Shaping single crystalline BaTiO3nanostructures by focused neon or helium ion milling.

The realization of perovskite oxide nanostructures with controlled shape and dimensions remains a challenge. Here, we investigate the use of helium and neon focused ion beam (FIB) milling in an ion microscope to fabricate BaTiO3nanopillars of sub-500 nm in diameter starting from BaTiO3(001) single crystals. Irradiation of BaTiO3with He ions induces the formation of nanobubbles inside the material, eventually leading to surface swelling and blistering. Ne-FIB is shown to be suitable for milling without inducing surface swelling. The resulting structures are defect-free single crystal nanopillars, which are enveloped, on the top and lateral sidewalls, by a point defect-rich crystalline region and an outer Ne-rich amorphous layer. The amorphous layer can be selectively etched by dipping in diluted HF. The geometry and beam-induced damage of the milled nanopillars depend strongly on the patterning parameters and can be well controlled. Ne ion milling is shown to be an effective method to rapidly prototype BaTiO3crystalline nanostructures.

Targeting ribosome biogenesis reinforces ERK-dependent senescence in pancreatic cancer.

Pancreatic adenocarcinomas (PDAC) often possess mutations in K-Ras that stimulate the ERK pathway. Aberrantly high ERK activation triggers oncogene-induced senescence, which halts tumor progression. Here we report that low-grade pancreatic intraepithelial neoplasia displays very high levels of phospho-ERK consistent with a senescence response. However, advanced lesions that have circumvented the senescence barrier exhibit lower phospho-ERK levels. Restoring ERK hyperactivation in PDAC using activated RAF leads to ERK-dependent growth arrest with senescence biomarkers. ERK-dependent senescence in PDAC was characterized by a nucleolar stress response including a selective depletion of nucleolar phosphoproteins and intranucleolar foci containing RNA polymerase I designated as senescence-associated nucleolar foci (SANF). Accordingly, combining ribosome biogenesis inhibitors with ERK hyperactivation reinforced the senescence response in PDAC cells. Notably, comparable mechanisms were observed upon treatment with the platinum-based chemotherapy regimen FOLFIRINOX, currently a first-line treatment option for PDAC. We thus suggest that drugs targeting ribosome biogenesis can improve the senescence anticancer response in pancreatic cancer.

Free-energy-based framework for early forecasting of stem cell differentiation.

Commitment of stem cells to different lineages is inherently stochastic but regulated by a range of environmental bio/chemo/mechanical cues. Here, we develop an integrated stochastic modelling framework for predicting the differentiation of hMSCs in response to a range of environmental cues, including sizes of adhesive islands, stiffness of substrates and treatment with ROCK inhibitors in both growth and mixed media. The statistical framework analyses the fluctuations of cell morphologies over approximately a 24 h period after seeding the cells in the specific environment and uses the cytoskeletal free-energy distribution to forecast the lineage the hMSCs will commit to. The cytoskeletal free energy which succinctly parametrizes the biochemical state of the cell is shown to capture hMSC commitment over a range of environments while simple morphological factors such as cell shape, tractions on their own are unable to correlate with lineages hMSCs adopt.

Tunable Energy Absorption Characteristics of Architected Honeycombs Enabled via Additive Manufacturing.

Tailoring of material architectures in three-dimensions enabled by additive manufacturing (AM) offers the potential to realize bulk materials with unprecedented properties optimized for location-specific structural and/or functional requirements. Here we report tunable energy absorption characteristics of architected honeycombs enabled via material jetting AM. We realize spatially tailored 3D printed honeycombs (guided by FE studies) by varying the cell wall thickness gradient and evaluate experimentally and numerically the energy absorption characteristics. The measured response of architected honeycombs characterized by local buckling (wrinkling) and progressive failure reveals over 110% increase in specific energy absorption (SEA) with a concomitant energy absorption efficiency of 65%. Design maps are presented that demarcate the regime over which geometric tailoring mitigates deleterious global buckling and collapse. Our analysis indicates that an energy absorption efficiency as high as 90% can be achieved for architected honeycombs, whereas the efficiency of competing microarchitected metamaterials rarely exceeds 50%. The tailoring strategy introduced here is easily realizable in a broad array of AM techniques, making it a viable candidate for developing practical mechanical metamaterials.

