Fibre optic magnetic field sensor based upon double long period fibre grating cascade and Galfenol rod

Human walking involves tightly coordinated movements of the right and left legs. We recently developed and tested a "dynamic treadmill walking" paradigm that changes the treadmill speed within a single step to provide asymmetric training for persons with gait dysfunction. We previously demonstrated that this approach could induce changes in human gait symmetry; however, if this approach is to be used in rehabilitation, we also need to understand how movements of the legs are coordinated to produce these asymmetric gait changes. The goal of this study was to examine the temporal (phase shift) and spatial (center of oscillation difference) aspects of interlimb coordination during dynamic treadmill walking in 10 young adults without gait impairment. We found that dynamic treadmill walking drove significant changes in phase shift and center of oscillation difference that were dependent on the timing of the treadmill speed change within the gait cycle. For example, slowing the treadmill during the stance phase extended the double limb support period, and these changes were strongly correlated with a phase shift between the two legs. Accelerating the treadmill late in stance led to extensions in the trailing limb angle that were strongly correlated with changes in the center of oscillation difference. Overall, dynamic treadmill walking can be configured to drive changes in many spatiotemporal, kinematic, and interlimb coordination parameters, creating a variety of options for restoring gait symmetry and targeting aspects of spatial and temporal interlimb coordination in clinical populations with heterogenous patterns of gait asymmetry.NEW & NOTEWORTHY Dynamic treadmill walking has been previously shown to drive asymmetric gait changes, but little is known about its effect on interlimb coordination. Here, we find that this approach induces significant changes in interlimb coordination (relative to normal walking) in both spatial and temporal domains. Altogether, dynamic treadmill walking offers a customizable gait rehabilitation strategy for asymmetric gait training that can induce changes in interlimb coordination using only a single-belt treadmill.

Engineering a genomically stable porcine myogenic cell line for serum-free cultured meat production.

The scalability of cultivated meat production depends on cost-effective, edible scaffolds that support attachment, proliferation and differentiation of adherent cells whilst meeting food safety and sensory requirements. However, most existing microcarriers are synthetic or of animal-origin, limiting their compatibility with food applications, increasing downstream processing costs, and raising ethical and environmental concerns associated with animal use. For the first time, we present mycelia-based microcarriers derived from food-grade Penicillium strains used in cheese production, as scaffolds for cultivated meat. Eight strains, including novel variants developed through non-GMO techniques (sexual breeding and ultraviolet mutagenesis), were screened for cytotoxicity using bovine adipose-derived stem cells. Out of these, four strains (P. camemberti Myc1; P. roqueforti Myc2, Myc3 and Myc4) were selected for further evaluation based on non-cytotoxic behaviour, ease of handling and pellet size comparable to commercial microcarriers. Morphological characterisation revealed that these strains form highly porous, fibrous pellets with estimated specific surface areas of approximately 4400–5100 cm2/g, providing a favourable architecture for cell growth. All four microcarriers supported strong initial cell attachment, meeting or exceeding industry benchmarks for mesenchymal stem cells in both serum-containing and animal-free media. Growth kinetics diverged between strains, with Myc3 and Myc4 displaying the highest growth rates (≥2-fold increase; μ ≈ 0.015 h−1), and doubling times of 47–48 h. These findings highlight the great promise of fungal pellets for the development of edible scaffolds for cultivated meat production, helping to address a central bottleneck in bringing affordable, high-quality protein to consumers.

Effect of [68Ga]Ga-PSMA-11 PET-CT in the diagnosis of prostate cancer in men with equivocal or clinically high-risk non-suspicious findings on multiparametric MRI (PRIMARY2): a multicentre, non-inferiority, phase 3, randomised controlled trial.

