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Some refractory linings that protect metallic vessels from the hot temperature of the products they contain are made of masonries that are built without mortar (dry joints). The joints between bricks allow a free expansion during the first part of the temperature increase, reducing the stresses in the masonries. To model the masonry behaviour, a solution is to replace the masonry by a homogeneous material that has an equivalent behaviour to that of the masonry. To validate this global approach, it is necessary to test the masonries in conditions close to those of an industrial vessel. A thermomechanical test was therefore performed on a laboratory pilot which represents a simplified steel ladle. It is made of a steel shell, a flat masonry in the bottom and a cylindrical masonry for the vertical wall. An internal temperature of 1000 °C was prescribed inside the pilot. Thermocouples were placed inside bricks and on the steel shell to determine the temperature field. Displacement sensors were used to determine the displacements of the bottom masonry, and strain gauges on the steel shell to determine the pilot deformation.

Detailed explorations of the model organisms Caenorhabditis elegans (elegant worm) and Drosophila melanogaster (vinegar fly) have substantially improved our knowledge and understanding of biological processes and pathways in metazoan organisms. Extensive functional genomic and multi-omic data sets have enabled the discovery and characterisation of ‘essential’ genes that are critical for the survival of these organisms. Recently, we showed that a machine learning (ML)-based pipeline could be utilised to predict essential genes in both C. elegans and D. melanogaster using features from DNA, RNA, protein and/or cellular data or associated information. As these distantly-related species are within the Ecdysozoa, we hypothesised that this approach could be suited for non-model organisms within the same group (phylum) of protostome animals. In the present investigation, we cross-predicted essential genes within the phylum Nematoda – between C. elegans and the parasitic filarial nematodes Brugia malayi and Onchocerca volvulus, and then ranked and prioritised these genes. Highly ranked genes were linked to key biological pathways or processes, such as ribosome biogenesis, translation and RNA processing, and were expressed at relatively high levels in the germline, gonad, hypodermis and/or nerves. The present in silico workflow is hoped to expedite the identification of drug targets in parasitic organisms for subsequent experimental validation in the laboratory.

Advances in single cell technologies are allowing investigations of a wide range of biological processes and pathways in animals, such as the multicellular model organism Caenorhabditis elegans – a free-living nematode. However, there has been limited application of such technology to related parasitic nematodes which cause major diseases of humans and animals worldwide. With no vaccines against the vast majority of parasitic nematodes and treatment failures due to drug resistance or inefficacy, new intervention targets are urgently needed, preferably informed by a deep understanding of these nematodes’ cellular and molecular biology – which is presently lacking for most worms. Here, we created the first single cell atlas for an early developmental stage of Haemonchus contortus – a highly pathogenic, C. elegans-related parasitic nematode. We obtained and curated RNA sequence (snRNA-seq) data from single nuclei from embryonating eggs of H. contortus (150,000 droplets), and selected high-quality transcriptomic data for > 14,000 single nuclei for analysis, and identified 19 distinct clusters of cells. Guided by comparative analyses with C. elegans, we were able to reproducibly assign seven cell clusters to body wall muscle, hypodermis, neuronal, intestinal or seam cells, and identified eight genes that were transcribed in all cell clusters/types, three of which were inferred to be essential in H. contortus. Two of these genes (i.e. Hc-eef-1A and Hc-eef1G), coding for eukaryotic elongation factors (called Hc-eEF1A and Hc-eEF1G), were also demonstrated to be transcribed and expressed in all key developmental stages of H. contortus. Together with these findings, sequence- and structure-based comparative analyses indicated the potential of Hc-eEF1A and/or Hc-eEF1G as intervention targets within the protein biosynthesis machinery of H. contortus. Future work will focus on single cell studies of all key developmental stages and tissues of H. contortus, and on evaluating the suitability of the two elongation factor proteins as drug targets in H. contortus and related nematodes, with a view to finding new nematocidal drug candidates.

Infections and diseases caused by parasitic nematodes have a major adverse impact on the health and productivity of animals and humans worldwide. The control of these parasites often relies heavily on the treatment with commercially available chemical compounds (anthelmintics). However, the excessive or uncontrolled use of these compounds in livestock animals has led to major challenges linked to drug resistance in nematodes. Therefore, there is a need to develop new anthelmintics with novel mechanism(s) of action. Recently, we identified a small molecule, designated UMW-9729, with nematocidal activity against the free-living model organism Caenorhabditis elegans. Here, we evaluated UMW-9729's potential as an anthelmintic in a structure-activity relationship (SAR) study in C. elegans and the highly pathogenic, blood-feeding Haemonchus contortus (barber's pole worm), and explored the compound-target relationship using thermal proteome profiling (TPP). First, we synthesised and tested 25 analogues of UMW-9729 for their nematocidal activity in both H. contortus (larvae and adults) and C. elegans (young adults), establishing a preliminary nematocidal pharmacophore for both species. We identified several compounds with marked activity against either H. contortus or C. elegans which had greater efficacy than UMW-9729, and found a significant divergence in compound bioactivity between these two nematode species. We also identified a UMW-9729 analogue, designated 25, that moderately inhibited the motility of adult female H. contortus in vitro. Subsequently, we inferred three H. contortus proteins (HCON_00134350, HCON_00021470 and HCON_00099760) and five C. elegans proteins (F30A10.9, F15B9.8, B0361.6, DNC-4 and UNC-11) that interacted directly with UMW-9729; however, no conserved protein target was shared between the two nematode species. Future work aims to extend the SAR investigation in these and other parasitic nematode species, and validate individual proteins identified here as possible targets of UMW-9729. Overall, the present study evaluates this anthelmintic candidate and highlights some challenges associated with early anthelmintic investigation.

