Iterative Evolution of Sympatric Seacow (Dugongidae, Sirenia) Assemblages during the Past ∼26 Million Years

Extant sirenians show allopatric distributions throughout most of their range. However, their fossil record shows evidence of multispecies communities throughout most of the past ∼26 million years, in different oceanic basins. Morphological differences among co-occurring sirenian taxa suggest that resource partitioning played a role in structuring these communities. We examined body size and ecomorphological differences (e.g., rostral deflection and tusk morphology) among sirenian assemblages from the late Oligocene of Florida, early Miocene of India and early Pliocene of Mexico; each with three species of the family Dugongidae. Although overlapping in several ecomorphological traits, each assemblage showed at least one dominant trait in which coexisting species differed. Fossil sirenian occurrences occasionally are monotypic, but the assemblages analyzed herein show iterative evolution of multispecies communities, a phenomenon unparalleled in extant sirenian ecology. As primary consumers of seagrasses, these communities likely had a strong impact on past seagrass ecology and diversity, although the sparse fossil record of seagrasses limits direct comparisons. Nonetheless, our results provide robust support for previous suggestions that some sirenians in these extinct assemblages served as keystone species, controlling the dominance of climax seagrass species, permitting more taxonomically diverse seagrass beds (and sirenian communities) than many of those observed today

Protosiren smithae, New Species (Mammalia, Sirenia), from the Late Middle Eocene of Wadi Hitan, Egypt

69-87http://deepblue.lib.umich.edu/bitstream/2027.42/48642/2/ID509.pd

Cranial Morphology of Protosiren fraasi (Mammalia, Sirenia) from the Middle Eocene of Egypt: A New Study Using Computed Tomography

41-67http://deepblue.lib.umich.edu/bitstream/2027.42/48641/2/ID508.pd

A New Early Oligocene Dugongid (Mammalia, Sirenia) from Fayum Province, Egypt

89-108http://deepblue.lib.umich.edu/bitstream/2027.42/48643/2/ID510.pd

Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

PURPOSE Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 (NCT02935257) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL. METHODS Patients age ≥ 16 years with r/r B-ALL were eligible. Primary outcomes were toxicity and manufacturing feasibility. Secondary outcomes were depth of response at 1 and 3 months, persistence of CAR-T, incidence and duration of hypogammaglobulinemia and B-cell aplasia, and event-free survival and overall survival at 1 and 2 years. RESULTS Twenty-five patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. The median age was 41.5 years; 25% had prior blinatumomab, 50% prior inotuzumab ozogamicin, and 65% prior allogeneic stem-cell transplantation. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. No patients experienced ≥ grade 3 cytokine release syndrome; 3 of 20 (15%) experienced grade 3 neurotoxicity that resolved to ≤ grade 1 within 72 hours with steroids. Seventeen of 20 (85%) achieved minimal residual disease–negative complete response at month 1, and 3 of 17 underwent allogeneic stem-cell transplantation while in remission. The event-free survival at 6 and 12 months was 68.3% (42.4-84.4) and 48.3% (23.1%-69.7%), respectively. High-level expansion (Cmax 127,152 copies/µg genomic DNA) and durable CAR-T persistence were observed with B-cell aplasia ongoing in 15 of 20 patients at last follow-up. CONCLUSION AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in r/r adult B-ALL. Preliminary data support further development of AUTO1 as a stand-alone treatment for r/r adult B-ALL

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n = 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3-5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL

What Happened to Gray Whales during the Pleistocene? The Ecological Impact of Sea-Level Change on Benthic Feeding Areas in the North Pacific Ocean

Gray whales (Eschrichtius robustus) undertake long migrations, from Baja California to Alaska, to feed on seasonally productive benthos of the Bering and Chukchi seas. The invertebrates that form their primary prey are restricted to shallow water environments, but global sea-level changes during the Pleistocene eliminated or reduced this critical habitat multiple times. Because the fossil record of gray whales is coincident with the onset of Northern Hemisphere glaciation, gray whales survived these massive changes to their feeding habitat, but it is unclear how.We reconstructed gray whale carrying capacity fluctuations during the past 120,000 years by quantifying gray whale feeding habitat availability using bathymetric data for the North Pacific Ocean, constrained by their maximum diving depth. We calculated carrying capacity based on modern estimates of metabolic demand, prey availability, and feeding duration; we also constrained our estimates to reflect current population size and account for glaciated and non-glaciated areas in the North Pacific. Our results show that key feeding areas eliminated by sea-level lowstands were not replaced by commensurate areas. Our reconstructions show that such reductions affected carrying capacity, and harmonic means of these fluctuations do not differ dramatically from genetic estimates of carrying capacity.Assuming current carrying capacity estimates, Pleistocene glacial maxima may have created multiple, weak genetic bottlenecks, although the current temporal resolution of genetic datasets does not test for such signals. Our results do not, however, falsify molecular estimates of pre-whaling population size because those abundances would have been sufficient to survive the loss of major benthic feeding areas (i.e., the majority of the Bering Shelf) during glacial maxima. We propose that gray whales survived the disappearance of their primary feeding ground by employing generalist filter-feeding modes, similar to the resident gray whales found between northern Washington State and Vancouver Island

Seagrass and submerged aquatic vegetation (VAS) habitats off the Coast of Brazil: state of knowledge, conservation and main threats

Seagrass meadows are among the most threatened ecosystems on earth, raising concerns about the equilibrium of coastal ecosystems and the sustainability of local fisheries. The present review evaluated the current status of the research on seagrasses and submerged aquatic vegetation (SAV) habitats off the coast of Brazil in terms of plant responses to environmental conditions, changes in distribution and abundance, and the possible role of climate change and variability. Despite an increase in the number of studies, the communication of the results is still relatively limited and is mainly addressed to a national or regional public; thus, South American seagrasses are rarely included or cited in global reviews and models. The scarcity of large-scale and long-term studies allowing the detection of changes in the structure, abundance and composition of seagrass habitats and associated species still hinders the investigation of such communities with respect to the potential effects of climate change. Seagrass meadows and SAV occur all along the Brazilian coast, with species distribution and abundance being strongly influenced by regional oceanography, coastal water masses, river runoff and coastal geomorphology. Based on these geomorphological, hydrological and ecological features, we characterised the distribution of seagrass habitats and abundances within the major coastal compartments. The current conservation status of Brazilian seagrasses and SAV is critical. The unsustainable exploitation and occupation of coastal areas and the multifold anthropogenic footprints left during the last 100 years led to the loss and degradation of shoreline habitats potentially suitable for seagrass occupation. Knowledge of the prevailing patterns and processes governing seagrass structure and functioning along the Brazilian coast is necessary for the global discussion on climate change. Our review is a first and much-needed step toward a more integrated and inclusive approach to understanding the diversity of coastal plant formations along the Southwestern Atlantic coast as well as a regional alert the projected or predicted effects of global changes on the goods and services provided by regional seagrasses and SAV