This study aimed to externally validate the European Association of Urology (EAU) biochemical recurrence (BCR) risk stratification in a North American population after radical prostatectomy (RP) and radiation therapy (RT), where validation remains lacking despite prior European and Asian validation. We identified all patients with BCR after RP or RT between 1995 and 2023 from a North American institutional database and classified them by EAU criteria. Primary outcome was prostate cancer-specific mortality (CSM). We calculated Harrell's concordance indices (C-index) and used competing-risk regression to assess associations between EAU risk groups and CSM, comparing performance to multivariable models including age, clinical stage, Gleason grade, PSA doubling time and time to BCR. Among the 940 patients (646 RP, 294 RT; 40.5% African American), 563 (59.9%) had low-risk and 377 (40.1%) high-risk BCR. The 10-year cumulative incidence of CSM was 3.6% versus 12% for low-risk versus high-risk RP patients and 18.4% versus 49.5% for low-risk versus high-risk RT patients. EAU high-risk BCR was associated with increased CSM in both groups (RP: HR 2.83, 95% CI 1.47-5.46; RT: HR 3.98, 95% CI 2.43-6.53). The EAU classification showed moderate discrimination (Harrell's C-index 0.62 for RP, 0.69 for RT). Multivariable models including clinical variables demonstrated a Harrell's C-index of 0.76 for both RP and RT. This first North American validation confirms moderate EAU discriminative ability. For RP patients, low 10-year CSM in low-risk BCR (3.6%) supports surveillance. However, low-risk RT BCR showed substantial CSM (18.4%), exceeding high-risk RP (12%), suggesting current criteria inadequately stratify risk after RT.

We aimed to generate a HepG2 cell clone stably overexpressing cytochrome P450 (CYP) 2C9 together with an empty vector (EV) control cell clone for pharmacological and toxicological studies of substances with CYP2C9-mediated biotransformation. A new HepG2 cell clone was generated by lentiviral transduction to functionally overexpress human CYP2C9. We found high CYP2C9 transcript and protein levels based on qRT-PCR, Western blot and immunofluorescence in the cell clone. Most importantly, specific enzyme activities of 62.9 ± 2.6 pmol 4-hydroxydiclofenac/min/106 cells as analyzed by diclofenac conversion via liquid chromatography-mass spectrometry were found in HepG2-CYP2C9 cells. CYP2C9 enzyme activity could successfully be inhibited by the application of the pan-CYP inhibitor 1-aminobenzotriazole or the CYP2C9-specific inhibitor sulfaphenazole. No changes in morphology or population doubling times were detected when comparing the clone to parental HepG2 cells. The corresponding EV control cell line was detected negative for CYP2C9 expression in all experimental setups and did not show any difference to the parental HepG2 cells. Thus, the newly established HepG2-CYP2C9 cell line is an appropriate tool to study metabolism and toxicity of substances depending on conversion by CYP2C9.

Tongue squamous cell carcinoma (TSCC) is the most prevalent and aggressive subtype of oral squamous cell carcinoma (OSCC), with a high incidence of lymph node metastasis even in early stages. The five-year overall survival rates remain low, around 50% in advanced stages. Cell line models are essential tools to understand the complexity of TSCC and develop new therapies. However, most commercially available TSCC cell lines are derived from patients with a history of tobacco use or have unknown exposure backgrounds. We established two novel TSCC cell lines, LMSCC03 and LMSCC16, derived from non-smoking and treatment naïve Brazilian patients. These cell lines were characterized by doubling time, 3D culture (spheroids and organoids), tumorigenicity through xenotransplantation in nude mice, immunohistochemical expression of key OSCC biomarkers and drug response. Genetic identity was confirmed by STR profiling. LMSCC03 and LMSCC16 displayed epithelial morphology and pan-cytokeratin staining. They demonstrated in vitro capacity to form spheroids and organoids, and generated tumors in vivo. STR profiling confirmed their novelty relative to existing cell lines in the DSMZ database. Protein analysis revealed high p53 nuclear levels in LMSCC16 cells. Interestingly, CD44 and c-Myc expression were observed only in fibroblast-enriched cultures, but not in the epithelial LMSCC03 and LMSCC16 cells. LMSCC16 also harbored two TP53 mutations and showed increased resistance to Cisplatin and Paclitaxel compared to established TSCC cell lines. Cisplatin treatment in spheroids reduced OCT4, CCND1, CCNB1, and CDH1 gene expression in LMSCC03. In contrast, LMSCC16 showed significant modulation of OCT4, increased CCND1 and CCNB1 expression, and reduced CDH1 levels following treatment. We established two novel TSCC cell lines that represent clinically relevant models to explore TSCC carcinogenesis and therapeutic responses, particularly in non-smoking populations.

