The peopling of Sahul (the combined continent of Australia and New Guinea) represents the earliest continental migration and settlement event of solely anatomically modern humans, but its patterns ...and ecological drivers remain largely conceptual in the current literature. We present an advanced stochastic-ecological model to test the relative support for scenarios describing where and when the first humans entered Sahul, and their most probable routes of early settlement. The model supports a dominant entry via the northwest Sahul Shelf first, potentially followed by a second entry through New Guinea, with initial entry most consistent with 50,000 or 75,000 years ago based on comparison with bias-corrected archaeological map layers. The model's emergent properties predict that peopling of the entire continent occurred rapidly across all ecological environments within 156-208 human generations (4368-5599 years) and at a plausible rate of 0.71-0.92 km year
. More broadly, our methods and approaches can readily inform other global migration debates, with results supporting an exit of anatomically modern humans from Africa 63,000-90,000 years ago, and the peopling of Eurasia in as little as 12,000-15,000 years via inland routes.
Eastern Australia has a climate characterised by extreme variability and the occurrence of multiple years of drought conditions. Arguably one of the severest droughts on record – the Big Dry ended in ...many areas with the La Niña of 2009/2010. A succession of subsequent dry years brought a return to drought conditions across much of eastern Australia in 2018 and 2019, ending with the catastrophic fires of 2019/2020. An analysis of river gauges in eastern Australia demonstrates that unregulated rivers have been subject to reduced monthly and total annual flow for far longer than the recent multi-year droughts. A breakpoint regression model on the annual streamflow data shows statistically significant declines in total annual flow (by up to a factor of three) since 1992/93 on the far South coast of New South Wales (NSW). In the monthly data, fifteen of the nineteen gauges analysed exhibit modelled breakpoints, but with statistically significant differences in monthly mean discharge between consecutive periods only occurring in three of these gauges (occurring between 1972 and 1993 in both the North and South coast). The trend toward reduced flow over the last few decades has, for many rivers, coincided with land use and river management changes resulting in increases in woody riparian vegetation. To show this we use a remote sensing technique and estimate the magnitude of vegetation change along all major rivers and their tributaries on the eastern seaboard of NSW (28 catchments with total river length assessed of 19,750 km) using a normalized difference vegetation index (NDVI) analysis of woody vs non-woody riparian vegetation extent. Predicted vegetation change between 1987 and 2020 is spatially variable across catchments but the mean increase in woody riparian vegetation across all catchments is 9–51% (0.2 and 0.1 NDVI increases). Such increases are perhaps the largest biogeomorphic change the SE Australian drainage network has experienced since the initial clearance of vegetation associated with European colonisation in the late 18th and early 19th centuries.
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•Climate change could impact annual streamflow.•Unregulated rivers in eastern Australia have declined in streamflow since 1990.•The decline in streamflow has coincided with regrowth of riparian woody vegetation.•Remote sensing of 19,750 km of river shows a 9–51% increase since 1987.•Riparian vegetation increase coincides with changes in river management and landuse.
Metastasis is the main cause of cancer-related mortality. Despite intense efforts to understand the mechanisms underlying the metastatic process, treatment of metastatic cancer is still challenging. ...Here we describe a chemotherapy-induced, host-mediated mechanism that promotes remodeling of the extracellular matrix (ECM), ultimately facilitating cancer cell seeding and metastasis. Paclitaxel (PTX) chemotherapy enhanced rapid ECM remodeling and mechanostructural changes in the lungs of tumor-free mice, and the protein expression and activity of the ECM remodeling enzyme lysyl oxidase (LOX) increased in response to PTX. A chimeric mouse model harboring genetic LOX depletion revealed chemotherapy-induced ECM remodeling was mediated by CD8
T cells expressing LOX. Consistently, adoptive transfer of CD8
T cells, but not CD4
T cells or B cells, from PTX-treated mice to naïve immunodeprived mice induced pulmonary ECM remodeling. Lastly, in a clinically relevant metastatic breast carcinoma model, LOX inhibition counteracted the metastasis-promoting, ECM-related effects of PTX. This study highlights the role of immune cells in regulating ECM and metastasis following chemotherapy, suggesting that inhibiting chemotherapy-induced ECM remodeling represents a potential therapeutic strategy for metastatic cancer. SIGNIFICANCE: Chemotherapy induces prometastatic pulmonary ECM remodeling by upregulating LOX in T cells, which can be targeted with LOX inhibitors to suppress metastasis.
