Browse Articles

TRECing down the source: naive and memory T cell generation in dirty mice and men

Abstract Healthy aging relies on the maintenance of a diverse T cell pool. This diversity is ensured by balancing thymic output, differentiation of naive into memory T cells, T cell proliferation and cell death. For naive T cells, the balance of these processes differs between standard laboratory mice and humans. This may be a true species difference or, alternatively, result from the vastly different amounts of antigens to which standard laboratory mice and humans are exposed. Using wildlings, that is, laboratory mice born to wild mice, we studied the impact of antigen-exposure through a natural microbiome on naive and memory T cell maintenance. We found that standard laboratory mice and wildlings maintain their naive T cell pools similarly: naive T cells rarely divide and are replaced by thymic emigrants at similar rates. The daily replacement rate of memory T cells, on the other hand, is about 50% faster in wildlings than in standard laboratory mice. In both types of mice, about 20% of newly produced memory T cells originate from recruitment of naive T cells, while the remaining cells are produced by their clonal expansion and by self-renewal. In older mice, this drops to 5%. In humans, a similarly large fraction of memory cells originate from recruitment of naive T cells. Unlike in mice, most naive T cells in human adults are formed by naive T cell proliferation. Thus, while both types of mice mimic the maintenance mechanisms of the memory T cell pool in humans, even wildlings fall short as a model for human naive T cell maintenance.

Phase-specific climatic sensitivities of under-five malaria in Ghana using epidemic modelling, NB-GAMs and SHAP explainability

Abstract Malaria transmission in Ghana remains perennial and climate-sensitive, yet the long-term transmission phases underlying disease progression and their differential climatic sensitivities are poorly understood. This study delineated latent, accelerated, and delayed phases of under-five malaria transmission and evaluated the phase-specific influence of rainfall and temperature on malaria incidence, severity, and mortality. Monthly under-five malaria incidence, severe admissions, and malaria-attributed deaths recorded in Tarkwa-Nsuaem Municipality, Ghana, from January 2013 to December 2023 (132 months) were linked with municipality-wide rainfall and temperature data. Epidemic phases were identified using logistic growth modelling and changepoint detection. Incidence, severity, and mortality trajectories were characterized using logistic, exponential–quadratic, and saturating epidemic functions, respectively. Climatic associations were evaluated using phase-specific negative binomial generalized additive models (NB-GAMs) with cyclic seasonal smooths. Model robustness was assessed through bootstrap resampling, cross-validation, basis-dimension diagnostics, and extreme-rainfall sensitivity analyses. SHapley Additive exPlanations (SHAP) were used to quantify predictor importance. The cumulative incidence trajectory exhibited an asymptotic burden of 115,052 cases (95% CI 107,390–125,844), with an inflection point at approximately 75 months and a growth scale of 23.9 months. Severe malaria declined rapidly, reaching functional decline around month 44, whereas mortality exhibited a slower decline, with functional reduction occurring near month 90. Climatic effects varied across transmission phases. Incidence was most climate-sensitive during the accelerated phase, where both temperature and rainfall were strongly associated with malaria transmission during this phase. Sensitivity analyses demonstrated that the accelerated-phase temperature association remained statistically significant after exclusion of extreme-rainfall months, indicating a robust climatic signal, whereas rainfall associations remained statistically detectable in the expanded-k incidence model but demonstrated greater sensitivity to extreme-rainfall observations than the corresponding temperature associations. Severe malaria showed no consistent climatic associations across alternative model specifications. Mortality exhibited temperature sensitivity primarily during the accelerated phase, with limited evidence of rainfall effects. SHAP analyses identified transmission phase, rainfall, and temperature as the most influential predictors of model-predicted incidence. Under-five malaria transmission in Tarkwa-Nsuaem follows distinct latent, accelerated, and delayed phases characterized by differing climatic sensitivities. Temperature demonstrated a stable association with transmission during the accelerated phase, whereas rainfall effects were strongly dependent on extreme hydrological conditions. The integration of epidemic phase delineation, phase-specific NB-GAMs, and explainable machine learning provides a robust framework for identifying climate-sensitive transmission periods and may inform phase-targeted malaria surveillance, preparedness, and intervention planning.

