A Late Pleistocene coastal ecosystem in French Guiana was hyperdiverse relative to today.

Warmer temperatures and higher sea level than today characterized the Last Interglacial interval [Pleistocene, 128 to 116 thousand years ago (ka)]. This period is a remarkable deep-time analog for temperature and sea-level conditions as projected for 2100 AD, yet there has been no evidence of fossil assemblages in the equatorial Atlantic. Here, we report foraminifer, metazoan (mollusks, bony fish, bryozoans, decapods, and sharks among others), and plant communities of coastal tropical marine and mangrove affinities, dating precisely from a ca. 130 to 115 ka time interval near the Equator, at Kourou, in French Guiana. These communities include ca. 230 recent species, some being endangered today and/or first recorded as fossils. The hyperdiverse Kourou mollusk assemblage suggests stronger affinities between Guianese and Caribbean coastal waters by the Last Interglacial than today, questioning the structuring role of the Amazon Plume on tropical Western Atlantic communities at the time. Grassland-dominated pollen, phytoliths, and charcoals from younger deposits in the same sections attest to a marine retreat and dryer conditions during the onset of the last glacial (ca. 110 to 50 ka), with a savanna-dominated landscape and episodes of fire. Charcoals from the last millennia suggest human presence in a mosaic of modern-like continental habitats. Our results provide key information about the ecology and biogeography of pristine Pleistocene tropical coastal ecosystems, especially relevant regarding the-widely anthropogenic-ongoing global warming.

Bayesian total-evidence dating revisits sloth phylogeny and biogeography: a cautionary tale on morphological clock analyses.

Combining morphological and molecular characters through Bayesian total-evidence dating allows inferring the phylogenetic and timescale framework of both extant and fossil taxa, while accounting for the stochasticity and incompleteness of the fossil record. Such an integrative approach is particularly needed when dealing with clades such as sloths (Mammalia: Folivora), for which developmental and biomechanical studies have shown high levels of morphological convergence whereas molecular data can only account for a limited percentage of their total species richness. Here, we propose an alternative hypothesis of sloth evolution that emphasizes the pervasiveness of morphological convergence and the importance of considering the fossil record and an adequate taxon sampling in both phylogenetic and biogeographic inferences. Regardless of different clock models and morphological datasets, the extant sloth Bradypus is consistently recovered as a megatherioid, and Choloepus as a mylodontoid, in agreement with molecular-only analyses. The recently extinct Caribbean sloths (Megalocnoidea) are found to be a monophyletic sister-clade of Megatherioidea, in contrast to previous phylogenetic hypotheses. Our results contradict previous morphological analyses and further support the polyphyly of "Megalonychidae", whose members were found in five different clades. Regardless of taxon sampling and clock models, the Caribbean colonization of sloths is compatible with the exhumation of islands along Aves Ridge and its geological time frame. Overall, our total-evidence analysis illustrates the difficulty of positioning highly incomplete fossils, although a robust phylogenetic framework was recovered by an a posteriori removal of taxa with high percentages of missing characters. Elimination of these taxa improved topological resolution by reducing polytomies and increasing node support. However, it introduced a systematic and geographic bias because most of these incomplete specimens are from northern South America. This is evident in biogeographic reconstructions, which suggest Patagonia as the area of origin of many clades when taxa are underrepresented, but Amazonia and/or Central and Southern Andes when all taxa are included. More generally, our analyses demonstrate the instability of topology and divergence time estimates when using different morphological datasets and clock models, and thus caution against making macroevolutionary inferences when node support is weak or when uncertainties in the fossil record are not considered.

Palaeoenvironments and hominin evolutionary dynamics in southeast Asia.