Fibroblast activation protein (FAP)-targeted radionuclide therapy is a promising approach for patients with advanced or metastatic medullary thyroid carcinoma (MTC). This study evaluates efficacy, safety, and survival outcomes of [177Lu]/[225Ac]-DOTAGA.Glu.(FAPi)₂ therapy in this population. Nineteen patients with progressive MTC were treated with either [¹⁷⁷Lu]Lu-DOTAGA.Glu.(FAPi)₂ or [²²⁵Ac]Ac-DOTAGA.Glu.(FAPi)₂, receiving a median of 5 cycles. The median cumulative activity administered was 20.3 GBq (Lu) and 6.66 MBq (Ac) and the median follow-up was 21 months. Of the 17 evaluable patients, radiological response was assessed in 15 patients using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The analysis demonstrated a partial response (PR) in 33% of patients, stable disease (SD) in 47%, and progressive disease (PD) in 20%, resulting in a disease control rate (DCR) of 80%. Positron emission tomography response criteria in solid tumors (PERCIST) evaluation (n = 15) showed 47% PR, 40% SD, and 13% PD. Biochemical response was evaluable in 14 patients: 64.2% showed stable or decreasing tumor markers. Median calcitonin doubling time was 6.7 months. Clinical progression occurred in 2 patients. Median PFS was 26 months; median OS was 42 months. No statistically significant difference in OS was observed between progression and non-progression groups (log-rank p-0.758). No Grade 4 or life-threatening toxicities were observed. Only two patients experienced Grade 3 adverse events-one with elevated alkaline phosphatase and one with worsening anemia. All other hematologic and biochemical toxicities were limited to Grade 1-2. [177Lu]/[225Ac]-DOTAGA.Glu.(FAPi)₂ therapy shows encouraging disease control, acceptable safety, and preliminary efficacy signals such as increased survival in the treated patients of advanced MTC.

This study analyzes relative motion dynamics for formation flying in cislunar space using the Bicircular Restricted Four-Body Problem (BCR4BP), incorporating solar gravitational attraction and Solar Radiation Pressure (SRP). Numerical simulations across Halo, Lyapunov, DRO, DPO, and LPO orbit families reveal that the stability and growth of relative motion are fundamentally determined by the choice of chief reference orbit. Solar gravity is the dominant mechanism, reducing the Lyapunov exponent by up to 91% for LPOs and L₂ Halos (enabling passive formation flying with λ ≈ 0.026-0.034day-1, final separation ≤ 6km, doubling time ≈ 20-26 days) while increasing it by over 1,000% for DROs (causing catastrophic divergence to 108-1011 km). SRP plays a secondary role, modifying λ by at most 30%. Critically, the CR3BP is fundamentally misleading: it overestimates DRO stability by six orders of magnitude and underestimates LPO/L₂ Halo stability by similar margins. The BCR4BP is not an optional refinement but an operational necessity for correct orbit selection, accurate stability assessment, and fuel-efficient formation flying mission design in the Earth-Moon system.

We investigated the real-world criteria and thresholds physicians use to classify patients with nonmetastatic castration-sensitive prostate cancer with biochemical recurrence as high risk, and how these align with guidelines. Descriptive analyses were conducted using data abstracted from an independent, retrospective, cross-sectional survey completed by urologists and radiation oncologists in the USA between April and November 2023. Physicians provided their perspectives and extracted chart data for the last 6-8patients they diagnosed with high-risk biochemical recurrence. The cohort included 87 physicians (79% urologist, 21% radiation oncologist), who reported data for 460 patients. Physicians believed in using multiple factors for risk stratification, notably prostate-specific antigen doubling time (94%), absolute prostate-specific antigen rise following definitive therapy (89%), and Gleason score (87%). Over half named prostate-specific antigen doubling time as the most important factor. Physicians used a median (interquartile range) prostate-specific antigen doubling time threshold of 6.0 (6.0-9.0) months when identifying patients with high-risk biochemical recurrence. At the patient level, prostate-specific antigen doubling time (58%), Gleason score (44%), and absolute prostate-specific antigen rise following definitive therapy (43%) were the most frequently reported factors used for determining high-risk biochemical recurrence in the real world. Physicians use multiple clinical factors to identify high-risk biochemical recurrence. These factors generally align with guidelines. However, physicians generally used a more restrictive prostate-specific antigen doubling time threshold than many guidelines recommend. Discrepancies present an opportunity for further education, potentially expanding the pool of patients with high-risk biochemical recurrence who may benefit from recent advances in management.

