SEPTEMBER 15, 2020

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www.pnas.org/cgi/doi/10.1073/iti3720117 PNAS | September 15, 2020 | vol. 117 | no. 37 | 22605–22608

Reconstructing ancient text using machine learning

Cuneiform, one of the earliest writing sys-tems in the world, was developed in Meso-potamia and used throughout the ancient Near East from the 3rd millennium BCE to the 1st century CE. Hundreds of thou-sands of inscribed clay tablets have been discovered in the past two centuries, but most contain sections that require resto-ration. Ethan Fetaya, Shai Gordin, et al. (pp. 22743–22751) report that modern machine-learning methods could help fill the gaps in ancient Babylonian cuneiform tablets. The authors explored an alterna-tive approach to manual restoration by experts, developing machine-learning algorithms to improve the current recon-struction process for partly preserved texts. The authors used 1,400 digitized texts from the 6th to 4th century BCE to train the algorithms, limiting the corpus to legal, economic, and administrative documents, which have a highly structured syntax. The algorithms reached 85% accuracy when automatically completing texts from which the authors had randomly removed tokens, or words. To extend the types of manuscripts to literary and scientific genres, the authors note, more digitized data is needed. According to the authors, the model represents a first step in restoring lost ancient heritage on a large scale, and the resulting online tool, Atrahasis, can aid scholarly analysis. — T.H.D.

Neural correlates of collaboration

Research on social interactions through hyper-scanning, the simultaneous imaging of multiple interacting brains, is limited. Hua Xie et al. (pp. 23066–23072) performed MRI scans of individu-als playing a game in groups of three. In total, 36 adult participants were grouped into 12 triads who played a version of Pictionary, a game in which play-ers must guess a word depicted by another player. Participants first worked alone to depict a word and evaluate other team members’ drawings, and then collaborated with team members to depict words together while seeing each other’s drawings on a shared screen. Compared with independently com-pleting the drawing task, collaboration increased activation and synchrony in brain regions implicated in social cognition and interaction, including the right temporo-parietal junction (TPJ). Increased synchrony in the right TPJ was also positively associated with

Line art and transliteration of Achaemenid-period Babylonian text YOS 7 51 from the Eanna archive in Uruk. Fragmentary upper half of obverse marked by a red square.

Hot color contrast map showing brain regions that are activated more intensely during collaboration than during independent tasks. Cool color map showing brain regions synchronized across participants during collaboration and associated positively with team performance.

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team performance, suggesting that the right TPJ may be essential for improving coordination. Furthermore, the right TPJ, which is thought to be associated with the reorientation of attention to unexpected stimuli, may also play a role during collaboration when team-mates provide novel and salient ideas, according to the authors. — M.S.

Multiplexed conditional CRISPR genome editingIn the fruit fly Drosophila melanogaster, CRISPR gene editing has so far relied almost entirely on the Cas9 nuclease. Fillip Port, Maja Starostecka, and Michael Boutros (pp. 22890–22899) developed a platform for efficient gene editing in Drosophila that uses a Cas12a nuclease, which recognizes sites orthog-onal to Cas9. The authors found that Cas12a from Lachnospiraceae bacterium (LbCas12a) can mediate robust mutagenesis of endogenous target genes in Drosophila. Activity of LbCas12a is highly dependent on temperature, enabling temperature-modulated genome editing. In addition, LbCas12a can directly use compact arrays of several CRISPR RNAs for mul-tiplexed genome engineering of several loci in paral-lel, and conditional expression of LbCas12a mediates tissue-specific mutagenesis. The authors also found that a D156R point mutation in LbCas12a rendered

the enzyme more active, and this variant, which they termed Cas12a+, outperformed wild-type LbCas12a as well as another Cas9 system in identifying essential genes. The authors conclude that a Cas12a nuclease system can perform efficient genome engineering in a variety of tissues in Drosophila and suggest that it enables targeting of previously inaccessible genomic target sites and facilitates simultaneous mutagenesis

of multiple loci. The findings highlight the advan-tages of a genetically encoded CRISPR-Cas12a sys-tem in a multicellular organism, according to the authors. — S.R.

Visual experience and face selectivityThe fusiform face area (FFA) is a brain region that selectively responds to and helps perceive faces, but it is unclear whether visual experience is required for face selectivity to develop. N. Apurva Ratan Murty et al. (pp. 23011–23020) tested whether face selectivity can arise in congenitally blind individuals. The authors

scanned sighted participants with functional MRI as the participants either viewed or haptically explored 3D-printed faces and three other control stimulus types, and found that the FFA had a significantly higher response to faces than to the other stimuli. Similar functional MRI scanning of congenitally blind individuals while they haptically explored 3D-printed faces and the other stimuli revealed robust face- selective activation in the brain’s lateral fusiform gyrus. Because most congenitally blind participants showed haptic face selectivity in a brain location similar to where visual face selectivity was found in sighted participants, the authors suggest that see-ing faces is not necessary for the development of face-selective regions in the brain. Resting functional MRI correlation fingerprints predictive of face selec-tivity were similar in sighted and blind participants,

22606 | www.pnas.org/cgi/doi/10.1073/iti3720117 In this issue

Tissue-specific expression of Cas12a in the Drosophila eye primordium.

Tactile functional MRI paradigm. Image credit: Steven P. Shannon (Massachusetts Institute of Technology, Cambridge, MA).

