Molecular motors in cells typically produce highly directed motion; however, the aggregate, incoherent effect of all active processes also creates randomly fluctuating forces, which drive ...diffusive-like, nonthermal motion. Here, we introduce force-spectrum-microscopy (FSM) to directly quantify random forces within the cytoplasm of cells and thereby probe stochastic motor activity. This technique combines measurements of the random motion of probe particles with independent micromechanical measurements of the cytoplasm to quantify the spectrum of force fluctuations. Using FSM, we show that force fluctuations substantially enhance intracellular movement of small and large components. The fluctuations are three times larger in malignant cells than in their benign counterparts. We further demonstrate that vimentin acts globally to anchor organelles against randomly fluctuating forces in the cytoplasm, with no effect on their magnitude. Thus, FSM has broad applications for understanding the cytoplasm and its intracellular processes in relation to cell physiology in healthy and diseased states.
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•Random intracellular motion is driven by active force fluctuations in the cytoplasm•The aggregate random forces enhance motion of small proteins and large organelles•We develop force spectrum microscopy to probe aggregate random cytoplasmic forces•The aggregate random forces are larger in malignant cancer cells than benign cells
A new technique called force spectrum microscopy allows probing random active force fluctuations in the cytoplasm of living cells. These forces drive a diffusive-like mechanism of transport of organelles and proteins in the cytoplasm and are more active in cancer than in normal cells.
Purpose Guidelines regarding the prevention, detection, and management of surgical site infections (SSI) have been published previously.1-3 This document is intended to update prior guidelines based ...on the current literature and to provide a concise summary of relevant topics.
Summary Background Abdominoperineal resection is the standard treatment for patients with distal T2 or T3 rectal cancers; however, the procedure is extensive and mutilating, and alternative treatment ...strategies are being investigated. We did a prospective observational trial to assess whether high-dose radiotherapy with concomitant chemotherapy followed by observation (watchful waiting) was successful for non-surgical management of low rectal cancer. Methods Patients with primary, resectable, T2 or T3, N0–N1 adenocarcinoma in the lower 6 cm of the rectum were given chemoradiotherapy (60 Gy in 30 fractions to tumour, 50 Gy in 30 fractions to elective lymph node volumes, 5 Gy endorectal brachytherapy boost, and oral tegafur-uracil 300 mg/m2 ) every weekday for 6 weeks. Endoscopies and biopsies of the tumour were done at baseline, throughout the course of treatment (weeks 2, 4, and 6), and 6 weeks after the end of treatment. We allocated patients with complete clinical tumour regression, negative tumour site biopsies, and no nodal or distant metastases on CT and MRI 6 weeks after treatment to the observation group (watchful waiting). We referred all other patients to standard surgery. Patients under observation were followed up closely with endoscopies and selected-site biopsies, with surgical resection given for local recurrence. The primary endpoint was local tumour recurrence 1 year after allocation to the observation group. This study is registered with ClinicalTrials.gov , number NCT00952926 . Enrolment is closed, but follow-up continues for secondary endpoints. Findings Between Oct 20, 2009, and Dec 23, 2013, we enrolled 55 patients. Patients were recruited from three surgical units throughout Denmark and treated in one tertiary cancer centre (Vejle Hospital, Vejle, Denmark). Of 51 patients who were eligible, 40 had clinical complete response and were allocated to observation. Median follow-up for local recurrence in the observation group was 23·9 months (IQR 15·3–31·0). Local recurrence in the observation group at 1 year was 15·5% (95% CI 3·3–26·3). The most common acute grade 3 adverse event during treatment was diarrhoea, which affected four (8%) of 51 patients. Sphincter function in the observation group was excellent, with 18 (72%) of 25 patients at 1 year and 11 (69%) of 16 patients at 2 years reporting no faecal incontinence at all and a median Jorge-Wexner score of 0 (IQR 0–0) at all timepoints. The most common late toxicity was bleeding from the rectal mucosa; grade 3 bleeding was reported in two (7%) in 30 patients at 1 year and one (6%) of 17 patients at 2 years. There were no unexpected serious adverse reactions or treatment-related deaths. Interpretation High-dose chemoradiotherapy and watchful waiting might be a safe alternative to abdominoperineal resection for patients with distal rectal cancer. Funding CIRRO—The Lundbeck Foundation Center for Interventional Research in Radiation Oncology and The Danish Council for Strategic Research.
The purpose of this study was to characterize the recurrence dynamics in breast cancer patients after delayed reconstruction. We hypothesized that surgical reconstruction might stimulate dormant ...micrometastases and reduce time to recurrence. All mastectomy breast cancer patients with delayed surgical reconstruction at Haukeland University Hospital, between 1977 and 2007,
n
= 312, were studied. Our control group consisted of 1341 breast cancer patients without reconstruction. For each case, all patients in the control group with identical T and N stages and age ±2 years were considered. A paired control was randomly selected from this group. 10 years after primary surgery, 39 of the cases had relapsed, compared to 52 of the matched controls. The reconstructed group was analyzed for relapse dynamics after mastectomy; the first peak in relapses was similarly timed, but smaller than for the controls, while the second peak was similar in time and size. Second, the relapse pattern was analyzed with reconstruction as the starting point. A peak in recurrences was found after 18 months, and a lower peak at the 5th–6th year. The height of the peak correlated with the extent of surgery and initial T and N stages. Timing of the peak was not affected, neither was the cumulative effect. The relapse pattern, when time origin is placed both at mastectomy and at reconstruction, is bimodal with a peak position at the same time points, at 2 years and at 5–6 years. The timing of the transition from dormant micrometastases into clinically detectable macrometastases might be explained by an enhancing effect of surgery.
