This paper illustrates the potential of a gyroscopic stabiliser for the stabilisation of single-track vehicles, at low and high speed as well as during braking. Alternative systems are considered, ...including single and twin counter-rotating gyroscopes, spinning and precessing with respect to different axes, either freely (passive stabilisers) or in a controlled way (active stabilisers). A suitable mathematical model has been developed and stability has been investigated both by eigenvalue calculation and time domain simulations. It has been found that the most effective configuration is one where the gyroscope(s) spin with respect to an axis parallel to the wheels' spin axis and swing with respect to the vehicle yaw axis. Passive systems may effectively stabilise both weave and wobble at medium and high speed, but cannot stabilise the vehicle at low and zero speed. On the contrary, actively controlled gyroscopes are capable of stabilising the vehicle in its whole range of operating speed, as well as during braking. The alteration of the original vehicle handling characteristics is negligible when active counter-rotating gyroscopes are used, and still acceptable if a single gyroscope is adopted instead.
Background Centralization of care to “centers of excellence” in Europe has led to improved oncologic outcomes; however, little is known regarding the impact of nonmandated regionalization of rectal ...cancer care in the United States. Methods The Statewide Planning and Research Cooperative System (SPARCS) was queried for elective abdominoperineal and low anterior resections for rectal cancer from 2000 to 2011 in New York with the use of International Classification of Diseases, Ninth Revision codes. Surgeon volume and hospital volume were grouped into quartiles, and high-volume surgeons (≥10 resections/year) and hospitals (≥25 resections/year) were defined as the top quartile of annual caseload of rectal cancer resection and compared with the bottom 3 quartiles during analyses. Bivariate and multilevel regression analyses were performed to assess factors associated with restorative procedures, 30-day mortality, and temporal trends in these endpoints. Results Among 7,798 rectal cancer resections, the overall rate of no-restorative proctectomy and 30-day mortality decreased by 7.7% and 1.2%, respectively, from 2000 to 2011. In addition, there was a linear increase in the proportion of cases performed by both high-volume surgeons and high-volume hospitals and a decrease in the number of surgeons and hospitals performing rectal cancer surgery. High-volume surgeons at high-volume hospitals were associated independently with both less nonrestorative proctectomies (odds ratio 0.65, 95% confidence interval 0.48–0.89) and mortality (odds ratio 0.43, 95% confidence interval 0.21–0.87) rates. No patterns of significant improvement within the volume strata of the surgeon and hospitals were observed over time. Conclusion This study suggests that the current trend toward regionalization of rectal cancer care to high-volume surgeons and high-volume centers has led to improved outcomes. These findings have implications regarding the policy of health care delivery in the United States, supporting referral to high-volume centers of excellence.
Hydration of biological macromolecules is important for their stability and function. Historically, attempts have been made to describe the degree of macromolecular hydration using a single parameter ...over a narrow range of values. Here, we describe a method to calculate two types of hydration: surface shell water and entrained water. A consideration of these two types of hydration helps to explain the “hydration problem” in hydrodynamics. The combination of these two types of hydration allows accurate calculation of hydrodynamic volume and related macromolecular properties such as sedimentation and diffusion coefficients, intrinsic viscosities, and the concentration-dependent non-ideality identified with sedimentation velocity experiments.
The set of available multi-objective optimisation algorithms continues to grow. This fact can be partially attributed to their widespread use and applicability. However, this increase also suggests ...several issues remain to be addressed satisfactorily. One such issue is the diversity and the number of solutions available to the decision maker (DM). Even for algorithms very well suited for a particular problem, it is difficult—mainly due to the computational cost—to use a population large enough to ensure the likelihood of obtaining a solution close to the DM's preferences. In this paper we present a novel methodology that produces additional Pareto optimal solutions from a Pareto optimal set obtained at the end run of any multi-objective optimisation algorithm for two-objective and three-objective problem instances.
In evolutionary multiobjective optimization, the task of the optimizer is to obtain an accurate and useful approximation of the true Pareto-optimal front. Proximity to the front and diversity of ...solutions within the approximation set are important requirements. Most established multiobjective evolutionary algorithms (MOEAs) have mechanisms that address these requirements. However, in many-objective optimization, where the number of objectives is greater than 2 or 3, it has been found that these two requirements can conflict with one another, introducing problems such as dominance resistance and speciation. In this paper, two diversity management mechanisms are introduced to investigate their impact on overall solution convergence. They are introduced separately, and in combination, and tested on a set of test functions with an increasing number of objectives (6-20). It is found that the inclusion of one of the mechanisms improves the performance of a well-established MOEA in many-objective optimization problems, in terms of both convergence and diversity. The relevance of this for many-objective MOEAs is discussed.
Many popular modes of scanning probe microscopy require a vertical feedback system to regulate the tip-sample interaction. Examples include constant-current scanning tunneling microscopy and ...constant-force atomic force microscopy. Due to the control of tip-sample interaction, these modes of microscopy provide precise topographic information and result in drastically reduced sample damage, hence their popularity. Unfortunately the vertical feedback controller also imposes a severe limit on the scan-speed of scanning probe microscopes. In this paper, the foremost bandwidth limitation is identified to be the low-frequency mechanical resonances of the scanner. To overcome this limitation, a dual-stage vertical positioner is proposed. This comprises the original scanner, plus an additional high-speed stage. The improved bandwidth provided by the high-speed stage allows a vast improvement in feedback gain and bandwidth. In this work, the bandwidth is increased from 83 Hz to 2.7 kHz. This improvement allows image quality to be retained with a speed increase of 33 times, or alternatively, feedback error can be reduced by 33 times if scan speed is not increased. The techniques proposed are mechanically and electrically simple and can be retrofitted to any scanning probe microscope.