Isolation, characterization and evaluation of growth kinetics and multilineage differentiation of ovine ovarian mesenchymal stem cells.

Antibody-drug conjugates (ADCs) are complex molecules, and many fail clinically despite promising preclinical data. Here, a modular, bottom-up modeling strategy employing mechanistic PK-PD models was developed to translate ADC efficacy and toxicity from bench to bedside and to guide ADC design. The models handle various antigens, payloads, and ADCs, validated using six ADCs (Enhertu, Kadcyla, Trodelvy, RC48, RN927C, and Datroway). Using determined cellular distribution of payloads/ADCs, payload killing parameters, and systemic parameters (assay volume, cell doubling time), ADC in vitro potency was predicted with 94.64% accuracy within a 2-fold range. Incorporating ADC and payload pharmacokinetic parameters enables prediction of in vivo efficacy comparable to cell line- and patient-derived xenograft data from the literature. Scaling parameters from mouse to human (PK, tumor volume, and tumor doubling time) led to the reproduction of clinical efficacy trends. Beyond efficacy, the approach predicts key hematologic toxicities such as neutropenia and thrombocytopenia, demonstrated for Kadcyla and Enhertu. Application to the clinically failed RN927C demonstrated how our modeling approach could have flagged issues and enabled suggestions for design modifications to widen the therapeutic window and prevent the clinical failure. In conclusion, our presented modeling strategy delivers accurate efficacy and toxicity translation from in vitro to humans utilizing easily accessible parameters as the foundation and deepens understanding of ADCs and their individual components, thereby supporting ADC design and candidate and patient selection and accelerating ADC development.

Incidence and lung cancer probability of new nodules in the UK lung screening trial.

Dental pulp is a valuable source of mesenchymal stem cells (MSCs), offering significant promise for cell therapy and regenerative medicine, particularly in treating oral and dental conditions. For clinical translation, understanding which dental stem cell source provides superior proliferative and differentiation capacity for specific tissue regeneration (bone vs. dentin) is essential. This study aimed to compare the gene expression profiles and osteogenic potential of MSCs derived from permanent (DPSCs) and deciduous (SHED) teeth. DPSCs and SHED were isolated and characterized using flow cytometry. Their differentiation potential into bone and fat cells was assessed, along with colony formation, doubling time (DT), cell viability, alkaline phosphatase (ALP) activity, and the expression of stemness genes (SOX2, OCT4, NANOG) and differentiation genes (OCN, DSPP, AMBN, SPARC, IBSP). SHEDs showed higher colony formation (33.66 vs. 28.33) and shorter doubling time (33.13h vs. 39.25h) compared to DPSCs. Importantly, SHEDs exhibited significantly higher ALP activity after osteogenic induction, confirming their superior early osteogenic differentiation potential. SHEDs also expressed stemness genes (OCT4, NANOG, SOX2) and osteogenic markers (AMBN, OCN) at higher levels, while DPSCs showed higher expression of odontogenic markers (DSPP, SPARC, IBSP). Overall, SHEDs in this study showed greater proliferative capacity, faster doubling times, and enhanced early osteogenic potential compared to DPSCs, whereas DPSCs showed stronger odontogenic differentiation potential. These findings suggest that SHEDs may be more suitable for bone and enamel-like tissue regeneration, while DPSCs are better suited for dentin-pulp complex repair, providing a rationale for stem cell selection in regenerative dentistry.

