Vascular cognitive impairment (VCI) is a common form of dementia associated with cerebrovascular dysfunction and chronic inflammation. Impaired cerebral perfusion is a result of atherosclerotic plaque build-up in the medium and large arteries in the brain and is exacerbated by numerous inflammatory triggers, including aging, high blood pressure, high cholesterol, and smoking. Previously, we demonstrated that receptor-interacting protein 1 kinase (RIPK1) promotes the progression of aortic atherosclerosis and NFκB activation in mice, and that atherosclerotic vascular disease was decreased by therapeutically inhibiting RIPK1 with antisense oligonucleotides. Given the relationship between atherosclerosis and cognitive impairment, we hypothesize that RIPK1 also contributes to the development of cerebrovascular disease and neuroinflammation in a mouse model of hyperlipidemia. Male and female Apoe-/- were fed a chow or Western diet (WD) for 16 weeks and subsequently treated for an additional 8 weeks with either scramble (control) or anti-RIPK1 antisense oligonucleotides (ASO) to systemically knockdown RIPK1 expression (RIPK1KD). WD feeding induced significant carotid atherosclerotic lesion burden and reduced cerebral blood flow compared to chow-fed mice. These vascular changes were associated with impaired spatial learning and memory, reduced hippocampal vascularity, and altered expression of neurovascular and inflammatory markers. Systemic RIPK1 silencing significantly reduced carotid artery lesion size, restored arterial stiffness and blood flow in the brain. Furthermore, treatment with RIPK1KD preserved vascularity in the hippocampus, restored blood flow in the brain and prevented the impairment in spatial learning and memory. Overall, our study identifies RIPK1 as a mediator of hyperlipidemia-induced cerebrovascular dysfunction and suggests that targeting RIPK1 may represent a therapeutic approach to limit cognitive impairment.

The APOEε4 allele and oestrogen deficiency independently predispose females to an increased risk of vascular and metabolic impairments, but their cerebrovascular effects are less understood. The purpose of this study was to determine the interaction between APOE genotype and oestrogen on cerebrovascular endothelial and mitochondrial function. We studied young female homozygous APOEε3 and APOEε4 mice (n = 19-20/group; ∼6 months old) that were fed a high-fat diet and were ovariectomized (OVX), OVX and supplemented with 17β-oestradiol, or left intact. In APOEε3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilatation, which was rescued by 17β-oestradiol. However, in APOEε4 mice, there was no effect of OVX or 17β-oestradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17β-oestradiol treatment in APOEε3 mice, but there was no impact of OVX or 17β-oestradiol in the APOEε4 mice. In cerebral arteries and arterioles, 17β-oestradiol led to higher mitochondrial complex I respiration in APOEε3 but not APOEε4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes and pro-inflammatory factors. Overall these results indicate that the APOE genotype modulates the impact of OVX and oestradiol on the cerebral vasculature. We found that 17β-oestradiol enhances cerebrovascular endothelial and mitochondrial function in OVX APOEε3 mice but not in APOEε4 mice. This suggests that 17β-oestradiol supplementation may have more cerebrovascular benefits for APOEε4 non-carriers. KEY POINTS: Females have twice the risk of Alzheimer's disease than males, and the APOEε4 genetic variant has a greater risk for Alzheimer's disease than the APOEε3 variant. The risk for Alzheimer's disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. There are highly inconsistent results among past studies examining the interaction between APOE genotype and oestrogens on brain outcomes, and their impact on the vasculature has not been studied. We aimed to determine the impact of APOEε4 genotype on the cerebrovascular response to ovariectomy and oestradiol. We found that oestradiol improved cerebral artery endothelial function and mitochondrial respiration in ovariectomized APOEε3 mice following ovariectomy. In contrast APOEε4 mice were resistant to the beneficial effects of ovarian hormones on cerebrovascular and mitochondrial function. This research suggests that APOE genotype may be a consideration when weighing the risks and benefits of prescribing hormone replacement therapy to postmenopausal females.

