Phylogeny and paleobiogeography of the enigmatic North American primate Ekgmowechashala illuminated by new fossils from Nebraska (USA) and Guangxi Zhuang Autonomous Region (China).

Ekgmowechashala is a poorly documented but very distinctive primate known only from the late early Oligocene (early Arikareean) of western North America. Because of its highly autapomorphous dentition and spatiotemporal isolation, the phylogenetic and biogeographic affinities of Ekgmowechashala have long been debated. Here, we describe the oldest known fossils of Ekgmowechashala from the Brown Siltstone Beds of the Brule Formation, White River Group of western Nebraska. We also describe a new ekgmowechashaline taxon from the Nadu Formation (late Eocene) in the Baise Basin of Guangxi Zhuang Autonomous Region in southern China. Phylogenetic analysis suggests that North American Ekgmowechashala and the new Chinese taxon are sister taxa that are nested within a radiation of southern Asian adapiforms that also includes Gatanthropus, Muangthanhinius, and Bugtilemur. The new Chinese ekgmowechashaline helps fill the considerable disparity in dental morphology between Ekgmowechashala and more primitive ekgmowechashalids known from southern Asia. Our study underscores the fundamental role of southern Asia as a refugium for multiple primate clades during the cooler and drier climatic regime that prevailed after the Eocene-Oligocene transition. The colonization of North America by Ekgmowechashala helps define the beginning of the Arikareean Land Mammal Age and corresponds to an example of the Lazarus effect, whereby a taxon (in this case, the order Primates) reappears suddenly in the fossil record after a lengthy hiatus.

Results from the Radiation Assessment Detector on the International Space Station: Part 1, the Charged Particle Detector.

We report the results of the first six years of measurements of the energetic particle radiation environment on the International Space Station (ISS) with the Radiation Assessment Detector (ISS-RAD), spanning the period from February 2016 to February 2022. The first RAD was designed and built for MSL, the Mars Science Laboratory rover, also known as Curiosity; it has been operating on Mars since 2012 and is referred to here as MSL-RAD. ISS-RAD combines two sensor heads, one nearly identical to the single MSL-RAD sensor head, the other with greatly enhanced sensitivity to fast neutrons. These two sensor heads are referred to as the Charged Particle Detector (CPD) and Fast Neutron Detector (FND), respectively. Despite its name, the CPD is also capable of measuring high-energy neutrons and γ-rays, as is MSL-RAD. ISS-RAD was flown to the ISS in December 2015 and was deployed in February 2016, initially in the USLab module. RAD was used as a survey instrument from January 2017 through May 2020, when the instrument was positioned in the USLab and set to a zenith-pointing orientation. The energetic particle environment on the ISS is complex and varies on short time scales owing to the orbit, which has a 51.6∘ inclination with respect to the equator and has had an altitude in the 400-440 km range in this time period. The ISS moves continuously through the geomagnetic field, the strength of which varies with latitude, longitude, and altitude. The orbit passes through the South Atlantic Anomaly (SAA) several times a day, where magnetically trapped protons and electrons produce large but transient increases in observed fluxes and absorbed dose rates. The environment inside the ISS is affected by the solar cycle, altitude, and the local shielding, which varies between different ISS modules. We report results for charged particle absorbed dose and dose equivalent rates in various positions in the ISS. In an accompanying paper, we report similar results for neutron dose equivalent rates obtained with the ISS-RAD Fast Neutron Detector.

Results from the Radiation Assessment Detector on the International Space Station, Part 2: The fast neutron detector.

We report the results of the first six years of measurements of so-called fast neutrons on the International Space Station (ISS) with the Radiation Assessment Detector (ISS-RAD), spanning the period from February 2016 to February 2022. ISS-RAD combines two sensor heads, one nearly identical to the single sensor head in the Mars Science Laboratory RAD (MSL-RAD). The latter is described in a companion article to this one. The novel sensor is the FND, or fast neutron detector, designed to measure neutrons with energies in the range from 200 keV to about 8 MeV. ISS-RAD was deployed in February 2016 in the USLAB module, and then served as a survey instrument from March 2017 until May 2020. Data were acquired in Node3, the Japanese Pressurized Module, Columbus, and Node2. At the conclusion of the survey portion of RAD's planned 10-year campaign on ISS, the instrument was stationed in the USLAB; current plans call for it to remain there indefinitely. The radiation environment on the ISS consists of a complex mix of charged and neutral particles that varies on short time scales owing to the Station's orbit. Neutral particles, and neutrons in particular, are of concern from a radiation protection viewpoint, because they are both highly penetrating (since they do not lose energy via direct ionization) and, at some energies, have high biological effectiveness. Neutrons are copiously produced by GCRs and other incident energetic particles when they undergo nuclear interactions in shielding. As different ISS modules have varying amounts of shielding, they also have varying neutron environments. We report results for neutron fluences and dose equivalent rates in various positions in the ISS.

