Osteochondral Tissue Engineering: The Potential of Electrospinning and Additive Manufacturing

The socioeconomic impact of osteochondral (OC) damage has been increasing steadily over time in the global population, and the promise of tissue engineering in generating biomimetic tissues replicating the physiological OC environment and architecture has been falling short of its projected potential. The most recent advances in OC tissue engineering are summarised in this work, with a focus on electrospun and 3D printed biomaterials combined with stem cells and biochemical stimuli, to identify what is causing this pitfall between the bench and the patients' bedside. Even though significant progress has been achieved in electrospinning, 3D-(bio)printing, and induced pluripotent stem cell (iPSC) technologies, it is still challenging to artificially emulate the OC interface and achieve complete regeneration of bone and cartilage tissues. Their intricate architecture and the need for tight spatiotemporal control of cellular and biochemical cues hinder the attainment of long-term functional integration of tissue-engineered constructs. Moreover, this complexity and the high variability in experimental conditions used in different studies undermine the scalability and reproducibility of prospective regenerative medicine solutions. It is clear that further development of standardised, integrative, and economically viable methods regarding scaffold production, cell selection, and additional biochemical and biomechanical stimulation is likely to be the key to accelerate the clinical translation and fill the gap in OC treatment

Renormalization of minimally doubled fermions

We investigate the renormalization properties of minimally doubled fermions, at one loop in perturbation theory. Our study is based on the two particular realizations of Borici-Creutz and Karsten-Wilczek. A common feature of both formulations is the breaking of hyper-cubic symmetry, which requires that the lattice actions are supplemented by suitable counterterms. We show that three counterterms are required in each case and determine their coefficients to one loop in perturbation theory. For both actions we compute the vacuum polarization of the gluon. It is shown that no power divergences appear and that all contributions which arise from the breaking of Lorentz symmetry are cancelled by the counterterms. We also derive the conserved vector and axial-vector currents for Karsten-Wilczek fermions. Like in the case of the previously studied Borici-Creutz action, one obtains simple expressions, involving only nearest-neighbour sites. We suggest methods how to fix the coefficients of the counterterms non-perturbatively and discuss the implications of our findings for practical simulations.Comment: 23 pages, 1 figur

Duration of shedding of respiratory syncytial virus in a community study of Kenyan children

Background: Our understanding of the transmission dynamics of respiratory syncytial virus (RSV) infection will be better informed with improved data on the patterns of shedding in cases not limited only to hospital admissions. Methods: In a household study, children testing RSV positive by direct immunofluorescent antibody test (DFA) were enrolled. Nasal washings were scheduled right away, then every three days until day 14, every 7 days until day 28 and every 2 weeks until a maximum of 16 weeks, or until the first DFA negative RSV specimen. The relationship between host factors, illness severity and viral shedding was investigated using Cox regression methods. Results: From 151 families a total of 193 children were enrolled with a median age of 21 months (range 1-164 months), 10% infants and 46% male. The rate of recovery from infection was 0.22/person/day (95% CI 0.19-0.25) equivalent to a mean duration of shedding of 4.5 days (95%CI 4.0-5.3), with a median duration of shedding of 4 days (IQR 2-6, range 1-14). Children with a history of RSV infection had a 40% increased rate of recovery i.e. shorter duration of viral shedding (hazard ratio 1.4, 95% CI 1.01-1.86). The rate of cessation of shedding did not differ significantly between males and females, by severity of infection or by age. Conclusion: We provide evidence of a relationship between the duration of shedding and history of infection, which may have a bearing on the relative role of primary versus re-infections in RSV transmission in the community

Evidence for Efimov quantum states in an ultracold gas of cesium atoms

Systems of three interacting particles are notorious for their complex physical behavior. A landmark theoretical result in few-body quantum physics is Efimov's prediction of a universal set of bound trimer states appearing for three identical bosons with a resonant two-body interaction. Counterintuitively, these states even exist in the absence of a corresponding two-body bound state. Since the formulation of Efimov's problem in the context of nuclear physics 35 years ago, it has attracted great interest in many areas of physics. However, the observation of Efimov quantum states has remained an elusive goal. Here we report the observation of an Efimov resonance in an ultracold gas of cesium atoms. The resonance occurs in the range of large negative two-body scattering lengths, arising from the coupling of three free atoms to an Efimov trimer. Experimentally, we observe its signature as a giant three-body recombination loss when the strength of the two-body interaction is varied. We also detect a minimum in the recombination loss for positive scattering lengths, indicating destructive interference of decay pathways. Our results confirm central theoretical predictions of Efimov physics and represent a starting point with which to explore the universal properties of resonantly interacting few-body systems. While Feshbach resonances have provided the key to control quantum-mechanical interactions on the two-body level, Efimov resonances connect ultracold matter to the world of few-body quantum phenomena.Comment: 18 pages, 3 figure