This study introduces an innovative approach for analyzing bending deformation and strength in textile-reinforced laminated composites, which is crucial for CubeSat structures. Our research develops a dual-scale modelling framework: a microscale model capturing the detailed viscoelastic-viscoplastic behaviour of fibres and matrices and a mesoscale model that integrates this with textile geometry, advanced shear deformation theories, and distributed damage effects. Extensive laboratory experiments validate our model, confirming its accuracy in predicting the composite behaviour under varied conditions. This work notably enhances the understanding and prediction of textile-reinforced composites, offering significant implications for CubeSat structural design and performance.

Space debris is a growing problem for low earth orbit (LEO) and geosynchronous orbit (GEO). The risk of space debris currently affects human activities in Space and is controlled by the collision avoidance alert. However, the risk is growing, which increases future space mission costs to avoid or shield against space debris impact.The project has evolved over four years, culminating in Meng/BEng graduation projects. At the heart of our innovation is utilising the naturally high temperatures in the exosphere and stratosphere, which can soar to 1200 °C. This environment is ideal for initiating a chemical reaction within a pressurised chamber containing a mix of H2-O2 gases, generating heat sufficient to ablate common space debris materials such as titanium, aluminium, and composites. We have crafted an initial satellite design and performed Multiphysics simulations using COMSOL to validate our concept. The project now seeks investment to enhance four critical areas: the satellite's mechanical design to ensure safe operation within a debris field, the development of a dynamic control system for debris collection and satellite navigation, the management of H2 and O2 tank refilling, and the creation of a mechanism for the safe release of ablated materials back into Space.

Poor long-term survival (Mean = 2.16 y; 95% CI 1.68–2.65) was identified in a captive population of thorny devils (Moloch horridus) held at the Alice Springs Desert Park in the Northern Territory, Australia, over a period of 27 years. There was no significant difference in survival time (after acquisition) of wild-caught individuals compared captive born animals, or males compared to females. Limited information was available regarding the cause(s) of death for animals found dead or euthanased. Health of the live population at the time of the study (n = 14) was assessed by clinical history review, physical examination, and faecal examination. Large numbers of coccidian oocysts measuring 20–24 μm in diameter were identified upon faecal examination. Molecular investigation of genomic DNA from these samples identified Isospora amphiboluri based on the sequences of partial regions of the mitochondrial cytochrome c oxidase subunit 1 gene (cox1) and the nuclear small subunit of ribosomal RNA gene (SSU). Isospora amphiboluri was originally described from the bearded dragon (Pogona barbata) and has since been recorded in the inland bearded dragon (Pogona vitticeps) and the central netted dragon (Ctenophorus nuchalis). The present case expands the host range for I. amphiboluri. Histological examination of tissues was not available, and therefore the potential role of I. amphiboluri in morbidity and mortality of M. horridus is not clear. Further research is required to understand if colonization with I. amphiboluri is pathogenic in this species.

