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Economic trends in Qing China: A response to Rawski's bold claims
Full text linkThomas Rawski challenges recent quantitative studies that find declining Chinese GDP per capita during 1700–1850 and suggests that the error margins around the component series for per capita grain supply should be widened, which would make it possible to accommodate stagnation, growth or decline. We show that there are good reasons to reject Rawski's wider error margins. We also reject Rawski's claim that there has previously been a consensus view of eighteenth‐century Qing prosperity and demonstrate that trends in the other variables examined by Rawski tend to support declining per capita grain supply
Spatial Imbalance of Innate-like T-Cell Niches Underlies Clinical Trajectories in Psoriasis
Full text linkInnate-like T cells (iLTCs) are rapid sentinels at epithelial surfaces, yet their spatial organisation and tissue-linked programmes in psoriatic inflammation remain incompletely defined. Spatial transcriptomics from independent cohorts maps γδT and mucosal-associated invariant T cells (MAIT) niches across psoriatic skin and reveals sharply divergent skin-layer arrangements. Psoriatic plaques show expansion of both niches, with γδT transcriptional signatures present in dermis and epidermis and MAIT signatures strongly enriched in the epidermis. Their compartment-specific positioning is mirrored by distinct transcriptional activities that support dermal-sentinel behaviour for γδT-enriched niches and epithelial-retention programmes for MAIT niches. Clinical severity associates with opposite niche dynamics, marked by decreasing dermal γδT frequencies and increasing epidermal MAIT abundance. Functional profiles reinforce this divergence, as dermal γδT niches display rising exhaustion-associated features with greater severity, whereas epidermal MAIT niches show stronger inflammatory and proliferation-related signals. Peripheral CITE-seq profiling identifies parallel systemic patterns, with reduced γδT frequencies and increased MAIT frequencies in blood, along with exhaustion-associated features in γδT cells and MAIT-specific trafficking cues that align with their behaviour in psoriatic tissue. Together the findings define a spatially imbalanced γδT-MAIT axis in psoriatic inflammation that is linked to layer-specific organisation to local inflammatory cues, systemic immune engagement and clinical severity
Improved Safety of New MicroRNA-Regulated Oncolytic Coxsackievirus B3 Observed After Intravenous Administration in Colorectal-Tumor-Bearing Mice
Full text linkOncolytic coxsackievirus B3 (oCVB3) strain PD-H has shown potent oncolytic efficacy and a remarkable safety profile in the treatment of colorectal cancer in vivo after intratumoral (i.t.) injection. In this study, we investigated the safety and efficiency of PD-H following intravenous (i.v.) virus administration. When injected i.v. into Balb/C mice bearing subcutaneous Colon-26 tumors, PD-H led to slightly reduced tumor progression and a significant increase in animal survival, but it also caused multi-organ infection and tissue damage. To improve the safety profile of PD-H, we inserted microRNA target sites (miR-TS) of the heart-specific miR-1, pancreas-specific miR-375, liver-specific miR-122, and brain-specific miR-124 or the tumor-suppressor miR-145 into the genome of PD-H and generated the viruses PD-622TS and PD-145TS. Both viruses replicated similarly and induced cytotoxicity comparable to that of PD-H in the colorectal carcinoma cell lines Colon-26 and CT-26Luc. Their replication was inhibited in HEK293T cells transiently transfected with the cognate microRNAs. In vivo, i.v. administration of PD-145TS and PD-622TS to healthy Balb/C mouse resulted in significantly lower viral titers in the organs of mice and led to significantly less-intense pathological alterations compared to PD-H. PD-622TS injected i.v. into Balb/C mice with CT-26Luc-induced peritoneal carcinomatosis did not induce off-target alterations in normal organs, but it failed to induce a therapeutic effect. These data indicate that PD-H or microRNA-regulated PD derivatives exhibit only limited therapeutic efficacy following i.v. injection in colorectal tumor-bearing mice. However, the newly engineered microRNA-regulated PD-H variants demonstrate improved safety profiles
On the Deepest Search for Galactic Center Pulsars and an Examination of an Intriguing Millisecond Pulsar Candidate
