A new avialan theropod from an emerging Jurassic terrestrial fauna.

Birds are descended from non-avialan theropod dinosaurs of the Late Jurassic period, but the earliest phase of this evolutionary process remains unclear owing to the exceedingly sparse and spatio-temporally restricted fossil record1-5. Information about the early-diverging species along the avialan line is crucial to understand the evolution of the characteristic bird bauplan, and to reconcile phylogenetic controversies over the origin of birds3,4. Here we describe one of the stratigraphically youngest and geographically southernmost Jurassic avialans, Fujianvenator prodigiosus gen. et sp. nov., from the Tithonian age of China. This specimen exhibits an unusual set of morphological features that are shared with other stem avialans, troodontids and dromaeosaurids, showing the effects of evolutionary mosaicism in deep avialan phylogeny. F. prodigiosus is distinct from all other Mesozoic avialan and non-avialan theropods in having a particularly elongated hindlimb, suggestive of a terrestrial or wading lifestyle-in contrast with other early avialans, which exhibit morphological adaptations to arboreal or aerial environments. During our fieldwork in Zhenghe where F. prodigiosus was found, we discovered a diverse assemblage of vertebrates dominated by aquatic and semi-aquatic species, including teleosts, testudines and choristoderes. Using in situ radioisotopic dating and stratigraphic surveys, we were able to date the fossil-containing horizons in this locality-which we name the Zhenghe Fauna-to 148-150 million years ago. The diversity of the Zhenghe Fauna and its precise chronological framework will provide key insights into terrestrial ecosystems of the Late Jurassic.

Fossil evidence sheds light on sexual selection during the early evolution of birds.

The impact of sexual selection on the evolution of birds has been widely acknowledged. Although sexual selection has been hypothesized as a driving force in the occurrences of numerous morphological features across theropod evolution, this hypothesis has yet to be comprehensively tested due to challenges in identifying the sex of fossils and by the limited sample size. Confuciusornis sanctus is arguably the best-known early avialan and is represented by thousands of well-preserved specimens from the Early Cretaceous Jehol lagerstätte, which provides us with a chance to decipher the strength of sexual selection on extinct vertebrates. Herein, we present a morphometric study of C. sanctus based on the largest sample size of this taxon collected up to now. Our results indicate that the characteristic elongated paired rectrices is a sexually dimorphic trait and statistically robust inferences of the sexual dimorphism in size, shape, and allometry that have been established, providing the earliest known sexual dimorphism in avian evolution. Our findings suggest that sexual selection, in conjunction with natural selection, does act upon body size and limb length ratio in early birds, thereby promoting a deeper understanding of the role of sexual selection in large-scale phylogenetic evolution.

Genomes, fossils, and the concurrent rise of modern birds and flowering plants in the Late Cretaceous.

The phylogeny and divergence timing of the Neoavian radiation remain controversial despite recent progress. We analyzed the genomes of 124 species across all Neoavian orders, using data from 25,460 loci spanning four DNA classes, including 5,756 coding sequences, 12,449 conserved nonexonic elements, 4,871 introns, and 2,384 intergenic segments. We conducted a comprehensive sensitivity analysis to account for the heterogeneity across different DNA classes, leading to an optimal tree of Neoaves with high resolution. This phylogeny features a novel Neoavian dichotomy comprising two monophyletic clades: a previously recognized Telluraves (land birds) and a newly circumscribed Aquaterraves (waterbirds and relatives). Molecular dating analyses with 20 fossil calibrations indicate that the diversification of modern birds began in the Late Cretaceous and underwent a constant and steady radiation across the KPg boundary, concurrent with the rise of angiosperms as well as other major Cenozoic animal groups including placental and multituberculate mammals. The KPg catastrophe had a limited impact on avian evolution compared to the Paleocene-Eocene Thermal Maximum, which triggered a rapid diversification of seabirds. Our findings suggest that the evolution of modern birds followed a slow process of gradualism rather than a rapid process of punctuated equilibrium, with limited interruption by the KPg catastrophe. This study places bird evolution into a new context within vertebrates, with ramifications for the evolution of the Earth's biota.

A new Jurassic scansoriopterygid and the loss of membranous wings in theropod dinosaurs.