Summary: Background: In isocitrate dehydrogenase (IDH)-mutant low-grade gliomas (LGGs), awake functional-based resection (i.e., resection based on intraoperative functional responses rather than anatomical margins) has emerged as an efficient method to reduce tumour volume (TV) while minimizing postoperative deficits. Here, our goal was to assess the long-term onco-functional outcomes after awake functional-based resection in IDH-mutant LGGs, in conjunction with clinico-radiological and molecular factors. Methods: We retrospectively studied a consecutive cohort (June 1997–January 2023) of 949 patients. Six hundred patients with IDH-mutant LGGs benefited from an awake functional-based resection with a median follow-up of 7.8 years (95% Confidence interval [CI]: 7.1–8.4 years). The main outcomes were the overall survival (OS), the OS with Karnofsky performance status ≥80% (OSKPS≥80%), cognition measures, and professional activities at 12 months post-surgery. Findings: 600 patients were included in the cohort (274 female [46.0%], median age: 36 years [Interquartile range, IQR: 30–44 years]). The rate of return to work was 93.7%. The impact of surgery on cognition was of limited magnitude. The median postsurgical TV of 2.5 mL (IQR: 0–8.0 mL). The median OS was over 20 years (median: NA, 95% CI: 17.0-NA years). The median OSKPS≥80% was 14.7 years (95% CI: 13.2–17.2 years). Factors associated with longer OS and OSKPS≥P80% were 1p19q codeletion (Hazard ratio [HR]OS: 0.27, 95% CI: 0.16–0.43, HRKPS≥80%:0.25, 95% CI: 0.17–0.36), supratotal resection (HROS: 0.08, 95% CI: 0.005–0.40, HRKPS≥80%:0.12, 95% CI: 0.03–0.34) and total resection (HROS: 0.31, 95% CI: 0.16–0.59, HRKPS≥80%:0.21, 95% CI: 0.12–0.36). Recursive partitioning analyses established three OS and OSKPS≥80% prognostic groups, highlighting the contributions of histomolecular status, extent of resection, postsurgical and presurgical TV. Further propensity-matching analyses confirmed the oncological benefits of supratotal resections. Interpretation: Awake functional-based resection surgery in newly diagnosed IDH-mutant grade 2 LGG, was an effective strategy associated with long survival (median OS over 20 years) and long-term preservation of autonomy. More complete tumor resections favored better onco-functional outcomes across all molecularly-defined subtypes. Short-term effects were of limited magnitude regarding postoperative cognitive and professional outcomes. Supratotal functional-based resections offered additional survival benefits. Funding: None.

Summary: Background: Schistosoma mansoni infection poses a substantial public health challenge globally, and the World Health Organization (WHO) aims for the elimination of schistosomiasis by 2030. This study aimed to assess the current prevalence of human S. mansoni infection in endemic regions worldwide between 2010 and 2024. Methods: We conducted a comprehensive search in PubMed/Medline and Scopus databases as well as other public sources from 1 January 2010 to 15 July 2024. Population-based studies reporting the prevalence of S. mansoni infection were eligible. We undertook a random-effects meta-analysis to estimate pooled prevalences with 95% confidence intervals (CIs) in WHO-defined regions and assessed potential risk factors associated with S. mansoni infection. The protocol for this study was registered on PROSPERO (CRD42023438455). Findings: We identified a total of 542 eligible studies involving 1,163,866 individuals who had been tested for S. mansoni infection in 38 countries. The overall, pooled global prevalence of S. mansoni infection in endemic region was 14.8% (95% CI, 13.5%–16.1%). The pooled prevalences (95% CI) in specific regions were: 15.3% (13.9–16.8%) in sub-Saharan Africa, 12.4% (8.9–16.4%) in South America and 9.5% (5.4–14.6%) in the Eastern Mediterranean region. There was a 52.6% decrease in prevalence of S. mansoni infection and a 37% decrease in high-intensity infection for studies conducted between 2010 and 2014 compared to those conducted between 2020 and 2023. The present analysis revealed that factors including male gender, bathing or swimming in natural water bodies, crossing rivers or lakes, and engaging in water irrigation activities such as fishing, working in rice paddies or maintaining irrigation canals were significantly associated with S. mansoni infection. Interpretation: The findings of this investigation revealed that, despite a decline in prevalence and high-intensity infection, 7–12% of people in endemic regions, notably in sub-Saharan Africa, remained affected by schistosomiasis mansoni between 2020 and 2024. This study provides data of relevance to policymakers to support efforts to eliminate this disease. Funding: This study received no funding.

Summary: Pledges at recent climate summits fall short for 1.5°C warming. Here, we calculate the CO2 emissions reduction required to stay below 1.5°C, considering available data on current emissions up to 2022, extending the time horizon to 2300, and using an approach different from the carbon budget to offer another perspective on what is required to stay below 1.5°C. For a 50% chance of staying below 1.5°C during this century, fossil fuel and industry CO2 emissions need to decrease linearly by about 5% per year, in line with other recent studies. However, extending the time horizon to 2300 leads to chances dropping to 30% for the same decarbonization scenario without sustained carbon dioxide removal beyond levels needed for offsetting residual CO2 emissions. We further show that the chances of staying below 1.5°C of global warming critically hinge on the assumed future land-use CO2 emissions and mitigation of non-CO2 forcers. Science for society: We used an observation-informed numerical model that differs from the traditional “carbon budget” approach to estimate fossil CO2 emissions cuts in line with limiting global warming, considering the latest data on emissions up to 2022. We showed that to have a 50% chance of staying below 1.5°C this century, emissions from fossil fuel burning and industrial processes must drop by about 5% each year (or equivalently, reach zero in 20 years). If we extend the timeframe to 2300, the chances drop to 30% even with this level of emissions reduction. The success of limiting warming also depends heavily on future land use (especially deforestation) and reducing other greenhouse gases besides CO2. This research highlights the importance of taking stronger action now to reduce emissions and finding ways to remove CO2 from the atmosphere. It also emphasizes the need for smart land-use practices and tackling other greenhouse gases to achieve our climate goals.