Bone metastases represent a devastating complication of primary cancers, significantly impacting patient survival and quality of life. Accelerating the development of novel and effective chemotherapeutic drugs requires reliable in vitro models. Current in vitro models largely rely on conventional 2D set-ups, while 3D spheroid cultures are emerging. However, the correlation between these 2D and 3D configurations regarding chemotherapeutic efficacy remains poorly defined due to discrepancies in cellular assessment methodologies. To achieve a direct, unconfounded comparison of cellular responses to cisplatin treatment, identical analytical assays were deployed across both 2D and 3D culture models. Cisplatin sensitivity was comparatively evaluated in metastatic human cancer cell lines (PC3 prostate adenocarcinoma and MDA-MB-231 breast adenocarcinoma) cultured in conventional 2D monolayers versus biomaterial-free 3D spheroids. Proliferation and viability assays were used to assess cytotoxicity, with human Bone Marrow Stromal Cells (hBMSCs) as non-malignant controls. Additionally, the effects of acute (24-hour) versus continuous cisplatin exposure regimens on cellular behavior were examined, and drug sensitivity was subsequently correlated with cell doubling time. For all cell types, 3D spheroid cultures exhibited significantly lower sensitivities to cisplatin compared to 2D cultures. This is likely related to both the dimensionality of the 3D spheroids, as evidenced by time- and concentration-dependent cisplatin penetration into hBMSC spheroids, and cell proliferation, as a correlation between cisplatin sensitivity and cell doubling time was observed across the various cell types used. Finally, we showed that continuous exposure to cisplatin affects cell viability in 2D and 3D culture models in a manner comparable to limited exposure during the initial 24 hours of culture, and that cisplatin sensitivity correlates with cell doubling time. Methodological similarities in analyzing cell viability were maintained for both 2D and 3D cell culture models when exploring cisplatin. Their dimensionality hampers penetration of cisplatin into the core of 3D spheroids. Overall, our data underscore the dependence of cisplatin sensitivity on the dimensionality of in vitro models (2D vs. 3D.

Aging impairs stem cell function, diminishing tissue regeneration. Dental pulp-derived mesenchymal stem cells (DPSCs) hold significant regenerative potential but are susceptible to senescence. Natural compounds like essential oils (EOs) offer low-toxicity strategies to enhance stem cell function. This study evaluated the in vitro senescence-modulating effects at the cellular level effects of Pistacia atlantica subsp. mutica green hull essential oil (PaEO) on senescent DPSCs. PaEO was extracted via hydrodistillation and characterized by GC-MS, identifying 22 major components (e.g., limonene, linalool, thymol, α/β-pinene). DPSCs were isolated from healthy third molars, cultured, and treated with varying PaEO concentrations. MTT assay and population doubling time (PDT) assessed viability and proliferation. Senescence-associated β-galactosidase (SA-β-gal) staining quantified senescent cells. Real-time PCR measured telomere-related genes (TRF1, RAP1). PaEO treatment significantly enhanced DPSC viability and proliferation dose-dependently. The highest concentration (1000µg/mL) increased viability by 18% and reduced senescent cells (SA-β-gal positive) by 19.9%. Furthermore, PaEO upregulated the expression of TRF1 and RAP1 genes, indicating improved telomere maintenance and genomic stability. Pistacia atlantica subsp. mutica essential oil exhibits potent anti-senescence effects on DPSCs. It enhances cell viability and proliferation, reduces senescence markers, and modulates telomere-related gene expression. These findings suggest that PaEO exerts senescence-modulating effects at the cellular level in DPSCs. Further in vivo and clinical studies are warranted to validate these promising in vitro results.

