DNA Nanodevices with Selective Immune Cell Interaction and Function

DNA nanotechnology produces precision nanostructures of defined chemistry. Expanding their use in biomedicine requires designed biomolecular interaction and function. Of topical interest are DNA nanostructures that function as vaccines with potential advantages over nonstructured nucleic acids in terms of serum stability and selective interaction with human immune cells. Here, we describe how compact DNA nanobarrels bind with a 400-fold selectivity via membrane anchors to white blood immune cells over erythrocytes, without affecting cell viability. The selectivity is based on the preference of the cholesterol lipid anchor for the more fluid immune cell membranes compared to the lower membrane fluidity of erythrocytes. Compacting DNA into the nanostructures gives rise to increased serum stability. The DNA barrels furthermore functionally modulate white blood cells by suppressing the immune response to pro-inflammatory endotoxin lipopolysaccharide. This is likely due to electrostatic or steric blocking of toll-like receptors on white blood cells. Our findings on immune cell-specific DNA nanostructures may be applied for vaccine development, immunomodulatory therapy to suppress septic shock, or the targeting of bioactive substances to immune cells

Selective mitochondrial antioxidant MitoTEMPO reduces renal dysfunction and systemic inflammation in experimental sepsis in rats

BACKGROUND: Excess mitochondrial reactive oxygen species (mROS) in sepsis is associated with organ failure, in part by generating inflammation through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. We determined the impact of a mitochondrial-targeted antioxidant (MitoTEMPO) on mitochondrial dysfunction in renal proximal tubular epithelial cells, peritoneal immune cell function ex vivo, and organ dysfunction in a rat model of sepsis. METHODS: The effects of MitoTEMPO were assessed ex vivo using adenosine triphosphate and lipopolysaccharide-stimulated rat peritoneal immune cells and fresh rat kidney slices exposed to serum from septic rats. We assessed mROS production and phagocytotic capacity (flow cytometry), mitochondrial functionality (multiphoton imaging, respirometry), and NLRP3 inflammasome activation in cell culture. The effect of MitoTEMPO on organ dysfunction was evaluated in a rat model of faecal peritonitis. RESULTS: MitoTEMPO decreased septic serum-induced mROS (P0.05). In vivo, compared with untreated septic animals, MitoTEMPO reduced systemic IL-1β (P=0.01), reduced renal oxidative stress as determined by urine isoprostane levels (P=0.04), and ameliorated renal dysfunction (reduced serum urea (P<0.001) and creatinine (P=0.05). CONCLUSIONS: Reduction of mROS by a mitochondria-targeted antioxidant reduced IL-1β, and protected mitochondrial, cellular, and organ functionality after septic insults

One- and two-photon resonant spectroscopy of hydrogen and anti-hydrogen atoms in external electric fields

The resonant spectra of hydrogen and anti-hydrogen atoms in the presence of an external electric field are compared theoretically. It is shown that nonresonant corrections to the transition frequency contain terms linear in the electric field. The existence of these terms does not violate space and time parity and leads to a difference in the resonant spectroscopic measurements for hydrogen and anti-hydrogen atoms in an external electric field. The one-photon 1s-2p and the two-photon 1s-2s resonances are investigated

A new developmental mechanism for the separation of the mammalian middle ear ossicles from the jaw

Multiple mammalian lineages independently evolved a definitive mammalian middle ear (DMME) through breakdown of Meckel's cartilage (MC). However, the cellular and molecular drivers of this evolutionary transition remain unknown for most mammal groups. Here, we identify such drivers in the living marsupial opossum Monodelphis domestica, whose MC transformation during development anatomically mirrors the evolutionary transformation observed in fossils. Specifically, we link increases in cellular apoptosis and TGF-BR2 signalling to MC breakdown in opossums. We demonstrate that a simple change in TGF-β signalling is sufficient to inhibit MC breakdown during opossum development, indicating that changes in TGF-β signalling might be key during mammalian evolution. Furthermore, the apoptosis that we observe during opossum MC breakdown does not seemingly occur in mouse, consistent with homoplastic DMME evolution in the marsupial and placental lineages

Physical activity through sustainable transport approaches (PASTA): protocol for a multi-centre, longitudinal study

