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Particle accelerators driven by laser-generated terahertz (THz) pulses promise unprecedented control over the energy–time phase space of particle bunches compared with conventional radiofrequency technology. Here we demonstrate acceleration of a relativistic electron beam in a THz-driven linear accelerator. Narrowband THz pulses were tuned to the phase-velocity-matched operating frequency of a rectangular dielectric-lined waveguide for extended collinear interaction with 35 MeV, 60 pC electron bunches, imparting multicycle energy modulation to chirped (6 ps) bunches and injection phase-dependent energy gain (up to 10 keV) to subcycle (2 ps) bunches. These proof-of-principle results establish a route to whole-bunch linear acceleration of subpicosecond particle beams, directly applicable to scaled-up and multistaged concepts capable of preserving beam quality, thus marking a key milestone for future THz-driven acceleration of relativistic beams.Relativistic 35 MeV electron bunches with charges of 60 pC are accelerated in a terahertz-wave-driven dielectric waveguide. When the terahertz pulse energy is 0.8 μJ, an accelerating gradient of 2 MeV m−1 and energy gain of 10 keV are achieved.

This epic history compares the empires built by Spain and Britain in the Americas, from Columbus's arrival in the New World to the end of Spanish colonial rule in the early nineteenth century. J. H. Elliott, one of the most distinguished and versatile historians working today, offers us history on a grand scale, contrasting the worlds built by Britain and by Spain on the ruins of the civilizations they encountered and destroyed in North and South America.Elliott identifies and explains both the similarities and differences in the two empires' processes of colonization, the character of their colonial societies, their distinctive styles of imperial government, and the independence movements mounted against them. Based on wide reading in the history of the two great Atlantic civilizations, the book sets the Spanish and British colonial empires in the context of their own times and offers us insights into aspects of this dual history that still influence the Americas.

When J. H. Elliott publishedSpain and Its World, 1500-1700some twenty years ago, one of many enthusiasts declared, \"For anyone interested in the history of empire, of Europe and of Spain, here is a book to keep within reach, to read, to study and to enjoy\" (Times Literary Supplement). Since then Elliott has continued to explore the history of Spain and the Hispanic world with originality and insight, producing some of the most influential work in the field. In this new volume he gathers writings that reflect his recent research and thinking on politics, art, culture, and ideas in Europe and the colonial worlds between 1500 and 1800. The volume includes fourteen essays, lectures, and articles of remarkable breadth and freshness, written with Elliott's characteristic brio. It includes an unpublished lecture in honor of the late Hugh Trevor-Roper. Organized around three themes-early modern Europe, European overseas expansion, and the works and historical context of El Greco, Velázquez, Rubens, and Van Dyck-the book offers a rich survey of the themes at the heart of Elliott's interests throughout a career distinguished by excellence and innovation.

We provide an insight into the role Drosophila has played in elucidating neurophysiological perturbations associated with Parkinson’s disease- (PD-) related genes. Synaptic signalling deficits are observed in motor, central, and sensory systems. Given the neurological impact of disease causing mutations within these same genes in humans the phenotypes observed in fly are of significant interest. As such we observe four unique opportunities provided by fly nervous system models of Parkinson’s disease. Firstly, Drosophila models are instrumental in exploring the mechanisms of neurodegeneration, with several PD-related mutations eliciting related phenotypes including sensitivity to energy supply and vesicular deformities. These are leading to the identification of plausible cellular mechanisms, which may be specific to (dopaminergic) neurons and synapses rather than general cellular phenotypes. Secondly, models show noncell autonomous signalling within the nervous system, offering the opportunity to develop our understanding of the way pathogenic signalling propagates, resembling Braak’s scheme of spreading pathology in PD. Thirdly, the models link physiological deficits to changes in synaptic structure. While the structure-function relationship is complex, the genetic tractability of Drosophila offers the chance to separate fundamental changes from downstream consequences. Finally, the strong neuronal phenotypes permit relevant first in vivo drug testing.