.
Ethnographic observations suggest that Indigenous peoples employed a distinct regime of frequent, low-intensity fires in the Australian landscape in the past. However, the timing of this behaviour ...and its ecological impact remain uncertain. Here, we present detailed analysis of charcoal, including a novel measure of fire severity using Fourier transform infrared (FTIR) spectroscopy, at a site in eastern Australia that spans the last two glacial/interglacial transitions between 135–104 ka and 18–0.5 ka BP (broadly equivalent to Marine Isotope Stage (MIS) 6-5 and 2-1, respectively). The accumulation of charcoal and vegetation composition was similar across both periods, correlating closely with Antarctic ice core records, and suggesting that climate is the main driver of fire regimes. Fire severity was lower over the past 18,000 years compared to the penultimate glacial/interglacial period and suggests increasing anthropogenic influence over the landscape during this time. Together with local archaeological records, our data therefore imply that Indigenous peoples have been undertaking cultural burning since the beginning of the Holocene, and potentially the end of the Last Glacial Maximum. We highlight the fact that this signal is not easily discernible in the other proxies examined, including widely used charcoal techniques, and propose that any anthropogenic signal will be subtle in the palaeo-environmental record. While early Indigenous people’s reasons for landscape burning were different from those today, our findings nonetheless suggest that the current land management directions are based on a substantive history and could result in a reduction in extreme fire events.
Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive ...treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients < 10 years. TDM data were collected retrospectively in 14 centres. Children treated with IFX were included if IFX was started as IBD treatment at age < 10 years (young patients, YP) and PK data were available. Older IBD patients aged 10–18 years were used as controls (older patients, OP). Two hundred and fifteen paediatric inflammatory bowel disease (PIBD) patients were eligible for the study (110 < 10 year; 105 ≥ 10 years). Median age was 8.3 years (IQR 6.9–8.9) in YP compared with 14.3 years (IQR 12.8–15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 μg/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0–12.9) vs. OP; 5.5 mg/kg (IQR 5.0–9.3);
p
< 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI − 1.2 to − 1.01);
p
< 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (
n
= 29) in YP vs. 58% (
n
= 45) in OP;
p
= 0.56).
Conclusion
: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years.
What is Known?
•Infliximab trough levels of paediatric IBD patients are influenced by several factors as dosing scheme, antibodies and inflammatory markers.
•In 4.5–30% of the paediatric IBD patients, infliximab treatment was stopped within the first year.
What is New?
•The majority of young PIBD (< 10 years) have inadequate IFX trough levels at the start of maintenance treatment.
•Young PIBD patients (< 10 years) were in need of a more intensive treatment regimen compared with older paediatric patients during 1 year of IFX treatment.
•The chance to develop antibodies to infliximab was relatively higher in young PIBD patients (< 10 years).
