Mass Movements of Warrumbungle National Park, New South Wales, Australia

The Warrumbungle Range is the mountainous eroded remnant of an Early Miocene shield volcanic complex located in the central west of New South Wales. A high-severity wildfire in Warrumbungle National Park in January 2013 was followed by intense rain, causing a number of debris flows. Several flows impacted on infrastructure such as roads and culverts and posed a severe risk to public safety, prompting a broader assessment of mass movement hazard within the park. High resolution LiDAR DEM revealed 542 locations with evidence of mass movement processes that pre-date the fire. The most common types of mass movement visible in the DEM are rotational slumps (353, 65%). The distribution of these indicated stratigraphic control, with 50% of slumps within 440 m of the volcanics-sandstone geologic contact, and typically occurring within unconsolidated volcanic colluvium and/or in situ deeply weathered volcanics. Debris flows are the next most common mass movement type after rotational slumps. Debris flow scour channels generally occurred on colluvial slopes in more elevated sites, within the volcanic rocks. DEM-extracted morphometric data was used to identify areas of debris flow hazard in WNP. Several large mass movements are morphometrically different, with some evidence for formation under different hydro-climatic conditions. A simple conceptual model of how mass movements contribute to the evolution of the Warrumbungle Range is proposed involving groundwater, deep weathering, slope retreat by mass failure, colluvial deposition and periodic incision by debris flows

A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities.

Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a drug atlas. The drug atlas represents the relations between drug effects and allows to identify independent processes for which the tumor might be particularly vulnerable when attacked by two drugs. Our approach enables the prediction of combination-therapy which can be linked to tumor-driving mutations. By using this strategy, we can uncover potential effective drug combinations on a pan-cancer scale. Predicted synergies are provided and have been validated in glioblastoma, breast cancer, melanoma and leukemia mouse-models, resulting in therapeutic synergy in 75% of the tested models. This indicates that we can accurately predict effective drug combinations with translational value

Human voltage-gated Na+ and K+ channel properties underlie sustained fast AP signaling

Human cortical pyramidal neurons are large, have extensive dendritic trees, and yet have unexpectedly fast input-output properties: Rapid subthreshold synaptic membrane potential changes are reliably encoded in timing of action potentials (APs). Here, we tested whether biophysical properties of voltage-gated sodium (Na+) and potassium (K+) currents in human pyramidal neurons can explain their fast input-output properties. Human Na+ and K+ currents exhibited more depolarized voltage dependence, slower inactivation, and faster recovery from inactivation compared with their mouse counterparts. Computational modeling showed that despite lower Na+ channel densities in human neurons, the biophysical properties of Na+ channels resulted in higher channel availability and contributed to fast AP kinetics stability. Last, human Na+ channel properties also resulted in a larger dynamic range for encoding of subthreshold membrane potential changes. Thus, biophysical adaptations of voltage-gated Na+ and K+ channels enable fast input-output properties of large human pyramidal neurons

Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening

The influence of formal instruction on segmental speech production by German learners of English The influence of formal instruction on segmental speech production by German learners of English

Abstract This study examines the influence of formal L2 English instruction (FEI) on pronunciation accuracy of similar and new vowels in the framework of Flege's Speech Learning Mode

Shifting States, Altered Fates: Divergent Fuel Moisture Responses after High Frequency Wildfire in an Obligate Seeder Eucalypt Forest

High frequency wildfires can shift the structure and composition of obligate seeder forests and initiate replacement with alternative vegetation states. In some forests, the alternative stable state is drier and more easily burned by subsequent fires, driving a positive feedback that promotes further wildfire and perpetuates alternative stable states. Mountain Ash (Eucalyptus regnans (F.Muell.)) forests are highly valued for their biodiversity, water, timber and carbon. Fires are a natural part of the lifecycle of these forests, but too frequent fires can eliminate Mountain Ash and trigger a transition to lower stature, non-eucalypt forests which are dominated by understorey species. This study sought to better understand the fuel moisture dynamics of alternative stable states resulting from high frequency wildfires. A vegetation mosaic in the Central Highlands, Victoria created a unique opportunity to measure fuel moisture in adjacent forest stands that differed in overstorey species composition and time since fire. Specifically, we measured fuel moisture and microclimate at two eucalypt sites (9 and 79 years old) and three non-eucalypt sites (two 9 year old and one 79 year old). Fuel availability, defined here as the number of days surface fuels were below 16% and dry enough to ignite and sustain fire, was calculated to estimate flammability. Fuel availability differed between sites, particularly as a function of time since fire, with recently burnt sites available to burn more often (4−17 versus 0−3 days). There were differences in fuel availability between non-eucalypt sites of the same age, suggesting that high frequency fire does not always lead to the same vegetation condition or outcome for fuel availability. This indicates there is potential for both positive and negative flammability feedbacks following state transition depending on the composition of the non-eucalypt state. This is the first study to provide empirical insight into the fuel moisture dynamics of alternative stable states in Mountain Ash forests