Fluid shear stress as a co-stimulatory cue to enhance T cell priming and restore activation in cancer patient T cells

Abstract Cancer patient-derived T cells often exhibit impaired activation and functional responsiveness due to chronic antigen exposure and therapy-induced immune dysregulation, limiting the efficacy of current immunotherapies. Mechanical forces, such as fluid shear stress (FSS), are emerging as critical regulators of immune cell activation, yet their role in modulating activation of patient-derived T cells remains largely unexplored. In this study, primary T cells isolated from patients with metastatic prostate cancer were exposed to FSS using a cone-and-plate viscometer during ex vivo activation in the presence and absence of bead-bound anti-CD3/CD28 monoclonal antibodies. FSS alone was sufficient to induce NF-κB phosphorylation and intracellular cytokine synthesis, demonstrating that mechanical stimulation can independently initiate T cell activation signaling. Moreover, FSS combined with anti-CD3/CD28 stimulation produced a synergistic increase in activation signaling, IL-2 and IFN-γ production, and CD25/CD69 expression. While trends were consistent across donors overall, inter-patient variability reflected differences in baseline T cell phenotype, with naïve-like cells displaying greater mechanosensitivity. These results indicate that cancer patient-derived T cells retain mechanotransduction capacity despite reduced antigen responsiveness. Incorporating FSS as a co-stimulatory signal during ex vivo expansion may be more effective at priming patient T cells for activation, enhancing effector function, and improving the efficacy of adoptive cell therapies.

The self-positivity bias of large language models

Abstract This study aims to investigate the self-positivity bias effect of large language models (LLMs) under different prompting conditions, compare differences in their response patterns when simulating AI versus participant roles, and examine the impact of social comparison on the self-evaluation of large models. Using a self-referential paradigm, large language models were required to generate self-referential descriptions in the role of AI and participant, assessing their self-association with positive and negative words. Additionally, different social comparison scenarios (no comparison, upward comparison, and downward comparison) were set up to observe changes in the self-positivity bias of the models under various contexts. The study found that large language models exhibited self-positivity bias when simulating both AI and humans, assigned higher scores to positive trait words and lower scores to negative trait words in self-referential evaluation. However, when simulating humans, the models assigned higher scores for negative trait words. The results of social comparison further revealed that large models simulating AI were not affected by social comparison, while models in human simulation tended to rate positive words as more self-descriptive and negative words as less self-descriptive, especially after no comparison and downward comparison compared to upward comparison, consistent with human social comparison experiences. Large language models can simulate human self-positivity bias, but there are cognitive differences between simulating AI and humans, and the social comparison effect is only observed when simulating humans. These findings provide important insights into the response characteristics of large models in self-referential tasks and their similarities and differences with human psychology.

Energy-efficient and secure routing in IoMT using FG-WHO-BWOA optimization with blockchain techniques

Abstract The Internet of Medical Things (IoMT) has numerous prospective applications for remote health monitoring in the medical field. The two main issues that significantly affect IoMT’s performance are end-to-end latency and energy efficiency. An energy-efficient architecture and reliable packet communication are necessary for design and implementation of an application. It is very crucial to transmit accurate packet with real time and reliable manner. A cluster-based and energy-efficient routing protocol using the Blockchain-enabled joint trust (FG-WHO-BWOA) method in IoMT has been presented to address these problems. It finds the network’s optimal cluster head (CH) and ensures secure packet communication. Here, the firefly and grey wolf optimization (FG-WHO) technique is applied to precisely pick CH. The vulnerable or malicious node appears in a cluster following the selection of CH. In order to identify the trusted path among the various routes, the multi-objective Beluga Whale Optimization Algorithm (BWOA) is suggested. Finally, the block chain receives the optimal chosen trust channels for safer and more reliable network transmission. Castalia Simulator is used to perform the simulation. High throughput, high efficiency, long network lifetime, high packet delivery ratio, low latency, low consumption of energy, low packet loss ratio and security are all attained by the suggested FG-WHO-BWOA. The performance validates that, in contrast to the current approaches, the mentioned strategy performs better.