Diseases affecting wild Australian saltwater crocodiles (Crocodylus porosus) are rarely reported due to the difficulty in capturing animals and obtaining samples. In this investigation, we identified two haemoparasites (Hepatozoon and a filarial nematode) in saltwater crocodiles in Darwin, Australia. Light microscopic examination identified Hepatozoon in 7/7 (100%) wild crocodiles and in 2/20 (10%) of captive ones. When genomic DNAs from these same samples were further investigated using polymerase chain reaction (PCR)-based sequencing, we detected Hepatozoon in all 27 blood samples. Using both microscopy and PCR-based sequencing, we detected a filarial worm (proposed to be Oswaldofilaria) in one of 20 captive crocodiles. The sequence data were compared with sequence data available in public databases, and phylogenetic analyses indicated that the operational taxonomic units of Hepatozoon and Oswaldofilaria discovered here in these crocodiles are likely new species. This study is the first to use molecular tools to explore haemoparasites in Australian saltwater crocodiles and highlights the importance of health investigations in poorly studied vertebrate hosts.

Within the context of our anthelmintic discovery program, we recently identified and evaluated a quinoline derivative, called ABX464 or obefazimod, as a nematocidal candidate; synthesised a series of analogues which were assessed for activity against the free-living nematode Caenorhabditis elegans; and predicted compound-target relationships by thermal proteome profiling (TPP) and in silico docking. Here, we logically extended this work and critically evaluated the anthelmintic activity of ABX464 analogues on Haemonchus contortus (barber's pole worm) – a highly pathogenic nematode of ruminant livestock. First, we tested a series of 44 analogues on H. contortus (larvae and adults) to investigate the nematocidal pharmacophore of ABX464, and identified one compound with greater potency than the parent compound and showed moderate activity against a select number of other parasitic nematodes (including Ancylostoma, Heligmosomoides and Strongyloides species). Using TPP and in silico modelling studies, we predicted protein HCON_00074590 (a predicted aldo-keto reductase) as a target candidate for ABX464 in H. contortus. Future work aims to optimise this compound as a nematocidal candidate and investigate its pharmacokinetic properties. Overall, this study presents a first step toward the development of a new nematocide.

Blastocystis is a genus of intestinal stramenopiles that infect vertebrates, and may cause disease of the alimentary tract. Currently, at least 40 genotypes (“subtypes”) of Blastocystis are recognised worldwide based on sequence data for the small subunit of the nuclear ribosomal RNA (SSU-rRNA) gene. Despite the numerous studies of Blastocystis worldwide, very few studies have explored Blastocystis in wild animals, particularly in Australia. Here, we used a PCR-based next generation sequencing (NGS)–phylogenetic approach to genetically characterise and classify Blastocystis variants from selected wildlife in the Australian state of Victoria. In total, 1658 faecal samples were collected from nine host species, including eastern grey kangaroo, swamp wallaby, common wombat, deer, European rabbit, canines and emu. Genomic DNA was extracted from these samples, a 500 bp region of the SSU-rRNA gene amplified by polymerase chain reaction (PCR) and, then, a subset of samples sequenced using Illumina technology. Primary PCR detected Blastocystis in 482 of the 1658 samples (29%), with the highest percentage in fallow deer (63%). Subsequent, Illumina-based sequencing of a subset of 356 samples revealed 55 distinct amplicon sequence variants (ASVs) representing seven currently-recognised subtypes (STs) [ST13 (prominent in marsupials), ST10, ST14, ST21, ST23, ST24 and ST25 (prominent in deer)] and two novel STs (ST45 and ST46) in marsupials. Mixed infections of different STs were observed in macropods, deer, emu and canids (fox, feral dog or dingo), but no infection was detected in rabbits or wombats. This study reveals marked genetic diversity within Blastocystis in a small number of species of wild animals in Australia, suggesting complexity in the genetic composition and transmission patterns of members of the genus Blastocystis in this country.

Objectives: One risk while high-altitude mountaineering despite falls or stranding are rock falls. Due to the climatic change such events might have become potentially more common yielding to the research question to elucidate rock falls while high-altitude mountaineering in the Alps of Switzerland. Design: A retrospective analysis was conducted from the central registry of the Swiss Alpine Club (SAC) during the observational period from 2009 to 2020. Results: A total of 266 cases of rock falls was detected during an observational period yielding to in average 22.2 ± 7 emergency cases per year. No increase nor decrease of the number of cases over time (R2 = 0.0019) was detected. The average age of a victim was 50.2 ± 18.6 years. The mean of the NACA-Score (NACA = National Advisory Committee for Aeronautics) was 2.7 ± 1.4 implying a moderate injury, however not life threatening. The NACA-Score slightly decreased over time indicating that emergencies have become less severe (R2 = 0.1379). The injury pattern was relatively equal distributed between upper and lower extremity. Conclusions: The slight decrease in the severity of the events might be a consequence of increasing security standards over the observational period. The fact that the average victim of an emergency action was around 50 years, might indicate that stone falls are a constant risk as it can be suggested that alpinists with this age are more risk averse than younger alpinists. As findings were analyzed in a retrospective design, a quasi-prospective design might be helpful while directly analyzing emergencies after occurrence with interviews of involved persons. These hints could be used constructively in order to improve security recommendations.

