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History, Identity, and Ownership in Mathematics
Get PDFExpanded text of lectures at the congress of the Pacific Rims Mathematics Association in Vancouver (December, 2022), the Topos Institute (November, 2023), the meeting of the European Research Centres of Mathematics in Edinburgh (March, 2024), and the International Center for Theoretical Sciences in Bengaluru (September, 2024)
NIR light-accelerated bioorthogonal drug uncaging and photothermal ablation by anisotropic Pd@Au plasmonic nanorods
Get PDFSelective activation of chemotherapeutics at the tumor site via bioorthogonal catalysis is a promising strategy to reduce collateral damage to healthy tissues and organs. Despite significant advances in this field, targeted drug activation by transition-metal catalysts is still limited by insufficient spatiotemporal control over the metal-mediated uncaging process. Herein, we report the development of anisotropic Pd@Au plasmonic nanorods with the capacity to accelerate dealkylation reactions under near-infrared (NIR) irradiation, thereby enabling precise control over when and where these catalytic devices are switched on. We also show that the stability and in cellulo chemical properties of Pd@Au nanorods are enhanced by Au–S functionalization with PEGylated phospholipids and report the development of a novel masking group for prodyes and prodrugs: the POxOC group, designed to improve physicochemical properties and the rate of the Pd-triggered dye/drug release process. NIR-photoactivation of lipo-Pd@Au nanorods is able to catalyze the uncaging of inactive drug precursors and release heat to the environment, killing cancer cells in culture and xenografted in zebrafish. This work provides a novel targeted strategy for photothermal chemotherapy by NIR-laser focalization
Crossover With Wideband Operation and High Isolation Using Anisotropy and Polarization-Sensitive Image Guides
Get PDFThis article presents a novel dielectric image guide crossover that exploits the engineered uniaxial anisotropic properties of subwavelength dielectric gratings for millimeter-wave (mmWave) and sub-terahertz (sub-THz) applications. The proposed structure exploits polarization differences in the dominant mode of orthogonal channels, utilizing anisotropic features to achieve a compact, high-isolation, and wideband crossover. Optimized parameters demonstrate competitive performances, including an ultrawide 30 dB isolation bandwidth from 22 to over 50 GHz, low insertion loss (~0.5 dB), and minimal group delay variations (~0.04 ns), and to the best of the authors’ knowledge, this is the first implementation of such an mmWave crossover. The design is highly versatile, adaptable to various frequency ranges and waveguide technologies, and compatible with CMOS fabrication, making it well-suited for next-generation radio frequency (RF) systems such as 6G. A fabricated prototype validates the analytical studies conducted via the finite-difference frequency-domain (FDFD) method and full-wave simulations. The combination of high isolation, low loss, compact size, minimal group delay variation, and wideband operation makes this crossover a promising solution for mmWave and sub-THz crossover circuit systems and other high-density transmission line (TL) scenarios
British Society of Gastroenterology guidelines on colorectal surveillance in inflammatory bowel disease
Get PDFPatients with inflammatory bowel disease (IBD) remain at increased risk for colorectal cancer and death from colorectal cancer compared with the general populationdespite improvements in inflammation control with advanced therapies, colonoscopic surveillance and reductions in environmental risk factors. This guideline update from 2010 for colorectal surveillance of patients over 16 years with colonic inflammatory bowel disease was developed by stakeholders representing UK physicians, endoscopists, surgeons, specialist nurses and patients with GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodological support. An a priori protocol was published describing the approach to three levels of statement: GRADE recommendations, good practice statements or expertopinion statements. A systematic review of 7599 publications, with appraisal and GRADE analysis of trials and network meta-analysis, where appropriate, was performed. Risk thresholding guided GRADE judgements. We made 73 statements for the delivery of an IBD colorectal surveillance service, including outcomestandards for service and endoscopist audit, and the importance of shared decision-making with patients. Core areas include: risk of colorectal cancer, IBD-relatedpost-colonoscopy colorectal cancer; service organisation and supporting patient concordance; starting and stopping surveillance, who should or should not receive surveillance; risk stratification, including web-based multivariate risk calculation of surveillance intervals; colonoscopic modalities, bowel preparation, biomarkers and artificial intelligence aided detection; chemoprevention; the role of non-conventionaldysplasia, serrated lesions and non-targeted biopsies; management of dysplasia, both endoscopic and surgical, and the structure and role of the multidisciplinary team in IBD dysplasia management; training in IBD colonoscopic surveillance, sustainability (green endoscopy), cost-effectiveness and patient experience. Sixteen research priorities are suggested