Results from the Radiation Assessment Detector on the International Space Station: Part 3, combined results from the CPD and FND.

The energetic particle radiation environment on the International Space Station (ISS) includes both charged and neutral particles. Here, we make use of the unique capabilities of the Radiation Assessment Detector (ISS-RAD) to measure both of these components simultaneously. The Charged Particle Detector (CPD) is, despite its name, capable of measuring neutrons in the energy range from about 4 MeV to a few hundred MeV. Combined with data from the Fast Neutron Detector (FND) in the 0.2 to 8 MeV range, we present the first broad-spectrum measurements of the neutron environments in various locations within the ISS since an early Bonner-Ball experiment that was conducted before the Station was fully constructed. The data presented here span the time period from February 2016 to February 2022. In addition to presenting broad-spectrum neutron fluence measurements, we show correlations of the measured neutron dose equivalent with charged-particle dose rates. The ratio of charged-particle dose to neutron dose equivalent is found to be relatively stable within the ISS.

Basal Primatomorpha colonized Ellesmere Island (Arctic Canada) during the hyperthermal conditions of the early Eocene climatic optimum.

Anthropogenically induced warming is transforming Arctic ecosystems across a geologically short timescale, but earlier episodes of Earth history provide insights on the nature and limitations of biotic change in a rapidly warming Arctic. Late early Eocene strata (~52 Ma) of the Margaret Formation on Ellesmere Island, Nunavut, Canada sample a warm temperate ecosystem with a polar light regime situated at ~77°N paleolatitude. This extinct boreal ecosystem hosted a diversity of early Cenozoic vertebrates, including thermophilic taxa such as crocodilians and tapiroid perissodactyls. Here we describe two new species of the early primatomorphan Ignacius from Ellesmere, which are by far the northernmost known records for Paleogene Primatomorpha. Ellesmere species of Ignacius are sister taxa, indicating a single colonization of Ellesmere from farther south in North America coincident with the onset of the hyperthermal Early Eocene Climatic Optimum (EECO). The Ellesmere Ignacius clade differs from closely related taxa inhabiting mid-latitudes in being larger (thereby conforming to Bergmann's rule) and having modified dentition and muscles of mastication for a dietary regime emphasizing hard objects, possibly reflecting an increased reliance on fallback foods during long polar winters. The late early Eocene mammalian fauna of Ellesmere indicates that its unique paleoenvironment rendered it uninhabitable to some clades, including euprimates, while selected taxa were able to adapt to its challenging conditions and diversify.

medna-metadata: an open-source data management system for tracking environmental DNA samples and metadata.

MOTIVATION: Environmental DNA (eDNA), as a rapidly expanding research field, stands to benefit from shared resources including sampling protocols, study designs, discovered sequences, and taxonomic assignments to sequences. High-quality community shareable eDNA resources rely heavily on comprehensive metadata documentation that captures the complex workflows covering field sampling, molecular biology lab work, and bioinformatic analyses. There are limited sources that provide documentation of database development on comprehensive metadata for eDNA and these workflows and no open-source software. RESULTS: We present medna-metadata, an open-source, modular system that aligns with Findable, Accessible, Interoperable, and Reusable guiding principles that support scholarly data reuse and the database and application development of a standardized metadata collection structure that encapsulates critical aspects of field data collection, wet lab processing, and bioinformatic analysis. Medna-metadata is showcased with metabarcoding data from the Gulf of Maine (Polinski et al., 2019). AVAILABILITY AND IMPLEMENTATION: The source code of the medna-metadata web application is hosted on GitHub (https://github.com/Maine-eDNA/medna-metadata). Medna-metadata is a docker-compose installable package. Documentation can be found at https://medna-metadata.readthedocs.io/en/latest/?badge=latest. The application is implemented in Python, PostgreSQL and PostGIS, RabbitMQ, and NGINX, with all major browsers supported. A demo can be found at https://demo.metadata.maine-edna.org/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Tolerogenic Delivery of a Hybrid Insulin Peptide Markedly Prolongs Islet Graft Survival in the NOD Mouse.

