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The aim of this study was to document tree encroachment on a 3 ha Wet Heathland in the Cape Conran region, East Gippsland, Victoria. Comparison of historical and modern aerial photographs indicated a clear loss of the heathland due to the establishment of forest trees. Southern Mahogany Eucalyptus botryoides (Myrtaceae) was the encroaching species, and this species dramatically changed the structure of the heathland to a forest. There was a 95% decline in the extent of the heathland between 1962 and 2013. In total, 89% of E. botryoides in the Wet Heathland had a girth over bark at breast height (GBBH) less than 50 cm, and most were <10 cm GBBH. Trees 50-200 cm GBBH were also observed in the Wet Heathland, hinting at earlier periods of establishment. It was hypothesised that the absence of fire from most of the site since 1990, extended drought between 1997 and 2010, and changes in local hydrology caused by the creation of a nearby road have all contributed to tree encroachment on Wet Heathland vegetation resulting in a structural shift to forest vegetation. Further research is necessary to unravel these complex, interacting processes. [ABSTRACT FROM AUTHOR]

Decompression sickness is an illness which occurs in divers and caisson workers on return to normal atmospheric pressure after working at very high pressures, and in aiRMEN on reaching very low pressures at great altitude. The disease seen after exposure to high pressure is described and compared with that seen on exposure to great altitude. Mild cases show little difference, but serious ones vary sufficiently to justify division of the disease into two distinct syndromes, high-pressure and high-altitude decompression sickness. Both syndromes are caused by the formation of gas bubbles in the blood and body fluids when the tension of dissolved gases becomes sufficiently greater than that of the surrounding atmosphere. These bubbles are composed of a mixture of gases, but their formation is determined mainly by the degree of supersaturation with nitrogen. The diver must first absorb excess nitrogen on exposure to pressure, and it is the subsequent release of this excess on return to the surface which causes decompression sickness; since his stay at pressure is limited, bubbles arise mainly from tissues which can absorb the excess gas readily. In the airman, on the other hand, all tissues are completely saturated with nitrogen before he is exposed to low pressure, and bubbles may arise equally well from any tissue. Nitrogen is much more soluble in fat than in water, so that fatty tissues can form a large reservoir of dissolved nitrogen which may later form a source of bubbles; but the blood supply of fat is poor and nitrogen diffuses slowly through it, hence although the potential capacity of the fatty tissues for excess nitrogen is great, they can only absorb it slowly. Obesity is therefore a major hazard in high-altitude decompression sickness, but relatively unimportant in the high-pressure syndrome. Liability to the airman's sickness increases markedly with age, but the incidence of the diver's syndrome is affected both much less and later in life. Decompression also involves great changes in the working atmosphere, and the effects of these and their possible influence on decompression sickness are discussed. [ABSTRACT FROM PUBLISHER]

Groundwater quality is critical for safe drinking water and irrigation supplies but can be threatened by geogenic toxins that are difficult to predict. In the arid, high desert San Luis Valley (SLV), Colorado, a groundwater basin serves as the primary water supply with observed arsenic concentrations exceeding the maximum contaminant level (MCL) of 10 μg/L set by the U.S. EPA. However, the sources and processes responsible for As occurrence are unclear. Through a community-engaged sampling effort, we collected 244 groundwater samples and measured major/trace element concentrations. Long-term land subsidence and depth-resolved sediment texture were computed at the same locations. We tested three plausible geochemical processes responsible for As release: (1) overpumping-induced dewatering of As-bearing clays (proxied by land subsidence), (2) pH-promoted desorption as well as reductive dissolution of As(V)/Fe(III) (hydr)oxides, and (3) incursion of higher-As geothermal fluids (proxied by lithium, boron, tungsten, and molybdenum) into groundwater. We find that statistics, statistical/machine learning, and aqueous thermodynamics all agree that geothermal fluid mixing within the aquifer is the main source of dissolved As. Our findings suggest that overpumping draws higher-As thermal fluid from the bottom of the aquifer to pumping depth, leading to increased concentrations of As in drinking/irrigation water supplies at wells.