Viruses are evolving biological entities whose perpetuation depends on their adaptive response to many selection pressures acting on them. Viruses are also solid objects that show some degree of deformability, brittleness, and strength when subjected to mechanical forces. Atomic force microscopy (AFM) allows the controlled application of mechanical force on individual virions, capsids and viral components under close to physiological conditions. In this way, the structure, dynamics, and mechanical properties of virus particles, and their changes by the action of biologically relevant effectors, can be investigated at the single-particle level. AFM-based studies have shown that the mechanical properties of some viruses can have an adaptive value for virus survival, that mechanical forces are among the selection pressures some viruses may be confronted with, and that some viruses can exert mechanical forces that also constitute adaptive traits. AFM studies of viruses under mechanical force are also providing new insights into the relationships between virus structure and dynamics, physical properties, and biological function, even in those cases where natural mechanical forces may not be involved. The knowledge being acquired on virus biomechanics is contributing to understand virus biology and to the development of new biomedical or nanotechnological applications. The present review is addressed to a general readership of virologists, and attempts to summarize the results of over 20 years of studies that have used AFM, in combination with other biophysical, biochemical and/or biological approaches, to explore the connections between virus biology and mechanical force.

Optical nanotweezers, which integrate nanophotonic structures such as plasmonic antennas, dielectric resonators, and metasurfaces, have emerged as powerful tools for manipulating nanoparticles, biomolecules, and viruses with high precision. However, traditional designs rely heavily on heuristic approaches and simple geometries, limiting performance. Inverse design offers a paradigm shift by using computational optimization methods to discover non-intuitive, high-performance structures for optical trapping. This Review provides an overview of key inverse design methodologies, including adjoint-based optimization, topology optimization, and machine learning approaches, and highlights their broader impact across nanophotonics. We then focus on their application to optical nanotweezers, where recent advances demonstrate enhanced trapping stiffness, reduced optical heating, and tailored trapping landscapes. Representative examples include algorithmic design of plasmonic nanotweezers, topology-optimized plasmonic nanoapertures, inverse-designed dielectric nanocavities, and force-centric designs based on Maxwell stress tensor engineering. Collectively, these studies illustrate how inverse design enables stable, efficient, and versatile optical trapping at the nanoscale. Despite these advances, challenges remain in fabrication, computational cost, and the interpretability of optimized structures. We conclude with a perspective on future directions, emphasising opportunities in reconfigurable tweezers, lab-on-a-chip integration, and quantum nanophotonics. By bridging photonic optimization with nanoscale manipulation, inverse-designed optical nanotweezers offer promising opportunities for future applications in biophysics, materials science, and quantum technologies.

The elasticity of sunflower wax (SFW)-based oleogels arises from the hierarchical organisation of their crystalline network. This study examines how cooling-rate-controlled crystallisation regulates elasticity through redistribution of coexisting lamellar periodicity populations. Small-angle X-ray diffraction reveals long- and slightly shorter-period lamellar components, while wide-angle X-ray diffraction confirms unchanged molecular packing, indicating no polymorphic transitions. The population of the slightly shorter-period component varies systematically with cooling rate. Peak broadening suggests differences in internal crystalline state, including accumulated strain and crystallite size, which may influence stiffness. In-situ time-resolved synchrotron measurements show that early-stage crystallisation kinetics affect subsequent structural heterogeneity. Shear-induced homogenisation reduces the shorter-period population and increases elasticity. Overall, mechanical properties are primarily associated with lamellar periodicity redistribution rather than changes in molecular packing, providing a structural basis for texture design in wax-structured edible oil systems.