Dynamic change of calcium-rich compartments during coccolithophore biomineralization
Get PDFCoccolithophores are abundant marine phytoplankton that produce biomineralized calcite scales, called coccoliths, which sequester substantial amounts of carbon and play a substantial role in biogeochemical cycles. However, mechanisms underlying the storage and transport of ions essential for calcification remain unresolved. We used ptychographic x-ray computed tomography under cryogenic conditions to visualize intracellular calcium-rich structures involved in the storage of calcium ions in the coccolithophore species Chrysotila carterae. During calcification, we observed a range of structures, from small electron-dense bodies within larger compartments to denser and distributed globular compartments, before returning to small bodies once scale formation is complete. Nanobeam-scanning x-ray fluorescence measurements further revealed that these electron-dense bodies are rich in phosphorus and calcium (molar ratio of ~4:1). The dynamic nature of structures suggests that these bodies are part of the required cellular calcium ion transport pathways, a fundamental process critical for understanding the response of coccolithophores to climate change
Freedom without Responsibility: How Government Ignored Engineering Competence whilst Deregulating Fire Safety Regulation in the 1980s
Get PDFProfessional status rests upon a social contract in which society allows specialists to monopolise certain roles on the understanding that they will do so ethically and with appropriate competence. Mechanisms to police such behaviour can be left to professional groups to organise or be legislated for by government, or some combination of the two. In the UK an opportunity to formalise the professional status of engineers arose with the publication of the Finniston Report in 1980. Its calls for a statutory authority to regulate the engineering professions found an unreceptive audience in a government committed to shrinking the state, and arguments for professional registration and licencing as a mechanism to ensure engineering competence were strongly opposed by the Health and Safety Executive. This in turn had serious consequences for the emerging field of fire safety engineering—and for the UK built environment more generally—because the Building Act 1984 offered building designers a new freedom to develop first principles solutions without providing any mechanism to ensure their competence. This paper describes and analyses the three key historical episodes at the heart of this development.</p
Pharmacy Homeless Outreach Engagement Non-medical Independent Prescribing Rx (PHOENIx) community pharmacy-based pilot randomized controlled trial
Get PDFRandomized controlled trials (RCTs) aiming to address the multiple health and social challenges of people experiencing homelessness (PEH) are lacking. Here we report the findings from a multicenter, open, pilot RCT. The intervention involved independent prescriber pharmacist from the National Health Service working on outreach in partnership with dedicated workers from Homeless Voluntary Charity or Social Enterprises (HVCSEs) (Pharmacist and third sector charity worker integrated Homeless Outreach Engagement Non-medical Independent prescriber Rx’-PHOENIx) in low threshold HVCSE venues or temporary accommodation addressing PEH participants’ health and wider needs through repeated outreach. The trial aimed to investigate whether sufficient numbers of participants could be recruited, retained, the intervention delivered as planned, and sufficient data collected to inform a subsequent definitive RCT. Clinical outcomes were also collected at follow-up (6 months). Participants were recruited from five community pharmacies and nearby venues in urban centers of Glasgow-Scotland and Birmingham-England, then randomized one-to-one into PHOENIx intervention in addition to usual care (UC) or UC only. A priori progression criteria were achieved: 55% of those assessed as eligible were recruited; at 6 months, 72% remained in the study, 91% had emergency department and mortality data available, and 72% completed questionnaire booklets. Fifty-three percent of participants received at least 50% of the planned PHOENIx intervention consultations (in-person or phone) at 6 months. Signs of improvement in clinical outcomes in the PHOENIx group included fewer ambulance call-outs, ED visits, and hospitalizations; higher outpatient attendances; and higher scores on self-reported health-related quality of life. A definitive RCT is merited.</p