BACKGROUND: Physical inactivity is one of the leading risk factors for non-communicable diseases, yet many are not sufficiently active. The Physical Activity through Sustainable Transport Approaches (PASTA) study aims to better understand active mobility (walking and cycling for transport solely or in combination with public transport) as an innovative approach to integrate physical activity into individuals' everyday lives. The PASTA study will collect data of multiple cities in a longitudinal cohort design to study correlates of active mobility, its effect on overall physical activity, crash risk and exposure to traffic-related air pollution. METHODS/DESIGN: A set of online questionnaires incorporating gold standard approaches from the physical activity and transport fields have been developed, piloted and are now being deployed in a longitudinal study in seven European cities (Antwerp, Barcelona, London, Oerebro, Rome, Vienna, Zurich). In total, 14000 adults are being recruited (2000 in each city). A first questionnaire collects baseline information; follow-up questionnaires sent every 13 days collect prospective data on travel behaviour, levels of physical activity and traffic safety incidents. Self-reported data will be validated with objective data in subsamples using conventional and novel methods. Accelerometers, GPS and tracking apps record routes and activity. Air pollution and physical activity are measured to study their combined effects on health biomarkers. Exposure-adjusted crash risks will be calculated for active modes, and crash location audits are performed to study the role of the built environment. Ethics committees in all seven cities have given independent approval for the study. DISCUSSION: The PASTA study collects a wealth of subjective and objective data on active mobility and physical activity. This will allow the investigation of numerous correlates of active mobility and physical activity using a data set that advances previous efforts in its richness, geographical coverage and comprehensiveness. Results will inform new health impact assessment models and support efforts to promote and facilitate active mobility in cities

Comparative Analysis of Percutaneous Drainage versus Operative Drainage of Intra-Abdominal Abscesses in a Resource-Limited Setting: The Tanzanian Experience

Background: Intra-abdominal abscesses (IAAs) are a major cause of morbidity and mortality worldwide. While image-guided percutaneous abscess drainage (PAD) has become the standard of care in many countries, over half of the global population does not have access to interventional radiology (IR) and are left with surgery as the only option for source control. Objective: The purpose of this study is to evaluate the development, implementation, and role of a PAD service in a resource-limited setting. Method: A retrospective cohort study was performed on all patients who underwent percutaneous or surgical abscess drainage (SAD) of IAAs at Tanzania’s national referral hospital from 10/2018 to 4/2021. Patients were identified through a match case search of institutional records and inclusion was confirmed through manual chart review. Demographics, patient presentation, procedural data, and clinical outcomes were recorded in a password-encrypted database and compared between groups. Findings: Sixty-three patients underwent abscess drainage: 32 percutaneously and 31 surgically. In the PAD group, there was a 100% technical success rate and a 0% complication rate. In the SAD group, there was a 64.5% technical success rate and ten deaths within 30 days (32.3%), and one additional complication requiring major therapy (3.2%) (p < 0.001). Conclusion: Results from this study demonstrate that PAD can be performed with high technical success and without complication by trained IR physicians in Tanzania. The development of a successful PAD program exemplifies the drastic need to support the growth of IR services in this setting

Transport mode choice and body mass index: Cross-sectional and longitudinal evidence from a European-wide study.

BACKGROUND: In the fight against rising overweight and obesity levels, and unhealthy urban environments, the renaissance of active mobility (cycling and walking as a transport mode) is encouraging. Transport mode has been shown to be associated to body mass index (BMI), yet there is limited longitudinal evidence demonstrating causality. We aimed to associate transport mode and BMI cross-sectionally, but also prospectively in the first ever European-wide longitudinal study on transport and health. METHODS: Data were from the PASTA project that recruited adults in seven European cities (Antwerp, Barcelona, London, Oerebro, Rome, Vienna, Zurich) to complete a series of questionnaires on travel behavior, physical activity levels, and BMI. To assess the association between transport mode and BMI as well as change in BMI we performed crude and adjusted linear mixed-effects modeling for cross-sectional (n = 7380) and longitudinal (n = 2316) data, respectively. RESULTS: Cross-sectionally, BMI was 0.027 kg/m2 (95%CI 0.015 to 0.040) higher per additional day of car use per month. Inversely, BMI was -0.010 kg/m2 (95%CI -0.020 to -0.0002) lower per additional day of cycling per month. Changes in BMI were smaller in the longitudinal within-person assessment, however still statistically significant. BMI decreased in occasional (less than once per week) and non-cyclists who increased cycling (-0.303 kg/m2, 95%CI -0.530 to -0.077), while frequent (at least once per week) cyclists who stopped cycling increased their BMI (0.417 kg/m2, 95%CI 0.033 to 0.802). CONCLUSIONS: Our analyses showed that people lower their BMI when starting or increasing cycling, demonstrating the health benefits of active mobility

Spectral Decomposition of Regulatory Thresholds for Climate-Driven Fluctuations in Hydro- and Wind Power Availability

Abstract Climate-driven fluctuations in the runoff and potential energy of surface water are generally large in comparison to the capacity of hydropower regulation, particularly when hydropower is used to balance the electricity production from covarying renewable energy sources such as wind power. To define the bounds of reservoir storage capacity, we introduce a dedicated reservoir volume that aggregates the storage capacity of several reservoirs to handle runoff from specific watersheds. We show how the storage bounds can be related to a spectrum of the climate-driven modes of variability in water availability and to the covariation between water and wind availability. A regional case study of the entire hydropower system in Sweden indicates that the longest regulation period possible to consider spans from a few days of individual subwatersheds up to several years, with an average limit of a couple of months. Watershed damping of the runoff substantially increases the longest considered regulation period and capacity. The high covariance found between the potential energy of the surface water and wind energy significantly reduces the longest considered regulation period when hydropower is used to balance the fluctuating wind power

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition