Factors influencing microplastic abundances in the sediments of a seagrass-dominated tropical atoll.

Seagrass meadows are one of the world's most diverse ecosystems offering habitats for an extensive array of species, as well as serving as protectors of coral reefs and vital carbon sinks. Furthermore, they modify hydrodynamics by diminishing water flow velocities and enhancing sediment deposition, indicating the potential for microplastic accumulation in their sediments. The build-up of microplastics could potentially have ecological impacts threatening to ecosystems, however little is known about microplastic abundance and controlling factors in seagrass sediments. Here we investigated microplastic characteristics and abundances within sediments underlying four seagrass meadow sites on the Turneffe Atoll, Belize. Sediment cores were collected and sub-sampled to include a range of replicate surface sediments (0-4 cm) and depth cores (sediment depths 0-2, 2-5, 5-10, 10-20 and 20-30 cm). These were analysed using 25 µm resolution µFTIR, with spectral maps processed using siMPle software. Microplastics were prevalent across the sites with an abundance range (limit of detection (LOD) blank-corrected) of < LOD to 17137 microplastics kg-1 dw found on the east side of the atoll. However, their abundances varied greatly between the replicate samples. Polyethylene and polypropylene were the most commonly detected polymers overall, although the dominant polymer type varied between sites. There were no differences in the abundance of microplastics between sites, nor could abundance distributions be explained by seagrass cover. However, abundances of microplastics were highest in sediments with lower proportions of fine grained particles (clay, <4 µm) suggesting that hydrodynamics override seagrass effects. Additionally, no patterns were seen between microplastic abundance and depth of sediment. This suggests that microplastic abundance and distribution in seagrass meadows may vary significantly depending on the specific geographical locations within those meadows, and that more complex hydrodynamic factors influence spatial variability at a localised scale.

Aging as a target for the prevention and treatment of Alzheimer's disease.

Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies. Aging is the most important risk factor for AD. Elucidating molecular mechanisms of aging may suggest novel therapeutic targets. While aging is inevitable, it may be accelerated by caloric excess and slowed by caloric restriction (CR) or intermittent fasting. As such, CR may slow aging and reduce the risk of all diseases of aging, including dementia due to AD. The literature on CR, intermittent fasting, and treatment with polyphenols such as resveratrol-a pharmacologic CR-mimetic-supports this hypothesis based on clinical outcomes as well as biomarkers of aging and AD. More studies exploring the role of CR in regulating aging and AD progression in man are needed to fill gaps in our understanding and develop safer and more effective strategies for the prevention and treatment of AD.

Back to the future for drought tolerance.

Global agriculture faces increasing pressure to produce more food with fewer resources. Drought, exacerbated by climate change, is a major agricultural constraint costing the industry an estimated US$80 billion per year in lost production. Wild relatives of domesticated crops, including wheat (Triticum spp.) and barley (Hordeum vulgare L.), are an underutilized source of drought tolerance genes. However, managing their undesirable characteristics, assessing drought responses, and selecting lines with heritable traits remains a significant challenge. Here, we propose a novel strategy of using multi-trait selection criteria based on high-throughput spectral images to facilitate the assessment and selection challenge. The importance of measuring plant capacity for sustained carbon fixation under drought stress is explored, and an image-based transpiration efficiency (iTE) index obtained via a combination of hyperspectral and thermal imaging, is proposed. Incorporating iTE along with other drought-related variables in selection criteria will allow the identification of accessions with diverse tolerance mechanisms. A comprehensive approach that merges high-throughput phenotyping and de novo domestication is proposed for developing drought-tolerant prebreeding material and providing breeders with access to gene pools containing unexplored drought tolerance mechanisms.

A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation.

Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein, which functions as an RNA regulator. Overexpression of HuR correlates with high grade tumours and poor patient prognosis, implicating it as an attractive therapeutic target. However, an effective small molecule antagonist to HuR for clinical use remains elusive. Here, a single domain antibody (VHH) that binds HuR with low nanomolar affinity was identified and shown to inhibit HuR binding to RNA. This VHH was used to engineer a TRIM21-based biological PROTAC (bioPROTAC) that could degrade endogenous HuR. Significantly, HuR degradation reverses the tumour-promoting properties of cancer cells in vivo by altering the HuR-regulated proteome, highlighting the benefit of HuR degradation and paving the way for the development of HuR-degrading therapeutics. These observations have broader implications for degrading intractable therapeutic targets, with bioPROTACs presenting a unique opportunity to explore targeted-protein degradation through a modular approach.