Secure environmental contexts are crucial for hominin interpretation and comparison. The discovery of a Denisovan individual and associated fauna at Tam Ngu Hao 2 (Cobra) Cave, Laos, dating back to 164-131 ka, allows for environmental comparisons between this (sub)tropical site and the Palearctic Denisovan sites of Denisova Cave (Russia) and Baishiya Karst Cave (China). Denisovans from northern latitudes foraged in a mix of forested and open landscapes, including tundra and steppe. Using stable isotope values from the Cobra Cave assemblage, we demonstrate that, despite the presence of nearby canopy forests, the Denisovan individual from Cobra Cave primarily consumed plants and/or animals from open forests and savannah. Using faunal evidence and proxy indicators of climates, results herein highlight a local expansion of rainforest at ~ 130 ka, raising questions about how Denisovans responded to this local climate change. Comparing the diet and habitat of the archaic hominin from Cobra Cave with those of early Homo sapiens from Tam Pà Ling Cave (46-43 ka), Laos, it appears that only our species was able to exploit rainforest resources.

An eosimiid primate of South Asian affinities in the Paleogene of Western Amazonia and the origin of New World monkeys.

Recent fossil discoveries in Western Amazonia revealed that two distinct anthropoid primate clades of African origin colonized South America near the Eocene/Oligocene transition (ca. 34 Ma). Here, we describe a diminutive fossil primate from Brazilian Amazonia and suggest that, surprisingly, a third clade of anthropoids was involved in the Paleogene colonization of South America by primates. This new taxon, Ashaninkacebus simpsoni gen. et sp. nov., has strong dental affinities with Asian African stem anthropoids: the Eosimiiformes. Morphology-based phylogenetic analyses of early Old World anthropoids and extinct and extant New World monkeys (platyrrhines) support relationships of both Ashaninkacebus and Amamria (late middle Eocene, North Africa) to the South Asian Eosimiidae. Afro-Arabia, then a mega island, played the role of a biogeographic stopover between South Asia and South America for anthropoid primates and hystricognathous rodents. The earliest primates from South America bear little adaptive resemblance to later Oligocene-early Miocene platyrrhine monkeys, and the scarcity of available paleontological data precludes elucidating firmly their affinities with or within Platyrrhini. Nonetheless, these data shed light on some of their life history traits, revealing a particularly small body size and a diet consisting primarily of insects and possibly fruit, which would have increased their chances of survival on a natural floating island during this extraordinary over-water trip to South America from Africa. Divergence-time estimates between Old and New World taxa indicate that the transatlantic dispersal(s) could source in the intense flooding events associated with the late middle Eocene climatic optimum (ca. 40.5 Ma) in Western Africa.

Robust High-Throughput Proteomics Identification and Deamidation Quantitation of Extinct Species up to Pleistocene with Ultrahigh-Resolution MALDI-FTICR Mass Spectrometry.

Peptide mass fingerprinting (PMF) using MALDI-TOF mass spectrometry allows the identification of bone species based on their type I collagen sequence. In the archaeological or paleontological field, PMF is known as zooarchaeology mass spectrometry (ZooMS) and is widely implemented to find markers for most species, including the extinct ones. In addition to the identification of bone species, ZooMS enables dating estimation by measuring the deamidation value of specific peptides. Herein, we report several enhancements to the classical ZooMS technique, which reduces to 10-fold the required bone sample amount (down to the milligram scale) and achieves robust deamidation value calculation in a high-throughput manner. These improvements rely on a 96-well plate samples preparation, a careful optimization of collagen extraction and digestion to avoid spurious post-translational modification production, and PMF at high resolution using matrix-assisted laser desorption ionization Fourier transform ion cyclotron resonance (MALDI-FTICR) analysis. This method was applied to the identification of a hundred bones of herbivores from the Middle Paleolithic site of Caours (Somme, France) well dated from the Eemian Last Interglacial climatic optimum. The method gave reliable species identification to bones already identified by their osteomorphology, as well as to more challenging samples consisting of small or burned bone fragments. Deamidation values of bones originating from the same geological layers have a low standard deviation. The method can be applied to archaeological bone remains and offers a robust capacity to identify traditionally unidentifiable bone fragments, thus increasing the number of identified specimens and providing invaluable information in specific contexts.

Cost Utility and Value of Information Analysis of Femtosecond Laser-Assisted Cataract Surgery.