The homeostatic ensemble for cells.

Cells are quintessential examples of out-of-equilibrium systems, but they maintain a homeostatic state over a timescale of hours to days. As a consequence, the statistics of all observables is remarkably consistent. Here, we develop a statistical mechanics framework for living cells by including the homeostatic constraint that exists over the interphase period of the cell cycle. The consequence is the introduction of the concept of a homeostatic ensemble and an associated homeostatic temperature, along with a formalism for the (dynamic) homeostatic equilibrium that intervenes to allow living cells to evade thermodynamic decay. As a first application, the framework is shown to accurately predict the observed effect of the mechanical environment on the in vitro response of smooth muscle cells. This includes predictions that both the mean values and diversity/variability in the measured values of observables such as cell area, shape and tractions decrease with decreasing stiffness of the environment. Thus, we argue that the observed variabilities are inherent to the entropic nature of the homeostatic equilibrium of cells and not a result of in vitro experimental errors.

Complete anatomic reduction and monosegmental fusion for lumbar spondylolisthesis of Grade II and higher: use of the minimally invasive "rocking" technique.

OBJECTIVE Different surgical approaches have been described for treatment of spondylolisthesis, including in situ fusions, reductions of various degrees, and inclusion of healthy adjacent segments into the fusion construct. To the authors' knowledge, there are only sparse reports describing consistent complete reduction and monosegmental transforaminal lumbar interbody fusion for spondylolisthesis using a minimally invasive technique. The authors assess the efficacy of this technique in the reduction of local deformity and correction of overall sagittal profile in single-level spondylolisthesis. METHODS This cohort study consists of a total of 36 consecutive patients treated over a period of 6 years. Patients with varying grades of lumbar spondylolisthesis (29 Meyerding Grade II and 7 Meyerding Grade III) were treated with operative reduction via minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) in which the "rocking" technique was used. The clinical outcomes were measured using the visual analog scale (VAS) for pain and the Revised Oswestry Disability Index (ODI) for low-back pain/dysfunction. Meyerding grade, pelvic incidence (PI), lumbar lordosis (LL), disc space angle (DSA), pelvic tilt (PT), and sacral slope (SS) were assessed to measure the radiological outcomes. These were reviewed for each patient for a minimum of 2 years. RESULTS At most recent follow-up, 94% of patients were pain free. There were 2 patients (6%) who had moderate pain (which corresponded to higher-grade of listhesis), but all showed an improvement in pain scores (p < 0.05). The mean VAS score improved from 6.5 (SD 1.5) preoperatively to 1.6 (SD 1.3) and the mean ODI score improved from 53.7 (SD 13.1) preoperatively to 22.5 (SD 15.5) at 2-year follow-up. All radiological parameters improved following surgery. Most significant improvement was noted for LL, DSA, and SS. Both LL and SS were found to decrease, while DSA increased postoperatively. PI remained relatively unchanged, while PT showed a mild increase, which was not significant. Good fusion was achieved with implants in situ at 2-year follow-up. A 100% complete reduction of all grades of spondylolisthesis was achieved. The overall sagittal profile improved dramatically. No major perioperative complications were encountered. CONCLUSIONS Minimally invasive monosegmental TLIF for spondylolisthesis reduction using this rocking technique is effective in the treatment of various grades of spondylolisthesis. Consistent complete reduction of the slippage as well as excellent correction of overall sagittal profile can be achieved, and the need for including healthy adjacent segments in the fusion construct can be avoided.

Analysis of electro-permeation of hydrogen in metallic alloys.