Full text linkWe report the results of one of the most sensitive pulsar surveys to date targeting the innermost region of the Galactic center (GC) using the Robert C. Byrd Green Bank Telescope at X band (8–12 GHz) using data from the Breakthrough Listen initiative. In total, we collected 9.5 hr of data covering the wider ∼8′ diameter of the GC bulge, and 11 hr on the inner 1 .′ 4 region between 2021 May and 2023 December. We conducted a comprehensive Fourier-domain periodicity search targeting both canonical pulsars (CPs) and millisecond pulsars (MSPs), using constant and linearly changing acceleration searches to improve sensitivity to compact binaries. Assuming weak scattering, our searches reached luminosity limits of Lmin≈0.14mJykpc2 for CPs and Lmin≈0.26mJykpc2 for MSPs—sensitive enough to detect the most luminous pulsars expected in the GC. Among 5282 signal candidates, we identify an interesting 8.19 ms MSP candidate (dispersion measure (DM) of 2775 pc cm−3), persistent in time and frequency across a 1 hr scan at a flux density of Smin≈0.007mJy . We introduce a novel randomization test for evaluating candidate significance against noise fluctuations, including signal persistence via Kolmogorov–Smirnov tests and flux-versus-DM behavior. We are unable to make a definitive claim about the candidate due to a mixed degree of confidence from these tests and, more broadly, its nondetection in subsequent observations. This deepens the ongoing missing pulsar problem in the GC, reinforcing the idea that strong scattering and/or extreme orbital dynamics may obscure pulsar signals in this region
Early individualized risk prediction using clinical data for children during the febrile phase of dengue in outpatient settings in Vietnam and Thailand
Full text linkDengue severity prediction models are usually developed using hospitalized patient data, but triage and hospital admission are mainly evaluated in outpatient settings. This study developed models using clinical and laboratory data from patients in outpatient settings during the febrile phase. Data from two cohort studies in Vietnam and Thailand were used to develop and validate six models: logistic regression with warning signs, Lasso-selected logistic regression, random forest, extreme gradient boosted classification, support vector machine, and artificial neural network. Models predicted dengue shock syndrome (DSS) as the primary endpoint and moderate plasma leakage and/or DSS as the secondary endpoint. We assessed model performance, discrimination, and calibration, using sensitivity, specificity, accuracy, Brier score, AUROC, CITL, calibration slope, calibration plots, and decision curve analysis. The optimal model was the Lasso-selected logistic regression for predicting DSS and the combined endpoint of moderate plasma leakage and/or DSS (Brier score: 0.044 [95% CI 0.043, 0.044] and 0.104 [95% CI 0.104, 0.105]; AUROC: 0.789 [95% CI 0.787, 0.791] and 0.741 [95% CI 0.740, 0.742]). We identified hematocrit, platelet count, lymphocyte count, and aspartate aminotransferase as predictors for DSS, and abdominal pain or tenderness, vomiting, mucosal bleeding, white blood cell count, lymphocyte count, platelet count, aspartate aminotransferase, and serum albumin as predictors for the secondary endpoint. Logistic regression and machine learning models using clinical and laboratory data during the febrile phase can support early prediction of severe disease in outpatient settings. Integrating risk prediction models into a decision support system could improve triage and optimize healthcare and resource allocation in endemic and resource-limited areas
Overpartitions with parts separated by parity
Full text linkIn this article, we generalize Andrews’ partitions separated by parity to overpartitions in two ways. We investigate the generating functions for overpartition families whose parts are separated by parity, and we prove various q-series identities for these functions. These identities include relations to modular forms, q-hypergeometric series, and mock modular forms
AI needs physics more than physics needs AI
