The long-standing assumption that aboveground plant litter inputs have a substantial influence on soil organic carbon storage (SOC) and dynamics has been challenged by a new paradigm for SOC formation and persistence. We tested the importance of plant litter chemistry on SOC storage, distribution, composition, and age by comparing two highly contrasting ecosystems: an old-growth coast redwood (Sequoia sempervirens) forest, with highly aromatic litter, and an adjacent coastal prairie, with more easily decomposed litter. We hypothesized that if plant litter chemistry was the primary driver, redwood would store more and older SOC that was less microbially processed than prairie. Total soil carbon stocks to 110 cm depth were higher in prairie (35 kg C m−2) than redwood (28 kg C m−2). Radiocarbon values indicated shorter SOC residence times in redwood than prairie throughout the profile. Higher amounts of pyrogenic carbon and a higher degree of microbial processing of SOC appear to be instrumental for soil carbon storage and persistence in prairie, while differences in fine-root carbon inputs likely contribute to younger SOC in redwood. We conclude that at these sites fire residues, root inputs, and soil properties influence soil carbon dynamics to a greater degree than the properties of aboveground litter.

The potential relationships between traumatic experiences and the onset and course of major mood disorders have always been controversial. Some experiences, most notably physical or sexual abuse, as well as substantive bullying in childhood, are clearly recognised as major risk factors for a range of mental disorders, as well as a range of linked phenomena including self-harm and suicidal behaviours (McKay et al., 2021; Zatti et al., 2017). There is considerable interest and ongoing research into how these adverse experiences come to be ‘encoded’ via neurobiological or genetic mechanisms that then transmit those effects into later-onset major mental disorders, substance misuse or other self-harming behaviours (Maddox et al., 2019).

The vertebrate fauna recovered from indurated conglomerates at Wallingford Roadside Cave (central Jamaica) is shown to be in excess of 100,000 yr old according to uranium series and electron spin resonance dating. The Wallingford local fauna is therefore pre-Wisconsinan in age, and Roadside Cave is now the oldest radiometrically dated locality in the West Indies containing identifiable species of land mammals. In the absence of a good radiometric record for Quaternary paleontological sites in the Caribbean, there is no satisfactory basis for determining whether most extinct Antillean mammals died out in a “blitzkrieg”-like event immediately following initial human colonization in the mid-Holocene. Fossils of Clidomys (Heptaxodontidae, Caviomorpha), the giant Wallingford rodent, have never been found in situ in sediments of demonstrably Holocene age, and its extinction may antedate the middle Holocene. This is also a possibility for the primate Xenothrix mcgregori, although its remains have been found in loose cave earth. A major, climate-driven bout of terrestrial vertebrate extinction at about 14,000–12,000 yr B.P. has been hypothesized for the West Indies by G. Pregill and S. L. Olson (Annual Review of Ecology and Systematics 12, 75–98, 1981), but at present there is nothing to connect the disappearance of Clidomys with this event either. Quaternary extinctions in the Caribbean may prove to be of critical significance for evaluating the reality of New World blitzkrieg, but not until an effort is mounted to constrain them rigorously using modern radiometric approaches.

Recent explorations in Cueva Charles Brewer, a large cave in a sandstone tepui, SE Venezuela, have revealed silica biospeleothems of unprecedented size and diversity. Study of one — a sub-spherical mass of opaline silica — reveals a complex, laminated internal structure consisting of three narrow dark bands alternating with two wider light bands. Uranium–thorium dating has produced 3 stratigraphically correct dates on the light bands from 298 ± 6 (MIS 9) to 390 ± 33 ka (MIS 11). U concentration is only 30–110 ppb. Initial 234U/238U ratios are high and increase over time from 1.8 to 5.3. Growth rate is very low, the fastest, at 0.37 ± 0.23 mm/ka, in MIS 9. Trace element and heavy metal content of the dark bands is distinctly higher than that of the light bands. It is hypothesized that the dark and light bands correlate with drier/glacial and wetter/interglacial periods, respectively, and that this sample probably began to grow in MIS 13. The cave is in a region that straddles a regionally important ecotone: the speleothem isotopic and trace element variations may preserve a useful paleoclimatic signal. This is the first published suite of U–Th dates from a single silica speleothem and the longest Quaternary record for this region.