A reaction-diffusion type modelling framework is presented to analyse both electro-permeation (EP) and thermal desorption spectrometry (TDS) measurements of hydrogen in metallic alloys. It is assumed that the kinetics of hydrogen motion is governed by diffusion through the lattice, along with trapping/detrapping at specific sites such as dislocations, grain boundaries, etc. It is shown that the trapping and detrapping rates are typically much faster than the diffusion rate, and consequently a simplification of the governing equations suffices such that local equilibrium exists between lattice and trapped hydrogen. Using this local equilibrium assumption, we then present an asymptotic analysis of the governing kinetic equation for the EP test. This asymptotic analysis reveals that four regimes of behaviour exist, ranging from negligible trapping to the complete filling of deep traps. The analysis suggests that EP tests should be so-arranged that three regimes of behaviour are spanned, in order to extract the relevant material properties associated with hydrogen transport. The numerical solutions presented in this study support the asymptotic analysis. The hydrogen kinetics framework is also deployed to analyse both EP and TDS tests on the same martensitic steel. The EP measurements all lie in regime I and are thus insufficient to uniquely determine both the trap density and binding energy. Reasonable agreement is obtained between measurements and numerical predictions of TDS tests using parameters estimated from the EP tests. Further improvements in measurements are required to confirm the fidelity of this modelling approach.This article is part of the themed issue 'The challenges of hydrogen and metals'.

Adjacent-level arthroplasty following cervical fusion.

OBJECTIVE Adjacent-level disc degeneration following cervical fusion has been well reported. This condition poses a major treatment dilemma when it becomes symptomatic. The potential application of cervical arthroplasty to preserve motion in the affected segment is not well documented, with few studies in the literature. The authors present their initial experience of analyzing clinical and radiological results in such patients who were treated with arthroplasty for new or persistent arm and/or neck symptoms related to neural compression due to adjacent-segment disease after anterior cervical discectomy and fusion (ACDF). METHODS During a 5-year period, 11 patients who had undergone ACDF anterior cervical discectomy and fusion (ACDF) and subsequently developed recurrent neck or arm pain related to adjacent-level cervical disc disease were treated with cervical arthroplasty at the authors' institution. A total of 15 devices were implanted (range of treated levels per patient: 1-3). Clinical evaluation was performed both before and after surgery, using a visual analog scale (VAS) for pain and the Neck Disability Index (NDI). Radiological outcomes were analyzed using pre- and postoperative flexion/extension lateral radiographs measuring Cobb angle (overall C2-7 sagittal alignment), functional spinal unit (FSU) angle, and range of motion (ROM). RESULTS There were no major perioperative complications or device-related failures. Statistically significant results, obtained in all cases, were reflected by an improvement in VAS scores for neck/arm pain and NDI scores for neck pain. Radiologically, statistically significant increases in the overall lordosis (as measured by Cobb angle) and ROM at the treated disc level were observed. Three patients were lost to follow-up within the first year after arthroplasty. In the remaining 8 cases, the duration of follow-up ranged from 1 to 3 years. None of these 8 patients required surgery for the same vertebral level during the follow-up period. CONCLUSIONS Artificial cervical disc replacement in patients who have previously undergone cervical fusion surgery appears to be safe, with encouraging early clinical results based on this small case series, but more data from larger numbers of patients with long-term follow-up are needed. Arthroplasty may provide an additional tool for the management of post-fusion adjacent-level cervical disc disease in carefully selected patients.

NEUDOSE: A CubeSat Mission for Dosimetry of Charged Particles and Neutrons in Low-Earth Orbit.

During space missions, astronauts are exposed to a stream of energetic and highly ionizing radiation particles that can suppress immune system function, increase cancer risks and even induce acute radiation syndrome if the exposure is large enough. As human exploration goals shift from missions in low-Earth orbit (LEO) to long-duration interplanetary missions, radiation protection remains one of the key technological issues that must be resolved. In this work, we introduce the NEUtron DOSimetry & Exploration (NEUDOSE) CubeSat mission, which will provide new measurements of dose and space radiation quality factors to improve the accuracy of cancer risk projections for current and future space missions. The primary objective of the NEUDOSE CubeSat is to map the in situ lineal energy spectra produced by charged particles and neutrons in LEO where most of the preparatory activities for future interplanetary missions are currently taking place. To perform these measurements, the NEUDOSE CubeSat is equipped with the Charged & Neutral Particle Tissue Equivalent Proportional Counter (CNP-TEPC), an advanced radiation monitoring instrument that uses active coincidence techniques to separate the interactions of charged particles and neutrons in real time. The NEUDOSE CubeSat, currently under development at McMaster University, provides a modern approach to test the CNP-TEPC instrument directly in the unique environment of outer space while simultaneously collecting new georeferenced lineal energy spectra of the radiation environment in LEO.

Discrete dislocation plasticity analysis of loading rate-dependent static friction.