Agentic formative assessment for object oriented programming through multi source evidence aggregation

Beyond majority voting: a new framework for evaluating AI diagnostic systems against expert consensus

Refining ammonia inventories through top-down inverse modelling in high-density swine farming regions

Coordinated charge-discharge scheduling of large-scale EVs in V2G scenarios

Retraction Note: Prediction of uniaxial compressive strength of limestone from ball mill grinding characteristics using supervised machine learning techniques

Characterization of hepatocellular carcinoma patient-derived organoids from patients receiving transarterial chemoembolization as a model for preclinical drug response assessment

Abstract Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and is often diagnosed at an intermediate stage in patients with chronic liver disease. Transarterial chemoembolization (TACE) is the first-line treatment in this setting. However, drug response remains variable and optimal chemotherapeutic selection unresolved. Idarubicin (IDA) has previously demonstrated antitumor activity comparable to doxorubicin (DOX), with improved emulsion stability and membrane permeability. 3D patient-derived organoids (PDOs) have also recently emerged as physiologically relevant systems that recapitulate tumor characteristics and inter-patient heterogeneity more accurately than conventional 2D cell cultures. In this study, we characterized HCC PDOs and investigated their utility as an ex vivo model to assess therapeutic responses. We generated organoids from tumor and non-tumor liver biopsies collected from HCC patients prior to TACE-treatment. PDOs partially preserved tumor architecture and phenotypic features. IDA exposure resulted in a concentration-dependent reduction in organoid growth, with marked inter-patient variability in drug response. Comparative analyses showed that IDA was more potent than DOX, with lower IC₅₀ values across all patient-derived samples. IDA also induced transcriptional changes associated with cellular stress, inflammation, and proliferation pathways. However, ex vivo drug‑sensitivity testing in PDOs did not correlate with clinical response to TACE. These findings confirm the feasibility of generating HCC PDOs and using them to evaluate differential sensitivity to TACE‑associated chemotherapeutic agents ex vivo, although their ability to predict clinical efficacy remains unproven. While IDA exhibited greater cytotoxic activity than DOX in organoid cultures, this observation was based on in vitro sensitivity assays and does not establish clinical superiority. Furthermore, the absence of correlation between PDO drug sensitivity and clinical TACE response indicates that PDO-based prediction of treatment outcome remains challenging in this setting.

Hybrid reinforcement learning and attention mechanism framework for intelligent fault diagnosis of rolling element bearings

The significance of turbulent coherent structures on the initiation and evolution of sub-orbital ripples

Abstract Motivated by the observation of vortices generated by ripples, numerous studies have focused on how vortex dynamics drive sediment transport and shape ripple geometry. However, during ripple initiation from a flat bed and for low-steepness ripples, such vortices are absent. Turbulent coherent structures (TCS), in contrast, exist within the boundary layer regardless of ripple steepness. This study investigates the role of TCS in ripple initiation and evolution under oscillatory flows using fully coupled three-dimensional Eulerian two-phase large-eddy simulations performed with SedFoam . The results show that TCS initiate ripple marks through localized pockets of turbulent sweep events, supporting the hypothesis that TCS drive ripple initiation from a flat bed. Quadrant analysis further reveals a strong preferential coupling between ejection (sweep) events and particle upward (downward) motion, demonstrating how TCS organize local sediment mobilization and redistribution during ripple initiation. The resulting ripple marks initially exhibit a cross-hatched pattern and subsequently evolve into quasi-two-dimensional rolling-grain ripples. Quantitative analyses further support the hypothesis that sub-orbital ripple evolution involves a transition from TCS-dominated initiation to increasingly wave-orbital-controlled growth and equilibrium development as ripple dimensions exceed the turbulence integral length scale. These findings provide new insights into the mechanisms governing sub-orbital ripple evolution and may help improve the prediction of low-steepness ripple geometry in coastal environments.