Volcaniclastic density currents explain widespread and diverse seafloor impacts of the 2022 Hunga Volcano eruption.

The impacts of large terrestrial volcanic eruptions are apparent from satellite monitoring and direct observations. However, more than three quarters of all volcanic outputs worldwide lie submerged beneath the ocean, and the risks they pose to people, infrastructure, and benthic ecosystems remain poorly understood due to inaccessibility and a lack of detailed observations before and after eruptions. Here, comparing data acquired between 2015 - 2017 and 3 months after the January 2022 eruption of Hunga Volcano, we document the far-reaching and diverse impacts of one of the most explosive volcanic eruptions ever recorded. Almost 10 km3 of seafloor material was removed during the eruption, most of which we conclude was redeposited within 20 km of the caldera by long run-out seafloor density currents. These powerful currents damaged seafloor cables over a length of >100 km, reshaped the seafloor, and caused mass-mortality of seafloor life. Biological (mega-epifaunal invertebrate) seafloor communities only survived the eruption where local topography provided a physical barrier to density currents (e.g., on nearby seamounts). While the longer-term consequences of such a large eruption for human, ecological and climatic systems are emerging, we expect that these previously-undocumented refugia will play a key role in longer-term ecosystem recovery.

Redirecting the specificity of tripartite motif containing-21 scaffolds using a novel discovery and design approach.

Hijacking the ubiquitin proteasome system to elicit targeted protein degradation (TPD) has emerged as a promising therapeutic strategy to target and destroy intracellular proteins at the post-translational level. Small molecule-based TPD approaches, such as proteolysis-targeting chimeras (PROTACs) and molecular glues, have shown potential, with several agents currently in clinical trials. Biological PROTACs (bioPROTACs), which are engineered fusion proteins comprised of a target-binding domain and an E3 ubiquitin ligase, have emerged as a complementary approach for TPD. Here, we describe a new method for the evolution and design of bioPROTACs. Specifically, engineered binding scaffolds based on the third fibronectin type III domain of human tenascin-C (Tn3) were installed into the E3 ligase tripartite motif containing-21 (TRIM21) to redirect its degradation specificity. This was achieved via selection of naïve yeast-displayed Tn3 libraries against two different oncogenic proteins associated with B-cell lymphomas, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) and embryonic ectoderm development protein (EED), and replacing the native substrate-binding domain of TRIM21 with our evolved Tn3 domains. The resulting TRIM21-Tn3 fusion proteins retained the binding properties of the Tn3 as well as the E3 ligase activity of TRIM21. Moreover, we demonstrated that TRIM21-Tn3 fusion proteins efficiently degraded their respective target proteins through the ubiquitin proteasome system in cellular models. We explored the effects of binding domain avidity and E3 ligase utilization to gain insight into the requirements for effective bioPROTAC design. Overall, this study presents a versatile engineering approach that could be used to design and engineer TRIM21-based bioPROTACs against therapeutic targets.

Fast and destructive density currents created by ocean-entering volcanic eruptions.

Volcanic eruptions on land create hot and fast pyroclastic density currents, triggering tsunamis or surges that travel over water where they reach the ocean. However, no field study has documented what happens when large volumes of erupted volcanic material are instead delivered directly into the ocean. We show how the rapid emplacement of large volumes of erupted material onto steep submerged slopes triggered extremely fast (122 kilometers per hour) and long-runout (>100 kilometers) seafloor currents. These density currents were faster than those triggered by earthquakes, floods, or storms, and they broke seafloor cables, cutting off a nation from the rest of the world. The deep scours excavated by these currents are similar to those around many submerged volcanoes, providing evidence of large eruptions at other sites worldwide.

Biologics-based degraders - an expanding toolkit for targeted-protein degradation.

