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Systems biology of Haemonchus contortus – Advancing biotechnology for parasitic nematode control
No full textParasitic nematodes represent a substantial global burden, impacting animal health, agriculture and economies worldwide. Of these worms, Haemonchus contortus – a blood-feeding nematode of ruminants – is a major pathogen and a model for molecular and applied parasitology research. This review synthesises some key advances in understanding the molecular biology, genetic diversity and host-parasite interactions of H. contortus, highlighting its value for comparative studies with the free-living nematode Caenorhabditis elegans. Key themes include recent developments in genomic, transcriptomic and proteomic technologies and resources, which are illuminating critical molecular pathways, including the ubiquitination pathway, protease/protease inhibitor systems and the secretome of H. contortus. Some of these insights are providing a foundation for identifying essential genes and exploring their potential as targets for novel anthelmintics or vaccines, particularly in the face of widespread anthelmintic resistance. Advanced bioinformatic tools, such as machine learning (ML) algorithms and artificial intelligence (AI)-driven protein structure prediction, are enhancing annotation capabilities, facilitating and accelerating analyses of gene functions, and biological pathways and processes. This review also discusses the integration of these tools with cutting-edge single-cell sequencing and spatial transcriptomics to dissect host-parasite interactions at the cellular level. The discussion emphasises the importance of curated databases, improved culture systems and functional genomics platforms to translate molecular discoveries into practical outcomes, such as novel interventions. New research findings and resources not only advance research on H. contortus and related nematodes but may also pave the way for innovative solutions to the global challenges with anthelmintic resistance
Converging Representations of Attention-Deficit/Hyperactivity Disorder and Autism on Social Media: Linguistic and Topic Analysis of Trends in Reddit Data
No full textBACKGROUND: Social media platforms have witnessed a substantial increase in mental health-related discussions, with particular attention focused on attention-deficit/hyperactivity disorder (ADHD) and autism. This heightened interest coincides with growing neurodiversity advocacy. The impact of these changes in the conceptualization of ADHD and autism, and the relationship between the 2 conditions, remains underexplored. OBJECTIVE: We aim to characterize and understand how the relationship between ADHD and autism has evolved in public discourse over the past decade and explore reasons for their growing alignment. METHODS: Using Reddit data from 2012 to 2022, we investigated the frequency of ADHD mentions in r/autism and autism mentions in r/ADHD, compared to commonly mentioned conditions. We analyzed user overlap between the 2 subreddits to track cross-subreddit discussions. Following this, we assessed changes in semantic similarity between ADHD and autism using Word2Vec embedding models, alongside commonly mentioned conditions. Finally, thematic changes in subreddit discussions were explored using BERT-based topic modeling across 2 time periods. RESULTS: Our analysis revealed that ADHD and autism have become progressively more associated across these multiple dimensions. In r/ADHD, there was a steep rise in the proportion of posts mentioning "autism" in 2021, overtaking "bipolar" and "OCD" (obsessive-compulsive disorder) to become the most frequently mentioned condition. Similarly, ADHD mentions increased steadily in r/autism, while the frequency of posts mentioning "OCD," "PTSD" (posttraumatic stress disorder), and "bipolar" remained stable and low. User overlap between these subreddits grew substantially beginning in 2020. Semantic analysis showed ADHD and autism becoming more closely related from 2019 onward, compared to other conditions. Last, topic modeling indicated growing thematic convergence in ADHD- and autism-related discussions, which reflected an increasing shared emphasis on the experiences of adults with ADHD and autism, challenges in accessing diagnostic assessments, and interpersonal difficulties. CONCLUSIONS: Our study clarifies how discourse around these 2 conditions has converged during a period when they have both attracted rising public attention. These findings contribute to wider discussions about the impacts of rising public interest in mental health concepts. They illustrate that public understandings of relationships between conditions are dynamic and changing in ways that diverge from diagnostic frameworks. Future research should continue investigating changing mental health conceptualizations on social media, as these dynamics are becoming increasingly important for the future of psychiatric practice
Exploiting dysregulated iron homeostasis to eradicate persistent high-grade serous ovarian cancer
No full textTreatments for high-grade serous ovarian cancer (HGSOC) are initially effective but most invariably fail. Although they can successfully suppress the bulk of the tumour cell population, residual cancer cells can enter alternative therapy-resistant cell fates highlighted by proliferative arrest. Understanding the nature of these fates and how cells may resume uncontrolled proliferation will lead to the development of new treatments for HGSOC. In this study, we examine the response of HGSOC cells to standard of care cisplatin chemotherapy and to the RNA Polymerase I transcription inhibitor CX-5461/Pidnarulex, two drugs that elicit a potent DNA damage response and growth arrest. Here, we identify that HGSOC cells exposed to these therapies show multiple hallmarks of therapy-induced senescence (TIS) and derive a core TIS gene expression signature irrespective of genetic background or senescence trigger. Given that TIS is a potentially escapable state, we have performed a focussed drug screen to identify drugs that eradicate senescent HGSOC cells. We identify that therapy-induced senescent HGSOC cells, including those with decreased sensitivity to senolytic drugs that inhibit the pro-survival protein BCL-XL, can be eliminated using drugs that induce ferroptosis, an iron-dependent form of cell death. Mechanistically, we demonstrate that senescent HGSOC cells have altered expression of regulators of iron metabolism leading to intracellular iron overload that underpins this targetable vulnerability. Together, we highlight elevated levels of iron as a TIS biomarker in HGSOC and the potential of inducing ferroptosis to eradicate residual HGSOC cells following initial therapy.10.1038/s41420-025-02716-