Development of an investigational medicinal stem cell gene therapy product to attempt curing human immunodeficiency virus infection

Abstract For most people living with Human immunodeficiency virus (HIV), virus control and sufficient immune function can be achieved with polypharmacotherapy. A minority is intolerant to thereto, and drug-resistant mutants are emerging. Additionally, people living with HIV (PLWH) have significantly higher risk of cardiovascular morbidity and malignant diseases. HIV is in principle immunogenic. If T-cell depletion could be avoided immunological HIV eradication should be achievable. The “Berlin patient” in whom allogeneic stem cell transplantation from a CCR5Δ32/Δ32 donor induced long-term remission without antiviral therapy raised the hope that stem cell gene therapy with CCR5-deleted autologous stem cells could provide a cure, but the strategy did not live up to expectations. We propose to test an alternative strategy, namely expression of a designer recombinase which specifically excises HIV provirus from the genome under a Tat-inducible promoter so that expression is restricted to infected cells. A cGMP-compliant manufacturing protocol and quality control strategy for this investigational medicinal product was developed, validated, and a manufacturing authorization obtained. A First-in-Human-clinical trial, testing engraftment, repopulation of peripheral specific immunity, and ability to control HIV infection without antiviral medication is in preparation. Protocols can be adapted to other stem cell gene therapies by transferring alternative lentviral cargo.

Unsupervised dietary-behavioral profiling identifies PFAS (per- and polyfluoroalkyl substances) and metal exposure patterns in Korean adults

Abstract Beyond “what and how much you eat,” modern nutritional epidemiology is paying attention to how dietary and behavioral patterns, which combine food selection and the context of cooking, packaging, and ingestion, organize health and environmental exposure. This cross-sectional secondary analysis used adult data from the 4th Korea National Environmental Health Survey (KoNEHS Cycle 4, 2018–2020; n  = 4239). Multi-question variables related to diet, cooking, packaging, and ingestion behaviors were mapped into a latent space through unsupervised learning, clusters were derived, and the exposure levels of PFAS, bisphenols, urinary cadmium, and blood lead biomarkers were compared by cluster. As a result, serum PFAS concentrations were higher in the “basic diet/seafood propensity” cluster, with weighted geometric means ranging from 10.998 to 21.767 µg/L for PFOS and from 5.082 to 8.323 µg/L for PFOA across clusters. In the “packaging/contact propensity” cluster, higher PFOA was observed in the adjusted analysis, while blood lead showed an elevated direction but was not robust after FDR correction. On the other hand, the differences between clusters for bisphenols and urinary cadmium were not robust when considering covariates and multiple comparisons, suggesting the possibility that the variability of single urine measurements, uncertainty in exposure assessment, and complexity of indicator characteristics may have affected the results. This study provides an empirical basis for identifying population-level dietary-behavioral exposure profiles and informing targeted risk communication by showing how lifestyle-based dietary and behavioral structures are associated with environmental exposure patterns before directly linking dietary patterns with diseases.

Recipient Endothelial IRF1 mediates IFNγ-driven tissue tolerance in mouse models of acute Graft-versus-Host Disease.

Recipient endothelial cells (ECs) actively respond to inflammation during allogeneic hematopoietic cell transplant (allo-HCT), yet mechanisms by which ECs influence acute graft-versus-host-disease (GVHD) pathology remain incompletely defined. Single cell RNA-sequencing of ECs isolated from a GVHD target organ, the liver, showed rapid, subset-specific transcriptional reprogramming after allo-HCT, with induction of canonical interferon-γ (IFNγ)-inducible genes including interferon regulatory factor 1 (IRF1), MHC II, and PD-L1 in lymphatic ECs (LECs). In allo-HCT recipients, circulating IFNγ peaked on day 4 (early), decreased but remained elevated at day 14 (late), and declined by day 21, with a concordant induction of IRF1+ LECs in the liver and GI tract. IFNγ neutralization with anti-IFNγ monoclonal antibody at either early or late time points attenuated IRF1⁺MHCII⁺PD-L1⁺ LEC activation. Notably, early donor T cell expansion was IFNγ-independent, whereas late IFNγ blockade selectively impaired donor Treg, but not Th1, expansion, leading to accelerated GVHD. Using in vitro LEC-CD4 T cell co-cultures and allo-HCT in Irf1-/- bone marrow chimera recipients, we show that recipient ECs that cannot mediate IFNγ-IRF1 signaling exhibit reduced activation and apoptosis, but also have impaired Treg expansion, increased donor Th1/Treg ratios, and worsened GVHD severity. Finally, pharmacological JAK inhibition in allo-HCT recipient mice spares IRF1+ LECs and Tregs while reducing pathogenic Th1 cells, correlating with reduced GVHD severity and improved survival. Our findings identify a role for the lymphatic endothelial IFNγ-IRF1 axis in regulating early vascular remodeling, donor T cell mediated tolerance, underscoring a potential "goldilocks" level of pathway activation required to improve post-transplant outcomes.