Targeted protein degradation (TPD) is a broadly useful proteome editing tool for biological research and therapeutic development. TPD offers several advantages over functional inhibition alone, including the ability to target previously undruggable proteins and the substantial and sustained knockout of protein activity. A variety of small molecule approaches hijack endogenous protein degradation machinery, but are limited to proteins with a cytosolic domain and suitable binding pocket. Recently, biologics-based methods have expanded the TPD toolbox by allowing access to extracellular and surface-exposed proteins and increasing target specificity. Here, we summarize recent advances in the use of biologics to deplete proteins through either the ubiquitin-proteasome system or the lysosomal degradation pathway, and discuss routes to their effective delivery as potential therapeutic interventions.

Elevated CO2 improves phosphorus nutrition and growth of citrate-secreting wheat when grown under adequate phosphorus supply on an Al3+ -toxic soil.

BACKGROUND: Understanding how climate change affects the phosphorus (P) nutrition of crops grown on acid soils is important in optimizing the management of P, and to secure future food production on these soils. This study assessed the impact of elevated CO2 (eCO2 ) on the P nutrition of wheat (Triticum aestivum) grown on Al3+ -toxic and P-deficient soils or in hydroponics. The aluminium-resistant near-isogenic wheat lines EGA-Burke (malate efflux only) and EGA-Burke TaMATE1B (malate and citrate efflux) were grown under ambient (400 µmol mol-1 ) and elevated CO2 (800 µmol mol-1 ) in growth chambers for 4-6 weeks. RESULTS: Elevated CO2 enhanced shoot growth and total P uptake of both lines at P rates >250 mg kg-1 , which was associated with improved root biomass allocation and thus increased root growth, but these effects were not apparent at lower P rates. Elevated CO2 decreased specific P uptake (P uptake per unit root length) at P supply >250 mg kg-1 , but did not significantly affect external or internal P requirements. This effect on the specific P uptake was less for EGA-Burke TaMATE1B than for EGA-Burke, possibly due to the increased citrate efflux and decreased Al concentration in root tips of EGA-Burke TaMATE1B. Compared to EGA-Burke, citrate-exuding EGA-Burke TaMATE1B had greater shoot P concentration and greater specific P uptake. CONCLUSION: Elevated CO2 improved root growth, and thus total P uptake and plant production of both lines when high P alleviated Al3+ toxicity and improved P nutrition in acid soils. The decreased P uptake efficiency under eCO2 was less for EGA-Burke TaMATE1B than EGA-Burke. © 2022 Society of Chemical Industry.

First source-to-sink monitoring shows dense head controls sediment flux and runout in turbidity currents.

Until recently, despite being one of the most important sediment transport phenomena on Earth, few direct measurements of turbidity currents existed. Consequently, their structure and evolution were poorly understood, particularly whether they are dense or dilute. Here, we analyze the largest number of turbidity currents monitored to date from source to sink. We show sediment transport and internal flow characteristic evolution as they runout. Observed frontal regions (heads) are fast (>1.5 m/s), thin (<10 m), dense (depth averaged concentrations up to 38%vol), strongly stratified, and dominated by grain-to-grain interactions, or slower (<1 m/s), dilute (<0.01%vol), and well mixed with turbulence supporting sediment. Between these end-members, a transitional flow head exists. Flow bodies are typically thick, slow, dilute, and well mixed. Flows with dense heads stretch and bulk up with dense heads transporting up to 1000 times more sediment than the dilute body. Dense heads can therefore control turbidity current sediment transport and runout into the deep sea.

Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure.

The dysregulated physical interaction between two intracellular membrane proteins, the sarco/endoplasmic reticulum Ca2+ ATPase and its reversible inhibitor phospholamban, induces heart failure by inhibiting calcium cycling. While phospholamban is a bona-fide therapeutic target, approaches to selectively inhibit this protein remain elusive. Here, we report the in vivo application of intracellular acting antibodies (intrabodies), derived from the variable domain of camelid heavy-chain antibodies, to modulate the function of phospholamban. Using a synthetic VHH phage-display library, we identify intrabodies with high affinity and specificity for different conformational states of phospholamban. Rapid phenotypic screening, via modified mRNA transfection of primary cells and tissue, efficiently identifies the intrabody with most desirable features. Adeno-associated virus mediated delivery of this intrabody results in improvement of cardiac performance in a murine heart failure model. Our strategy for generating intrabodies to investigate cardiac disease combined with modified mRNA and adeno-associated virus screening could reveal unique future therapeutic opportunities.