Background: In jargonaphasia, speech is fluent but meaningless. While neuropsychological evaluation may distinguish a neologistic component characterised by non-word production and a semantic component where pronounced words are real but speech is senseless, how this relates to the underlying white matter anatomy is debated. Objective: To identify white matter pathways causally involved in jargonaphasia. Methods: We retrospectively screened the intraoperative brain mapping data of 571 awake oncological resections using direct cortico-subcortical electrostimulation. Jargonaphasia was induced in 17 patients (19 sites) during a naming task. Stimulation sites were normalized to the Montreal Neurological Institute template space and used to generate individual disconnectome maps. Non-parametric voxelwise one and two sample t-tests were performed to identify the underlying white matter anatomy. Results: Jargonaphasia was induced only during stimulation of the left hemisphere. No cortical stimulation generated jargonaphasia. Subcortical sites causally associated with jargonaphasia clustered in 3 regions: in the temporal lobe (middle to inferior temporal gyri; n = 12), in the parietal lobe (supramarginal gyrus; n = 3) and in the temporal stem (n = 4). Disconnectome analysis indicated the inferior-fronto-occipital fasciculus (IFOF) was damaged in both neologistic and semantic jargonaphasia, while the involvement of the arcuate fasciculus was specific to neologistic jargonaphasia. Conclusion: For the first time, we show that jargonaphasia is induced by white matter stimulation, hinting at disconnection. As IFOF disconnection unites both variants, these may represent a continuum of disorders distinguished by semantic impairment. Conversely, damage to the arcuate fasciculus in addition to the IFOF is specific to neologistic jargonaphasia, thus suggesting a dual-disconnection syndrome.

A significant number of chronic venous ulcers (CVUs) fail to heal despite guideline-conform standards of care. Skin-derived ABCB5+ mesenchymal stem cells can dampen the sustained IL-1β‒driven inflammation present in chronic wounds. On the basis of their wound healing‒facilitating effects in a mouse CVU model and an autologous first-in-human study, ABCB5+ mesenchymal stem cells have emerged as a potential candidate for cell-based advanced therapy of nonhealing CVUs. In this interventional, multicenter, single-arm, phase I/IIa clinical trial, subjects whose CVUs had emerged as standard therapy resistant received one or two topical applications of 1 × 106 allogeneic ABCB5+ mesenchymal stem cells per cm2 wound area, in addition to standard treatment. Of 83 treatment-emergent adverse events, only three were judged related to the cell product; they were mild or moderate and recovered without sequelae. Wound size markedly decreased from baseline to week 12, resulting in a median wound size reduction of 76% (full analysis set, n = 31), 78% (per-protocol set, n = 27), and 87% (subset of responders, n = 21). In conclusion, the study treatment was well-tolerated and safe. The treatment elicited a profound wound size reduction within 12 weeks, identifying ABCB5+ mesenchymal stem cells as a potential candidate for adjunctive therapy of otherwise incurable CVUs. These results justify the conduct of a larger, randomized, controlled trial to confirm clinical efficacy.

Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer and effective treatment regimens are yet to be established. Tyrosine kinase inhibitors (TKI) have widely been used as ccRCC therapeutics, but their efficacy is limited due to accompanying resistance mechanisms. Previous studies have provided substantial evidence for crosstalk between cAMP and the MAPK/ERK signaling pathway. Low levels of intracellular cAMP have been found in several human malignancies and some data suggest that elevation of cAMP expression can be achieved by phosphodiesterase 4 (PDE4) inhibition, resulting in cell growth arrest and/or cell death. The effects of crosstalk between cAMP and the MAPK/ERK pathway on the development progression in ccRCR, however, remain to be fully understood. In this study, we sought to explore the involvement of PDE4 in ccRCC and to assess its potential as a target for therapeutic intervention. We demonstrated that PDE4D is the predominant subtype of PDE4 expressed in healthy and cancerous renal cell lines, particularly in metastatic Caki-1 cells. We generated a CRISPR/Cas9-mediated PDE4D-KO Caki-1 cell model and showed that PDE4D depletion reduced cell proliferation and recovered cAMP expression in these cells. PDE4D-KO and/or PDE4 inhibition with the FDA approved PDE4 inhibitor, roflumilast, also attenuated MAPK/ERK signaling in a CRAF-dependent manner. Most interestingly, we showed that PDE4D-KO enhanced the effectiveness of the TKI, sorafenib, to stunt cell survival. In conclusion, we provide preliminary evidence of PDE4 involvement in ccRCC and suggest a rationale for dual tyrosine kinase/PDE4D targeting in patients with CRAF-dependent MAPK activation.