The induction of antigen (Ag)-specific tolerance and replacement of islet ß-cells are major ongoing goals for the treatment of type 1 diabetes (T1D). Our group previously showed that a hybrid insulin peptide (2.5HIP) is a critical autoantigen for diabetogenic CD4+ T cells in the NOD mouse model. In this study, we investigated whether induction of Ag-specific tolerance using 2.5HIP-coupled tolerogenic nanoparticles (NPs) could protect diabetic NOD mice from disease recurrence upon syngeneic islet transplantation. Islet graft survival was significantly prolonged in mice treated with 2.5HIP NPs, but not NPs containing the insulin B chain peptide 9-23. Protection in 2.5HIP NP-treated mice was attributed both to the simultaneous induction of anergy in 2.5HIP-specific effector T cells and the expansion of Foxp3+ regulatory T cells specific for the same Ag. Notably, our results indicate that effector function of graft-infiltrating CD4+ and CD8+ T cells specific for other ß-cell epitopes was significantly impaired, suggesting a novel mechanism of therapeutically induced linked suppression. This work establishes that tolerance induction with an HIP can delay recurrent autoimmunity in NOD mice, which could inform the development of an Ag-specific therapy for T1D.

The earliest Asian bats (Mammalia: Chiroptera) address major gaps in bat evolution.

Bats dispersed widely after evolving the capacity for powered flight, and fossil bats are known from the early Eocene of most continents. Until now, however, bats have been conspicuously absent from the early Eocene of mainland Asia. Here, we report two teeth from the Junggar Basin of northern Xinjiang, China belonging to the first known early Eocene bats from Asia, representing arguably the most plesiomorphic bat molars currently recognized. These teeth combine certain bat synapomorphies with primitive traits found in other placental mammals, thereby potentially illuminating dental evolution among stem bats. The Junggar Basin teeth suggest that the dentition of the stem chiropteran family Onychonycteridae is surprisingly derived, although their postcranial anatomy is more primitive than that of any other Eocene bats. Additional comparisons with stem bat families Icaronycteridae and Archaeonycteridae fail to identify unambiguous synapomorphies for the latter taxa, raising the possibility that neither is monophyletic as currently recognized. The presence of highly plesiomorphic bats in the early Eocene of central Asia suggests that this region was an important locus for the earliest, transitional phases of bat evolution, as has been demonstrated for other placental mammal orders including Lagomorpha and Rodentia.

A new parapithecine (Primates: Anthropoidea) from the early Oligocene of Libya supports parallel evolution of large body size among parapithecids.

Parapithecines are an extinct subfamily of stem anthropoid primates previously known only from the Jebel Qatrani Formation in Egypt. Here, we describe isolated teeth pertaining to Simonsius harujensis sp. nov., a relatively small-bodied parapithecine from strata near Zallah Oasis in the Sirt Basin of central Libya that is estimated to date to ∼31 Ma on the basis of mammalian biostratigraphy. The dental morphology of S. harujensis sp. nov. is generally intermediate between that of the closely related parapithecines Parapithecus fraasi and Simonsius grangeri, highlighting some of the anatomical features distinguishing the latter taxa and providing further support for their generic separation. A phylogenetic analysis using parsimony methods was performed on a character-taxon matrix incorporating data from the new Libyan parapithecine, virtually all other parapithecids and the proteopithecid Proteopithecus sylviae. Results of this analysis suggest that parapithecids comprise a basal clade consisting of three species of Biretia and a more derived clade including Parapithecinae (Parapithecus and Simonsius) and Qatraniinae (Qatrania, Ucayalipithecus, and Apidium). Body mass estimates for parapithecids were calculated on the basis of regression equations generated to predict body mass from the occlusal area of upper and lower cheek teeth in extant anthropoids. The relatively small body mass of S. harujensis sp. nov. and its reconstructed phylogenetic position as the sister group of S. grangeri, which is the largest known parapithecid, support the convergent acquisition of body mass larger than 500 g among multiple clades of early Oligocene African anthropoids. The new Libyan parapithecine augments previously reported evidence supporting a substantial degree of faunal provincialism across northern Africa/Arabia during the early Oligocene.

Correction: Eocene metatherians from Anatolia illuminate the assembly of an island fauna during Deep Time.

[This corrects the article DOI: 10.1371/journal.pone.0206181.].

Identification of Hybrid Insulin Peptides (HIPs) in Mouse and Human Islets by Mass Spectrometry.