Powered flight evolved independently in vertebrates in the pterosaurs, birds and bats, each of which has a different configuration of the bony elements and epidermal structures that form the wings1,2. Whereas the early fossil records of pterosaurs and bats are sparse, mounting evidence (primarily from China) of feathered non-avian dinosaurs and stemward avians that derive primarily from the Middle-Upper Jurassic and Lower Cretaceous periods has enabled the slow piecing together of the origins of avian flight3,4. These fossils demonstrate that, close to the origin of flight, dinosaurs closely related to birds were experimenting with a diversity of wing structures3,5. One of the most surprising of these is that of the scansoriopterygid (Theropoda, Maniraptora) Yi qi, which has membranous wings-a flight apparatus that was previously unknown among theropods but that is used by both the pterosaur and bat lineages6. This observation was not universally accepted7. Here we describe a newly identified scansoriopterygid-which we name Ambopteryx longibrachium, gen. et sp. nov.-from the Upper Jurassic period. This specimen provides support for the widespread existence of membranous wings and the styliform element in the Scansoriopterygidae, as well as evidence for the diet of this enigmatic theropod clade. Our analyses show that marked changes in wing architecture evolved near the split between the Scansoriopterygidae and the avian lineage, as the two clades travelled along very different paths to becoming volant. The membranous wings supported by elongate forelimbs that are present in scansoriopterygids probably represent a short-lived experimentation with volant behaviour, and feathered wings were ultimately favoured during the later evolution of Paraves.

Author Correction: A new Jurassic scansoriopterygid and the loss of membranous wings in theropod dinosaurs.

Change history: In this Letter, it should have been acknowledged that the silhouettes of Scansoriopterygidae in Fig. 3a were modified from a sketch by Jaime Headden. The original Letter has been corrected online.

Early evolution of diurnal habits in owls (Aves, Strigiformes) documented by a new and exquisitely preserved Miocene owl fossil from China.

SignificanceOwls, with their largely nocturnal habits, contrast strikingly with the vast majority of diurnal birds. A new spectacular late Miocene owl skeleton from China unexpectedly preserves the oldest evidence for daytime behavior in owls. The extinct owl is a member of the clade Surniini, which contains most living diurnal owl species. Analysis of the preserved eye bones documents them as consistent with diurnal birds, and phylogenetically constrained character mapping coincides with a reconstruction of an early evolutionary reversal away from nocturnal habits in this owl group. These results support a potential Miocene origin of nonnocturnal habits in a globally distributed owl group, which may be linked to steppe habitat expansion and climatic cooling in the late Miocene.

Spatiotemporal evolution of the Jehol Biota: Responses to the North China craton destruction in the Early Cretaceous.

The Early Cretaceous Jehol Biota is a terrestrial lagerstätte that contains exceptionally well-preserved fossils indicating the origin and early evolution of Mesozoic life, such as birds, dinosaurs, pterosaurs, mammals, insects, and flowering plants. New geochronologic studies have further constrained the ages of the fossil-bearing beds, and recent investigations on Early Cretaceous tectonic settings have provided much new information for understanding the spatiotemporal distribution of the biota and dispersal pattern of its members. Notably, the occurrence of the Jehol Biota coincides with the initial and peak stages of the North China craton destruction in the Early Cretaceous, and thus the biotic evolution is related to the North China craton destruction. However, it remains largely unknown how the tectonic activities impacted the development of the Jehol Biota in northeast China and other contemporaneous biotas in neighboring areas in East and Central Asia. It is proposed that the Early Cretaceous rift basins migrated eastward in the northern margin of the North China craton and the Great Xing'an Range, and the migration is regarded to have resulted from eastward retreat of the subducting paleo-Pacific plate. The diachronous development of the rift basins led to the lateral variations of stratigraphic sequences and depositional environments, which in turn influenced the spatiotemporal evolution of the Jehol Biota. This study represents an effort to explore the linkage between terrestrial biota evolution and regional tectonics and how plate tectonics constrained the evolution of a terrestrial biota through various surface geological processes.

The appearance and duration of the Jehol Biota: Constraint from SIMS U-Pb zircon dating for the Huajiying Formation in northern China.