Genetic control - the deliberate introduction of genetic traits to control a pest or vector population - offers a powerful tool to augment conventional mosquito control tools that have been successful in reducing malaria burden but that are compromised by a range of operational challenges. Self-sustaining genetic control strategies have shown great potential in laboratory settings, but hesitancy due to their invasive and persistent nature may delay their implementation. Here, instead, we describe a self-limiting strategy, designed to have geographically and temporally restricted effect, based on a Y chromosome-linked genome editor (YLE). The YLE comprises a CRISPR-Cas9 construct that is always inherited by males yet generates an autosomal dominant mutation that is transmitted to over 90% of the offspring and results in female-specific sterility. To our knowledge, our system represents a pioneering approach in the engineering of the Y chromosome to generate a genetic control strain for mosquitoes. Mathematical modelling shows that this YLE technology is up to seven times more efficient for population suppression than optimal versions of other self-limiting strategies, such as the widely used Sterile Insect Technique or the Release of Insects carrying a Dominant Lethal gene., Competing Interests: Competing interests: A.C. is a founder of Biocentis, Ltd. A.C. and T.N. have equity interest in Biocentis, Ltd. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Meningiomas are the most common primary brain tumors in adults with management varying widely based on World Health Organization (WHO) grade. However, there are limited datasets available for researchers to develop and validate radiomic models. The purpose of our manuscript is to report on the first dataset of meningiomas in The Cancer Imaging Archive (TCIA)., Acquisition and Validation Methods: The dataset consists of pre-operative MRIs from 96 patients with meningiomas who underwent resection from 2010-2019 and include axial T1post and T2-FLAIR sequences-55 grade 1 and 41 grade 2. Meningioma grade was confirmed based on the 2016 WHO Bluebook classification guideline by two neuropathologists and one neuropathology fellow. The hyperintense T1post tumor and hyperintense T2-FLAIR regions were manually contoured on both sequences and resampled to an isotropic resolution of 1 × 1 × 1 mm 3 . The entire dataset was reviewed by a certified medical physicist., Data Format and Usage Notes: The data was imported into TCIA for storage and can be accessed at https://doi.org/10.7937/0TKV-1A36. The total size of the dataset is 8.8GB, with 47 519 individual Digital Imaging and Communications in Medicine (DICOM) files consisting of 384 image series, and 192 structures., Potential Applications: Grade 1 and 2 meningiomas have different treatment paradigms and are often treated based on radiologic diagnosis alone. Therefore, predicting grade prior to treatment is essential in clinical decision-making. This dataset will allow researchers to create models to auto-differentiate grade 1 and 2 meningiomas as well as evaluate for other pathologic features including mitotic index, brain invasion, and atypical features. Limitations of this study are the small sample size and inclusion of only two MRI sequences. However, there are no meningioma datasets on TCIA and limited datasets elsewhere although meningiomas are the most common intracranial tumor in adults., (© 2023 American Association of Physicists in Medicine.)

The Grade of meningioma has significant implications for selecting treatment regimens ranging from observation to surgical resection with adjuvant radiation. For most patients, meningiomas are diagnosed radiologically, and Grade is not determined unless a surgical procedure is performed. The goal of this study is to train a novel auto-classification network to determine Grade I and II meningiomas using T1-contrast enhancing (T1-CE) and T2-Fluid attenuated inversion recovery (FLAIR) magnetic resonance (MR) images. Ninety-six consecutive treatment naïve patients with pre-operative T1-CE and T2-FLAIR MR images and subsequent pathologically diagnosed intracranial meningiomas were evaluated. Delineation of meningiomas was completed on both MR images. A novel asymmetric 3D convolutional neural network (CNN) architecture was constructed with two encoding paths based on T1-CE and T2-FLAIR. Each path used the same 3 × 3 × 3 kernel with different filters to weigh the spatial features of each sequence separately. Final model performance was assessed by tenfold cross-validation. Of the 96 patients, 55 (57%) were pathologically classified as Grade I and 41 (43%) as Grade II meningiomas. Optimization of our model led to a filter weighting of 18:2 between the T1-CE and T2-FLAIR MR image paths. 86 (90%) patients were classified correctly, and 10 (10%) were misclassified based on their pre-operative MRs with a model sensitivity of 0.85 and specificity of 0.93. Among the misclassified, 4 were Grade I, and 6 were Grade II. The model is robust to tumor locations and sizes. A novel asymmetric CNN with two differently weighted encoding paths was developed for successful automated meningioma grade classification. Our model outperforms CNN using a single path for single or multimodal MR-based classification., (© 2022. The Author(s).)

