Publications

Direct measurement of mitochondrial oxygen tension in vivo provides direct information on tissue metabolism and could facilitate new approaches in disease detection, function monitoring, and treatment efficacy assessment with cellular level data, with far superior sensitivity to oxygen changes than blood saturation measures. Here, a platform system was engineered to quantify fast sampling of oxygen partial pressure (pO2) inside tissue by utilizing the inherent rolling shutter readout of a smartphone CMOS camera detector for measuring the oxygen-sensitive time-resolved delayed fluorescence (DF) signal from Protoporphyrin IX (PpIX) which naturally occur in mitochondria for most tissues. The CMOS rolling shutter readout produces a microsecond-level time difference in the pixels row-by-row detection of light, here utilized as a time-gated shutter to sample the time distributed DF intensity. This novel technique eliminated the necessity of high-speed intensified camera with excitation isolation facility as well as advanced precise time synchronization system as required in the conventional time-resolved fluorescence lifetime measurement platforms for quantifying time-dependent very low intensity DF distribution of PpIX conjugated with prompt fluorescence. Both steady state and dynamic performance of the instrument were validated in tissue phantoms at different PpIX concentrations (0.5-10 μM) for wide range of pO2 detection (0-160 mmHg) with tunable fast response time (1-3.5 s) which is substantially faster than electrode-based systems that measure over 10's of seconds. Finally, it was tested in vivo to assess the impact of dynamic inhaled oxygen concentration variation on skin tissue pO2 under the conditions of normoxia, hyperoxia and hypoxia.

Deficient extinction learning and memory are hypothesized mechanisms for pathological anxiety that are associated with sleep disturbance. fMRI neural activations to threat conditioning, extinction learning, and extinction recall were measured. Activations were compared, in persons with Generalized Anxiety Disorder (GAD), between those with moderate to severe Insomnia Disorder (ID) and those with absent or sub-threshold ID. Relationships of activations with measures of sleep quality and physiology were examined. Between-group comparisons and whole-sample correlation with sleep parameters were examined in relation to large-scale brain networks using a liberal cluster-determining threshold. Localized activations were then identified using family-wise error correction. Activations to the reinforced stimulus (CS+) that increased from the beginning to end ("across") threat conditioning were more extensive within the GAD+ID group. Increased activations to the CS+ across extinction learning were greater within the GAD-ID than the GAD+ID group, and delayed 24 h in the latter. Greater sleep efficiency was associated with decreased activations across threat conditioning, but with increased activations across extinction learning. Better sleep quality promoted greater engagement of neural substrates of extinction learning. The GAD+ID group failed to engage brain areas supporting extinction learning immediately following threat conditioning, but did so when stimuli were again presented following a delay.

Fear is an evolutionarily adaptive mechanism that enables organisms to detect and respond to potential threats. Over the past century, theories of fear have evolved from Pavlovian and behavioral frameworks to neuroscientific models that emphasize specific neural circuits, neurotransmission, and plasticity. This pictorial review synthesizes key concepts underlying the neuroscience of fear, starting with a historical narrative of fear as conceptualized by conditioning and behaviorism theories, to the roles of different neurobiology structures, networks, to concepts of memory consolidation, reconsolidation, and plasticity. We highlight how pathological fear is implicated in disease, integrating evidence from conditioning theories, neuroscience, and additional considerations (ie. Culture and psychosocial context). Finally, we outline therapeutic approaches that leverage neuroscience to target maladaptive fear circuits. Understanding these mechanisms provides a foundation for advancing personalized treatments for fear-related psychopathology.