Hierarchically porous 3D-printed ceramic scaffolds for bone tissue engineering
No full textSacrificial templating offers the ability to create interconnected pores within 3D printed filaments and to control pore morphology. Beta-tricalcium phosphate (TCP) bone tissue engineering (BTE) scaffolds were fabricated with multiscale porosity: (i) macropores from direct ink writing (DIW, a material extrusion 3D printing technique), (ii) micropores from oil templating, and (iii) smaller micropores from partial sintering. The hierarchically porous scaffolds possessed a total porosity of 58-70 %, comprising 54-63 % interconnected open pores. The in vitro results demonstrated that scaffolds with macroporosity promoted human osteoblast growth more than scaffolds with only microporosity. The elongated pores from the capillary suspension filament microstructure induced greater cell spreading than the sphere-like pores from the emulsion. Overall, the hierarchically porous scaffold with capillary suspension TCP filaments provided a superior microenvironment for significantly higher cell viability and proliferation than the other scaffolds, including a poly(ε-caprolactone) (PCL) control, a material currently used clinically as porous BTE scaffolds. The cellular response was further enhanced when macropore size was in the range of 570-590 μm. Therefore, the hierarchically porous scaffolds in this study are promising as BTE scaffolds, and the reported process of DIW of oil-templated colloidal pastes is a feasible strategy with potential for further customization
Three-Dimensional Morphological Characterisation of Human Cortical Organoids Using a Customised Image Analysis Workflow
No full textSummary Statement: A tailored image analysis workflow was applied to quantify cortical organoid health, development, morphology and cellular composition over time. The assessment of cellular composition and viability of stem cell-derived organoid models is a complex but essential approach to understanding the mechanisms of human development and disease. Aim: Our study was motivated by the need for an image-analysis workflow, including high-cell content, high-throughput methods, to measure the architectural features of developing organoids. We assessed stem cell-derived cortical organoids at 4 and 6 months post-induction using immunohistochemistry-labelled sections as the analysis testbed. The workflow leveraged fluorescence imaging tailored to classify cells as viable and dying or non-viable and assign neuronal and astrocytic perinuclear markers to count cells. Results/Outcomes: Image acquisition was accelerated by capturing the organoid slice in 3D using widefield-fluorescence microscopy. This method used computational clearing to resolve nuclear and perinuclear markers and retain their spatial information within the organoid’s heterogeneous structure. The customised workflow analysed over 1.5 million cells using DAPI-stained nuclei, filtering and quantifying viable and non-viable cells and the necrotic-core regions. Temporal analyses of neuronal cell number derived from perinuclear labelling were consistent with organoid maturation from 4 to 6 months of in vitro differentiation. Overall: We have provided a comprehensive and enhanced image analysis workflow for organoid structural evaluation, creating the ability to gather cellular-level statistics in control and disease models
Roadmap on atomic-scale semiconductor devices
No full textSpin states in semiconductors provide exceptionally stable and noise-resistant environments for qubits, positioning them as optimal candidates for reliable quantum computing technologies. The proposal to use nuclear and electronic spins of donor atoms in silicon, introduced by Kane in 1998, sparked a new research field focused on the precise positioning of individual impurity atoms for quantum devices, utilising scanning tunnelling microscopy and ion implantation. This roadmap article reviews the advancements in the 25 years since Kane’s proposal, the current challenges, and the future directions in atomic-scale semiconductor device fabrication and measurement. It covers the quest to create a silicon-based quantum computer and expands to include diverse material systems and fabrication techniques, highlighting the potential for a broad range of semiconductor quantum technological applications. Key developments include phosphorus in silicon devices such as single-atom transistors, arrayed few-donor devices, one- and two-qubit gates, three-dimensional architectures, and the development of a toolbox for future quantum integrated circuits. The roadmap also explores new impurity species like arsenic and antimony for enhanced scalability and higher-dimensional spin systems, new chemistry for dopant precursors and lithographic resists, and the potential for germanium-based devices. Emerging methods, such as photon-based lithography and electron beam manipulation, are discussed for their disruptive potential. This roadmap charts the path toward scalable quantum computing and advanced semiconductor quantum technologies, emphasising the critical intersections of experiment, technological development, and theory