Importance: The efficacy and safety of femtosecond laser-assisted cataract surgery is well documented. An important requirement for decision makers is the evaluation of the cost-effectiveness of femtosecond laser-assisted cataract surgery (FLACS) over a sufficiently long horizon. Evaluating the cost-effectiveness of this treatment was a preplanned secondary objective of the Economic Evaluation of Femtosecond Laser Assisted Cataract Surgery (FEMCAT) trial. Objective: To estimate the cost utility of FLACS compared with phacoemulsification cataract surgery (PCS) on a 12-month time horizon. Design, Setting, and Participants: This multicenter randomized clinical trial compared FLACS with PCS in parallel groups. All FLACS procedures were performed using the CATALYS precision system. Participants were recruited and treated in ambulatory surgery settings in 5 university-hospital centers in France. All consecutive patients eligible for a unilateral or bilateral cataract surgery 22 years or older with written informed consent were included. Data were collected from October 2013 to October 2018, and data were analyzed from January 2020 to June 2022. Interventions: FLACS or PCS. Main Outcomes and Measures: Utility was measured through the Health Utility Index questionnaire. Costs of cataract surgery were estimated by microcosting. All inpatient and outpatient costs were collected from the French National Health Data System. Results: Of 870 randomized patients, 543 (62.4%) were female, and the mean (SD) age at surgery was 72.3 (8.6) years. A total of 440 patients were randomized to receive FLACS and 430 to receive PCS; the rate of bilateral surgery was 63.3% (551 of 870). The mean (SD) costs of cataract surgery were €1124.0 (€162.2; US $1235) for FLACS and €565.5 (€61.4; US $621) for PCS. The total mean (SD) cost of care at 12 months was €7085 (€6700; US $7787) in participants treated with FLACS and €6502 (€7323; US $7146) in participants treated with PCS. FLACS yielded a mean (SD) of 0.788 (0.009) quality-adjusted life-years (QALYs), and PCS yielded 0.792 (0.009) QALYs. The difference in mean costs was €545.9 (95% CI, -434.1 to 1525.8; US $600), and the difference in QALYs was -0.004 (95% CI, -0.028 to 0.021). The incremental cost-effectiveness ratio (ICER) was -€136 476 (US $150 000) per QALY. The cost-effectiveness probability of FLACS compared with PCS was 15.7% for a cost-effectiveness threshold of €30 000 (US $32 973) per QALY. At this threshold, the expected value of perfect information was €246 139 079 (US $270 530 231). Conclusions and Relevance: The ICER of FLACS compared with PCS was not within the $50 000 to $100 000 per QALY range frequently cited as cost-effective. Additional research and development on FLACS is needed to improve its effectiveness and lower its price. Trial Registration: ClinicalTrials.gov Identifier: NCT01982006.

Diversification dynamics in the Neotropics through time, clades, and biogeographic regions.

The origins and evolution of the outstanding Neotropical biodiversity are a matter of intense debate. A comprehensive understanding is hindered by the lack of deep-time comparative data across wide phylogenetic and ecological contexts. Here, we quantify the prevailing diversification trajectories and drivers of Neotropical diversification in a sample of 150 phylogenies (12,512 species) of seed plants and tetrapods, and assess their variation across Neotropical regions and taxa. Analyses indicate that Neotropical diversity has mostly expanded through time (70% of the clades), while scenarios of saturated and declining diversity account for 21% and 9% of Neotropical diversity, respectively. Five biogeographic areas are identified as distinctive units of long-term Neotropical evolution, including Pan-Amazonia, the Dry Diagonal, and Bahama-Antilles. Diversification dynamics do not differ across these areas, suggesting no geographic structure in long-term Neotropical diversification. In contrast, diversification dynamics differ across taxa: plant diversity mostly expanded through time (88%), while a substantial fraction (43%) of tetrapod diversity accumulated at a slower pace or declined towards the present. These opposite evolutionary patterns may reflect different capacities for plants and tetrapods to cope with past climate changes.

A Middle Pleistocene Denisovan molar from the Annamite Chain of northern Laos.