The most frequent missense mutations in familial Parkinson’s disease (PD) occur in the highly conserved LRRK2/PARK8 gene with G2019S mutation. We previously established a fly model of PD carrying the LRRK2-G2019S mutation that exhibited the parkinsonism-like phenotypes. An herbal medicine , Gastrodia elata Blume (GE), has been reported to have neuroprotective effects in toxin-induced PD models. However, the underpinning molecular mechanisms of GE beneficiary to G2019S-induced PD remain unclear. Here, we show that these G2019S flies treated with water extracts of GE (WGE) and its bioactive compounds, gastrodin and 4-HBA, displayed locomotion improvement and dopaminergic neuron protection. WGE suppressed the accumulation and hyperactivation of G2019S proteins in dopaminergic neurons and activated the antioxidation and detoxification factor Nrf2 mostly in the astrocyte-like and ensheathing glia. Glial activation of Nrf2 antagonizes G2019S-induced Mad/Smad signaling. Moreover, we treated LRRK2-G2019S transgenic mice with WGE and found that the locomotion declines, the loss of dopaminergic neurons, and the number of hyperactive microglia were restored. WGE also suppressed the hyperactivation of G2019S proteins and regulated the Smad2/3 pathways in the mice brains. We conclude that WGE prevents locomotion defects and the neuronal loss induced by G2019S mutation via glial Nrf2/Mad signaling, unveiling a potential therapeutic avenue for PD. Parkinson’s disease is a brain disorder that leads to tremors and difficulties with balance and coordination. These symptoms are caused by the loss of neurons which release a chemical messenger that is needed to regulate movement called dopamine. Most treatments for this disease work by boosting levels of dopamine in the brain, but this can lead to severe side effects and these drugs often become less effective over time. A traditional Chinese medicine called Gastrodia elata Blume (or GE for short) has previously been reported to relieve symptoms of Parkinson’s disease in both human and animal studies when administered as a decoction or formula. However, it is unclear how GE protects dopamine-producing neurons and if this mechanism involves another type of brain cell known as glia that has also been linked to Parkinson’s disease. To investigate, Lin et al. studied fruit flies and mice that carry a genetic mutation that produces the symptoms and molecular characteristics of Parkinson’s disease. The experiments showed that when the flies and mice were fed food containing water extracts of GE, they experienced less difficulties moving and had a higher number of intact dopamine-producing neurons. Lin et al. found that GE switched on a protein in glial cells located near dopamine-producing neurons. Activation of this protein, called Nrf2, inhibited a signaling pathway in degenerating neurons that leads to the disease state. As a result, less dopamine-producing neurons were damaged and the animals’ coordination and balance were maintained. These findings suggest that GE could potentially provide an alternative or complementary therapy for Parkinson’s disease, although it still needs to be studied further in humans. If the same effect is observed, the specific compounds in GE that have this protective effect could be isolated and analyzed to see if they could be used for treatment.

There is increasing evidence for a strong genetic basis for autism, with many genetic models being developed in an attempt to replicate autistic symptoms in animals. However, current animal behaviour paradigms rarely match the social and cognitive behaviours exhibited by autistic individuals. Here, we instead assay another functional domain—sensory processing—known to be affected in autism to test a novel genetic autism model in Drosophila melanogaster . We show similar visual response alterations and a similar development trajectory in Nhe3 mutant flies (total n = 72) and in autistic human participants (total n = 154). We report a dissociation between first- and second-order electrophysiological visual responses to steady-state stimulation in adult mutant fruit flies that is strikingly similar to the response pattern in human adults with ASD as well as that of a large sample of neurotypical individuals with high numbers of autistic traits. We explain this as a genetically driven, selective signalling alteration in transient visual dynamics. In contrast to adults, autistic children show a decrease in the first-order response that is matched by the fruit fly model, suggesting that a compensatory change in processing occurs during development. Our results provide the first animal model of autism comprising a differential developmental phenotype in visual processing.