From a microscopic point of view, the frictional force associated with the relative sliding of rough surfaces originates from deformation of the material in contact, by adhesion in the contact interface or both. We know that plastic deformation at the size scale of micrometres is not only dependent on the size of the contact, but also on the rate of deformation. Moreover, depending on its physical origin, adhesion can also be size and rate dependent, albeit different from plasticity. We present a two-dimensional model that incorporates both discrete dislocation plasticity inside a face-centred cubic crystal and adhesion in the interface to understand the rate dependence of friction caused by micrometre-size asperities. The friction strength is the outcome of the competition between adhesion and discrete dislocation plasticity. As a function of contact size, the friction strength contains two plateaus: at small contact length [Formula: see text], the onset of sliding is fully controlled by adhesion while for large contact length [Formula: see text], the friction strength approaches the size-independent plastic shear yield strength. The transition regime at intermediate contact size is a result of partial de-cohesion and size-dependent dislocation plasticity, and is determined by dislocation properties, interfacial properties as well as by the loading rate.

Prediction of failure in notched carbon-fibre-reinforced-polymer laminates under multi-axial loading.

A damage-based finite-element model is used to predict the fracture behaviour of centre-notched quasi-isotropic carbon-fibre-reinforced-polymer laminates under multi-axial loading. Damage within each ply is associated with fibre tension, fibre compression, matrix tension and matrix compression. Inter-ply delamination is modelled by cohesive interfaces using a traction-separation law. Failure envelopes for a notch and a circular hole are predicted for in-plane multi-axial loading and are in good agreement with the observed failure envelopes from a parallel experimental study. The ply-by-ply (and inter-ply) damage evolution and the critical mechanisms of ultimate failure also agree with the observed damage evolution. It is demonstrated that accurate predictions of notched compressive strength are obtained upon employing the band broadening stress for microbuckling, highlighting the importance of this damage mode in compression. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'.

Minimally invasive transforaminal lumbar interbody fusion-indications and clinical experience.

BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) has emerged as one of the common procedures performed by spine surgeons. Back pain and radiculopathy due to degenerative disc disease, spondylolisthesis, or deformity are the usual indications. Minimally invasive surgery (MIS) techniques have proven to be effective in TLIF as they are associated with less blood loss, fewer wound complications and infections, faster recovery, and decreased hospital costs. The novel technique described in this study helps to achieve a circumferential lumbar fusion using a unilateral posterior approach, via a muscle-dilating exposure, thereby minimizing the approach-related morbidity. OBJECTIVES: An overview of the minimally invasive TLIF (MIS-TLIF) procedures including indications, techniques, and clinical experience along with a review of the medical literature is hereby presented. METHODS: All patients who underwent MIS-TLIF for various indications at our institution from 2009 to 2014 were retrospectively reviewed. All patients in this series had low back pain as their predominant symptom, with varying degrees of radicular pain and neurologic symptoms. The data collected retrospectively for analysis were age, gender, previous diagnoses, revision diagnosis, duration of symptoms, levels of fusion, operating time, intraoperative blood loss, clinical and radiographic results after surgery, and complications. Back and leg pain quantified by visual analog scale scores preoperatively, postoperatively, and at the last follow-up were assessed for clinical outcomes. CONCLUSIONS: Our clinical experience along with a review of the medical literature indicates that TLIF can be effectively and safely performed in a minimally invasive fashion for a wide variety of indications.

A thermodynamically motivated model for stress-fiber reorganization.

We present a model for stress-fiber reorganization and the associated contractility that includes both the kinetics of stress-fiber formation and dissociation as well as the kinetics of stress-fiber remodeling. These kinetics are motivated by considering the enthalpies of the actin/myosin functional units that constitute the stress fibers. The stress, strain and strain rate dependence of the stress-fiber dynamics are natural outcomes of the approach. The model is presented in a general 3D framework and includes the transport of the unbound stress-fiber proteins. Predictions of the model for a range of cyclic loadings are illustrated to rationalize hitherto apparently contrasting observations. These observations include: (1) For strain amplitudes around 10 % and cyclic frequencies of about 1 Hz, stress fibers align perpendicular to the straining direction in cells subjected to cyclic straining on a 2D substrate while the stress fibers align parallel with the straining direction in cells constrained in a 3D tissue. (2) At lower applied cyclic frequencies, stress fibers in cells on 2D substrates display no sensitivity to symmetric applied strain versus time waveforms but realign in response to applied loadings with a fast lengthening rate and slow shortening. (3) At very low applied cyclic frequencies (on the order of mHz) with symmetric strain versus time waveforms, cells on 2D substrates orient perpendicular to the direction of cyclic straining above a critical strain amplitude.