Variation in isocentre location of an Elekta Unity MR-linac through full gantry rotation.

Objective. The objective of this study was to separately quantify the stability of the megavoltage imager (MVI) and radiation head of an Elekta Unity MRL, throughout full gantry rotation.Approach. A ball-bearing (BB) phantom was attached to the radiation head of the Unity, while a single BB was placed at isocentre. Images were acquired during rotation, using the MVI. These images were processed using an in-house developed MATLAB program to reduce the errors resulted by noise, and the positions of the BBs in the images were analysed to extract MVI and radiation head sag data.Main results. The results returned by this method showed reproducibility, with a mean standard deviation of 7µm for the position of BBs across all gantry angles. The radiation head was found to sag throughout rotation, with a maximum course of movement of 0.59 mm. The sag pattern was stable over a period greater than a year but showed some dependence on gantry rotation direction.Significance. As MRL is a relatively new system, it is promising to have data supporting the high level of precision on one Elekta Unity machine. Isolating and quantifying the sources of uncertainty in radiation delivery may allow more sophisticated analysis of how the system performance may be improved.

Well-differentiated papillary mesothelioma found incidentally with concurrent struma ovarii: A case report.

This is the first report of well-differentiated papillary mesothelioma (WDPM) found concurrently with struma ovarii. These rare tumors have no know association, and are considered benign, though malignant transformation of WDPM has been described. After treatment of WDPM, follow-up surveillance has been suggested in the literature, though a method has not been described and an evidence base is lacking. Pre-operative imaging by computed tomography and ultrasound did not identify the WDPM, calling into question the role of imaging-based follow-up. Furthermore, malignant transformation has been reported only outside of the typical 5-year follow-up window. The authors of this case report suggest rationalization of follow-up of WDPM, acknowledging the risks and unknown harms of scheduled imaging follow-up.

Exploiting genotype × management interactions to increase rainfed crop production: a case study from south-eastern Australia.

Crop yield must increase to keep pace with growing global demand. Past increases in crop production have rarely been attributable to an individual innovation but have occurred when technologies and practices combine to form improved farming systems. Inevitably this has involved synergy between genotypic and management improvements. We argue that research focused on developing synergistic systems that overcome clear production constraints will accelerate increases in yield. This offers the opportunity to better focus and multiply the impact of discipline-focused research. Here we use the rainfed grain production systems of south-eastern Australia as a case study of how transformational change in water productivity can be achieved with research focused on genotype × management synergies. In this region, rainfall is low and variable and has declined since 1990. Despite this, growers have maintained yields by implementing synergistic systems combining innovations in (i) soil water conservation, (ii) crop diversity, (iii) earlier sowing, and (iv) matching nitrogen fertilizer to water-limited demand. Further increases are emerging from synergies between genetic improvements to deliver flowering time stability, adjusted sowing times, and potential dual-purpose use. Collaboration between agronomists, physiologists, and crop breeders has led to development of commercial genotypes with stable flowering time that are in early phases of testing and adoption.

Selective CRAF Inhibition Elicits Transactivation.

Discovering molecules that regulate closely related protein isoforms is challenging, and in many cases the consequences of isoform-specific pharmacological regulation remains unknown. RAF isoforms are commonly mutated oncogenes that serve as effector kinases in MAP kinase signaling. BRAF/CRAF heterodimers are believed to be the primary RAF signaling species, and many RAF inhibitors lead to a "paradoxical activation" of RAF kinase activity through transactivation of the CRAF protomer; this leads to resistance mechanisms and secondary tumors. It has been hypothesized that CRAF-selective inhibition might bypass paradoxical activation, but no CRAF-selective inhibitor has been reported and the consequences of pharmacologically inhibiting CRAF have remained unknown. Here, we use bio-orthogonal ligand tethering (BOLT) to selectively target inhibitors to CRAF. Our results suggest that selective CRAF inhibition promotes paradoxical activation and exemplify how BOLT may be used to triage potential targets for drug discovery before any target-selective small molecules are known.