The megafaunal rodent Amblyrhiza inundatafrom Anguilla and St. Martin is often cited in lists of late Quaternary human-induced extinctions, but its date of disappearance has never been established. Here, we present a suite of uranium-series disequilibrium dates from three independent Amblyrhizasites in Anguilla, all of which cluster in marine isotope Stage 5. Thus, there is no indication that Amblyrhizasurvived into the late Holocene, when islands of the northern Lesser Antilles were first invaded by humans. We argue that the most probable cause of the extinction of Amblyrhizawas a failure of island populations to adjust to catastrophic reductions in available range which accompanied last interglacial sea-level maxima. We support this argument with quantitative extinction probability estimates drawn from persistence time models. Amblyrhizaexhibits body-size hypervariability, a common but underemphasized feature of island megafaunal species. We argue that hypervariability is a record of morphological response to oscillating natural selection, which in turn is driven by asymmetries in the relationship of population size, body mass, and persistence time. The fate of Amblyrhizastands in marked contrast to that of most other West Indian land mammals, whose losses increasingly appear to have been anthropogenically mediated.

Glioblastoma (GBM) is an aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. We hypothesize that brain tumor initiating cells (BTICs), a subpopulation of treatment-resistant cells with stem cell properties cause tumor relapse and a subset of neural stem cell genes regulate BTIC self-renewal, driving GBM recurrence. We adapted the existing treatment protocol for adults with primary GBM for in vivo treatment of immunocompromised mice engrafted with GBMs. Post-chemoradiotherapy, the recovered GFP+GBMs were profiled for self-renewal and expression of critical stem cell genes. Using invitro and invivo gain-of-function/loss-of-function experiments, we investigated the regulatory functions of Bmi1 in primary neural stem & progenitor cells (NSPCs) and GBM tumor formation. Finally, global RNA-Seq profiling was performed to understand the consequences of Bmi1 dysregulation on target gene expression. GBM cells showed an increase in Bmi1 levels post-chemoradiotherapy, suggesting the presence of a treatment-refractory BTICs. GFP+cells extracted from treated xenografts had higher self-renewal and BTIC marker expression. Although treated mice responded to therapy, we observed tumor relapse with increased Bmi1 expression. Knockdown of Bmi1 diminished self-renewal and proliferation of GBM cells and delayed tumorigenesis, highlighting a critical role for Bmi1 in tumor maintenance. Conversely, over-expressing Bmi1 in NSPCs failed to initiate tumor formation in vivo. Using high-throughput sequencing data, we generated a map of signaling pathways dysregulated in GBM that may lead to tumor recurrence. Our data confirms the existence of a rare treatment-refractory BTIC population with enhanced self-renewal capacity that escapes therapy and drives tumor relapse.

Medulloblastoma (MB) is the most common malignant pediatric brain tumour, and is categorized into four molecular subgroups, with Group 3 MB having the worst prognosis due to the highest rate of metastatic dissemination and relapse. In this work, we describe the epigenetic regulator Bmi1 as a novel therapeutic target for treatment of recurrent Group 3 MB. Through comparative profiling of primary and recurrent MB, we show that Bmi1 defines a treatment-refractory cell population that is uniquely targetable by a novel class of small molecule inhibitors. We have optimized an in vivo mouse-adapted therapy model that has the advantage of generating recurrent, human, treatment-refractory MBs. Our preliminary studies showed that although chemoradiotherapy administered to mice engrafted with human MB showed reduction in tumour size, Bmi1 expression was enriched in the post-treatment residual tumour. Furthermore, we found that knockdown of Bmi1 in human recurrent MB cells decreases proliferation and self-renewing capacities of MB cells in vitro as well as both tumour size and extent of spinal leptomeningeal metastases in vivo. Oral administration of a potent Bmi1 inhibitor, PTC 028, resulted in a marked reduction in tumour burden and an increased survival in treatment cohort. Bmi1 inhibitors showed high specificity for MB cells and spared normal human neural stem cells, when treated with doses relevant for MB cells. As Group 3 medulloblastoma is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious agent such as Bmi1 inhibitor could be rapidly transitioned to clinical trials.

Despite aggressive multimodal therapy, human glioblastoma (hGBM), a highly malignant grade IV astrocytic tumour, remains incurable and inevitably relapses. Recent data has implicated intratumoral heterogeneity as the driver of therapy resistance and tumour relapse in hGBM. Thus models that capture the evolving hGBM biology in response to chemoradiotherapy will allow for the identification of cellular pathways that govern GBM therapy failure. In this study, we have developed a novel model to profile the clonal evolution of treatment naïve brain tumour initiating cell (BTIC) enriched hGBMs through chemoradiotherapy using: stem cell assays, BTIC marker expression and transcriptome analysis, immunohistochemistry, and cellular DNA barcoding technology. We report that treatment of hGBM BTICs leads to increased self-renewal capacity and higher transcript expression of stem cell genes Bmi1 and Sox2. Based on global transcriptome analysis of the in vitro treated hGBM, we also identify a hyper-aggressive form of glioma. Using our therapy-adapted hGBM-mouse xenograft model, we discover that despite tumour regression and increased mouse survival post-therapy, tumour relapse remains inevitable. The treatment-refractory cells again have increased self-renewal capacity and higher expression of Bmi1 and Sox2. Furthermore, by combining cellular DNA barcoding technology, which barcodes hGBM at single cell resolution, with our novel in vitro and in vivo therapy models, we are able to determine whether a pre-existing or a therapy driven subpopulation(s) seeds hGBM tumour relapse. Profiling the dynamic nature of heterogeneous hGBM subpopulations through disease progression and treatment may lead to the identification of novel therapeutic targets for the treatment of recurrent hGBM.