Cord IGF-I concentrations in Indian newborns: associations with neonatal body composition and maternal determinants.

BACKGROUND: Indian newborns have been described as 'thin-fat' compared with European babies, but little is known about how this phenotype relates to the foetal growth factor IGF-I (insulin-like growth factor I) or its binding protein IGFBP-3. OBJECTIVE: To assess cord IGF-I and IGFBP-3 concentrations in a sample of Indian newborns and evaluate their associations with neonatal adiposity and maternal factors. METHODS: A prospective cohort study of 146 pregnant mothers with dietary, anthropometric and biochemical measurements at 28 and 34 weeks gestation. Neonatal weight, length, skin-folds, circumferences, and cord blood IGF-I and IGFBP-3 concentrations were measured at birth. RESULTS: Average cord IGF-I and IGFBP-3 concentrations were 46.6 (2.2) and 1269.4 (41) ng mL(-1) , respectively. Girls had higher mean IGF-I than boys (51.4 ng mL(-1) vs. 42.9 ng mL(-1) ; P < 0.03), but IGFBP-3 did not differ. Cord IGF-I was positively correlated with all birth size measures except length, and most strongly with neonatal sum-of-skin-folds (r = 0.50, P < 0.001). IGFBP-3 was positively correlated with ponderal index, sum-of-skin-folds and placenta weight (r = 0.21, 0.19, 0.16, respectively; P < 0.05). Of maternal demographic and anthropometric characteristics, only parity was correlated with cord IGF-I (r = 0.27, P < 0.001). Among dietary behaviours, maternal daily milk intake at 34 weeks gestation predicted higher cord IGF-I compared to no-milk intake (51.8 ng mL(-1) vs. 36.5 ng mL(-1) , P < 0.01) after controlling for maternal characteristics, placental weight, and newborn gestational age, sex, weight and sum-of-skin-folds. Sum-of-skin-folds were positively associated with cord IGF-I in this multivariate model (57.3 ng mL(-1) vs. 35.1 ng mL(-1) for highest and lowest sum-of skin-fold quartile, P < 0.001). IGFBP-3 did not show significant relationships with these covariates. CONCLUSION: In this Indian study, cord IGF-I concentration was associated with greater adiposity among newborns. Maternal milk intake may play a role in this relationship.

Simulation of the cytoskeletal response of cells on grooved or patterned substrates.

We analyse the response of osteoblasts on grooved substrates via a model that accounts for the cooperative feedback between intracellular signalling, focal adhesion development and stress fibre contractility. The grooved substrate is modelled as a pattern of alternating strips on which the cell can adhere and strips on which adhesion is inhibited. The coupled modelling scheme is shown to capture some key experimental observations including (i) the observation that osteoblasts orient themselves randomly on substrates with groove pitches less than about 150 nm but they align themselves with the direction of the grooves on substrates with larger pitches and (ii) actin fibres bridge over the grooves on substrates with groove pitches less than about 150 nm but form a network of fibres aligned with the ridges, with nearly no fibres across the grooves, for substrates with groove pitches greater than about 300 nm. Using the model, we demonstrate that the degree of bridging of the stress fibres across the grooves, and consequently the cell orientation, is governed by the diffusion of signalling proteins activated at the focal adhesion sites on the ridges. For large groove pitches, the signalling proteins are dephosphorylated before they can reach the regions of the cell above the grooves and hence stress fibres cannot form in those parts of the cell. On the other hand, the stress fibre activation signal diffuses to a reasonably spatially homogeneous level on substrates with small groove pitches and hence stable stress fibres develop across the grooves in these cases. The model thus rationalizes the responsiveness of osteoblasts to the topography of substrates based on the complex feedback involving focal adhesion formation on the ridges, the triggering of signalling pathways by these adhesions and the activation of stress fibre networks by these signals.