The Lower Cretaceous Huajiying Formation of the Sichakou Basin in northern Hebei Province, northern China contains key vertebrate taxa of the early Jehol Biota, e.g., Protopteryx fengningensis, Archaeornithura meemannae, Peipiaosteus fengningensis, and Eoconfuciusornis zhengi This formation arguably documents the second-oldest bird-bearing horizon, producing the oldest fossil records of the two major Mesozoic avian groups Enantiornithes and Ornithuromorpha. Hence, precisely determining the depositional ages of the Huajiying Formation would advance our understanding of the evolutionary history of the Jehol Biota. Here we present secondary ion mass spectrometry (SIMS) U-Pb zircon analysis results of eight interbedded tuff/tuffaceous sandstone samples from the Huajiying Formation. Our findings, combined with previous radiometric dates, suggest that the oldest enantiornithine and ornithuromorph birds in the Jehol Biota are ∼129-131 Ma, and that the Jehol Biota most likely first appeared at ∼135 Ma. This expands the biota's temporal distribution from late Valanginian to middle Aptian with a time span of about 15 My.

Effect of Argatroban Plus Intravenous Alteplase vs Intravenous Alteplase Alone on Neurologic Function in Patients With Acute Ischemic Stroke: The ARAIS Randomized Clinical Trial.

Importance: Previous studies suggested a benefit of argatroban plus alteplase (recombinant tissue-type plasminogen activator) in patients with acute ischemic stroke (AIS). However, robust evidence in trials with large sample sizes is lacking. Objective: To assess the efficacy of argatroban plus alteplase for AIS. Design, Setting, and Participants: This multicenter, open-label, blinded end point randomized clinical trial including 808 patients with AIS was conducted at 50 hospitals in China with enrollment from January 18, 2019, through October 30, 2021, and final follow-up on January 24, 2022. Interventions: Eligible patients were randomly assigned within 4.5 hours of symptom onset to the argatroban plus alteplase group (n = 402), which received intravenous argatroban (100 µg/kg bolus over 3-5 minutes followed by an infusion of 1.0 µg/kg per minute for 48 hours) within 1 hour after alteplase (0.9 mg/kg; maximum dose, 90 mg; 10% administered as 1-minute bolus, remaining infused over 1 hour), or alteplase alone group (n = 415), which received intravenous alteplase alone. Both groups received guideline-based treatments. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 1 at 90 days. All end points had blinded assessment and were analyzed on a full analysis set. Results: Among 817 eligible patients with AIS who were randomized (median [IQR] age, 65 [57-71] years; 238 [29.1%] women; median [IQR] National Institutes of Health Stroke Scale score, 9 [7-12]), 760 (93.0%) completed the trial. At 90 days, 210 of 329 participants (63.8%) in the argatroban plus alteplase group vs 238 of 367 (64.9%) in the alteplase alone group had an excellent functional outcome (risk difference, -1.0% [95% CI, -8.1% to 6.1%]; risk ratio, 0.98 [95% CI, 0.88-1.10]; P = .78). The percentages of participants with symptomatic intracranial hemorrhage, parenchymal hematoma type 2, and major systemic bleeding were 2.1% (8/383), 2.3% (9/383), and 0.3% (1/383), respectively, in the argatroban plus alteplase group and 1.8% (7/397), 2.5% (10/397), and 0.5% (2/397), respectively, in the alteplase alone group. Conclusions and Relevance: Among patients with acute ischemic stroke, treatment with argatroban plus intravenous alteplase compared with alteplase alone did not result in a significantly greater likelihood of excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03740958.

Dual Antiplatelet Therapy vs Alteplase for Patients With Minor Nondisabling Acute Ischemic Stroke: The ARAMIS Randomized Clinical Trial.