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www.pnas.org/cgi/doi/10.1073/iti3720117 PNAS | September 15, 2020 | vol. 117 | no. 37 | 22607

suggesting a role for long-range connectivity in determining the location of face selectivity in the brain. According to the authors, the findings suggest that visual experience is not necessary for the devel-opment of face-selective circuits in the brain. — S.R.

Illusory motion in stationary patternsCertain stationary patterns, such as sawtooth luminance gradients, can elicit the perception of illusory motion in diverse vertebrate species. How-ever, the mechanisms underlying these illusions remain unclear. Using fruit flies as a model system, Margarida Agrochao, Ryosuke Tanaka, et al. (pp. 23044–23053) combined behavioral measurements, genetic silencing, and neural imaging to explore the mechanisms. The authors positioned tethered fruit flies on air-supported balls and presented station-ary sawtooth luminance gradients on panoramic screens. The patterns triggered a turning response, which is known to be elicited by certain rotating patterns, suggesting that the flies perceived illu-sory motion. Genetic silencing and calcium imag-ing experiments showed that motion-detecting T4 and T5 neurons mediate the perception of illusory motion, which is driven by imbalanced contribu-tions of the responses of direction-selective neurons to stationary edges. Psychophysical experiments involving 11 humans suggest that similar neuronal mechanisms may underlie the same kind of illusory motion perception across diverse phyla, pointing to convergent evolution of common strategies for motion detection. According to the authors, this illusory motion perception may be a byproduct of the brain’s strategies to efficiently process motion in natural environments. — J.W.

Mechanism of thalidomide’s hypnotic effect Thalidomide had been prescribed as a nonbarbi-turate hypnotic to treat insomnia before the drug was withdrawn for causing severe teratogenic, or birth, defects. Although the drug was subsequently reintroduced to treat certain forms of cancer, the mechanism of the drug’s hypnotic effect is unclear. Yuki Hirose et al. (pp. 23106–23112) examined whether direct inhibition or modification of the cereblon (CRBN)-mediated ubiquitin/proteasome pathway— the mechanism of thalidomide’s teratogenic and cancer-fighting action—also explains the drug’s hyp-notic mode of action. Using mice with a thalidomide- resistant mutant allele of the CRBN gene, the authors found that thalidomide produced similar hypnotic effects on mutants and their wild-type littermates, including comparable increases in non-REM sleep time, decreases in excitatory synaptic transmission, and patterns of neuronal signaling consistent with sleep induction. Because the hypnotic effects were

indistinguishable between mutant and wild-type mice, the authors suggest that thalidomide acts via some of the same downstream mechanisms as gen-eral anesthetics and sedatives such as benzodiaze-pine, which enhance the neurotransmitter GABA. The findings also suggest that the hypnotic effects of thalidomide can potentially be disassociated from its teratogenicity, according to the authors. — T.J.

Species interactions, biodiversity, and climate change A growing number of field studies have documented how shifts in temperature and precipitation can change species diversity, and how the rate and direc-tion of the change depend on contextual differences between individual sites. Vigdis Vandvik et al. (pp. 22858–22865) report that site-specific responses to climate change can be simplified by rescaling climatic predictors to use proxies for key biotic interactions. Using 12 sites spanning different temperature and precipitation ranges, the authors transplanted entire montane grassland communities in the direction of predicted climate change, according to regional

Fjord landscapes of western Norway harbor steep bioclimatic gradients that support diverse alpine vegetation.

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22608 | www.pnas.org/cgi/doi/10.1073/iti3720117 In this issue

Eye-color phenotypes of adult A. gambiae mosquitoes. Wild-type female (Left), a gene-drive female with the cardinal red eye (Middle), and cyan-fluorescent-protein blue eye (Right). Image credit: Rebeca Carballar-Lejarazú and Kiona Parker (University of California, Irvine, CA).

climate models, and tracked how species composi-tion changed in response to the new climate regime. The authors observed that bryophytes at these sites, as well as specific groups of vascular plants, repre-sented the primary influence on plant biodiversity, both limiting colonization by new species and com-bining with new colonists to drive species extinction. The study suggests that the response of specific bio-logical proxies to climate variables contains sufficient information to model the biodiversity impacts of cli-mate change, according to the authors. — T.J.

Next-generation gene drive and malaria control Gene drives aimed at preventing the transmission of parasites by disease vectors must meet stringent technical criteria before field use, including parame-ters tied to efficiency, specificity, and effects on the fitness of drive-bearing vectors. Rebeca Carballar- Lejarazú et al. (pp. 22805–22814) report a genetically engineered strain of malaria-transmitting Anoph-eles gambiae mosquitoes carrying a Cas9/guide

RNA-based gene drive. The drive could facilitate the development of future mosquito strains that can be field-tested for malaria-mosquito population con-trol. The drive-bearing strain, AgNosCd-1, targets the mosquito’s cardinal gene, which encodes an enzyme involved in synthesizing eye color pigment. The drive showed an average efficiency of 96.7% in both sexes, minimal off-target effects in vitro, few adverse effects on the fitness of drive-bearing mos-quitoes, and a low frequency of potentially resistant alleles that could counteract it. Importantly, trials in small cages in the lab revealed that a single release of drive-bearing males at 1:1 ratio (AgNosCd-1:wild-type) was sufficient to ensure that every mosquito carried at least one copy of the drive construct within four to six generations, which represents a period of 6 months and falls within a single annual malaria transmission cycle. Hence, AgNosCd-1 can serve as an efficient vehicle to ferry antiparasite effector genes into mosquitoes. According to the authors, the drive could help speed the development of mosquito strains for future field tests, which would require risk assessment, regulatory oversight, and community engagement. — P.N.

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