We recently discovered hybrid insulin peptides (HIPs) as a novel class of post-translationally modified peptides in murine-derived beta cell tumors, and we demonstrated that these molecules are autoantigens in type 1 diabetes (T1D). A HIP consists of an insulin fragment linked to another secretory granule peptide via a peptide bond. We verified that autoreactive CD4 T cells in both mouse and human autoimmune diabetes recognize these modified peptides. Here, we use mass spectrometric analyses to confirm the presence of HIPs in both mouse and human pancreatic islets. We also present criteria for the confident identification of these peptides. This work supports the hypothesis that HIPs are autoantigens in human T1D and provides a foundation for future efforts to interrogate this previously unknown component of the beta cell proteome.

Eocene metatherians from Anatolia illuminate the assembly of an island fauna during Deep Time.

Island biotas have disproportionately influenced the history and development of evolutionary biology, but understanding their genesis and evolution across geological timescales has been hindered by a poor fossil record. Here we augment the insular Eocene (~43 Ma) mammalian fauna known from the Pontide terrane of central Anatolia by describing two new metatherian taxa (stem marsupials) from the Lülük Member of the Uzunçarsidere Formation in the Orhaniye Basin. Geological and paleontological data indicate that the Pontide terrane was an island on the northern margin of Neotethys during the middle Eocene. Reflecting its geodynamic context in a region of active tectonic convergence, the Eocene Pontide terrane hosted a unique combination of Laurasian and Gondwanan mammals, including an anachronistic radiation of pleuraspidotheriids (archaic ungulates) that went extinct on the European mainland ~13 Ma earlier. Most of the mammalian clades occupying the Pontide terrane colonized it by dispersal across marine barriers rather than being stranded there through vicariance. Endemic radiations of pleuraspidotheriid ungulates and polydolopimorphian metatherians on the Pontide terrane reveal that in situ diversification was an important factor contributing to faunal assembly and evolution. The insular fauna that arose on the Pontide terrane is highly analogous to that of modern Sulawesi, which evolved under strikingly similar geological conditions. Illustrating the ephemeral nature of insular biotas across macroevolutionary timescales, the demise of the Pontide fauna coincided with paleogeographic changes enabling more cosmopolitan taxa to reach it for the first time. The high level of endemism shown by the mammalian fauna of the Uzunçarsidere Formation eliminates the Pontide terrane as a potential early Eocene dispersal corridor between western Europe and India.

Anti-LFA-1 induces CD8 T-cell dependent allograft tolerance and augments suppressor phenotype CD8 cells.

The induction of tolerance to transplanted organs is a major objective in transplantation immunology research. Lymphocyte function-associated antigen-1 (LFA-1) interactions have been identified as a key component of the T-cell activation process that may be interrupted to lead to allograft tolerance. In mice, αLFA-1 mAb is a potent monotherapy that leads to the induction of donor-specific transferable tolerance. By interrogating important adaptive and innate immunity pathways, we demonstrate that the induction of tolerance relies on CD8+T-cells. We further demonstrate that αLFA-1 induced tolerance is associated with CD8+CD28-T-cells with a suppressor phenotype, and that while CD8 cells are present, the effector T-cell response is abrogated. A recent publication has shown that CD8+CD28- cells are not diminished by cyclosporine or rapamycin, therefore CD8+CD28- cells represent a clinically relevant population. To our knowledge, this is the first time that a mechanism for αLFA-1 induced tolerance has been described.

Nasolacrimal anatomy and haplorhine origins.

Computed tomography X-ray imaging of the internal face in well-preserved primate fossil crania permits reconstruction of the nature of their nasal anatomy, including some soft-tissue features. These features are diagnostic of the primate suborder Haplorhini, and allow reevaluation of the phylogenetic status of several purported early members of the group. Here we examine the nasolacrimal morphology of a broad sample of extant primates, as well as a number of Paleogene fossils. The extant sample confirms the distinctiveness of the two suborders. Of the fossils studied, only Shoshonius cooperi from the late-early Eocene exhibits evidence of a haplorhine nose. This suggests that the haplorhine oronasal complex may have evolved before the postorbital septum, and strengthens the claim that Shoshonius is a close relative of tarsiers and anthropoids. These results indicate that Omomyiformes is not a monophyletic group, and that few of its members possessed the derived oronasal morphology that characterizes crown haplorhines.

Phalangeal morphology of Shanghuang fossil primates.