The political economy of investment protection reform in South American PTAs
Get PDFIn South America, investment chapters have been used by some governments, notably in Chile, Colombia and Peru, to replace outdated bilateral investment treaties and extend countries’ investment protection commitments. In other countries, such as Brazil, investment chapters are a means to rethink the governance of foreign investment altogether. This chapter traces the evolution of South America’s PTA investment chapters from 2001 to 2022, focusing on the types of reforms adopted and the domestic factors that shape the reforms governments are willing to accept. It finds that PTA investment chapters exhibit an increasing diversity of reforms over time, although the vast majority of agreements are designed to maintain traditional investment protection standards. This variation is partly driven by the legitimacy crisis of international investment law. Arguably, this crisis has created more political space for South American preferences in investment treaty lawmaking. However, who dominates reform debates is just as important for countries’ reform preferences as their experience with investor-state arbitration. Regardless of reform preferences, the main outcome of PTA investment chapters has been further fragmentation in an already complex and incomplete area of international economic law. This fragmentation, if allowed to continue, may exacerbate the very challenges that governments are seeking to address through their reform efforts in order to promote sustainable and inclusive development
Regarding the existence of the internal language model in CTC-based E2E ASR
Get PDFSome End-to-End (E2E) Automatic Speech Recognition (ASR) models, such as Attention-based Encoder-Decoder (AED) and Recurrent Neural Network Transducer (RNN-T) are known to have components that effectively act as internal language models (ILM), implicitly modelling the prior probability of the output sequence. However, the existence of an ILM in pure Connectionist Temporal Classification (CTC) ASR systems remains debated. In this paper, we investigate the existence and strength of an ILM in CTC systems. Since CTC posterior probabilities cannot be analytically factorised, we propose a novel empirical method to probe the ILM. After validating our method on a hybrid DNN model with various external language models, we apply it to CTC models trained under different conditions, examining the effects of training data, modelling units, and training or pre-training methods. Our results show no strong evidence of an ILM in CTC-based ASR systems, even with the largest training dataset in our experiments. However, we make the surprising finding that when a CTC encoder is jointly trained with an AED loss, an ILM emerges, even when only the CTC component is used in decoding
Cancer-associated fibroblast driven paracrine 1 IL-6/STAT3 signaling promotes migration and dissemination in invasive lobular carcinoma
Get PDFBACKGROUND: Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer after invasive ductal carcinoma of no special type (NST), accounting for 10-15% of diagnoses. Despite the myriad molecular, histological and clinical differences between ILC and NST tumors, patients are treated in the same way, and although prognosis initially is good, ILC patients have poorer long-term outcomes. Understanding the differences between these two subtypes and identifying ILC-enriched therapeutic targets is necessary to improve patient care.METHODS: Human and mouse cancer-associated fibroblasts (CAFs), ILC cell lines and patient-derived organoids were used for in vitro and in vivo studies, including western blotting, migration, organotypic invasion assays and dissemination in zebrafish embryos. RNASeq was used to identify CAF and interleukin-6 (IL-6)-derived gene signatures. Bioinformatic analysis of public databases and immunohistochemical of human tumor microarrays was carried out.RESULTS: We identified IL-6 as a paracrine CAF-derived factor that activates Signal-Transducer-and-Activator-of-Transcription-3 (STAT3) in human and mouse ILC models. Analysis of human breast tumors showed that the IL-6/JAK/STAT3 pathway is enriched in ER + ILC compared to ER + NST. A 42-gene CAF dependent IL-6 gene signature and 64-gene consensus IL-6 gene signature were generated and were significantly enriched in ER + ILC, with many of the genes overexpressed in ILC tumors. IL-6 treatment suppressed downstream estrogen signaling and also led to the acquisition of a more mesenchymal-like phenotype associated with increased migration and invasion. Finally, IL-6 treatment significantly increased ILC cell dissemination following injection into zebrafish embryos.CONCLUSIONS: CAF-derived IL-6 drives paracrine activation of the IL6/JAK/STAT3 signaling pathway which is enriched in ILC. This leads to the acquisition of pro-tumorigenic phenotypes, highlighting the pathway as a potential therapeutic target in ILC.</p
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