Purposes: Preimplant diagnostic magnetic resonance imaging is the gold standard for image-guided tandem-and-ovoids (T&O) brachytherapy for cervical cancer. However, high dose rate brachytherapy planning is typically done on postimplant CT-based high-risk clinical target volume (HR-CTV CT ) because the transfer of preimplant Magnetic resonance (MR)-based HR-CTV (HR-CTV MR ) to the postimplant planning CT is difficult due to anatomical changes caused by applicator insertion, vaginal packing, and the filling status of the bladder and rectum. This study aims to train a dual-path convolutional neural network (CNN) for automatic segmentation of HR-CTV CT on postimplant planning CT with guidance from preimplant diagnostic MR., Methods: Preimplant T2-weighted MR and postimplant CT images for 65 (48 for training, eight for validation, and nine for testing) patients were retrospectively solicited from our institutional database. MR was aligned to the corresponding CT using rigid registration. HR-CTV CT and HR-CTV MR were manually contoured on CT and MR by an experienced radiation oncologist. All images were then resampled to a spatial resolution of 0.5 × 0.5 × 1.25 mm. A dual-path 3D asymmetric CNN architecture with two encoding paths was built to extract CT and MR image features. The MR was masked by HR-CTV MR contour while the entire CT volume was included. The network put an asymmetric weighting of 18:6 for CT: MR. Voxel-based dice similarity coefficient (DSC V ), sensitivity, precision, and 95% Hausdorff distance (95-HD) were used to evaluate model performance. Cross-validation was performed to assess model stability. The study cohort was divided into a small tumor group (<20 cc), medium tumor group (20-40 cc), and large tumor group (>40 cc) based on the HR-CTV CT for model evaluation. Single-path CNN models were trained with the same parameters as those in dual-path models., Results: For this patient cohort, the dual-path CNN model improved each of our objective findings, including DSC V , sensitivity, and precision, with an average improvement of 8%, 7%, and 12%, respectively. The 95-HD was improved by an average of 1.65 mm compared to the single-path model with only CT images as input. In addition, the area under the curve for different networks was 0.86 (dual-path with CT and MR) and 0.80 (single-path with CT), respectively. The dual-path CNN model with asymmetric weighting achieved the best performance with DSC V of 0.65 ± 0.03 (0.61-0.70), 0.79 ± 0.02 (0.74-0.85), and 0.75 ± 0.04 (0.68-0.79) for small, medium, and large group. 95-HD were 7.34 (5.35-10.45) mm, 5.48 (3.21-8.43) mm, and 6.21 (5.34-9.32) mm for the three size groups, respectively., Conclusions: An asymmetric CNN model with two encoding paths from preimplant MR (masked by HR-CTV MR ) and postimplant CT images was successfully developed for automatic segmentation of HR-CTV CT for T&O brachytherapy patients., (© 2022 American Association of Physicists in Medicine.)

CRISPR-based homing gene drives can be designed to disrupt essential genes whilst biasing their own inheritance, leading to suppression of mosquito populations in the laboratory. This class of gene drives relies on CRISPR-Cas9 cleavage of a target sequence and copying ('homing') therein of the gene drive element from the homologous chromosome. However, target site mutations that are resistant to cleavage yet maintain the function of the essential gene are expected to be strongly selected for. Targeting functionally constrained regions where mutations are not easily tolerated should lower the probability of resistance. Evolutionary conservation at the sequence level is often a reliable indicator of functional constraint, though the actual level of underlying constraint between one conserved sequence and another can vary widely. Here we generated a novel adult lethal gene drive (ALGD) in the malaria vector Anopheles gambiae, targeting an ultra-conserved target site in a haplosufficient essential gene (AGAP029113) required during mosquito development, which fulfils many of the criteria for the target of a population suppression gene drive. We then designed a selection regime to experimentally assess the likelihood of generation and subsequent selection of gene drive resistant mutations at its target site. We simulated, in a caged population, a scenario where the gene drive was approaching fixation, where selection for resistance is expected to be strongest. Continuous sampling of the target locus revealed that a single, restorative, in-frame nucleotide substitution was selected. Our findings show that ultra-conservation alone need not be predictive of a site that is refractory to target site resistance. Our strategy to evaluate resistance in vivo could help to validate candidate gene drive targets for their resilience to resistance and help to improve predictions of the invasion dynamics of gene drives in field populations., Competing Interests: The authors have declared that no competing interests exist.