Electrophysiological studies indicate altered contrast processing in some Parkinson’s Disease (PD) patients. We recently demonstrated that vision is altered in Drosophila PD models and hypothesised that different types of genetic and idiopathic PD may affect dopaminergic visual signalling pathways differently. Here we asked whether visual responses in Drosophila could be used to identify PD mutations. To mimic a clinical setting a range of flies was used. Young flies from four control lines were compared to three early-onset PD mutations (PINK1 , DJ-1α and DJ-1β ) and to two other neurodegenerative mutations, one in the fly LRRK2 orthologue ( dLRRK ) the other in eggroll , a model of general neurodegeneration in Drosophila . Stimuli were contrast reversing gratings spanning 64 spatiotemporal frequency combinations. We recorded the steady-state visually-evoked response amplitude across all combinations. We found that the pattern of neuronal responses differed between genotypes. Wild-type and early-onset PD flies formed separate clusters; the late-onset mutation is an outlier. Neuronal responses in early-onset PD flies were stronger than in wild-types. Multivariate pattern analysis grouped flies by PD/non-PD genotype with an accuracy >85%. We propose that machine learning algorithms may be useful in increasing the diagnostic specificity of human electrophysiological measurements in both animal models and PD patients.

In a number of Drosophila models of genetic Parkinson’s disease (PD) flies climb more slowly than wild-type controls. However, this assay does not distinguish effects of PD-related genes on gravity sensation, “arousal”, central pattern generation of leg movements, or muscle. To address this problem, we have developed an assay for the fly proboscis extension response (PER). This is attractive because the PER has a simple, well-identified reflex neural circuit, in which sucrose sensing neurons activate a pair of “command interneurons”, and thence motoneurons whose activity contracts the proboscis muscle. This circuit is modulated by a single dopaminergic neuron (TH-VUM). We find that expressing either the G2019S or I2020T (but not R1441C , or kinase dead) forms of human LRRK2 in dopaminergic neurons reduces the percentage of flies that initially respond to sucrose stimulation. This is rescued fully by feeding l -DOPA and partially by feeding kinase inhibitors, targeted to LRRK2 (LRRK2-IN-1 and BMPPB-32). High-speed video shows that G2019S expression in dopaminergic neurons slows the speed of proboscis extension, makes its duration more variable, and increases the tremor. Testing subsets of dopaminergic neurons suggests that the single TH-VUM neuron is likely most important in this phenotype. We conclude the Drosophila PER provides an excellent model of LRRK2 motor deficits showing bradykinesia, akinesia, hypokinesia, and increased tremor, with the possibility to localize changes in neural signaling. Disease models: A reflex reaction A simple reflex in flies can be used to test the effectiveness of therapies that slow neurodegeneration in Parkinson’s disease (PD). Christopher Elliott and colleagues at the University of York in the United Kingdom investigated the contraction of the proboscis muscle which mediates a taste behavior response and is regulated by a single dopaminergic neuron. Flies bearing particular mutations in the PD-associated gene leucine-rich repeat kinase 2 (LRRK2) in dopaminergic neurons lost their ability to feed on a sweet solution. This was due to the movement of the proboscis muscle becoming slower and stiffer, hallmark features of PD. The authors rescued the impaired reflex reaction by feeding the flies l -DOPA or LRRK2 inhibitors. These findings highlight the proboscis extension response as a useful tool to identify other PD-associated mutations and test potential therapeutic compounds.

This book contains a substantial extract from William H. Prescott's major work A History of the Conquest of Mexico . Prescott lived from 1796-1859 and his book was a pioneering view of the Aztec civilisation. The country of the ancient Mexicans or Aztecs, as they were known, formed but a very small part of the extensive territories which make up modern Mexico. The story of the life of Hernando Cortes, the Conqueror and the tragic story of Moctezuma the Aztec king are essential to this history. It has been immortalised in works such as the play The Royal Hunt of the Sun . In his fascinating introduction J.H. Elliott sets Prescott's work against the background of the growth of historical research. The extracts from Prescott's book demonstrate that he is among the finest of English prose stylists.