Summary: Signal transduction and activator of transcription 3 (STAT3) is a key transcription factor implicated in the pathogenesis of kidney fibrosis. Although Stat3 deletion in tubular epithelial cells is known to protect mice from fibrosis, vFoxd1 cells remains unclear. Using Foxd1-mediated Stat3 knockout mice, CRISPR, and inhibitors of STAT3, we investigate its function. STAT3 is phosphorylated in tubular epithelial cells in acute kidney injury, whereas it is expanded to interstitial cells in fibrosis in mice and humans. Foxd1-mediated deletion of Stat3 protects mice from folic-acid- and aristolochic-acid-induced kidney fibrosis. Mechanistically, STAT3 upregulates the inflammation and differentiates pericytes into myofibroblasts. STAT3 activation increases migration and profibrotic signaling in genome-edited, pericyte-like cells. Conversely, blocking Stat3 inhibits detachment, migration, and profibrotic signaling. Furthermore, STAT3 binds to the Collagen1a1 promoter in mouse kidneys and cells. Together, our study identifies a previously unknown function of STAT3 that promotes kidney fibrosis and has therapeutic value in fibrosis.

Summary: Here, we describe a fractionation protocol optimized to quantify changes in relative abundance of the chromatin-bound proteome (chromatome) by tandem mass tag multiplexing-based tandem mass spectrometry. It has been applied to yeast cells before and after exposure to DNA-damaging drugs to characterize changes in chromatin composition induced by the DNA damage response. We detail steps for stringent chromatin fractionation, sample preparation for mass spectrometry, and its evaluation.For complete details on the use and execution of this protocol, please refer to Challa et al. (2021).

Objectives: This study investigated how different concentrations of doxorubicin (DOX) can affect the function of cardiac cells. This study also examined whether activation of prokineticin receptor (PKR)-1 by a nonpeptide agonist, IS20, prevents DOX-induced cardiovascular toxicity in mouse models. Background: High prevalence of heart failure during and following cancer treatments remains a subject of intense research and therapeutic interest. Methods: This study used cultured cardiomyocytes, endothelial cells (ECs), and epicardium-derived progenitor cells (EDPCs) for in vitro assays, tumor-bearing models, and acute and chronic toxicity mouse models for in vivo assays. Results: Brief exposure to cardiomyocytes with high-dose DOX increased the accumulation of reactive oxygen species (ROS) by inhibiting a detoxification mechanism via stabilization of cytoplasmic nuclear factor, erythroid 2. Prolonged exposure to medium-dose DOX induced apoptosis in cardiomyocytes, ECs, and EDPCs. However, low-dose DOX promoted functional defects without inducing apoptosis in EDPCs and ECs. IS20 alleviated detrimental effects of DOX in cardiac cells by activating the serin threonin protein kinase B (Akt) or mitogen-activated protein kinase pathways. Genetic or pharmacological inactivation of PKR1 subdues these effects of IS20. In a chronic mouse model of DOX cardiotoxicity, IS20 normalized an elevated serum marker of cardiotoxicity and vascular and EDPC deficits, attenuated apoptosis and fibrosis, and improved the survival rate and cardiac function. IS20 did not interfere with the cytotoxicity or antitumor effects of DOX in breast cancer lines or in a mouse model of breast cancer, but it did attenuate the decreases in left ventricular diastolic volume induced by acute DOX treatment. Conclusions: This study identified the molecular and cellular signature of dose-dependent, DOX-mediated cardiotoxicity and provided evidence that PKR-1 is a promising target to combat cardiotoxicity of cancer treatments.

In the present study, the anthelmintic activity of a human tyrosine kinase inhibitor, AG-1295, and 14 related tetrahydroquinoxaline analogues against Haemonchus contortus was explored. These compounds were screened against parasitic larvae - exsheathed third-stage (xL3) and fourth-stage (L4) - using a whole-organism screening assay. All compounds were shown to have inhibitory effects on larval motility, development and growth, and induced evisceration through the excretory pore in xL3s. The estimated IC50 values ranged from 3.5 to 52.0 μM for inhibition of larval motility or development. Cytotoxicity IC50 against human MCF10A cells was generally higher than 50 μM. Microscopic studies revealed that this eviscerated (Evi) phenotype occurs rapidly (

