Diarrhoeal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite Cryptosporidium to be a leading cause of paediatric diarrhoea, with particularly grave impact on infants and immunocompromised individuals. There is neither a vaccine nor an effective treatment. Here we establish a drug discovery process built on scalable phenotypic assays and mouse models that take advantage of transgenic parasites. Screening a library of compounds with anti-parasitic activity, we identify pyrazolopyridines as inhibitors of Cryptosporidium parvum and Cryptosporidium hominis. Oral treatment with the pyrazolopyridine KDU731 results in a potent reduction in intestinal infection of immunocompromised mice. Treatment also leads to rapid resolution of diarrhoea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection. Our results suggest that the Cryptosporidium lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) is a target for pyrazolopyridines and that KDU731 warrants further preclinical evaluation as a drug candidate for the treatment of cryptosporidiosis.

Squeezed states(1-4) of electromagnetic radiation have quantum fluctuations below those of the vacuum field. They offer a unique resource for quantum information systems(5) and precision metrology(6), including gravitational wave detectors, which require unprecedented sensitivity(7). Since the first experiments on this non-classical form of light(8,9), quantum analysis has been based on homodyning techniques and photon correlation measurements(10,11). These methods currently function in the visible to near-infrared and microwave(12) spectral ranges. They require a well-defined carrier frequency, and photons contained in a quantum state need to be absorbed or amplified. Quantum non-demolition experiments(13,14) may be performed to avoid the influence of a measurement in one quadrature, but this procedure comes at the expense of increased uncertainty in another quadrature. Here we generate mid-infrared time-locked patterns of squeezed vacuum noise. After propagation through free space, the quantum fluctuations of the electric field are studied in the time domain using electro-optic sampling with few-femtosecond laser pulses(15,16). We directly compare the local noise amplitude to that of bare (that is, unperturbed) vacuum. Our nonlinear approach operates off resonance and, unlike homodyning or photon correlation techniques, without absorption or amplification of the field that is investigated. We find subcycle intervals with noise levels that are substantially less than the amplitude of the vacuum field. As a consequence, there are enhanced fluctuations in adjacent time intervals, owing to Heisenberg's uncertainty principle, which indicate generation of highly correlated quantum radiation. Together with efforts in the far infrared(17,18), this work enables the study of elementary quantum dynamics of light and matter in an energy range at the boundary between vacuum and thermal background conditions.

Both language and genes evolve by transmission over generations with opportunity for differential replication of forms(1). The understanding that gene frequencies change at random by genetic drift, even in the absence of natural selection, was a seminal advance in evolutionary biology(2). Stochastic drift must also occur in language as a result of randomness in how linguistic forms are copied between speakers(3,4). Here we quantify the strength of selection relative to stochastic drift in language evolution. We use time series derived from large corpora of annotated texts dating from the 12th to 21st centuries to analyse three well-known grammatical changes in English: the regularization of past-tense verbs(5-9), the introduction of the periphrastic 'do'(10), and variation in verbal negation(11). We reject stochastic drift in favour of selection in some cases but not in others. In particular, we infer selection towards the irregular forms of some past-tense verbs, which is likely driven by changing frequencies of rhyming patterns over time. We show that stochastic drift is stronger for rare words, which may explain why rare forms are more prone to replacement than common ones(6,9,12). This work provides a method for testing selective theories of language change against a null model and reveals an underappreciated role for stochasticity in language evolution.

Elucidation of the evolutionary history and interrelatedness of Plasmodium species that infect humans has been hampered by a lack of genetic information for three human-infective species: P. malariae and two P. ovale species (P. o. curtisi and P. o. wallikeri)(1). These species are prevalent across most regions in which malaria is endemic(2,3) and are often undetectable by light microscopy(4), rendering their study in human populations difficult(5). The exact evolutionary relationship of these species to the other human-infective species has been contested(6,7). Using a new reference genome for P. malariae and a manually curated draft P. o. curtisi genome, we are now able to accurately place these species within the Plasmodium phylogeny. Sequencing of a P. malariae relative that infects chimpanzees reveals similar signatures of selection in the P. malariae lineage to another Plasmodium lineage shown to be capable of colonization of both human and chimpanzee hosts. Molecular dating suggests that these host adaptations occurred over similar evolutionary timescales. In addition to the core genome that is conserved between species, differences in gene content can be linked to their specific biology. The genome suggests that P. malariae expresses a family of heterodimeric proteins on its surface that have structural similarities to a protein crucial for invasion of red blood cells. The data presented here provide insight into the evolution of the Plasmodium genus as a whole.

Spontaneous symmetry breaking is a fundamental concept in many areas of physics, including cosmology, particle physics and condensed matter(1). An example is the breaking of spatial translational symmetry, which underlies the formation of crystals and the phase transition from liquid to solid. Using the analogy of crystals in space, the breaking of translational symmetry in time and the emergence of a 'time crystal' was recently proposed(2,3), but was later shown to be forbidden in thermal equilibrium(4-6). However, non-equilibrium Floquet systems, which are subject to a periodic drive, can exhibit persistent time correlations at an emergent subharmonic frequency(7-10). This new phase of matter has been dubbed a 'discrete time crystal'(10). Here we present the experimental observation of a discrete time crystal, in an interacting spin chain of trapped atomic ions. We apply a periodic Hamiltonian to the system under many-body localization conditions, and observe a subharmonic temporal response that is robust to external perturbations. The observation of such a time crystal opens the door to the study of systems with long-range spatio-temporal correlations and novel phases of matter that emerge under intrinsically nonequilibrium conditions(7).

DNA is an excellent medium for archiving data. Recent efforts have illustrated the potential for information storage in DNA using synthesized oligonucleotides assembled in vitro(1-6). A relatively unexplored avenue of information storage in DNA is the ability to write information into the genome of a living cell by the addition of nucleotides over time. Using the Cas1-Cas2 integrase, the CRISPR-Cas microbial immune system stores the nucleotide content of invading viruses to confer adaptive immunity(7). When harnessed, this system has the potential to write arbitrary information into the genome(8). Here we use the CRISPR-Cas system to encode the pixel values of black and white images and a short movie into the genomes of a population of living bacteria. In doing so, we push the technical limits of this information storage system and optimize strategies to minimize those limitations. We also uncover underlying principles of the CRISPR-Cas adaptation system, including sequence determinants of spacer acquisition that are relevant for understanding both the basic biology of bacterial adaptation and its technological applications. This work demonstrates that this system can capture and stably store practical amounts of real data within the genomes of populations of living cells.