The Pleistocene presence of the genus Homo in continental Southeast Asia is primarily evidenced by a sparse stone tool record and rare human remains. Here we report a Middle Pleistocene hominin specimen from Laos, with the discovery of a molar from the Tam Ngu Hao 2 (Cobra Cave) limestone cave in the Annamite Mountains. The age of the fossil-bearing breccia ranges between 164-131 kyr, based on the Bayesian modelling of luminescence dating of the sedimentary matrix from which it was recovered, U-series dating of an overlying flowstone, and U-series-ESR dating of associated faunal teeth. Analyses of the internal structure of the molar in tandem with palaeoproteomic analyses of the enamel indicate that the tooth derives from a young, likely female, Homo individual. The close morphological affinities with the Xiahe specimen from China indicate that they belong to the same taxon and that Tam Ngu Hao 2 most likely represents a Denisovan.

COVID-19 outbreak and increased risk of amblyopia and epidemic myopia: Insights from EUROCOVCAT group.

The most common cause of vision impairment in children is amblyopia. It is defined as impaired visual acuity in one or both eyes that is present with no demonstrable abnormality of the visual pathway and is not immediately resolved by wearing glasses. After the World Health Organization (WHO) recognized COVID-19 as a global pandemic on March 11, 2020, widespread changes and restrictions to social and sanitary practices have presented significant issues in access to eye care during the COVID-19 pandemic. A reduction of more than 80% in pediatric eye care volume up to its total cessation has been observed in different departments. In this scenario, reduced or absent eyesight, due to delay in timely treatment of amblyopic conditions, could create major, long-lasting effects on all aspects of life, including daily personal activities, interacting with the community, school and work opportunities and the ability to access public services. Processes coming out of lockdown should be gradually easing restrictions giving priority to ophthalmology and eye care facilities so that amblyopia does not remain unattended and irreversible as in adults due to lack of timely treatments. If not reversible, this process could lead to a dramatic increase in disability and unsustainable social costs for many governments.

Late middle Miocene caviomorph rodents from Tarapoto, Peruvian Amazonia.

Miocene deposits of South America have yielded several species-rich assemblages of caviomorph rodents. They are mostly situated at high and mid- latitudes of the continent, except for the exceptional Honda Group of La Venta, Colombia, the faunal composition of which allowed to describe the late middle Miocene Laventan South American Land Mammal Age (SALMA). In this paper, we describe a new caviomorph assemblage from TAR-31 locality, recently discovered near Tarapoto in Peruvian Amazonia (San Martín Department). Based on mammalian biostratigraphy, this single-phased locality is unambiguously considered to fall within the Laventan SALMA. TAR-31 yielded rodent species found in La Venta, such as the octodontoid Ricardomys longidens Walton, 1990 (nom. nud.), the chinchilloids Microscleromys paradoxalis Walton, 1990 (nom. nud.) and M. cribriphilus Walton, 1990 (nom. nud.), or closely-related taxa. Given these strong taxonomic affinities, we further seize the opportunity to review the rodent dental material from La Venta described in the Ph.D. volume of Walton in 1990 but referred to as nomina nuda. Here we validate the recognition of these former taxa and provide their formal description. TAR-31 documents nine distinct rodent species documenting the four extant superfamilies of Caviomorpha, including a new erethizontoid: Nuyuyomys chinqaska gen. et sp. nov. These fossils document the most diverse caviomorph fauna for the middle Miocene interval of Peruvian Amazonia to date. This rodent discovery from Peru extends the geographical ranges of Ricardomys longidens, Microscleromys paradoxalis, and M. cribriphilus, 1,100 km to the south. Only one postcranial element of rodent was unearthed in TAR-31 (astragalus). This tiny tarsal bone most likely documents one of the two species of Microscleromys and its morphology indicates terrestrial generalist adaptations for this minute chinchilloid.

Trophic ecology of a Late Pleistocene early modern human from tropical Southeast Asia inferred from zinc isotopes.