Women's health remains inadequately served due to the historical predominance of males as the biological reference in medical research, leading to persistent sex-based gaps in the understanding, diagnosis, and management of disease. As healthcare moves toward decentralization, e.g., through the collection of person-generated health data, point-of-care diagnostics, and wearable devices, there is a critical need for tools tailored to women's unique conditions and presentations. Ultrasound technologies, recognized for their versatility and safety, have evolved from imaging to multifunctional platforms, with growing roles in diagnosis and therapy. Diagnostic ultrasound non-invasively assesses anatomical features and functional information, and therapeutic ultrasound can perform targeted interventions, including neuromodulation, immunomodulation, thermal ablation, and drug delivery. By exploring the fundamental physical principles of ultrasound, including acoustic streaming, cavitation, and thermal interactions, and linking these mechanisms to cellular and tissue responses, this review highlights the capability of ultrasound to address female-specific health disparities, especially in conditions that are undertreated or differentially expressed in women. Advancements in ultrasound technologies could significantly enhance clinical outcomes and improve the quality of life for women affected by conditions currently underserved by traditional medical interventions.

Pseudomonas aeruginosa is a clinically significant, opportunistic pathogen adept at thriving in both host-associated and environmental settings. We sought to define the extent to which P. aeruginosa isolates specialize across niches using a comprehensive study of whole-genome sequencing with paired phenotypic characterization of 125 P. aeruginosa isolates from diverse clinical and environmental sites. We evaluated virulence-associated traits, including motility, cytotoxicity, biofilm formation, pyocyanin production, and antimicrobial resistance to eight antibiotics. Our results show that genomic diversity does not correlate with isolation source or most virulence phenotypes. Instead, we find that, in agreement with prior studies, the two major P. aeruginosa clades (groups A and B) clearly segregate by cytotoxicity, with group B strains showing significantly higher cytotoxicity than group A. Sequence analysis revealed previously uncharacterized alleles of genes encoding type III secretion effector proteins. We observed high variability among strains and isolation sources in the four assayed virulence phenotypes. Antimicrobial resistance was exclusively observed in clinical isolates, whereas it was absent in environmental isolates, reflecting antibiotic exposure-driven selection. Bacterial genome-wide association studies (GWAS) revealed an association between cytotoxicity and exoU presence, and we identified a novel exoU allelic variant with decreased cytotoxicity, demonstrating that functional diversity of well-characterized virulence factors may influence pathogenic outcomes. Overall, our analysis supports the hypothesis that the ability of P. aeruginosa to thrive across diverse niches is driven not by niche-specific accessory genes but by its core genome. Thus, P. aeruginosa isolates are capable of broad niche colonization without initial genetic adaptations.IMPORTANCEPseudomonas aeruginosa is a clinically significant opportunistic pathogen adept at thriving in both host-associated and environmental niches. A major gap in our understanding of this difficult-to-treat pathogen is whether niche specialization occurs in the context of human disease. Addressing this question is critical for guiding effective infection control strategies. Previous large-scale studies have focused solely on genotypic or phenotypic analyses; when paired, they have been limited to a single phenotypic assay or to a small number of isolates from one source, or relied on PCR-based methods targeting a restricted set of genes. To comprehensively uncover niche specialization and pathogenic versatility, we performed whole-genome sequencing and phenotypic characterization of five virulence-associated traits, including antimicrobial susceptibility of 125 clinical and environmental P. aeruginosa isolates. Our systems-level findings challenge reductionist models of bacterial niche specialization, instead supporting an integrated view where conserved genomic systems enable opportunistic pathogenesis across diverse environments.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent hepatic pathology worldwide, with significant potential for progression to cirrhosis and ultimately end-stage liver disease. Accordingly, a wide range of preclinical models have been developed to better understand the disease mechanisms and progression as well as to accelerate drug discovery. These include in vitro, ex vivo, and in vivo models, which offer unique advantages yet differ in terms of disease driver, species used, and biological complexity-ranging from benchtop cellular systems to whole organs and organisms. In this review, we provide a comprehensive overview of the technologies currently used for the study of MASLD, with a focus on how standardization of disease progression across models may aid therapeutic development.

Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). However, it is known that other pathways independent of APOE also play a role in AD. Disentangling APOE-dependent and independent effects is instrumental for understanding the biology of AD. We conducted an APOE-stratified multi-omic analysis in multiple large datasets to identify AD-associated plasma proteins and metabolites. More than 64% of the identified proteins were not found in non-APOE stratified studies, and 17% of the proteins showed APOE-specific trends. Mitochondrial dysfunction was associated in AD independently of APOE and was accompanied by disruptions in glucose and lipid metabolism and cell death and increased in inflammatory signaling activation. Lipid upregulation was found in AD cases when compared with controls with the same APOE genotype, indicating that additional factors beyond APOE affect lipid regulation and AD risk. These findings may be informative in guiding the development of effective medications for AD.