This article presents a brief survey on some of the latest developments in the area of reliability-based design optimization of structural systems under stochastic excitation. The contributions are ...grouped into three main categories, namely, sequential optimization approaches, stochastic search based techniques, and schemes based on augmented reliability spaces. The different approaches are described and summarized. In addition, remarks are provided about their range of application, advantages, disadvantages, relevance, and potential research directions. The literature review indicates that computational aspects play a key role in the solution of this class of optimization problems. Besides, this overview suggests that methods for optimal design in stochastic structural dynamics are no longer restricted to academic-type of problems but they can be used as tools in a class of engineering design problems as well.
•Recent advances for reliability-based optimization of structural systems under stochastic excitation are presented.•Underlying reliability models are high-dimensional.•Available approaches are compared in terms of their scope of applications.•Computational aspects play a key role in solving this type of problems.•Current methods can be used in a class of practical-type of problems.•Further research can lead to significant advancements in this area.
Purpose
The aim of this study was to summarize and evaluate the current scientific literature on stress and strain on seafarers on board as defined by maritime field surveys.
Methods
Using a ...systematic review, 109 studies on the stress and strain experienced by seafarers were identified for the period January 1990 to January 2012.
Results
Only 13 of the identified maritime studies were conducted as field studies, and in 10 of these studies, the focus was on the watch system and/or on fatigue. According to the study results, sleepiness tends to be stronger in the 2-watch system than in the 3-watch system (particularly between 4:00 and 6:00 a.m.). Occasional short sleep episodes appear to provide adequate recovery. Fatigue does not appear to depend on the seafarers’ age and is often associated with poor sleep quality; noise and night shifts are also considered to contribute to fatigue. Stress among the seafarers was primarily recorded in sleep diaries (9 times) and with devices for measuring physical activity (4 times). As a rule, a questionnaire was used to assess the strain on the crew on board; 7 studies also additionally recorded biometrical parameters. Only in 6 cases were several groups with different ranks on board investigated.
Conclusion
The conducted literature review makes it clear that most maritime field studies have focused on fatigue and watch systems in the shipping industry—in each case as univariate parameters. Thus, scientific field studies with comprehensive multivariate stress and strain analyses on board are required.
Cells alter their mechanical properties in response to their local microenvironment; this plays a role in determining cell function and can even influence stem cell fate. Here, we identify a robust ...and unified relationship between cell stiffness and cell volume. As a cell spreads on a substrate, its volume decreases, while its stiffness concomitantly increases. We find that both cortical and cytoplasmic cell stiffness scale with volume for numerous perturbations, including varying substrate stiffness, cell spread area, and external osmotic pressure. The reduction of cell volume is a result of water efflux, which leads to a corresponding increase in intracellular molecular crowding. Furthermore, we find that changes in cell volume, and hence stiffness, alter stem-cell differentiation, regardless of the method by which these are induced. These observations reveal a surprising, previously unidentified relationship between cell stiffness and cell volume that strongly influences cell biology.
Measuring molecular diffusion is widely used for characterizing materials and living organisms noninvasively. This characterization relies on relations between macroscopic diffusion metrics and ...structure at the mesoscopic scale commensurate with the diffusion length. Establishing such relations remains a fundamental challenge, hindering progress in materials science, porous media, and biomedical imaging. Here we show that the dynamical exponent in the time dependence of the diffusion coefficient distinguishes between the universality classes of the mesoscopic structural complexity. Our approach enables the interpretation of diffusion measurements by objectively selecting and modeling the most relevant structural features. As an example, the specific values of the dynamical exponent allow us to identify the relevant mesoscopic structure affecting MRI-measured water diffusion in muscles and in brain, and to elucidate the structural changes behind the decrease of diffusion coefficient in ischemic stroke.
We synthesized policy implications of tourism and hospitality research by reviewing 12,269 articles published in 10 leading journals from 2012 to 2021. The most common rationale for policies (i.e., ...the why) is market failure, while the most typical role of policies (i.e., the how) is to create incentives. In addition, policies are typically hybrid and include suggestions for formal and informal institutional setups (i.e., the what). Because our review revealed that only 114 articles (i.e., 0.93%) included the why, how, and what of actual policies, we offer a theory-based research agenda on policy-making focused on making tourism and hospitality more inclusive and focusing on evolutionary dynamics, providing an understanding of the impact of crises and contemporary solutions, focusing on resilience and institutional complexity, and addressing the actors and time dimension. Our results, combined with those of our suggested research directions, will benefit organizations and society and simultaneously enhance the perceived societal value-added, contributions, and stature of tourism and hospitality research.
Real-world observable physical and chemical characteristics are increasingly being calculated from the 3D structures of biomolecules. Methods for calculating pKa values, binding constants of ligands, ...and changes in protein stability are readily available, but often the limiting step in computational biology is the conversion of PDB structures into formats ready for use with biomolecular simulation software. The continued sophistication and integration of biomolecular simulation methods for systems- and genome-wide studies requires a fast, robust, physically realistic and standardized protocol for preparing macromolecular structures for biophysical algorithms. As described previously, the PDB2PQR web server addresses this need for electrostatic field calculations (Dolinsky et al., Nucleic Acids Research, 32, W665-W667, 2004). Here we report the significantly expanded PDB2PQR that includes the following features: robust standalone command line support, improved pKa estimation via the PROPKA framework, ligand parameterization via PEOE_PB charge methodology, expanded set of force fields and easily incorporated user-defined parameters via XML input files, and improvement of atom addition and optimization code. These features are available through a new web interface (http://pdb2pqr.sourceforge.net/), which offers users a wide range of options for PDB file conversion, modification and parameterization.
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