Tam Pà Ling, a cave site in northeastern Laos, has yielded the earliest skeletal evidence of Homo sapiens in mainland Southeast Asia. The reliance of Pleistocene humans in rainforest settings on plant or animal resources is still largely unstudied, mainly due to poor collagen preservation in fossils from tropical environments precluding stable nitrogen isotope analysis, the classical trophic level proxy. However, isotopic ratios of zinc (Zn) in bioapatite constitute a promising proxy to infer trophic and dietary information from fossil vertebrates, even under adverse tropical taphonomic conditions. Here, we analyzed the zinc isotope composition (66Zn/64Zn expressed as δ66Zn value) in the enamel of two teeth of the Late Pleistocene (63-46 ka) H. sapiens individual (TPL1) from Tam Pà Ling, as well as 76 mammal teeth from the same site and the nearby Nam Lot cave. The human individual exhibits relatively low enamel δ66Zn values (+0.24‰) consistent with an omnivorous diet, suggesting a dietary reliance on both plant and animal matter. These findings offer direct evidence of the broad utilization of resources from tropical rainforests by one of the earliest known anatomically modern humans in Southeast Asia.

A multi-proxy approach to exploring Homo sapiens' arrival, environments and adaptations in Southeast Asia.

The capability of Pleistocene hominins to successfully adapt to different types of tropical forested environments has long been debated. In order to investigate environmental changes in Southeast Asia during a critical period for the turnover of hominin species, we analysed palaeoenvironmental proxies from five late Middle to Late Pleistocene faunas. Human teeth discoveries have been reported at Duoi U'Oi, Vietnam (70-60 ka) and Nam Lot, Laos (86-72 ka). However, the use of palaeoproteomics allowed us to discard the latter, and, to date, no human remains older than ~ 70 ka are documented in the area. Our findings indicate that tropical rainforests were highly sensitive to climatic changes over that period, with significant fluctuations of the canopy forests. Locally, large-bodied faunas were resilient to these fluctuations until the cooling period of the Marine Isotope Stage 4 (MIS 4; 74-59 ka) that transformed the overall biotope. Then, under strong selective pressures, populations with new phenotypic characteristics emerged while some other species disappeared. We argue that this climate-driven shift offered new foraging opportunities for hominins in a novel rainforest environment and was most likely a key factor in the settlement and dispersal of our species during MIS 4 in SE Asia.

Ancient and modern genomes unravel the evolutionary history of the rhinoceros family.

Only five species of the once-diverse Rhinocerotidae remain, making the reconstruction of their evolutionary history a challenge to biologists since Darwin. We sequenced genomes from five rhinoceros species (three extinct and two living), which we compared to existing data from the remaining three living species and a range of outgroups. We identify an early divergence between extant African and Eurasian lineages, resolving a key debate regarding the phylogeny of extant rhinoceroses. This early Miocene (∼16 million years ago [mya]) split post-dates the land bridge formation between the Afro-Arabian and Eurasian landmasses. Our analyses also show that while rhinoceros genomes in general exhibit low levels of genome-wide diversity, heterozygosity is lowest and inbreeding is highest in the modern species. These results suggest that while low genetic diversity is a long-term feature of the family, it has been particularly exacerbated recently, likely reflecting recent anthropogenic-driven population declines.

Correction: Eocene intra-plate shortening responsible for the rise of a faunal pathway in the northeastern Caribbean realm.

[This corrects the article DOI: 10.1371/journal.pone.0241000.].

Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors.

Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3ζ) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling, and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity, and specificity, pCAR T cells consistently elicit superior anti-tumor activity compared with T cells that express traditional linear CARs.

Early impact of COVID-19 outbreak on eye care: Insights from EUROCOVCAT group.

The recent outbreak of coronavirus disease 2019 (COVID-19) has been declared a public health emergency worldwide. The scientific community has put in much effort and published studies that described COVID-19's biology, transmission, clinical diagnosis, candidate therapeutics, and vaccines. However, to date, only a few data are available on the impact of COVID-19 pandemic on ophthalmological care in different health care systems, its future consequences in terms of disability, and access to sight-saving cures for many patients. To reduce human-to-human transmission of the virus and also ensure supply of infrastructures, human resources, and disposable medical devices to many regions, it is crucial to assess risks and postpone non-essential outpatient visits and elective surgical procedures, especially in older patients and those with comorbidities. This delay or suspension in essential eye procedures may cause significant and rapid vision impairment to irreversible blindness. Determining the risk-benefit profile of treating these ocular pathologies is a public health issue of supreme priority, even though many patients benefiting from therapeutic treatments are elderly, who are more vulnerable to COVID-19. If not reversible, this process could lead to a dramatic increase in disability and unsustainable social costs for many Governments.