Exercise-based physical therapy is effective for managing Achilles tendinopathy. Despite these successes, up to 45% of patients do not respond to therapy. The mechanisms differentiating patients who improve and those who do not remain unclear, although differences in pre-rehabilitation pain, tendon structure and function might explain this individual variability. The aim was to explore differences in pain, structure, and functional changes between patients with and without meaningful self-perceived resolution following a 12-week eccentric rehabilitation protocol for Achilles tendinopathy. Thirty-seven patients with chronic midportion Achilles tendinopathy (28 M/9F; 46 ± 12 years) followed a 12-week eccentric rehabilitation protocol. Functional and structural measurements and questionnaires were assessed pre- and post-intervention to evaluate pain, tendon structure, and function. A blinded medical doctor classified treatment response based on patient-perceived resolution, grouping participants into those with meaningful improvement (N = 28) and those without (N = 9). Patients without meaningful improvement had significantly higher VISA-A scores, greater free Achilles tendon stiffness, and higher pain-onset hopping repetitions (all p < 0.05) pre-intervention compared to those who reported meaningful improvement. After 12 weeks of rehabilitation, VISA-A and pain-onset hopping repetitions showed significant effects for time (p = 0.010; p = 0.024), group (p = 0.022; p = 0.003), and interaction (p = 0.032; p = 0.002). Tendon stiffness, maximal voluntary contraction, and palpation pain changed significantly over time (p = 0.009; p = 0.016; p = 0.044, respectively). Achilles tendon loading during dynamic exercises showed no between-group differences (all p > 0.05). Higher baseline functioning was linked to reduced improvement following rehabilitation, indicating that baseline functional status may influence treatment outcomes. Recognizing such baseline differences could help predict patient-perceived resolution and guide individualized interventions.

Torsion is the preferred mode of loading for ex vivo whole-bone mechanical testing due to its robustness to alignment artifacts and ease of implementation. Results from a nondestructive torsion test are usually reported as torsional stiffness, S, or the slope of the torque-angle curve. However, torsional stiffness depends on specimen working length and cannot be compared between experiments with different bone lengths or test setups. Alternatively, the length-independent torsional rigidity can be calculated as GJ = S×L, using the working length L of the specimen. This paper presents evidence that the effective working length exceeds the length of the unpotted bone segment and depends on the amount of twisting allowed by the fixture through the potted ends. Multiple fixture design parameters were systematically varied to quantify how each individual change influenced the effective working length. Common variations in design parameters related to potting contributed up to 5.15% variation in effective working length, while changing the method of coupling the sample to the test frame contributed up to 17.1% variation. These results suggest that effective working length calibration is essential to enable data aggregation between experiments conducted with different setups. To assist other researchers who wish to calibrate their own setups, this investigation also provides practical guidance on how to determine the effective working length of a complex torsion test assembly using finite element analysis with nonlinear contact mechanics. Detailed procedures for setting up a contact solution are documented with recommendations on adjustments to achieve convergence.

Despite notable advancements in autologous chondrocyte implantation (ACI) over the past three decades, persistent challenges including uneven cell distribution, low seeding density, and limited extracellular matrix formation continue to hinder outcomes. This study suggests a novel approach to matrix-assisted ACI (MACI) that integrates reactive jet impingement (ReJI) bioprinting with Chondro-Gide® (Ch-G) membranes to give an in theatre bioprinting approach with the potential to control cell distribution and density at the point of implantation. A collagen-alginate-fibrin (CAF) hydrogel was formulated as a bioink to maintain high cell viability and enable accurate deposition of chondrocytes at both low and high densities. Bone marrow-derived immortalised stem cells were differentiated into chondrocytes and bioprinted using the ReJI system onto Ch-G substrates. Constructs were evaluated over 14 days for cytotoxicity, morphology, gene expression, extracellular matrix (ECM) deposition, and mechanical properties. Live/dead assays confirmed high cell viability across all conditions. Immunofluorescence and scanning electron microscope (SEM) analyses showed enhanced cell alignment, surface migration, and ECM formation, particularly in high-density Chondro-Gide®/CAF samples (Ch-G/CAF). ACAN and SOX9 showed significant upregulation from day 1 to day 14 and immunohistochemical analysis confirmed robust deposition of collagen II and sulphated glycosaminoglycans (sGAGs). Mechanical testing demonstrated increased compressive modulus over time, with Ch-G/CAF constructs exhibiting superior stiffness and volumetric stability. These findings suggest that ReJI bioprinting of CAF hydrogels onto Chondro-Gide® membranes supports enhanced chondrogenic activity and matrix formation, offering a promising strategy for next-generation MACI.