We assess the evolution of glaciological structures during the 2003–05 surge in the Paulabreen glacier system, Svalbard. Glaciological structures on the glacier surface were mapped using aerial ...photographs captured in the early stages of the surge (2003) and 5 years after surge termination (2011). Three-dimensional measurements of glaciological structures were collected at the tidewater front in 2013. These datasets document the physical changes during (1) the late quiescent phase; (2) the early phase of the surge as the surge front propagated down Skobreen and advanced into Paulabreen and (3) the final stages of the surge following the surge front reaching the glacier terminus. Crevasse patterns and clusters of arcuate shear planes record zones of compressive and extensional flow associated with the downglacier progression of the surge front. The transfer of surging ice from Skobreen into Paulabreen caused lateral displacement of the medial moraines to the northeast. At the ice front, this movement tilted glaciological structures in the same direction. Structures at the southwest margin record strike–slip faulting and the elevation of debris into the ice in a zone of compression and transpression. We summarise these observations in a schematic reconstruction of structural evolution during the surge.
The outer membrane of Gram-negative bacteria is a unique asymmetric lipid bilayer composed of phospholipids (PLs) in the inner leaflet and lipopolysaccharides (LPSs) in the outer leaflet. Its ...function as a selective barrier is crucial for the survival of bacteria in many distinct environments, and it also renders Gram-negative bacteria more resistant to antibiotics than their Gram-positive counterparts. Here, we report the structural properties of a model of the Escherichia coli outer membrane and its interaction with outer membrane phospholipase A (OmpLA) utilizing molecular dynamics simulations. Our results reveal that given the lipid composition used here, the hydrophobic thickness of the outer membrane is ∼3 Å thinner than the corresponding PL bilayer, mainly because of the thinner LPS leaflet. Further thinning in the vicinity of OmpLA is observed due to hydrophobic matching. The particular shape of the OmpLA barrel induces various interactions between LPS and PL leaflets, resulting in asymmetric thinning around the protein. The interaction between OmpLA extracellular loops and LPS (headgroups and core oligosaccharides) stabilizes the loop conformation with reduced dynamics, which leads to secondary structure variation and loop displacement compared to that in a DLPC bilayer. In addition, we demonstrate that the LPS/PL ratios in asymmetric bilayers can be reliably estimated by the per-lipid surface area of each lipid type, and there is no statistical difference in the overall membrane structure for the outer membranes with one more or less LPS in the outer leaflet, although individual lipid properties vary slightly.
Thermodynamic stabilities are pivotal for understanding structure–function relationships of proteins, and yet such determinations are rare for membrane proteins. Moreover, the few measurements that ...are available have been conducted under very different experimental conditions, which compromises a straightforward extraction of physical principles underlying stability differences. Here, we have overcome this obstacle and provided structure–stability comparisons for multiple membrane proteins. This was enabled by measurements of the free energies of folding and the m values for the transmembrane proteins PhoP/PhoQ-activated gene product (PagP) and outer membrane protein W (OmpW) from Escherichia coli . Our data were collected in the same lipid bilayer and buffer system we previously used to determine those parameters for E. coli outer membrane phospholipase A (OmpLA). Biophysically, our results suggest that the stabilities of these proteins are strongly correlated to the water-to-bilayer transfer free energy of the lipid-facing residues in their transmembrane regions. We further discovered that the sensitivities of these membrane proteins to chemical denaturation, as judged by their m values, was consistent with that previously observed for water-soluble proteins having comparable differences in solvent exposure between their folded and unfolded states. From a biological perspective, our findings suggest that the folding free energies for these membrane proteins may be the thermodynamic sink that establishes an energy gradient across the periplasm, thus driving their sorting by chaperones to the outer membranes in living bacteria. Binding free energies of these outer membrane proteins with periplasmic chaperones support this energy sink hypothesis.
Heart failure encompasses a heterogeneous set of clinical features that converge on impaired cardiac contractile function
and presents a growing public health concern. Previous work has highlighted ...changes in both transcription and protein expression in failing hearts
, but may overlook molecular changes in less prevalent cell types. Here we identify extensive molecular alterations in failing hearts at single-cell resolution by performing single-nucleus RNA sequencing of nearly 600,000 nuclei in left ventricle samples from 11 hearts with dilated cardiomyopathy and 15 hearts with hypertrophic cardiomyopathy as well as 16 non-failing hearts. The transcriptional profiles of dilated or hypertrophic cardiomyopathy hearts broadly converged at the tissue and cell-type level. Further, a subset of hearts from patients with cardiomyopathy harbour a unique population of activated fibroblasts that is almost entirely absent from non-failing samples. We performed a CRISPR-knockout screen in primary human cardiac fibroblasts to evaluate this fibrotic cell state transition; knockout of genes associated with fibroblast transition resulted in a reduction of myofibroblast cell-state transition upon TGFβ1 stimulation for a subset of genes. Our results provide insights into the transcriptional diversity of the human heart in health and disease as well as new potential therapeutic targets and biomarkers for heart failure.
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