Multi-domain magnetic particles in speleothems as a proxy for past cave-stream flooding: A 33 kyr record from central North Island, Aotearoa New Zealand
No full textSpeleothems are a key archive for past terrestrial climate information due to their potential for long, continuous, high-resolution, precisely-dated proxy records. The concentration and grain-size distribution of allogenic magnetic minerals incorporated into speleothems can be used to reconstruct past hydrological regimes. We use principal component analysis of first-order reversal curves to characterise the magnetic minerals incorporated into a 33 kyr flowstone record from Aotearoa New Zealand. Three end members (EMs) represent (1) a component with a broad spectrum of grain sizes, similar to that found in the overlying soil (EM1); (2) a coarse multi-domain component, with grains ranging up to several hundred microns (EM2); and (3) a fine, single-domain to vortex component (EM3). We interpret EM1 and especially EM2 as proxies for cave stream flooding and EM3 as a proxy for soil erodibility and transport through infiltration or possibly aeolian processes. We find increased soil erodibility during the period 30-20 kyr BP, corresponding to the extended Last Glacial Maximum (eLGM). Flooding frequency is high during the periods 27-25 kyr BP and 9-0 kyr BP. eLGM flooding episodes as recorded in the flowstone may be enhanced by the deposition of the Kawakawa/Oruanui tephra, providing a rich source of magnetic material. This study shows the potential for coarse, multi-domain magnetic material incorporated in speleothems as a source of palaeoenvironmental information, especially in regions characterised by magnetite-rich soils and frequent, high-energy hydrologic events
Comparison of 5-Day Multidaily Neuronavigated Theta-Burst Sessions With 6-Week Standard Repetitive Transcranial Magnetic Stimulation (the Dutch Depression Outcome Trial): Protocol for a Randomized Controlled Trial.
No full textBACKGROUND: Novel therapies are crucial for patients with major depressive disorder, as more than 33% of patients do not respond to first-line treatments. A promising novel treatment strategy is an intensive 5-day course of personalized, functional connectivity-guided accelerated intermittent theta-burst stimulation (PAiT), modeled after the Stanford neuromodulation therapy protocol. This new form of repetitive transcranial magnetic stimulation (rTMS) may lead to higher remission rates in patients with treatment-resistant depression (TRD). However, it remains unclear how this accelerated strategy compares to the standard once-daily 10 Hz rTMS at inducing remission of depression. OBJECTIVE: This study aims to compare cost-effectiveness using the PAiT protocol and the standard 10 Hz rTMS in patients with TRD. METHODS: A total of 108 patients will be enrolled in this multicenter randomized controlled trial. Patients will receive stimulation over the left dorsolateral prefrontal cortex using either the PAiT protocol (10 sessions per day over 5 days, resulting in 50 sessions in total and 90,000 pulses) or standard 10 Hz rTMS (once daily for 6 weeks, resulting in 30 sessions in total and 90,000 pulses). Personalized targets will be identified in the accelerated intermittent theta-burst stimulation condition based on negative functional coupling between the subgenual anterior cingulate cortex and the dorsolateral prefrontal cortex. In the rTMS condition, the dorsolateral prefrontal cortex target locations are identified using the standard Beam-F3 method. In both conditions, coil placement is performed with neuronavigation, navigating either to the personalized functional connectivity target or the Beam-F3 location. Patients will undergo pre- and posttreatment functional magnetic resonance imaging scans, including cognitive and emotional tasks. Four follow-up assessments are scheduled at 7, 12, 26, and 31 weeks after baseline. We expect that the PAiT protocol is more cost-effective than the standard 10 Hz rTMS. RESULTS: Recruitment for this randomized controlled trial started in February 2024. As of December 2024, we had enrolled 31 patients; the last participant is expected to complete their posttreatment assessments in January 2027. CONCLUSIONS: To our knowledge, this study is the first clinical trial to compare the cost- effectiveness of PAiT to standard 10 Hz rTMS as treatment for patients with TRD. The results of our study will offer professionals evidence from a sufficiently powered trial to determine whether the PAiT protocol is more effective than standard high-frequency rTMS. Specifically, it will assess whether PAiT leads to a shorter treatment duration for depression and greater societal or occupational participation among patients with TRD. In addition, this trial will provide further insights into the underlying mechanisms related to treatment effect, the effects of rTMS or accelerated intermittent theta-burst stimulation on cognitive domains such as executive functioning and emotion, possible differences in side effects, long-term effects, and factors contributing to possible relapse. TRIAL REGISTRATION: ClinicalTrials.gov NCT05900271; https://clinicaltrials.gov/study/NCT05900271. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/70121
Φ-Space: continuous phenotyping of single-cell multi-omics data
No full textThe prevalence of single-cell multi-omics datasets calls for automated cell type annotation methods that can characterize novel cell states. We developed Φ-Space, a computational framework for the continuous phenotyping of single-cell multi-omics data. We adopt a highly versatile modeling strategy to characterize query cell identity in a low-dimensional phenotype space, defined by reference phenotypes. The phenotype space embedding enables various downstream analyses, including insightful visualizations, clustering, and cell type labeling. Φ-Space is applicable to a wide range analytical tasks beyond cell type transfer. Its ability to model complex phenotypic variations will facilitate biological discoveries from different omics types