Importance: Intravenous thrombolysis is increasingly used in patients with minor stroke, but its benefit in patients with minor nondisabling stroke is unknown. Objective: To investigate whether dual antiplatelet therapy (DAPT) is noninferior to intravenous thrombolysis among patients with minor nondisabling acute ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded end point, noninferiority randomized clinical trial included 760 patients with acute minor nondisabling stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤5, with ≤1 point on the NIHSS in several key single-item scores; scale range, 0-42). The trial was conducted at 38 hospitals in China from October 2018 through April 2022. The final follow-up was on July 18, 2022. Interventions: Eligible patients were randomized within 4.5 hours of symptom onset to the DAPT group (n = 393), who received 300 mg of clopidogrel on the first day followed by 75 mg daily for 12 (±2) days, 100 mg of aspirin on the first day followed by 100 mg daily for 12 (±2) days, and guideline-based antiplatelet treatment until 90 days, or the alteplase group (n = 367), who received intravenous alteplase (0.9 mg/kg; maximum dose, 90 mg) followed by guideline-based antiplatelet treatment beginning 24 hours after receipt of alteplase. Main Outcomes and Measures: The primary end point was excellent functional outcome, defined as a modified Rankin Scale score of 0 or 1 (range, 0-6), at 90 days. The noninferiority of DAPT to alteplase was defined on the basis of a lower boundary of the 1-sided 97.5% CI of the risk difference greater than or equal to -4.5% (noninferiority margin) based on a full analysis set, which included all randomized participants with at least 1 efficacy evaluation, regardless of treatment group. The 90-day end points were assessed in a blinded manner. A safety end point was symptomatic intracerebral hemorrhage up to 90 days. Results: Among 760 eligible randomized patients (median [IQR] age, 64 [57-71] years; 223 [31.0%] women; median [IQR] NIHSS score, 2 [1-3]), 719 (94.6%) completed the trial. At 90 days, 93.8% of patients (346/369) in the DAPT group and 91.4% (320/350) in the alteplase group had an excellent functional outcome (risk difference, 2.3% [95% CI, -1.5% to 6.2%]; crude relative risk, 1.38 [95% CI, 0.81-2.32]). The unadjusted lower limit of the 1-sided 97.5% CI was -1.5%, which is larger than the -4.5% noninferiority margin (P for noninferiority <.001). Symptomatic intracerebral hemorrhage at 90 days occurred in 1 of 371 participants (0.3%) in the DAPT group and 3 of 351 (0.9%) in the alteplase group. Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke presenting within 4.5 hours of symptom onset, DAPT was noninferior to intravenous alteplase with regard to excellent functional outcome at 90 days. Trial Registration: ClinicalTrials.gov Identifier: NCT03661411.

Novel evolution of a hyper-elongated tongue in a Cretaceous enantiornithine from China and the evolution of the hyolingual apparatus and feeding in birds.

The globally distributed extinct clade Enantiornithes comprises the most diverse early radiation of birds in the Mesozoic with species exhibiting a wide range of body sizes, morphologies, and ecologies. The fossil of a new enantiornithine bird, Brevirostruavis macrohyoideus gen. et sp. nov., from the Lower Cretaceous Jiufotang Formation in Liaoning Province, northeastern China, preserves a few important skeletal features previously unknown among early stem and extant birds, including an extremely elongate bony hyoid element (only slightly shorter than the skull), combined with a short cranial rostrum. The long hyoid provides direct evidence for the evolution of specialized feeding in this extinct species, and appears similar to the highly mobile tongue that is mobilized by the paired epibranchials present in living hummingbirds, honeyeaters, and woodpeckers. The likely linkage between food acquisition and tongue protrusion might have been a key factor in the independent evolution of particularly elongate hyobranchials in early birds.

Origin of the avian predentary and evidence of a unique form of cranial kinesis in Cretaceous ornithuromorphs.

The avian predentary is a small skeletal structure located rostral to the paired dentaries found only in Mesozoic ornithuromorphs. The evolution and function of this enigmatic element is unknown. Skeletal tissues forming the predentary and the lower jaws in the basal ornithuromorph Yanornis martini are identified using computed-tomography, scanning electron microscopy, and histology. On the basis of these data, we propose hypotheses for the development, structure, and function of this element. The predentary is composed of trabecular bone. The convex caudal surface articulates with rostromedial concavities on the dentaries. These articular surfaces are covered by cartilage, which on the dentaries is divided into 3 discrete patches: 1 rostral articular cartilage and 2 symphyseal cartilages. The mechanobiology of avian cartilage suggests both compression and kinesis were present at the predentary-dentary joint, therefore suggesting a yet unknown form of avian cranial kinesis. Ontogenetic processes of skeletal formation occurring within extant taxa do not suggest the predentary originates within the dentaries, nor Meckel's cartilage. We hypothesize that the predentary is a biomechanically induced sesamoid that arose within the soft connective tissues located rostral to the dentaries. The mandibular canal hosting the alveolar nerve suggests that the dentary teeth and predentary of Yanornis were proprioceptive. This whole system may have increased foraging efficiency. The Mesozoic avian predentary apparently coevolved with an edentulous portion of the premaxilla, representing a unique kinetic morphotype that combined teeth with a small functional beak and persisted successfully for ∼60 million years.

Evolution of the vomer and its implications for cranial kinesis in Paraves.

