11 cocultures consisting of a Pseudomonas strain and Paenibacillus sp. SZ31 could resist the predator, and only when Pseudomonas sp. SZ57 produced lipopeptides called syringafactins. But syringafactins did not directly kill the amoeba. Instead, the cocultures produced metabolites that degraded the syringafactins into fragments that were highly toxic to the amoeba. Specifically, exposure of Paenibacillus sp. SZ31 to syringafactin activated genes encoding peptidases—enzymes that can break down lipopeptides. According to the authors, the results underscore the importance of studying communities of distinct types of bacteria to discover bioactive natural products with ecological relevance and potential health benefits as antibiotics, anticancer agents, or other drugs. — J.W.
PNAS e2013759118 (2021)
EVOLUTION
Relatedness and cooperation in the gut microbiome
Microbiome sequencing sample kit. Image credit: Flickr/Tony Webster, licensed under CC BY 2.0.
Hamilton’s kin selection theory predicts that cooperation among individuals should increase with the genetic relatedness between them. Several arguments have cast doubt on the validity of this prediction, particularly in microbes, but the general relationship between relatedness and cooperation in microbes—i.e., over broad evolutionary history—has not been directly tested. Camille Simonet and Luke McNally compared genetic relatedness and various forms of microbial cooperation among more than 100 bacterial species, representing 37 genera, in gut microbiomes from 239 people. Relatedness was determined by comparing the genetic similarity of all representatives of a species within a single host versus similarity across all hosts. The authors assessed species’ propensity for cooperation by counting the number of genes related to each of six broad classes of cooperation: secreted products, biofilm formation, quorum sensing, siderophores, antibiotic degradation, and secretion systems. Relatedness was significantly associated with the number of genes coding for secreted products, siderophores, and biofilm formation, as well as for cooperative gene content overall. The results suggest that genetic relatedness predicts the evolution of cooperation across a broad diversity of microbes in real-world communities. According to the authors, manipulation of relatedness may enable engineering of the microbiome to enhance human health. — B.D.
PNAS e2016046118 (2021)
ENVIRONMENTAL SCIENCES
To predict the success of tree-planting schemes, look to villagers’ involvement
Community-led monitoring and direct benefits to communities are good indicators of success for tree-planting schemes in villages such as this one, in the Himalayan foothills. Image credit: Pushpendra Rana.
Posted on January 29, 2021
Amy McDermott
Tree-planting projects are sprouting up worldwide in an effort to sequester carbon. Acres of saplings are quick to plant but don’t necessarily have staying power: many die or are cut down before the trees grow to maturity. A recent study in World Development is among the first to empirically validate early predictors of long-term success for tree-planting projects. “We want to have accountability,” says coauthor Daniel Miller, an environmental social scientist at the University of Illinois at Urbana–Champaign. “Stakeholders want to know, is their money being well spent?” Continue Reading⇒