Due to the widespread occurrence and spread of anthelmintic resistance, there is a need to develop new drugs against resistant parasitic nematodes of livestock animals. The Nobel Prize-winning discovery and development of the anti-parasitic drugs avermectin and artemisinin has renewed the interest in exploring natural products as anthelmintics. In the present study, we screened 7500 plant extracts for in vitro-activity against the barber's pole worm, Haemonchus contortus, a highly significant pathogen of ruminants. The anthelmintic extracts from two plants, Cryptocarya novoguineensis and Piper methysticum, were fractionated by high-performance liquid chromatography (HPLC). Subsequently, compounds were purified from fractions with significant biological activity. Four α-pyrones, namely goniothalamin (GNT), dihydrokavain (DHK), desmethoxyyangonin (DMY) and yangonin (YGN), were purified from fractions from the two plants, GNT from C. novoguineensis, and DHK, DMY and YGN (= kavalactones) from P. methysticum. The three kavalactones induced a lethal, eviscerated (Evi) phenotype in treated exsheathed third-stage larvae (xL3s), and DMY and YGN had moderate potencies (IC50 values of 31.7 ± 0.23 μM and 23.7 ± 2.05 μM, respectively) at inhibiting the development of xL3s to fourth-stage larvae (L4s). Although GNT had limited potency (IC50 of 200–300 μM) at inhibiting L4 development, it was the only compound that reduced L4 motility (IC50 of 6.25–12.50 μM). The compounds purified from each plant affected H. contortus in an irreversible manner. These findings suggest that structure-activity relationship studies of α-pyrones should be pursued to assess their potential as anthelmintics. Keywords: Haemonchus contortus, Anthelmintic, Natural products, Cryptocarya novoguineensis, Piper methysticum, α-pyrones

This oceanographic dataset was gathered during the TIC-MOC cruise, which was designed to characterize the dynamics of the Brazil-Malvinas Confluence. The cruise was carried on board the R/V Hespérides, with departure from Ushuaia and arrival to Salvador de Bahía. A total of 66 conductivity-temperature-depth (CTD) stations were completed between 8 and 22 March 2015, offshore from the continental platform and within 45°S-35°S and 61°W-50°W. At each station, water samples were collected, which were used to calibrate the CTD salinity-oxygen sensors and to determine inorganic nutrient concentrations, and the horizontal current was measured. Along its track, the vessel recorded surface temperature and salinity, as well as the horizontal flow down to about 700 m. Lastly, eight position-transmitting drifters were launched and two profiling floats were deployed and later recovered.

The availability of whole-genome sequences and associated multi-omics data sets, combined with advances in gene knockout and knockdown methods, has enabled large-scale annotation and exploration of gene and protein functions in eukaryotes. Knowing which genes are essential for the survival of eukaryotic organisms is paramount for an understanding of the basic mechanisms of life, and could assist in identifying intervention targets in eukaryotic pathogens and cancer. Here, we studied essential gene orthologs among selected species of eukaryotes, and then employed a systematic machine-learning approach, using protein sequence-derived features and selection procedures, to investigate essential gene predictions within and among species. We showed that the numbers of essential gene orthologs comprise small fractions when compared with the total number of orthologs among the eukaryotic species studied. In addition, we demonstrated that machine-learning models trained with subsets of essentiality-related data performed better than random guessing of gene essentiality for a particular species. Consistent with our gene ortholog analysis, the predictions of essential genes among multiple (including distantly-related) species is possible, yet challenging, suggesting that most essential genes are unique to a species. The present work provides a foundation for the expansion of genome-wide essentiality investigations in eukaryotes using machine learning approaches. Keywords: Machine-learning, Essential genes, Essentiality prediction, Eukaryotes

Due to widespread drug resistance in parasitic nematodes, there is a need to develop new anthelmintics. Given the cost and time involved in developing a new drug, the repurposing of known chemicals can be a promising, alternative approach. In this context, we tested a library (n = 600) of natural product-inspired pesticide analogues against exsheathed third stage-larvae (xL3s) of Haemonchus contortus (barber's pole worm) using a whole-organism, phenotypic screening technique that measures the inhibition of motility and development in treated larvae. In the primary screen, we identified 32 active analogues derived from chemical scaffolds of arylpyrrole or fipronil. The seven most promising compounds, selected based on their anthelmintic activity and/or limited cytotoxicity, are arylpyrroles that reduced the motility of fourth-stage larvae (L4s) with significant potency (IC50 values ranged from 0.04 ± 0.01 μM to 4.25 ± 0.82 μM, and selectivity indices ranged from 10.6 to 412.5). Since the parent structures of the active compounds are uncouplers of oxidative phosphorylation, we tested the effect of selected analogues on oxygen consumption in xL3s using the Seahorse XF24 flux analyser. Larvae treated with the test compounds showed a significant increase in oxygen consumption compared with the untreated control, demonstrating their uncoupling activity. Overall, the results of the present study have identified natural product-derived molecules that are worth considering for chemical optimisation as anthelmintic drug leads. Keywords: Arylpyrrole, Fipronil, Haemonchus contortus, Anthelmintic, Drug discovery