CRISPR-based gene drives offer promising means to reduce the burden of pests and vector-borne diseases. These techniques consist of releasing genetically modified organisms carrying CRISPR-Cas nucleases designed to bias their inheritance and rapidly propagate desired modifications. Gene drives can be intended to reduce reproductive capacity of harmful insects or spread anti-pathogen effectors through wild populations, even when these confer fitness disadvantages. Technologies capable of halting the spread of gene drives may prove highly valuable in controlling, counteracting, and even reverting their effect on individual organisms as well as entire populations. Here we show engineering and testing of a genetic approach, based on the germline expression of a phage-derived anti-CRISPR protein (AcrIIA4), able to inactivate CRISPR-based gene drives and restore their inheritance to Mendelian rates in the malaria vector Anopheles gambiae. Modeling predictions and cage testing show that a single release of male mosquitoes carrying the AcrIIA4 protein can block the spread of a highly effective suppressive gene drive preventing population collapse of caged malaria mosquitoes.

Checkpoint inhibitors and T-cell therapies have highlighted the critical role of T cells in anti-cancer immunity. However, limitations associated with these treatments drive the need for alternative approaches. Here, we engineer red blood cells into artificial antigen-presenting cells (aAPCs) presenting a peptide bound to the major histocompatibility complex I, the costimulatory ligand 4-1BBL, and interleukin (IL)-12. This leads to robust, antigen-specific T-cell expansion, memory formation, additional immune activation, tumor control, and antigen spreading in tumor models in vivo. The presence of 4-1BBL and IL-12 induces minimal toxicities due to restriction to the vasculature and spleen. The allogeneic aAPC, RTX-321, comprised of human leukocyte antigen-A*02:01 presenting the human papilloma virus (HPV) peptide HPV16 E7 11-19 , 4-1BBL, and IL-12 on the surface, activates HPV-specific T cells and promotes effector function in vitro. Thus, RTX-321 is a potential 'off-the-shelf' in vivo cellular immunotherapy for treating HPV + cancers, including cervical and head/neck cancers.

Homing-based gene drives use a germline source of nuclease to copy themselves at specific target sites in a genome and bias their inheritance. Such gene drives can be designed to spread and deliberately suppress populations of malaria mosquitoes by impairing female fertility. However, strong unintended fitness costs of the drive and a propensity to generate resistant mutations can limit a gene drive's potential to spread. Alternative germline regulatory sequences in the drive element confer improved fecundity of carrier individuals and reduced propensity for target site resistance. This is explained by reduced rates of end-joining repair of DNA breaks from parentally deposited nuclease in the embryo, which can produce heritable mutations that reduce gene drive penetrance. We tracked the generation and selection of resistant mutations over the course of a gene drive invasion of a population. Improved gene drives show faster invasion dynamics, increased suppressive effect and later onset of target site resistance. Our results show that regulation of nuclease expression is as important as the choice of target site when developing a robust homing-based gene drive for population suppression., Competing Interests: The authors have declared that no competing interests exist.

Only female insects transmit diseases such as malaria, dengue and Zika; therefore, control methods that bias the sex ratio of insect offspring have long been sought. Genetic elements such as sex-chromosome drives can distort sex ratios to produce unisex populations that eventually collapse, but the underlying molecular mechanisms are unknown. We report a male-biased sex-distorter gene drive (SDGD) in the human malaria vector Anopheles gambiae. We induced super-Mendelian inheritance of the X-chromosome-shredding I-PpoI nuclease by coupling this to a CRISPR-based gene drive inserted into a conserved sequence of the doublesex (dsx) gene. In modeling of invasion dynamics, SDGD was predicted to have a quicker impact on female mosquito populations than previously developed gene drives targeting female fertility. The SDGD at the dsx locus led to a male-only population from a 2.5% starting allelic frequency in 10-14 generations, with population collapse and no selection for resistance. Our results support the use of SDGD for malaria vector control.