Forest Structure Drives Fuel Moisture Response across Alternative Forest States

Climate warming is expected to increase fire frequency in many productive obligate seeder forests, where repeated high-intensity fire can initiate stand conversion to alternative states with contrasting structure. These vegetation–fire interactions may modify the direct effects of climate warming on the microclimatic conditions that control dead fuel moisture content (FMC), which regulates fire activity in these high-productivity systems. However, despite the well-established role of forest canopies in buffering microclimate, the interaction of FMC, alternative forest states and their role in vegetation–fire feedbacks remain poorly understood. We tested the hypothesis that FMC dynamics across alternative states would vary to an extent meaningful for fire and that FMC differences would be attributable to forest structural variability, with important implications for fire-vegetation feedbacks. FMC was monitored at seven alternative state forested sites that were similar in all aspects except forest type and structure, and two proximate open-weather stations across the Central Highlands in Victoria, Australia. We developed two generalised additive mixed models (GAMMs) using daily independent and autoregressive (i.e., lagged) input data to test the importance of site properties, including lidar-derived forest structure, in predicting FMC from open weather. There were distinct differences in fuel availability (days when FMC < 16%, dry enough to sustain fire) leading to positive and negative fire–vegetation feedbacks across alternative forest states. Both the independent (r2 = 0.551) and autoregressive (r2 = 0.936) models ably predicted FMC from open weather. However, substantial improvement between models when lagged inputs were included demonstrates nonindependence of the automated fuel sticks at the daily level and that understanding the effects of temporal buffering in wet forests is critical to estimating FMC. We observed significant random effects (an analogue for forest structure effects) in both models (p < 0.001), which correlated with forest density metrics such as light penetration index (LPI). This study demonstrates the importance of forest structure in estimating FMC and that across alternative forest states, differences in fuel availability drive vegetation–fire feedbacks with important implications for forest flammability

Understanding global brain network alterations in glioma patients

INTRODUCTION: Glioma patients show increased global brain network clustering relating to poorer cognition and epilepsy. However, it is unclear whether this increase is spatially widespread, localized in the (peri)tumor region only, or decreases with distance from the tumor. MATERIALS AND METHODS: Weighted global and local brain network clustering was determined in 71 glioma patients and 53 controls using magnetoencephalography. Tumor clustering was determined by averaging local clustering of regions overlapping with the tumor, and vice versa for non-tumor regions. Euclidean distance was determined from the tumor centroid to the centroids of other regions. RESULTS: Patients showed higher global clustering compared to controls. Clustering of tumor and non-tumor regions did not differ and local clustering was not associated with distance from the tumor. Post-hoc analyses revealed that in the patient group, tumors were located more often in regions with higher clustering in controls, but it seemed that tumors of patients with high global clustering were located more often in regions with lower clustering in controls. CONCLUSIONS: Glioma patients show non-local network disturbances. Tumors of patients with high global clustering may have a preferred localization, namely regions with lower clustering in controls, suggesting that tumor localization relates to the extent of network disruption

WEE1 Kinase Targeting Combined with DNA-Damaging Cancer Therapy Catalyzes Mitotic Catastrophe

WEE1 kinase is a key molecule in maintaining G₂-cell-cycle checkpoint arrest for premitotic DNA repair. Whereas normal cells repair damaged DNA during G₁-arrest, cancer cells often have a deficient G₁-arrest and largely depend on G₂-arrest. The molecular switch for the G₂-M transition is held by WEE1 and is pushed forward by CDC25. WEE1 is overexpressed in various cancer types, including glioblastoma and breast cancer. Preclinical studies with cancer cell lines and animal models showed decreased cancer cell viability, reduced tumor burden, and improved survival after WEE1 inhibition by siRNA or small molecule inhibitors, which is enhanced by combination with conventional DNA-damaging therapy, such as radiotherapy and/or cytostatics. Mitotic catastrophe results from premature entry into mitosis with unrepaired lethal DNA damage. As such, cancer cells become sensitized to conventional therapy by WEE1 inhibition, in particular those with insufficient G₁-arrest due to deficient p53 signaling, like glioblastoma cells. One WEE1 inhibitor has now reached clinical phase I studies. Dose-limiting toxicity consisted of hematologic events, nausea and/or vomiting, and fatigue. The combination of DNA-damaging cancer therapy with WEE1 inhibition seems to be a rational approach to push cancer cells in mitotic catastrophe. Its safety and efficacy are being evaluated in clinical studie