Many freshwater snails of the genus Bulinus act as intermediate hosts in the life-cycles of schistosomes in Africa and adjacent regions. Currently, 37 species of Bulinus representing four groups are recognised. The mitochondrial cytochrome c oxidase subunit 1 (cox1) gene has shown utility for identifying and differentiating Bulinus species and groups, but taxonomic relationships based on genetic data are not entirely consistent with those inferred using morphological and biological features. To underpin future systematic studies of members of the genus, we characterised here the mitochondrial genome of Bulinus truncatus (from a defined laboratory strain) using a combined second- and third-generation sequencing and informatics approach, enabling taxonomic comparisons with other planorbid snails for which mitochondrial (mt) genomes were available. Analyses showed consistency in gene order and length among mitochondrial genomes of representative planorbid snails, with the lowest and highest nucleotide diversities being in the cytochrome c oxidase and nicotinamide dehydrogenase subunit genes, respectively. This first mt genome for a representative of the genus Bulinus should provide a useful resource for future investigations of the systematics, population genetics, epidemiology and/or ecology of Bulinus and related snails. The sequencing and informatic workflow employed here should find broad applicability to a range of other snail intermediate hosts of parasitic trematodes.

Despite advances in high-throughput sequencing and bioinformatics, molecular investigations of snail intermediate hosts that transmit parasitic trematodes are scant. Here, we report the first transcriptome for Bulinus truncatus – a key intermediate host of Schistosoma haematobium – a blood fluke that causes urogenital schistosomiasis in humans. We assembled this transcriptome from short- and long-read RNA-sequence data. From this transcriptome, we predicted 12,998 proteins, 58% of which had orthologs in Biomphalaria glabrata – an intermediate host of Schistosoma mansoni – a blood fluke that causes hepato-intestinal schistosomiasis. We predicted that select protein groups are involved in signal transduction, cell growth and death, the immune system, environmental adaptation and/or the excretory/secretory system, suggesting roles in immune responses, pathogen defence and/or parasite-host interactions. The transcriptome of Bu. truncatus provides a useful resource to underpin future molecular investigations of this and related snail species, and its interactions with pathogens including S. haematobium. The present resource should enable comparative investigations of other molluscan hosts of socioeconomically important parasites in the future.

Cryptosporidium is a group of protistan parasites of a range of vertebrates including mammals and birds. Stimulated by previous work that revealed “zoonotic” Cryptosporidium meleagridis subtypes (i.e. IIIbA26G1R1b and IIIbA22G1R1c) in diarrhoeic children and domestic chickens in Wuhan city and environs in Hubei Province, China, here we explored whether zoonotic C. meleagridis subtypes might also occur in pet birds in Wuhan city. From 11 bird markets in this city, we collected 322 faecal samples from 48 species of birds (representing six taxonomic orders), isolated genomic DNA and then conducted PCR-based sequencing of genetic markers in the small subunit (SSU) of the nuclear ribosomal RNA and the 60 kDa glycoprotein (gp60) genes of Cryptosporidium. Using SSU, Cryptosporidium was detected in 55 (17%) of the 322 samples. Cryptosporidium avium, C. baileyi, C. meleagridis, C. muris and C. proventriculi were characterised in 18%, 47%, 11%, 2% and 20% of the 55 samples, respectively, and a novel Cryptosporidium galli-like taxon in one sample. Using gp60, only one subtype (IIIeA17G2R1) of C. meleagridis was identified, which had not been detected in a previous study of diarrhoeic children in Wuhan. However, IIIe subtypes have been found in both humans and birds around the world. The relatively high prevalence and genetic diversity of Cryptosporidium recorded here in pet birds raise awareness about possible reservoirs of zoonotic variants of Cryptosporidium in birds in Wuhan, and potentially, other provinces in China.

Lipidomics is a relatively recent molecular research field, and explores lipids (fats) and their biology using advanced mass spectrometry technologies. Although this field has expanded significantly in biomedical and biotechnological disciplines, it is still in its infancy in molecular parasitology. Our goal here is to review and discuss technical aspects of MS-based lipidomics and its recent applications to parasitic worms, as well as challenges and future directions for worm lipid research. In a multi-omic paradigm, we expect that the exploration of lipidomic data for parasitic worms will yield important insights into lipid-associated biological pathways and processes, including the regulation of essential signalling pathways, parasite invasion, establishment, adaptation and development.

Summary: SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The Spike glycoproteins of SARS-CoV-2 mediate viral entry and are the main targets for neutralizing antibodies. Understanding the antibody response directed against SARS-CoV-2 is crucial for the development of vaccine, therapeutic, and public health interventions. Here, we perform a cross-sectional study on 106 SARS-CoV-2-infected individuals to evaluate humoral responses against SARS-CoV-2 Spike. Most infected individuals elicit anti-Spike antibodies within 2 weeks of the onset of symptoms. The levels of receptor binding domain (RBD)-specific immunoglobulin G (IgG) persist over time, and the levels of anti-RBD IgM decrease after symptom resolution. Although most individuals develop neutralizing antibodies within 2 weeks of infection, the level of neutralizing activity is significantly decreased over time. Our results highlight the importance of studying the persistence of neutralizing activity upon natural SARS-CoV-2 infection.