King grass is a fast-growing C4 perennial with high biomass potential, yet its productivity is limited by cold stress. WRKY transcription factors (TFs) regulate abiotic stress responses, but their roles in king grass cold adaptation remain unclear. WRKY TFs were identified genome-wide using BLASTP and HMMER, followed by phylogenetic classification, transcriptome profiling, promoter cis-element analysis, weighted gene co-expression network analysis (WGCNA), molecular docking, and yeast heterologous expression assays. Sixty-two PsiWRKY genes were identified and classified into three groups. Time-series transcriptome analysis across nine cold-stress time points revealed four expression patterns, with 29 genes significantly induced (> 2-fold), mainly during late acclimation (48-72h). qRT-PCR confirmed RNA-seq trends (R² = 0.742). Functional enrichment and WGCNA analyses indicated that cold-responsive PsiWRKYs coordinate abscisic acid-gibberellin antagonism and sugar metabolism. Molecular docking predicted interactions between PsiWRKY proteins and Calvin cycle enzymes, with PsiWRKY16 and PsiWRKY55 showing the highest structural confidence (pTM > 0.75). Network analysis identified PsiWRKY16 and PsiWRKY50 as hub regulators linking GA signaling genes (GID1/DELLA) with sugar metabolism enzymes such as GAPDH and PRK. Yeast assays quantitatively confirmed enhanced cold tolerance, as heterologous expression of PsiWRKY16 reduced doubling time by 0.56h and increased area under the curve and carrying capacity by 26.20 and 3.39, respectively, while PsiWRKY50 increased these values by 14.45 and 1.43. Promoter analysis showed enrichment of ABRE and DRE elements (p = 0.00061), and integrative target prediction identified 193 genes co-regulated by WRKY and CBF pathways, supporting ABA-CBF signaling convergence. PsiWRKYs exhibit subgroup-specific and time-resolved responses to cold stress. PsiWRKY16, PsiWRKY50, and PsiWRKY55 are implicated in coordinating hormonal signaling and metabolic reprogramming, providing candidate targets for cold-tolerant breeding in king grass.

In May 2022, mpox (formerly monkeypox) spread to non-endemic countries rapidly. Human judgment is a forecasting approach that has been sparsely evaluated during the beginning of an outbreak. We collected-between May 19, 2022 and July 31, 2022-1275 forecasts from 442 individuals of six questions about the mpox outbreak where ground truth data are now available. Individual human judgment forecasts and an equally weighted ensemble were evaluated, as well as compared to a random walk, autoregressive, and doubling time model. We found (1) individual human judgment forecasts underestimated outbreak size, (2) the ensemble forecast median moved closer to the ground truth over time but uncertainty around the median did not appreciably decrease, and (3) compared to computational models, for 2-8 week ahead forecasts, the human judgment ensemble outperformed all three models when using median absolute error and weighted interval score; for one week ahead forecasts a random walk outperformed human judgment. We propose two possible explanations: at the time a forecast was submitted, the mode was correlated with the most recent (and smaller) observation that would eventually determine ground truth. Several forecasts were solicited on a logarithmic scale which may have caused humans to generate forecasts with unintended, large uncertainty intervals. To aide in outbreak preparedness, platforms that solicit human judgment forecasts may wish to assess whether specifying a forecast on logarithmic scale matches an individual's intended forecast, support human judgment by finding cues that are typically used to build forecasts, and, to improve performance, tailor their platform to allow forecasters to assign zero probability to events.

We investigated tumor volume doubling time (TVDT) during active surveillance of papillary thyroid microcarcinoma (PTMC) and reviewed clinical factors including BRAF mutation associated with tumor progression. Patients with PTMC who deferred surgery for more than 1 year after diagnosis between 2014 and 2021 and were followed until 2023 were enrolled. Inclusion criteria were papillary thyroid carcinoma confirmed by fine needle aspiration cytology (Bethesda categories V-VI), maximal tumor diameter ≤1 cm, and available BRAF mutation testing. A total of 85 patients were included. The median age was 49 years, and 63 patients (74%) were female. The positivity rate for BRAF mutation was 51% in the study cohort, and 16 patients (19%) showed rapid-growing disease, defined by a TVDT of less than 5 years. The median follow-up duration was 4.4 years, and 23 patients (27%) underwent surgery after a median of 3.2 years. When TVDT groups were analyzed using logistic regression, sonographic features with microcalcification were associated with tumor growth in binary regression (odds ratio for the group combining slowly and rapid-growing disease was 4.34; 95% confidence interval [CI], 1.41 to 13.35; P=0.010), and BRAF mutation was associated with rapid-growing disease in multinomial regression (odds ratio for rapid-growing disease was 4.48; 95% CI, 1.08 to 18.51; P=0.038). BRAF mutation is presumed to be associated with tumor progression and may predict growth of PTMC. Genetic testing including BRAF testing may help distinguishing rapid-growing thyroid cancer.