The tumor‐stroma ratio (TSR) has proven to be a strong prognostic factor in breast cancer, demonstrating better survival for patients with stroma‐low tumors. Since the role of the TSR as a predictive ...marker for neoadjuvant chemotherapy outcome is yet unknown, this association was evaluated for HER2‐negative breast cancer in the prospective DIRECT and NEOZOTAC trials. The TSR was assessed on 375 hematoxylin and eosin‐stained sections of pre‐treatment biopsies. Associations between the TSR and chemotherapy response according to the Miller‐Payne (MP) grading system, and between the TSR and pathological response were examined using Pearson's chi‐square, Cochran‐Armitage test for trend and regression analyses. A stroma‐low tumor prior to neoadjuvant chemotherapy was significantly associated with a higher MP score (P = .005). This relationship remained significant in the estrogen receptor (ER)‐negative subgroup (P = .047). The univariable odds ratio (OR) of a stroma‐low tumor on pathological complete response (pCR) was 2.46 (95% CI 1.34‐4.51, P = .004), which attenuated to 1.90 (95% CI 0.85‐4.25, P = .119) after adjustment for relevant prognostic factors. Subgroup analyses revealed an OR of 5.91 in univariable analyses for ER‐negativity (95% CI 1.19‐29.48, P = .030) and 1.48 for ER‐positivity (95% CI 0.73‐3.01, P = .281). In conclusion, a low amount of stroma on pre‐treatment biopsies is associated with a higher MP score and pCR rate. Therefore, the TSR is a promising biomarker in predicting neoadjuvant treatment outcome. Incorporating this parameter in routine pathological diagnostics could be worthwhile to prevent overtreatment and undertreatment.
Abstract
Long-standing interpretations of the Last Glacial Maximum (21,000 ± 2000 years ago) in Australia suggest that the period was extremely cold and arid, during which the Indo-Australian summer ...monsoon system collapsed, and human populations declined and retreated to ecological refuges to survive. Here, we use transient iTRACE simulations, combined with palaeoclimate proxy records and archaeological data to re-interpret the late Last Glacial Maximum and terminal Pleistocene (21,000 – 11,000 years) in Australia. The model suggests climates during the peak Last Glacial Maximum were cooler than present (−4 to −11 °C), but there is no evidence of monsoon collapse or substantial decreases in moisture balance across Australia. Kernel Density Estimates of archaeological ages show relatively stable and persistent human activity across most regions throughout the late Last Glacial Maximum and terminal Pleistocene, consistent with genetic evidence. Spatial coverage of archaeological sites steadily increased across the terminal Pleistocene; however, substantial population change is not evident.
Using continental SGCs built by
Fu et al. (2020)
can save significant machine time for constructing SGCs when compared to traditional SGC methods, which need significantly more time for building ...sample-specific or regional SGCs. In this study, the reliability of continental SGCs is tested using coarse quartz grains (180–212 µm) from Lake Woods in Northern Australia. D
e
values obtained by continental SGCs are consistent with D
e
values obtained by regional SGCs and by the SAR procedures.
The filling of Kati Thanda-Lake Eyre (KT-LE), Australia’s ‘inland sea’ has captured scientific and cultural interest for over a century and a half. However, despite the presence of multiple ...shorelines around the modern playa at or near the modern maximum lake-filling levels, no quantitative estimates of major late-Holocene filling events have ever been documented. We develop a preliminary chronological data set using single-grain optically stimulated luminescence (OSL) on lake shoreline samples in order to determine the timing of large lake-filling events (equivalent to 1974 Common Era (CE) as Australia’s wettest year on record) for KT-LE, Australia’s largest lake basin. Despite quartz grains with very low natural dose luminescence (Ln) signal, we derive palaeodoses from geologically recent deposits (decades to centuries) using standard rejection criteria and highlight no signs of partial bleaching but occasional bioturbation in modern deposits. Major modern filling episodes, such as the1974 and 1949/1950 filling events, are successfully captured in the geochronological record, as are two major lake-filling episodes in 1854 ± 21 CE years and 1598–1654 CE. Two additional periods of potential lake-filling events have been identified at 1.2 ± 0.09 and 1.9 ± 0.14 ka, but stratigraphic control on these events is less robust. These chronostratigraphic records, while discontinuous, provide important hydrological evidence for extreme pluvial events akin to 1974 or 1949/1950, and the approach holds promise for identifying climate extremes and landscape response over the late Holocene.
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