Eocene intra-plate shortening responsible for the rise of a faunal pathway in the northeastern Caribbean realm.

Intriguing latest Eocene land-faunal dispersals between South America and the Greater Antilles (northern Caribbean) has inspired the hypothesis of the GAARlandia (Greater Antilles Aves Ridge) land bridge. This landbridge, however, should have crossed the Caribbean oceanic plate, and the geological evolution of its rise and demise, or its geodynamic forcing, remain unknown. Here we present the results of a land-sea survey from the northeast Caribbean plate, combined with chronostratigraphic data, revealing a regional episode of mid to late Eocene, trench-normal, E-W shortening and crustal thickening by ∼25%. This shortening led to a regional late Eocene-early Oligocene hiatus in the sedimentary record revealing the location of an emerged land (the Greater Antilles-Northern Lesser Antilles, or GrANoLA, landmass), consistent with the GAARlandia hypothesis. Subsequent submergence is explained by combined trench-parallel extension and thermal relaxation following a shift of arc magmatism, expressed by a regional early Miocene transgression. We tentatively link the NE Caribbean intra-plate shortening to a well-known absolute and relative North American and Caribbean plate motion change, which may provide focus for the search of the remaining connection between 'GrANoLA' land and South America, through the Aves Ridge or Lesser Antilles island arc. Our study highlights the how regional geodynamic evolution may have driven paleogeographic change that is still reflected in current biology.

Comparative isotope ecology of western Amazonian rainforest mammals.

Closed-canopy rainforests are important for climate (influencing atmospheric circulation, albedo, carbon storage, etc.) and ecology (harboring the highest biodiversity of continental regions). Of all rainforests, Amazonia is the world's most diverse, including the highest mammalian species richness. However, little is known about niche structure, ecological roles, and food resource partitioning of Amazonian mammalian communities over time. Through analyses of δ13Cbioapatite, δ13Chair, and δ15Nhair, we isotopically characterized aspects of feeding ecology in a modern western Amazonian mammalian community in Peru, serving as a baseline for understanding the evolution of Neotropical rainforest ecosystems. By comparing these results with data from equatorial Africa, we evaluated the potential influences of distinct phylogenetic and biogeographic histories on the isotopic niches occupied by mammals in analogous tropical ecosystems. Our results indicate that, despite their geographical and taxonomic differences, median δ13Cdiet values from closed-canopy rainforests in Amazonia (-27.4‰) and equatorial Africa (-26.9‰) are not significantly different, and that the median δ13Cdiet expected for mammalian herbivores in any closed-canopy rainforest is -27.2‰. Amazonian mammals seem to exploit a narrower spectrum of dietary resources than equatorial African mammals, however, as depicted by the absence of highly negative δ13Cdiet values previously proposed as indicative of rainforests (<-31‰). Finally, results of keratin and bioapatite δ13C indicate that the predictive power of trophic relationships, and traditional dietary ecological classifications in bioapatite-protein isotopic offset expectations, must be reconsidered.

New material of Epiaceratherium and a new species of Mesaceratherium clear up the phylogeny of early Rhinocerotidae (Perissodactyla).

Reduction of the anterior dentition (i.e. incisors and canines) is a major adaptative trait of the Rhinocerotidae among Perissodactyla. However, the corresponding evolutionary sequence was lacking a robust phylogenetic frame to support it thus far. Here, we describe a new Oligocene species of Rhinocerotinae, Mesaceratherium sp. nov. from the Swiss locality of Bumbach (MP25 reference level). In addition, we identify the only known complete mandible of Epiaceratherium magnum, an early-branching rhinocerotid, as well as one of the earliest European rhinoceroses. We also compute a parsimony analysis based on morpho-anatomical characters to assess their phylogenetic position and elucidate the early evolution of the Rhinocerotidae. Our results allow to propose a new scenario for the reduction of the anterior dentition in which upper and lower dentitions would have undergone distinct evolutionary trajectories.