Full text linkArtificial intelligence (AI) is commonly depicted as transformative. Yet, after more than a decade of hype, its measurable impact remains modest outside a few high-profile scientific and commercial successes. The 2024 Nobel Prizes in Chemistry and Physics recognized AI’s potential, but broader assessments indicate the impact to date is often more promotional than technical. We argue that while current AI may influence physics, physics has significantly more to offer this generation of AI. Current architectures—large language models, reasoning models, and agentic AI–can depend on trillions of meaningless parameters, suffer from distributional bias, lack uncertainty quantification, provide no mechanistic insights, and fail to capture even elementary scientific laws. We review critiques of these limits, highlight opportunities in quantum AI and analogue computing, and lay down a roadmap for the adoption of ‘Big AI’: a synthesis of theory-based rigour with the flexibility of machine learning
Sir Roy Calne: a renaissance man of modern medicine
Full text linkIt is a challenging task to encapsulate the prolific life and accomplishments of Sir Roy Calne, a unique individual and pioneer who transformed the impossible into clinical reality, forging a new era of organ transplantation. In the annals of medical history, few figures embody the intersection of science and humanity as did Sir Roy Calne. A pioneering transplant surgeon, scientist, accomplished artist, visionary leader, and devoted family man, Calne's multifaceted legacy continues to influence both medical science and the arts, demonstrating how these two fields can intersect to advance human understanding and compassion. Sir Roy Calne died peacefully in Cambridge on January 6, 2024, leaving behind a legacy that continues to define the field of transplantation
Influence of Hydrogen‐Incorporation on the Bulk Electronic Structure and Chemical Bonding in Palladium
Full text linkPalladium hydride is a model system for studying metal‐hydrogen interactions. Yet, its bulk electronic structure has proven difficult to directly probe, with most studies to date limited to surface‐sensitive photoelectron spectroscopy approaches. This work reports the first in situ ambient‐pressure hard X‐ray photoelectron spectroscopy (AP‐HAXPES) study of hydrogen incorporation in Pd thin films, providing direct access to bulk chemical and electronic information at elevated hydrogen pressures. Structural characterization by in situ X‐ray diffraction and neutron reflectometry under comparable conditions establishes a direct correlation between hydrogen loading, lattice expansion, and electronic modifications. Comparison with density functional theory (DFT) reveals how hydrogen stoichiometry and site occupancy govern the density of occupied states near the Fermi level. These results resolve long‐standing questions regarding PdH and establish AP‐HAXPES as a powerful tool for probing the bulk electronic structure of metal hydrides under realistic conditions
The impact of accessory receptors on T cell activation by chimeric antigen receptors
Full text linkT-cells can be redirected against novel targets, such as cancer cells, by engineering them to express alternative antigen recognition machinery in the form of chimeric antigen receptors (CARs). Despite promising results in treating blood cancers, their efficacy is limited and this has partly been traced to their poor antigen sensitivity. The reason for this is unclear. We show that CARs have a 46–2800 fold lower sensitivity than the T-cell receptor (TCR) when antigen is presented by antigen presenting cells (APCs) but have a similar 0.83–3.5 fold change in sensitivity when antigen is presented as purified protein in isolation. By systematically adding purified ligands to other, accessory, receptors expressed on CD8+ T cells, we identify that the CD2 and LFA-1 co-signalling receptors dramatically improve TCR antigen sensitivity (125 and 22-fold respectively) but not CAR antigen sensitivity (<5-fold). We found that CAR antigen sensitivity can be improved by fusing the CAR variable domains to the CD3ε subunit of the TCR (a TRuC), and restored to TCR levels by exchanging the variable regions of the TCRαβ chains with those of a CAR (a STAR). These improvements are predicted by the improved ability of these receptors to exploit CD2 and LFA-1. The binding of CD2 to its ligand CD58 is thought to improve antigen recognition by precisely aligning membranes to the ∼14 nm spanned by the TCR/pMHC interaction. We hypothesised that the CAR/antigen interaction may have a size incompatible with CD2/CD58 and therefore, engineered a panel of elongated CD2 receptors. We find that the antigen sensitivity increases by elongating CD2, with a different elongated CD2 being optimal for different antigen receptors. Taken together, CARs display a large defect in antigen sensitivity by their inefficient exploitation of the CD2 and LFA-1 interaction and engineered CD2 molecules can rescue their antigen sensitivity