Most living birds exhibit cranial kinesis-movement between the rostrum and braincase-in which force is transferred through the palatal and jugal bars. The palate alone distinguishes the Paleognathae from the Neognathae, with cranial kinesis more developed in neognaths. Most previous palatal studies were based on 2D data and rarely incorporated data from stem birds despite great interest in their kinetic abilities. Here we reconstruct the vomer of the Early Cretaceous stem bird Sapeornis and the troodontid Sinovenator, taxa spanning the dinosaur-bird transition. A 3D shape analysis including these paravians and an extensive sampling of neornithines reveals their strong similarity to paleognaths and indicates that morphological differences in the vomer between paleognaths and neognaths are intimately related to their different kinetic abilities. These results suggest the skull of Mesozoic paravians lacked the kinetic abilities observed in neognaths, a conclusion also supported by our identification of an ectopterygoid in Sapeornis here. We conclude that cranial kinesis evolved relatively late, likely an innovation of the Neognathae, and is linked to the transformation of the vomer. This transformation increased palatal mobility, enabling the evolution of a diversity of kinetic mechanisms and ultimately contributing to the extraordinary evolutionary success of this clade.

The molecular evolution of feathers with direct evidence from fossils.

Dinosaur fossils possessing integumentary appendages of various morphologies, interpreted as feathers, have greatly enhanced our understanding of the evolutionary link between birds and dinosaurs, as well as the origins of feathers and avian flight. In extant birds, the unique expression and amino acid composition of proteins in mature feathers have been shown to determine their biomechanical properties, such as hardness, resilience, and plasticity. Here, we provide molecular and ultrastructural evidence that the pennaceous feathers of the Jurassic nonavian dinosaur Anchiornis were composed of both feather ß-keratins and α-keratins. This is significant, because mature feathers in extant birds are dominated by ß-keratins, particularly in the barbs and barbules forming the vane. We confirm here that feathers were modified at both molecular and morphological levels to obtain the biomechanical properties for flight during the dinosaur-bird transition, and we show that the patterns and timing of adaptive change at the molecular level can be directly addressed in exceptionally preserved fossils in deep time.

The patterns and modes of the evolution of disparity in Mesozoic birds.

The origin of birds from non-avian theropod dinosaurs is one of the greatest transitions in evolution. Shortly after diverging from other theropods in the Late Jurassic, Mesozoic birds diversified into two major clades-the Enantiornithes and Ornithuromorpha-acquiring many features previously considered unique to the crown group along the way. Here, we present a comparative phylogenetic study of the patterns and modes of Mesozoic bird skeletal morphology and limb proportions. Our results show that the major Mesozoic avian groups are distinctive in discrete character space, but constrained in a morphospace defined by limb proportions. The Enantiornithines, despite being the most speciose group of Mesozoic birds, are much less morphologically disparate than their sister clade, the Ornithuromorpha-the clade that gave rise to living birds, showing disparity and diversity were decoupled in avian history. This relatively low disparity suggests that diversification of enantiornithines was characterized in exhausting fine morphologies, whereas ornithuromorphs continuously explored a broader array of morphologies and ecological opportunities. We suggest this clade-specific evolutionary versatility contributed to their sole survival of the end-Cretaceous mass extinction.

A new clade of basal Early Cretaceous pygostylian birds and developmental plasticity of the avian shoulder girdle.

Early members of the clade Pygostylia (birds with a short tail ending in a compound bone termed "pygostyle") are critical for understanding how the modern avian bauplan evolved from long-tailed basal birds like Archaeopteryx However, the currently limited known diversity of early branching pygostylians obscures our understanding of this major transition in avian evolution. Here, we describe a basal pygostylian, Jinguofortis perplexus gen. et sp. nov., from the Early Cretaceous of China that adds important information about early members of the short-tailed bird group. Phylogenetic analysis recovers a clade (Jinguofortisidae fam. nov.) uniting Jinguofortis and the enigmatic basal avian taxon Chongmingia that represents the second earliest diverging group of the Pygostylia. Jinguofortisids preserve a mosaic combination of plesiomorphic nonavian theropod features such as a fused scapulocoracoid (a major component of the flight apparatus) and more derived flight-related morphologies including the earliest evidence of reduction in manual digits among birds. The presence of a fused scapulocoracoid in adult individuals independently evolved in Jinguofortisidae and Confuciusornithiformes may relate to an accelerated osteogenesis during chondrogenesis and likely formed through the heterochronic process of peramorphosis by which these basal taxa retain the scapulocoracoid of the nonavian theropod ancestors with the addition of flight-related modifications. With wings having a low aspect ratio and wing loading, Jinguofortis may have been adapted particularly to dense forest environments. The discovery of Jinguofortis increases the known ecomorphological diversity of basal pygostylians and highlights the importance of developmental plasticity for understanding mosaic evolution in early birds.

