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Turner‚ Bird‚ Eratosthenes: an eternal burning thread
Get PDFFunctional programmers have many things for which to thank the late David Turner: design decisions he made in his languages SASL, KRC, and Miranda over the last 50 years are still influential and inspirational now. In particular, Turner was a strong advocate of lazy evaluation and of list comprehensions. As an illustration of these techniques, he popularized a one-line recursive “sieve” to generate the infinite list of prime numbers.
Turner called this algorithm The Sieve of Eratosthenes. In a lovely paper called “The Genuine Sieve of Eratosthenes”, Melissa O’Neill argued that Turner’s program is not in fact a faithful implementation of the algorithm, and gave a detailed presentation using priority queues of the real thing. She included a variation by Richard Bird, which uses only lists but makes clever use of circular programming. Bird describes his circular program again in his textbook “Thinking Functionally with Haskell”, and sets its proof of correctness as an exercise. In particular, why is this circular program productive? Unfortunately, Bird’s hint for a solution is incorrect. So what should a proof look like?
One of the last projects Turner worked on was the notion of “Total Functional Programming”. He observed that most programs are already structurally recursive or corecursive, therefore guaranteed respectively terminating or productive; he conjectured that “with more practice we will find this is always true”. We explore Bird’s circular Sieve of Eratosthenes as a challenge problem for Turner’s Total Functional Programming
Structural basis for the ligand-dependent activation of heterodimeric AHR-ARNT complex
Get PDFThe aryl hydrocarbon receptor (AHR) possesses an extraordinary capacity to sense and respond to a wide range of small-molecule ligands, ranging from polycyclic aromatic hydrocarbons to endogenous compounds. Upon ligand binding, AHR translocates from the cytoplasm to nucleus, forming a transcriptionally active complex with aryl hydrocarbon receptor nuclear translocator (ARNT), for DNA binding and initiation of gene expression programs that include cellular detoxification pathways and immune responses. Here, we examine the molecular mechanisms governing AHR’s high-affinity binding and activation by a diverse group of ligands. Crystal structures of the AHR-ARNT-DNA complexes, bound with each of six established AHR ligands, including Tapinarof, 6-formylindolo[3,2-b]carbazole (FICZ), benzo[a]pyrene (BaP), β-naphthoflavone (BNF), Indigo and Indirubin, reveal an unconventional mode of subunit assembly with intimate association between the PAS-B domains of AHR and ARNT. AHR’s PAS-B domain utilizes eight conserved residues whose dynamic rearrangements account for the ability to bind to ligands through hydrophobic and π-π interactions. Our findings further reveal the structural underpinnings of a ligand-driven activation mechanism, whereby a segment of the AHR protein undergoes a structural transition from chaperone engagement to ARNT heterodimer stabilization, to generate the transcriptionally competent assembly. Our results provide key information for the future development of AHR-targeting drugs
Health impact and economic evaluation of expanded program on immunization in China from 1974 to 2024: a modelling study
Get PDFBackground The Expanded Program on Immunization (EPI), initiated by WHO in 1974, is a cornerstone of public health. China's EPI covers more than a sixth of the world's population and includes eight routine vaccines with high coverage rates. This study aimed to estimate health and economic impacts of China's EPI over the past 50 years (1974–2024). Methods This study mathematically modelled the impact of all eight routine vaccines in China's EPI against eight pathogens (measles, pertussis, hepatitis B, tuberculosis, hepatitis A, Japanese encephalitis, meningitis A, and poliomyelitis) based on data availability and their substantial disease burden, particularly accounting for non-linearities in vaccine impact. Health and economic outcomes were determined using mathematical models between a counterfactual scenario without vaccination (vaccine coverage set to zero) and the current vaccination scenario (routine vaccination scheduled at age 0–6 years), based on calendar year and birth cohort approaches. The health impact of China's EPI from 1974 to 2024 was measured in the number of cases, deaths, and disability-adjusted life-years (DALYs) averted. Findings We estimated that China's EPI averted 703·02 million cases (95% credible interval 699·51–722·80) and 2·48 million deaths (2·14–2·97) in 1974–2024 based on the calendar year approach, equivalent to averting an estimated 160·22 million DALYs (145·05–196·99). Using the birth cohort approach, we predicted 707·41 million cases (703·93–727·03) and 7·01 million deaths (6·95–7·87) averted over the lifetime, corresponding to 279·02 million DALYs (265·78–316·12). From a societal perspective, the aggregated cost of vaccination was estimated to be US贜·06 billion (120·49–127·49), although the benefits amounted to ·85 billion (2359·38–2710·35). China's EPI yielded an aggregate benefit–cost ratio of 19·48 (18·82–22·08) from the societal perspective and 8·02 (7·64–8·80) from the provider's perspective. Interpretation China's EPI has shown remarkable health and economic achievements, contributing to worldwide EPI success in the past 50 years. Further investment in EPI is warranted to sustain coverage and expand vaccine inclusion in China and globally. Funding Beijing Natural Science Foundation. Translation For the Chinese translation of the abstract see Supplementary Materials section
Enteral and parenteral nutrition in patients with cancer: complication rates compared—updated systematic review and meta-analysis
Get PDFBackground: The aim of this systematic review and meta-analysis is to compare the complication rates of enteral nutrition (EN) (oral or tube feeding (TF)) and parenteral nutrition (PN) in patients with any cancer. Methods: A systematic review of the literature until 2024 was conducted, including randomised controlled trials comparing EN and PN with respect to one or more of four endpoints: (1) infection, (2) nutrition support complications, (3) major complications and (4) mortality. A meta-analysis was conducted to generate summary effect estimates. Analysis was stratified by paediatric (≤21 years old) versus adults (>21 years old) patients. Subgroup analyses were conducted, based on including patients with (vs without) protein–energy malnutrition (PEM) and type of EN. Cumulative meta-analysis and leave-one-out analysis was conducted. Type I error was set at 0.05. Results: 49 studies reporting on 6361 patients were included: 41 reported on adults and 8 on children. Among adults, the infection rate was higher for PN compared with EN (risk ratio=1.07, 95% CI: 1.00 to 1.14), with no differences in rates of nutrition support complications, major complications or mortality. Among children, there were no differences in all four endpoints. On cumulative meta-analysis, EN was overall marginally superior to PN for infection, although results fluctuated over time between superiority and no difference. Subgroup analysis found no differences in effects among patients with (vs without) PEM and patients provided with EN options of standard care versus TF. Discussion: From the perspective of complications, EN and PN are equivalent, with EN demonstrating marginal superiority for infection among adults
Astley's Amphitheatre and the early circus in England, 1768-1830
Get PDFFounded in Lambeth in 1768 by the ex-cavalry sergeant Philip Astley (1742-1814), Astley's was one of the first entertainments to mix traditional acrobatic feats with the new trick-riding in a ring, thus founding the modern circus. As the leading example of the artform, the permanent Amphitheatre just south of Westminster Bridge went on to be immortalised by Dickens and parodied by Punch, before closure in 1893. This thesis charts the formative years of the institution and its contribution to an important yet distinctly arcane popular genre whose story has hitherto chiefly been the province of specialists and dilettanti, rather than the object of systematic historical, cultural and aesthetic analysis.