Silencing TNF-α in macrophages and dendritic cells for arthritis treatment.

OBJECTIVES: Tumour necrosis factor (TNF)-α secreted by macrophages and dendritic cells (DCs) plays a predominant role in arthritis. Our previous studies suggest that a small peptide, RVG-9R (29-aa peptide derived from the rabies virus glycoprotein, fused to 9R residues), can deliver small interfering RNA (siRNA) to macrophages and DCs. We therefore tested whether knockdown of TNF-α expression in macrophages and DCs by RVG-9R/bound siRNA targeting TNF-α reduces the severity of collagen antibody-induced arthritis (CAIA) in mice. METHOD: Arthritis was induced in mice by injecting a combination of antibodies to collagen followed by lipopolysaccharide (LPS) treatment. Mice were also injected with TNF-α siRNA complexed with RVG-9R peptide or an irrelevant peptide RVMAT-9R on days 1, 3, 5, and 7. As a positive control, dexamethasone was injected intravenously. Paw thickness was measured every 2 days and the mice were killed on day 10 for testing synovial TNF-α levels and histological analysis of joints. RESULTS: In control mice, arthritis developed on day 4 and reached its peak between day 7 and day 9. Treatment with siTNF-α bound to RVG-9R, but not to RVMAT-9R, resulted in reducing paw thickness scores to the same level as dexamethasone treatment, associated with reduced TNF-α level in synovial fluid. Histological analysis of joints in the control RVMAT-9R/TNF-α siRNA-treated mice showed marked pannus formation and destruction of cartilage and subchondrial bone, as well as severe infiltration of inflammatory cells into the synovium. By contrast, the joint pathology was markedly reduced in RVG-9R/TNF-α siRNA-treated mice resembling the dexamethasone-treated mice. CONCLUSIONS: Suppression of TNF-α expression in macrophages and DCs by RVG-9R-mediated siRNA delivery could potentially be a clinically viable strategy for treatment of arthritis.

Establishment of Normative data for Monaural Recordings of Auditory Brainstem Response and its Application in Screening Patients with Hearing Loss: A Cohort Study.

OBJECTIVES: To establish normative data required for recording Auditory Brainstem Response (ABR) using monaural stimulations in children with normal hearing. METHODS: This study was conducted on 40 apparently healthy children. Database was collected after assessing with otological questionnaire, otoscopic examination and audiometric evaluation. Brainstem Evoked Response Audiometry (BERA) was used as a tool for establishment of normative data. ABR recordings by monaural presentation were obtained by following the standard test protocol given by Hall. RESULTS: ABR parameters like Absolute latencies, amplitudes, amplitude ratios, Inter- peak latencies and thresholds were assessed for their normative values which are required to establish a baseline data. The Interaural latency difference was less than 0.2 ms (milliseconds) and was found to be normal limit. Mean values of absolute latencies for left ear were1.66 ms 3.68 ms and 5.64 ms respectively and for right ear these were 1.66 ms, 3.65 ms and 5.59 ms respectively. Mean values for amplitude of wave I and V for left ear were 0.32 uV and 0.41 uV respectively. For right values were 0.31 uV and 0.36 uV respectively. Mean values of amplitude ratio (V/I) for left and right ears were 1.81 and 1.74 respectively. Mean values of interpeak latencies of wave I-III, III-V, I-V were 2.02 ms, 2.02 ms and 3.92 ms respectively for left ear and for right ear values were 2.04 ms, 1.98 ms and 4.03 ms respectively. Mean values for left and right ear hearing threshold was 25.25 dBnHL. CONCLUSION: ABR parameters shows variation in values depending upon age, myelination process, maturation of auditory pathway, environmental factors, laboratory setup etc. Hence it is concluded that each laboratory should have its own normative data which can be used as a baseline data for screening of patients with hearing loss.

Correlation between glycated haemoglobin and glucose testing for diabetes mellitus screening.

Hemoglobin A1C is used to screen and diagnose diabetes but measurement of glucose in the blood is subject to several limitations, many of which are not widely appreciated. Blood glucose testing should be taken into consideration before taking the patient to be diabetic on the basis of abnormal HbA1c values.