Archaeorhynchus preserving significant soft tissue including probable fossilized lungs.

We describe a specimen of the basal ornithuromorph Archaeorhynchus spathula from the Lower Cretaceous Jiufotang Formation with extensive soft tissue preservation. Although it is the fifth specimen to be described, unlike the others it preserves significant traces of the plumage, revealing a pintail morphology previously unrecognized among Mesozoic birds, but common in extant neornithines. In addition, this specimen preserves the probable remnants of the paired lungs, an identification supported by topographical and macro- and microscopic anatomical observations. The preserved morphology reveals a lung very similar to that of living birds. It indicates that pulmonary specializations such as exceedingly subdivided parenchyma that allow birds to achieve the oxygen acquisition capacity necessary to support powered flight were present in ornithuromorph birds 120 Mya. Among extant air breathing vertebrates, birds have structurally the most complex and functionally the most efficient respiratory system, which facilitates their highly energetically demanding form of locomotion, even in extremely oxygen-poor environments. Archaeorhynchus is commonly resolved as the most basal known ornithuromorph bird, capturing a stage of avian evolution in which skeletal indicators of respiration remain primitive yet the lung microstructure appears modern. This adds to growing evidence that many physiological modifications of soft tissue systems (e.g., digestive system and respiratory system) that characterize living birds and are key to their current success may have preceded the evolution of obvious skeletal adaptations traditionally tracked through the fossil record.

Ultramicrostructural reductions in teeth: implications for dietary transition from non-avian dinosaurs to birds.

BACKGROUND: Tooth morphology within theropod dinosaurs has been extensively investigated and shows high disparity throughout the Cretaceous. Changes or diversification in feeding ecology, i.e., adoption of an herbivorous diet (e.g., granivorous), is proposed as a major driver of tooth evolution in Paraves (e.g., Microraptor, troodontids and avialans). Here, we studied the microscopic features of paravian non-avian theropod and avialan teeth using high-spatial-resolution synchrotron transmission X-ray microscopy and scanning electron microscopy. RESULTS: We show that avialan teeth are characterized by the presence of simple enamel structures and a lack of porous mantle dentin between the enamel and orthodentin. Reduced internal structures of teeth took place independently in Early Cretaceous birds and a Microraptor specimen, implying that shifts in diet in avialans from that of closely related dinosaurs may correlate with a shift in feeding ecology during the transition from non-avian dinosaurs to birds. CONCLUSION: Different lines of evidence all suggest a large reduction in biting force affecting the evolution of teeth in the dinosaur-bird transition. Changes in teeth microstructure and associated dietary shift may have contributed to the early evolutionary success of stemward birds in the shadow of other non-avian theropods.

Randomized trial of argatroban plus recombinant tissue-type plasminogen activator for acute ischemic stroke (ARAIS): Rationale and design.

BACKGROUND: Previous studies have implied the efficacy and safety of argatroban plus recombinant tissue-type plasminogen activator (r-tPA) in patients with acute ischemic stroke. Further trials are needed to establish convincing conclusions in a large sample size. RESEARCH DESIGN AND METHODS: Argatroban plus r-tPA for Acute Ischemic Stroke (ARAIS) trial is a multicenter, prospective, randomized, open-label, and blind-end point trial. The trial proposes to randomize 808 patients with acute ischemic stroke National Institutes of Health Stroke Scale (NIHSS score≥ 6 at the time of randomization) within 4.5 hours of symptom onset to receive argatroban (100 µg/kg bolus followed by an infusion of 1.0 µg/kg per minute for 48 hours) plus r-tPA or r-tPA alone. The primary end point is the proportion of patients with an excellent outcome of no clinically significant residual stroke deficits (modified Rankin scale 0-1) at 90 days. Secondary end points include the proportion of patients with a good outcome (modified Rankin scale 0-2) at 90 days, early neurological improvement (NIHSS score ≥2-point decrease) at 48 hours, early neurological deterioration (NIHSS score ≥4-point increase) at 48 hours, decrease in the NIHSS score from baseline to 14 days, and stroke recurrence or other vascular events at 90 days. Safety end points include symptomatic intracerebral hemorrhage, parenchymal hematoma type 2, and major systemic bleeding. CONCLUSION: ARAIS trial will evaluate whether argatroban plus r-tPA is superior to r-tPA alone in improving functional outcomes in acute ischemic stroke patients in a large sample population.