The chapters introduce the main artistic and organisational developments at Astley's and its rivalry with the neighbouring Royal Circus. This brought a stage into the formula and resulted in the grand ‘hippodramas,’ or equestrian plays, of the nineteenth century. Subsequent investigations are made into a social and economic life which is belied by the circus’ later image of separatism; and Astley's early struggles with the law and, to a lesser extent, respectability. The second half is devoted to Astleian spectacle: firstly the key role of its overall presentation and marketing in the development of graphic design, theatre architecture and stagecraft; secondly its various ingredients from ‘high,’ ‘low’ and possibly archaic cultures; and thirdly the generally conservative and imperialistic view of the geographical, political and natural world that Astley's communicated with its socially wide-ranging audiences
Employment dynamics in a rapid decarbonization of the US power sector
Get PDFWe analyze the employment dynamics of a rapid decarbonization of the US power sector, reducing emissions by 95% before 2035. We couple an input-output model with an occupational mobility network and identify three labor market phases: “scale-up,” “scale-down,” and a long-term, low-carbon, “steady state.” During the scale-up (2023–2034), for every job lost in an industry, 12 new jobs are created elsewhere. However, few occupations see sustained growth throughout the transition. We predict that skill mismatches will create frictions during the transition, especially in the scale-down phase. Compared with the size and fluctuations of the US labor market, the impact of this transition is modest, particularly if the US increases exports of clean energy technologies to counteract the domestic scale-down phase. However, without proper planning, rapidly growing industries will struggle to find skilled labor during the scale-up phase, while displaced workers might struggle finding jobs during the scale-down phase
In-silico platform for the multifunctional design of 3D printed conductive components
Get PDFThe effective electric resistivity of conductive thermoplastics manufactured by filament extrusion methods is determined by both the material constituents and the printing parameters. The former determines the multifunctional nature of the composite, whereas the latter dictates the mesostructural characteristics such as filament adhesion and void distribution. This work provides a multi-scale computational framework to evaluate the thermo-electro-mechanical behaviour of printed conductive polymers. A full-field homogenisation model first provides the influence of material and mesostructural features (i.e., filament orientations, voids and adhesion between filaments). Then, a macroscopic continuum model elucidates the effects of thermo-electro-mechanical mixed boundary conditions. The in-silico multi-scale methodology is validated with extensive original multi-physical experiments and a functional application consisting of an electro-heatable printing cartridge. Overall, this work establishes the foundations to virtually break the gap between mesoscopic and macroscopic multifunctional responses in conductive components manufactured by additive manufacturing techniques
Machine learning for classifying chronic kidney disease and predicting creatinine levels using at-home measurements
Get PDFChronic kidney disease (CKD) is a global health concern with early detection playing a pivotal role in effective management. Machine learning models demonstrate promise in CKD detection, yet the impact on detection and classification using different sets of clinical features remains under-explored. In this study, we focus on CKD classification and creatinine prediction using three sets of features: at-home, monitoring, and laboratory. We employ artificial neural networks (ANNs) and random forests (RFs) on a dataset of 400 patients with 25 input features, which we divide into three feature sets. Using 10-fold cross-validation, we calculate metrics such as accuracy, true positive rate (TPR), true negative rate (TNR), and mean squared error. Our results reveal RF achieves superior accuracy (92.5%) in at-home CKD classification over ANNs (82.9%). ANNs achieve a higher TPR (92.0%), but a lower TNR (67.9%) compared with RFs (90.0% and 95.8%, respectively). For monitoring and laboratory features, both methods achieve accuracies exceeding 98%. The R2 score for creatinine regression is approximately 0.3 higher with laboratory features than at-home features. Feature importance analysis identifies the key clinical variables hemoglobin and blood urea, and key comorbidities hypertension and diabetes mellitus, in agreement with previous studies. Machine learning models, particularly RFs, exhibit promise in CKD diagnosis and highlight significant features in CKD detection. Moreover, such models may assist in screening a general population using at-home features—potentially increasing early detection of CKD, thus improving patient care and offering hope for a more effective approach to managing this prevalent health condition