Medulloblastoma (MB), the most common malignant pediatric brain tumor, is categorized into four molecular subgroups. Given the high rate of metastatic dissemination at diagnosis and recurrence in Group 3 MBs, these patients have the worst clinical outcome with a 5-year survivorship of approximately 50%. By adapting the existing COG (Children’s Oncology Group) Protocol for children with newly diagnosed high-risk MB, for treatment of immuno-deficient mice intracranially engrafted with human MB brain tumour initiating cells we aim to identify and characterize the treatment-refractory cell population in Group 3 MBs. Mice were sacrificed at multiple time points during the course of tumor development and therapy: (i) at engraftment; (ii) post-radiation; (iii) post-radiation and chemotherapy; and (iv) at MB recurrence. MB cell populations recovered separately from brains and spines were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy. We report a higher expression of CD133, Sox2 and Bmi1 in addition to increased self-renewal capacity following chemoradiotherapy treatment. The enrichment map constructed from global gene expression analysis showed an increase in pathways regulating self-renewal, DNA repair and chemoresistance post-therapy despite the apparent decrease in tumour size and vascularity. Additionally, from gene expression at MB recurrence, we identified a list of genes that negatively correlate with survival in patients diagnosed with Group 3 MB. A differential genomic profile of the “treatment-responsive” tumors against those that fail therapy may contribute to discovery of novel therapeutic approaches for the most aggressive subgroup of MB.

Brain Metastases (BM) represent a leading cause of cancer mortality. While metastatic lesions contain subclones derived from their primary lesion, their functional characterization has been limited by a paucity of preclinical models accurately recapitulating the stages of metastasis. This work describes the isolation of a unique subset of metastatic stem-like cells from primary human patient samples of BM, termed brain metastasis initiating cells (BMICs). Utilizing these BMICs we have established a novel patient-derived xenograft (PDX) model of BM that recapitulates the entire metastatic cascade, from primary tumor initiation to micro-metastasis and macro-metastasis formation in the brain. We then comprehensively interrogated human BM to identify genetic regulators of BMICs using in vitro and in vivo RNA interference screens, and validated hits using both our novel PDX model as well as primary clinical BM specimens. We identified SPOCK1 and TWIST2 as novel BMIC regulators, where in our model SPOCK1 regulated BMIC self-renewal and tumor initiation, and TWIST2 specifically regulated cell migration from lung to brain. A prospective cohort of primary lung cancer specimens was used to establish that SPOCK1 and TWIST2 were only expressed in patients who ultimately developed BM, thus establishing both clinical and functional utility for these gene products. This work offers the first comprehensive preclinical model of human brain metastasis for further characterization of therapeutic targets, identification of predictive biomarkers, and subsequent prophylactic treatment of patients most likely to develop BM. By blocking this process, metastatic lung cancer would effectively become a localized, more manageable disease.

The US Naval Research Laboratory (NRL) is developing technologies that will enable Navy-relevant missions with the smallest practical Micro Air Vehicles (MAVs). The NRL Micro Tactical Expendable (MITE) air vehicle is a result of this research. MITE is a hand-launched, dual-propeller, fixed-wing air vehicle, with a 25cm chord and a wingspan of 25–47cm, depending on payload weight. Vehicle gross weight is 130–350g. Miniature autopilot systems, based on visual imaging techniques, are being developed for MITE. These will be used in conjunction with conventional autopilot sensors to allow the MITE to fly autonomously. This paper provides an overview of the MITE development, including aerodynamic design considerations, electric propulsion, and vision-based autopilot research. Also presented is a rationale for the development of control laws that can direct the behavior of large groups of MAVs or other vehicle agents. Dubbed ‘physicomimetics,’ this process can bring about the self-assembly of complex MAV formations, though individual MAVs have minimal onboard processing power and limited local sensing capabilities.