Here, we describe hundreds of isolated phalanges attributed to middle Eocene fossil primates from the Shanghuang fissure-fillings from southern Jiangsu Province, China. Extending knowledge based on previous descriptions of postcranial material from Shanghuang, this sample of primate finger and toe bones includes proximal phalanges, middle phalanges, and over three hundred nail-bearing distal phalanges. Most of the isolated proximal and middle phalanges fall within the range of small-bodied individuals, suggesting an allocation to the smaller haplorhine primates identified at Shanghuang, including eosimiids. In contrast to the proximal and middle phalanges from Shanghuang, there are a variety of shapes, sizes, and possible taxonomic allocations for the distal phalanges. Two distal phalangeal morphologies are numerically predominant at Shanghuang. The sample of larger bodied specimens is best allocated to the medium-sized adapiform Adapoides while the smaller ones are allocated to eosimiids on the basis of the commonality of dental and tarsal remains of these taxa at Shanghuang. The digit morphology of Adapoides is similar morphologically to that of notharctines and cercamoniines, while eosimiid digit morphology is unlike living anthropoids. Other primate distal phalangeal morphologies at Shanghuang include grooming "claws" as well as specimens attributable to tarsiids, tarsiiforms, the genus Macrotarsius, and a variety of adapiforms. One group of distal phalanges at Shanghuang is morphologically indistinguishable from those of living anthropoids. All of the phalanges suggest long fingers and toes for the fossil primates of Shanghaung, and their digit morphology implies arboreality with well-developed digital flexion and strong, grasping hands and feet.

Disruption of Transplant Tolerance by an "Incognito" Form of CD8 T Cell-Dependent Memory.

Several approaches successfully achieve allograft tolerance in preclinical models but are challenging to translate into clinical practice. Many clinically relevant factors can attenuate allograft tolerance induction, including intrinsic genetic resistance, peritransplant infection, inflammation, and preexisting antidonor immunity. The prevailing view for immune memory as a tolerance barrier is that the host harbors memory cells that spontaneously cross-react to donor MHC antigens. Such preexisting "heterologous" memory cells have direct reactivity to donor cells and resist most tolerance regimens. In this study, we developed a model system to determine if an alternative form of immune memory could also block tolerance. We posited that host memory T cells could potentially respond to donor-derived non-MHC antigens, such as latent viral antigens or autoantigens, to which the host is immune. Results show that immunity to a model nonself antigen, ovalbumin (OVA), can dramatically disrupt tolerance despite undetectable initial reactivity to donor MHC antigens. Importantly, this blockade of tolerance was CD8+ T cell-dependent and required linked antigen presentation of alloantigens with the test OVA antigen. As such, this pathway represents an unapparent, or "incognito," form of immunity that is sufficient to prevent tolerance and that can be an unforeseen additional immune barrier to clinical transplant tolerance.

Differential Impact of Chronic Hyperglycemia on Humoral Versus Cellular Primary Alloimmunity.

Diabetes is prevalent among solid organ transplant recipients and is universal among islet transplant recipients. Whereas diabetes is often considered to result in an immune-compromised state, the impact of chronic hyperglycemia on host alloimmunity is not clear. Potential immune-modifying effects of obesity, autoimmunity, or diabetogenic agents like streptozotocin may confound understanding alloimmunity in experimental models of diabetes. Therefore, we sought to determine the role of chronic hyperglycemia due to insulinopenia on alloimmunity using the nonautoimmune, spontaneously diabetic H-2b-expressing C57BL/6 Ins2Akita mice (Akita). Akita mice harbor a mutated Ins2 allele that dominantly suppresses insulin secretion, resulting in lifelong diabetes. We used BALB/c donors (H-2d) to assess alloimmunization and islet transplantation outcomes in Akita recipients. Surprisingly, chronic hyperglycemia had little effect on primary T-cell reactivity after alloimmunization. Moreover, Akita mice readily rejected islet allografts, and chronic hyperglycemia had no impact on the magnitude or quality of intragraft T-cell responses. In contrast, allospecific IgM and IgG were significantly decreased in Akita mice after alloimmunization. Thus, whereas diabetes influences host immune defense, hyperglycemia itself does not cause generalized alloimmune impairment. Our data suggest that immune compromise in diabetes due to hyperglycemia may not apply to cellular rejection of transplants.

Oligocene primates from China reveal divergence between African and Asian primate evolution.

Profound environmental and faunal changes are associated with climatic deterioration during the Eocene-Oligocene transition (EOT) roughly 34 million years ago. Reconstructing how Asian primates responded to the EOT has been hindered by a sparse record of Oligocene primates on that continent. Here, we report the discovery of a diverse primate fauna from the early Oligocene of southern China. In marked contrast to Afro-Arabian Oligocene primate faunas, this Asian fauna is dominated by strepsirhines. There appears to be a strong break between Paleogene and Neogene Asian anthropoid assemblages. Asian and Afro-Arabian primate faunas responded differently to EOT climatic deterioration, indicating that the EOT functioned as a critical evolutionary filter constraining the subsequent course of primate evolution across the Old World.