Note: The intermodulation lockin analyzer

Nonlinear systems can be probed by driving them with two or more pure tones while measuring the intermodulation products of the drive tones in the response. We describe a digital lockin analyzer which is designed explicitly for this purpose. The analyzer is implemented on a field-programmable gate array, providing speed in analysis, real-time feedback, and stability in operation. The use of the analyzer is demonstrated for intermodulation atomic force microscopy. A generalization of the intermodulation spectral technique to arbitrary drive waveforms is discussed.     

Grid resource brokering algorithms enabling advance reservations and resource selection based on performance predictions

We present algorithms, methods, and software for a Grid resource manager, that performs resource brokering and job scheduling in production Grids. This decentralized broker selects computational resources based on actual job requirements, job characteristics, and information provided by the resources, with the aim to minimize the total time to delivery for the individual application. The total time to delivery includes the time for program execution, batch queue waiting, and transfer of executable and input/output data to and from the resource. The main features of the resource broker include two alternative approaches to advance reservations, resource selection algorithms based on computer benchmark results and network performance predictions, and a basic adaptation facility. The broker is implemented as a built-in component of a job submission client for the NorduGrid/ARC middleware.     

Nonlinear buckling optimization of composite structures

The paper presents an approach to nonlinear buckling fiber angle optimization of laminated composite shell structures. The approach accounts for the geometrically nonlinear behaviour of the structure by utilizing response analysis up until the critical point. Sensitivity information is obtained efficiently by an estimated critical load factor at a precritical state. In the optimization formulation, which is formulated as a mathematical programming problem and solved using gradient-based techniques, a number of the lowest buckling factors are included such that the risk of “mode switching” during optimization is avoided. The presented optimization formulation is compared to the traditional linear buckling formulation and two numerical examples, including a large laminated composite wind turbine main spar, to clearly illustrate the pitfalls of the traditional formulation and the advantage and potential of the presented approach.     

Cost efficiency comparison of four video-based techniques for assessing upper arm postures

Many video-based techniques for assessing postures at work have been developed. Choosing the most appropriate technique should be based on an evaluation of different alternatives in terms of their ability to produce posture information at low input costs, i.e. their cost efficiency. This study compared four video-based techniques for assessing upper arm postures, using cost and error data from an investigation on hairdressers. Labour costs associated with the posture assessments from the video recordings were the dominant factor in the cost efficiency comparison. Thus, a work sampling technique associated with relatively large errors appeared, in general, to be the most cost-efficient because it was labour-saving. Measurement bias and other costs than labour cost for posture assessment influenced the ranking and economic evaluation of techniques, as did the applied measurement strategy, i.e. the numbers of video recordings and repeated assessments of them. PRACTITIONER SUMMARY: The cost efficiency of four video-based techniques for assessing upper arm postures was compared. Work sampling techniques were in general more cost efficient than continuous observations since they were labour-saving. Whilst a labour cost dominated the comparison, 'hidden costs', bias and measurement strategy also influenced this dominance.     

Molecular pharmacology of voltage-dependent calcium channels

Voltage-dependent Ca2+ channels serve as the only link to transduce membrane depolarization into cellular Ca(2+)-dependent reactions. A wide variety of chemical substances that have the ability to modulate Ca2+ channels have been demonstrated both for their clinic utility and for importance in elucidating the molecular basis of various biological responses. Recently, introduction of molecular biology to pharmacology has brought a great deal of information about the molecular basis of drug action in Ca2+ channels. In this review, we attempt to overview recent progress in understanding the interactions between Ca2+ channels and their blockers, namely Ca2+ antagonists, from a molecular and structural point of view.     

Early Osteogenic Marker Expression in hMSCs Cultured onto Acid Etching-Derived Micro- and Nanotopography 3D-Printed Titanium Surfaces

Polyetheretherketone (PEEK) titanium composite (PTC) is a novel interbody fusion device that combines a PEEK core with titanium alloy (Ti6Al4V) endplates. The present study aimed to investigate the in vitro biological reactivity of human bone-marrow-derived mesenchymal stem cells (hBM-MSCs) to micro- and nanotopographies produced by an acid-etching process on the surface of 3D-printed PTC endplates. Optical profilometer and scanning electron microscopy were used to assess the surface roughness and identify the nano-features of etched or unetched PTC endplates, respectively. The viability, morphology and the expression of specific osteogenic markers were examined after 7 days of culture in the seeded cells. Haralick texture analysis was carried out on the unseeded endplates to correlate surface texture features to the biological data. The acid-etching process modified the surface roughness of the 3D-printed PTC endplates, creating micro- and nano-scale structures that significantly contributed to sustaining the viability of hBM-MSCs and triggering the expression of early osteogenic markers, such as alkaline phosphatase activity and bone-ECM protein production. Finally, the topography of 3D-printed PTC endplates influenced Haralick’s features, which in turn correlated with the expression of two osteogenic markers, osteopontin and osteocalcin. Overall, these data demonstrate that the acid-etching process of PTC endplates created a favourable environment for osteogenic differentiation of hBM-MSCs and may potentially have clinical benefit.     

Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment

Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types.     

Localized Heat Therapy Improves Mitochondrial Respiratory Capacity but Not Fatty Acid Oxidation

AIM: Mild heat stress can improve mitochondrial respiratory capacity in skeletal muscle. However, long-term heat interventions are scarce, and the effects of heat therapy need to be understood in the context of the adaptations which follow the more complex combination of stimuli from exercise training. The purpose of this work was to compare the effects of 6 weeks of localized heat therapy on human skeletal muscle mitochondria to single-leg interval training. METHODS: Thirty-five subjects were assigned to receive sham therapy, short-wave diathermy heat therapy, or single-leg interval exercise training, localized to the quadriceps muscles of the right leg. All interventions took place 3 times per week. Muscle biopsies were performed at baseline, and after 3 and 6 weeks of intervention. Mitochondrial respiratory capacity was assessed on permeabilized muscle fibers via high-resolution respirometry. RESULTS: The primary finding of this work was that heat therapy and exercise training significantly improved mitochondrial respiratory capacity by 24.8 ± 6.2% and 27.9 ± 8.7%, respectively (p < 0.05). Fatty acid oxidation and citrate synthase activity were also increased following exercise training by 29.5 ± 6.8% and 19.0 ± 7.4%, respectively (p < 0.05). However, contrary to our hypothesis, heat therapy did not increase fatty acid oxidation or citrate synthase activity. CONCLUSION: Six weeks of muscle-localized heat therapy significantly improves mitochondrial respiratory capacity, comparable to exercise training. However, unlike exercise, heat does not improve fatty acid oxidation capacity.     

Alternative Tilings for Improved Surface Area Estimates by Local Counting Algorithms

In this paper, we first review local counting methods for perimeter estimation of piecewise smooth binary figures on square, hexagonal, and triangular grids. We verify that better perimeter estimates, using local counting algorithms, can be obtained using hexagonal or triangular grids. We then compare surface area estimates using local counting techniques for binary three-dimensional volumes under the three semi-regular polyhedral tilings: the cubic, truncated octahedral, and rhombic dodecahedral tilings. It is shown that for surfaces of random orientation with a uniform distribution, the expected error of surface area estimates is smaller for the truncated octahedral and rhombic dodecahedral tilings than for the standard cubic or rectangular prism tilings of space. Additional properties of these tessellations are reviewed and potential applications of better surface area estimates are discussed.