Three's a crowd: A very rare form of polyorchidism with sertoli cell adenomas.

Polyorchidism is rare with fewer than 200 cases reported in literature. We present a case of a 26 year old male with chronic pain secondary to a very rare form of polyorchidism, with histology showing Sertoli cell adenomas. Orchiectomy should be considered in patients with chronic pain due to polyorchidism.

Impacts of elevated CO2 on plant resistance to nutrient deficiency and toxic ions via root exudates: A review.

Elevated atmospheric CO2 (eCO2) concentration can increase root exudation into soils, which improves plant tolerance to abiotic stresses. This review used a meta-analysis to assess effect sizes of eCO2 on both efflux rates and total amounts of some specific root exudates, and dissected whether eCO2 enhances plant's resistance to nutrient deficiency and ion toxicity via root exudates. Elevated CO2 did not affect efflux rates of total dissolved organic carbon, a measure of combined root exudates per unit of root biomass or length, but increased the efflux amount of root systems per plant by 31% which is likely attributed to increased root biomass (29%). Elevated CO2 increased efflux rates of soluble-sugars, carboxylates, and citrate by 47%, 111%, and 16%, respectively, but did not affect those of amino acids and malate. The increased carbon allocation to roots, increased plant requirements of mineral nutrients, and heightened detoxification responses to toxic ions under eCO2 collectively contribute to the increased efflux rates despite lacking molecular evidence. The increased efflux rates of root exudates under eCO2 were closely associated with improved nutrient uptake whilst less studies have validated the associations between root exudates and resistance to toxic ions of plants when grown under eCO2. Future studies are required to reveal how climate change (eCO2) affect the efflux of specific root exudates, particularly organic anions, the corresponding nutrient uptake and toxic ion resistance from plant molecular biology and soil microbial ecology perspectives.

Evaluation of G × E × M Interactions to Increase Harvest Index and Yield of Early Sown Wheat.

Harvest index (HI) is the ratio of grain to total shoot dry matter and is as a measure of reproductive efficiency. HI is determined by interactions between genotypes (G), environment (E), and crop management (M). Historic genetic yield gains due to breeding in wheat have largely been achieved by increasing HI. Environmental factors are important for HI and include seasonal pattern of water supply and extreme temperatures during crop reproductive development. Wheat production in Australia has been dominated by fast-developing spring cultivars that when sown in late-autumn will flower at an optimal time in early spring. Water limited potential yield can be increased by sowing slower developing wheats with a vernalization requirement (winter wheat) earlier than currently practiced such that their development is matched to environment and they flower at the optimal time. This means a longer vegetative phase which increases rooting depth, proportion of water-use transpired, and transpiration efficiency by allowing more growth during winter when vapour pressure deficit is low. All these factors can increase biomass accumulation, grain number and thus grain yield potential. However higher yields are not always realized due to a lower HI of early sown slow developing wheats compared to fast developing wheats sown later. Here, we evaluate genotype × management practices to improve HI and yield in early sown slow developing wheat crops using 6 field experiments conducted across south eastern Australia from 2014 to 2018 in yield environments ranging from ~1 to ~4.7 t/ha. Practices included low plant densities (30-50 plants/m²), mechanical defoliation, and deferred application of nitrogen fertilizer. Lower plant densities had similar yield and HI to higher plant densities. Defoliation tended to increase HI but reduce yield except when there was severe stem frost damage. Deferring nitrogen had a variable effect depending on starting soil N and in crop rainfall. All management strategies evaluated gave variable HI and yield responses with small effect sizes, and we conclude that none of them can reliably increase HI in early sown wheat. We propose that genetic improvement is the most promising avenue for increasing HI and yield in early sown wheat, and postulate that this could be achieved more rapidly through early generation screening for HI in slow developing genotypes than by crop management.