Digital PCR methods improve detection sensitivity and measurement precision of low abundance mtDNA deletions

Mitochondrial DNA (mtDNA) mutations are a common cause of primary mitochondrial disorders, and have also been implicated in a broad collection of conditions, including aging, neurodegeneration, and cancer. Prevalent among these pathogenic variants are mtDNA deletions, which show a strong bias for the loss of sequence in the major arc between, but not including, the heavy and light strand origins of replication. Because individual mtDNA deletions can accumulate focally, occur with multiple mixed breakpoints, and in the presence of normal mtDNA sequences, methods that detect broad-spectrum mutations with enhanced sensitivity and limited costs have both research and clinical applications. In this study, we evaluated semi-quantitative and digital PCR-based methods of mtDNA deletion detection using double-stranded reference templates or biological samples. Our aim was to describe key experimental assay parameters that will enable the analysis of low levels or small differences in mtDNA deletion load during disease progression, with limited false-positive detection. We determined that the digital PCR method significantly improved mtDNA deletion detection sensitivity through absolute quantitation, improved precision and reduced assay standard error

Observation of an Efimov spectrum in an atomic system

In 1970 V. Efimov predicted a puzzling quantum-mechanical effect that is still of great interest today. He found that three particles subjected to a resonant pairwise interaction can join into an infinite number of loosely bound states even though each particle pair cannot bind. Interestingly, the properties of these aggregates, such as the peculiar geometric scaling of their energy spectrum, are universal, i.e. independent of the microscopic details of their components. Despite an extensive search in many different physical systems, including atoms, molecules and nuclei, the characteristic spectrum of Efimov trimer states still eludes observation. Here we report on the discovery of two bound trimer states of potassium atoms very close to the Efimov scenario, which we reveal by studying three-particle collisions in an ultracold gas. Our observation provides the first evidence of an Efimov spectrum and allows a direct test of its scaling behaviour, shedding new light onto the physics of few-body systems.Comment: 10 pages, 3 figures, 1 tabl

Exploring the structure of glass-forming liquids using high energy X-ray diffraction, containerless methodology and molecular dynamics simulation

High energy X-ray diffraction can be combined with containerless techniques to provide information on the atomic arrangements in glass-forming liquids in stable and metastable regimes. The high incident energies provide bulk diffraction data to high values of scattering vector which enables significantly more robust analysis of the local and medium-range order that influences important physical properties such as viscosity and crystal nucleation. These combined techniques have been applied to a range of oxide liquids. In this contribution we illustrate addition of further dimensions to phase space by controlling the partial pressure of oxygen that permits the study liquids containing iron. The advantages of rapid data acquisition are also demonstrated in a study of tellurite glass-forming systems where a transition from ergodic to non-ergodic regimes in the deeply supercooled liquid is shown. Finally we demonstrate how descriptions of the liquid structure can be developed by combining HEXRD with molecular dynamics simulations

Exploring the structure of glass-forming liquids using high energy X-ray diffraction, containerless methodology and molecular dynamics simulation

High energy X-ray diffraction can be combined with containerless techniques to provide information on the atomic arrangements in glass-forming liquids in stable and metastable regimes. The high incident energies provide bulk diffraction data to high values of scattering vector which enables significantly more robust analysis of the local and medium-range order that influences important physical properties such as viscosity and crystal nucleation. These combined techniques have been applied to a range of oxide liquids. In this contribution we illustrate addition of further dimensions to phase space by controlling the partial pressure of oxygen that permits the study liquids containing iron. The advantages of rapid data acquisition are also demonstrated in a study of tellurite glass-forming systems where a transition from ergodic to non-ergodic regimes in the deeply supercooled liquid is shown. Finally we demonstrate how descriptions of the liquid structure can be developed by combining HEXRD with molecular dynamics simulations

A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, and Env gp 140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p =  0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccineinduced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The approach did however affect other immune responses; neutralizing antibody responses, seen only to Tier 1 pseudoviruses, were poorer when the vaccines were combined and while T-cell responses were seen in >80% individuals in both groups and similarly CD4 and Env dominant, their breadth/polyfunctionality tended to be lower when the vaccines were combined, suggesting attenuation of immunogenicity and cautioning against this accelerated regimen