OBJECTIVES: To evaluate the feasibility, safety, and technical performance of robot-assisted CT-guided cryoablation for pulmonary metastases.

MATERIALS AND METHODS: A single-centre IDEAL stage 2a prospective development study of 26 participants (median age 62 years, IQR 47-71; 14 men) who underwent 30 procedures targeting 37 lung metastases using a robotic navigation system. Median tumour diameter was 9.8 mm (IQR 5.1-12.8). All procedures were performed under general anaesthesia with high-frequency jet ventilation. Feasibility, safety, and technical performance (targeting accuracy, manipulations, radiation dose) were recorded.

RESULTS: Robotic guidance was successfully completed without conversion in 35/37 tumours (95%). One major complication occurred (3%, CTCAE grade 3 pneumothorax requiring 4 days of drainage); all others were grade 1-2. Pneumothoraces were managed by observation (n = 7) or prophylactic intraprocedural chest drain insertion (n = 11). No bronchopleural fistulas were observed. Median hospital stay was 1 night (IQR 1-2). A total of 54 cryoprobes were used. Median Euclidean targeting error on first insertion was 6.1 mm (IQR 2.9-9.7) and lateral error 4.2 mm (IQR 2.2-6.5). The median number of manipulations per probe was 1 (IQR 0-2.5), with one-third requiring no adjustment. Once integrated into the workflow, the "chopstick" technique was frequently applied, supporting conformal ablation. Median total procedure time was 66.5 min (IQR 56.6-92.8). Twelve-month local tumour progression-free survival was 97%.

CONCLUSION: Robot-assisted CT-guided cryoablation of pulmonary metastases was feasible, safe, and accurate, achieving high targeting precision with minimal cryoprobe manipulation. These findings support evaluation in prospective comparative trials.

KEY POINTS: Question Robotic-assisted CT-guided cryoablation of lung metastases is feasible and safe, achieving high targeting accuracy and minimal probe manipulation, even in anatomically challenging cases. Findings Robotic trajectory planning supported complex multiprobe configurations. Procedural refinements-including patient positioning, probe selection, and adoption of "chopstick" configurations-were introduced to address bleeding risk and optimise energy delivery. Clinical relevance Robot-assisted navigation is particularly advantageous in cryoablation, enabling minimal manipulations and accurate probe placement despite the often-necessary complex trajectories.

BACKGROUND: Given the recognized link between periodontal disease and cardiovascular conditions, the authors tested whether omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), could reduce key inflammatory markers.

METHODS: In this secondary analysis, 240 patients with stable coronary artery disease undergoing statin therapy were randomized to receive 3.36 g/d of EPA and DHA (test group) or no supplementation (control group) for 30 months. Of these, 199 patients had gingival crevicular fluid collected in the maxillary left and right quadrants. Oral and systemic inflammatory markers were compared.

RESULTS: The EPA and DHA group had significantly lower gingival crevicular fluid levels of macrophage inflammatory protein-1β in the left quadrant (P = .038) and a lower systemic neutrophil to lymphocyte ratio (P = .021) than the control group. The authors hypothesized that handedness may account for the localized anti-inflammatory effect in the left quadrant because right-handed people have better plaque removal on the left side.

CONCLUSIONS: EPA and DHA supplementation lowered oral and systemic inflammation, potentially contributing to improved periodontal health and reducing cardiovascular risk. The site-specific difference may be influenced by means of handedness or toothbrushing behavior and warrants further investigation.

PRACTICAL IMPLICATIONS: Supplementation with EPA and DHA can complement mechanical oral hygiene. Recommending powered toothbrushes may eliminate handedness-related differences, providing a more uniform anti-inflammatory effect alongside EPA and DHA supplementation. This clinical trial was registered at ClinicalTrials.gov. The registration number is NCT01624727.