Retraction Note: A novel malignant mesothelioma organoids-T cell co-culture platform for personalized immunochemotherapy testing

Boosting anti-leukemia cytotoxicity of CD4 and CD8 T cells through combined inhibition of MEK and HDAC

Acute myeloid leukemia (AML) is an aggressive blood cancer with a 5-year overall survival rate of ~30%. Although immunotherapies engaging T cells demonstrate remarkable success in treating many solid tumors and blood cancers, they show little to no efficacy in treating AML. Therefore, immunotherapies are traditionally underappreciated and underdeveloped in AML. Through a drug re-purpose screen, we identified and validated that combined MEK and HDAC inhibitions via trametinib and quisinostat (TQ) potently inhibited the growth of mouse and human NRAS;ASXL1-AML (NA-AML), MLLr, and NPM1 mutated AML cells in vitro. In NA-AML mice, TQ drastically slowed down AML progression and prolonged their survival. The survival benefits of TQ largely relied on T cell functions. We show that TQ synergized to downregulate immune checkpoint ligands and upregulate STAT1- and CIITA-mediated expression of MHC-I and MHC-II in NA-AML cells. In addition, TQ treatment significantly reprogrammed transcriptome and epigenetic landscape of T cells, activated STAT1 signaling, and upregulated genes and pathways promoting activation, survival, and cytotoxicity of CD4 and CD8 T cells. A cytotoxic cluster was thus expanded in central memory and effector memory T cells in TQ-treated NA-AML mice. More importantly, TQ directly acted on AML-associated mouse and human T cells, reverting them from a dysfunctional state to an active state. In leukemia:T cell co-cultures, TQ-treated T cells demonstrated greatly improved MHC-dependent leukemia killing. Our findings suggest that the dual actions of TQ on NA-AML and T cells enhance leukemia recognition and anti-leukemia killing of endogenous T cells, leading to effective AML clearance.

Spatial patterns and factors associated with suicide death among individuals with suicide attempts in northern Iran

Functional restoration of immune defects in STAT1 gain-of-function disease following stem cell gene editing

Germline gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) gene cause a dominantly inherited inborn error of immunity (IEI) characterized by chronic mucocutaneous candidiasis, autoimmunity, severe opportunistic infections and an increased risk of malignancy. Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is curative but is associated with increased risk of morbidity and mortality in STAT1 GOF patients compared to other IEI. To develop a curative, autologous alternative to HSCT, we evaluated gene editing strategies in STAT1 GOF model cell lines, primary T cells, and patient-derived HSCs. Universal and mutation-specific strategies using CRISPR/Cas-mediated homology-directed repair (HDR) were limited by low efficacy (<25%), poor viability, and a lack of allele-specificity. In contrast, adenine base editing corrected the recurrent and highly pathogenic p.T385M mutation with upwards of 90% efficiency in patient T cells and HSCs without significant unintended on- or off-target genomic aberrations. Gene editing functionally restored total STAT1 expression (p<0.0217), STAT1 phosphorylation (p<0.0056), interferon-stimulated gene expression (OAS1; p=0.0005) and improved IL-17 production (p<0.0001). Edited HSCs retained multilineage differentiation capacity and sustained engraftment with persistence of the corrected allele at 16 weeks in humanized immunodeficient mice. These data demonstrate efficient and precise correction of STAT1 GOF mutations by base editing, with maintenance of the correction through long-term engraftment in vivo. This represents the first application of gene editing to correct a dominant gain-of-function mutation causing immunodeficiency, with potential applicability to other genetic disorders associated with heterozygous and gain-of-function mutations.