Peering from the outside in: viscoelastic properties of the extracellular matrix dictate spatial organization and apoptosis resistance in mammary epithelial cells

The compliance of the extracellular matrix (ECM) differs between tissues and is altered in tumors. We examined the consequence of modifying the viscoelastic properties of the ECM on mammary epithelial cell (MEC) morphogenesis and apoptosis regulation. Results showed that the elastic modulus of the ECM exerts a profound effect on MEC tissue organization and gene expression that correlates with changes in actin organization and apoptosis resistance. Altering the rigidity of the ECM directly influences integrin expression and additionally modifies integrin-induced gene expression in association with actin reorganization. These data suggest that the compliance of the ECM may cooperatively regulate cell behavior by altering integrin function. Studies are now underway to investigate the possibility that these effects are mediated via changes in integrin-actin cytoskeletal dynamics

Unsteady interactions among multiple ships with free-surface effects

Ships often have to pass each other in proximity inharbor area and waterways in dense shipping trafficenvironment. Hydrodynamic interaction occurs whena ship is overtaking (or being overtaken) orencountering other ships. Such an interactive effectcould be magnified in confined waterways, e.g.shallow and narrow rivers. Since Yeung (1978)published his initial work on ship-interaction inshallow water, progress on unsteady interactionamong multiple ships has been slow though steadyover the following decades. With some exceptions,nearly all the published studies on ship-to-shipproblem neglected free-surface effects, and a rigidwall condition has often been applied on the watersurface as the boundary condition. When the speed ofthe ships is low, this assumption is reasonablyaccurate, as the hydrodynamic interaction is mainlyinduced by near-field disturbances. However, in manymaneuvering operations, the encountering orovertaking speeds are actually moderately high(Froude number Fn>0.2, where ≡ / , U isship speed, g the gravitational acceleration and L theship length), especially when the lateral separationbetween ships is the order of ship length. Here, the farfieldeffects arising from ship waves can be important.The hydrodynamic interaction model must take intoaccount of the surface-wave effects.Classical potential-flow formulation is only ableto deal with the boundary value problem (BVP) whenthere is only one speed involved in the free-surfaceboundary condition. For multiple ships travelling withdifferent speeds, it is not possible to express the freesurfaceboundary condition by a single velocitypotential. Instead, a superposition method can beapplied to account for the velocity field induced byeach vessel with its own and unique speed. The mainobjective of the present paper is to propose a rationalsuperposition method to handle the unsteady freesurfaceboundary condition containing two or morespeed terms, and validate its feasibility in predictingthe hydrodynamic behaviour of the ships duringovertaking or encountering operations. The solutionmethodology used in the present paper is a threedimensionalboundary-element method (BEM) basedon a Rankine-type (infinite-space) source function,initiated introduced in Bai & Yeung (1974). Thenumerical simulations are conducted by using an inhousedeveloped multi-body hydrodynamicinteraction program "MHydro". Waves generated andforces (or moments) are calculated when ships areencountering or passing each other. Published modeltestresults are used to validate our calculations andvery good agreement has been observed. Thenumerical results show that free-surface effects needto be taken into account for Fn > 0.2

Free-surface effects on interaction of multiple ships moving at different speeds

Ships often have to pass each other in proximity in harbor areas and waterways in dense shipping-traffic environment. Hydrodynamic interaction occurs when a ship is overtaking (or being overtaken) or encountering other ships. Such an interactive effect could be magnified in confined waterways, e.g., shallow and narrow rivers. Since Yeung published his initial work on ship interaction in shallow water, progress on unsteady interaction among multiple ships has been slow, though steady, over the following decades. With some exceptions, nearly all the published studies on ship-to-ship problem neglected free-surface effects, and a rigid-wall condition has often been applied on the water surface as the boundary condition. When the speed of the ships is low, this assumption is reasonably accurate as the hydrodynamic interaction is mainly induced by near-field disturbances. However, in many maneuvering operations, the encountering or overtaking speeds are actually moderately high (Froude number F n > 0.2, where F n ≡ U / g L , U is ship speed, g is the gravitational acceleration, and L is the ship length), especially when the lateral separation between ships is the order of ship length. Here, the far-field effects arising from ship waves can be important. The hydrodynamic interaction model must take into account the surface-wave effects. Classical potential-flow formulation is only able to deal with the boundary value problem when there is only one speed involved in the free-surface boundary condition. For multiple ships traveling with different speeds, it is not possible to express the free-surface boundary condition by a single velocity potential. Instead, a superposition method can be applied to account for the velocity field induced by each vessel with its own and unique speed. The main objective of the present article is to propose a rational superposition method to handle the unsteady free-surface boundary condition containing two or more speed terms, and validate its feasibility in predicting the hydrodynamic behavior in ship encountering. The methodology used in the present article is a three-dimensional boundary-element method based on a Rankine-type (infinite-space) source function, initially introduced by Bai and Yeung. The numerical simulations are conducted by using an in-house–developed multibody hydrodynamic interaction program “MHydro.” Waves generated and forces (or moments) are calculated when ships are encountering or passing each other. Published model-test results are used to validate our calculations, and very good agreement has been observed. The numerical results show that free-surface effects need to be taken into account for F n > 0.2

The effectiveness of dietary approaches to stop hypertension (DASH) counselling on estimated 10-year cardiovascular risk among patients with newly diagnosed grade 1 hypertension : a randomised clinical trial

The Dietary Approaches to Stop Hypertension (DASH) has been shown to lower blood pressure in the West. However, the real-life impact of DASH on reducing cardiovascular (CV) risk in routine clinical setting has not been studied. Methods A parallel-group, open-labelled, physician-blinded, randomised controlled trial was conducted in January–June 2013 and followed up for 6- and 12-months in primary care settings in Hong Kong. Patients newly diagnosed with grade 1 hypertension (aged 40–70 years) who had no concomitant medical conditions requiring dietary modifications were consecutively recruited. Subjects were randomised to standard education (usual care) (n = 275), or usual care plus dietitian-delivered DASH-based dietary counselling in a single one-to-one session (intervention) (n = 281). Primary outcomes were the changes in estimated 10-year CV risk. Results Outcome data were available for 504 (90.6%) and 485 (87.2%) patients at 6 and 12 months, respectively. There was no difference in the reduction of 10-year CV risk between the two groups at 6 months (−0.13%, 95% confidence interval [95% CI] −0.50% to 0.23%, p = 0.477) and 12 months (−0.08%, 95% CI −0.33% to 0.18%, p = 0.568). Multivariate regression analyses showed that male subjects, younger patients, current smokers, subjects with lower educational level, and those who dined out for main meals for ≥4 times in a typical week were significantly associated with no improvements in CV risk. Conclusions The findings may not support automatic referral of newly diagnosed grade 1 hypertensive patients for further one-to-one dietitian counselling on top of primary care physician's usual care. Patients with those risk factors identified should receive more clinical attention to reduce their CV risk

Radio Astronomy

Contains reports on eleven research projects.National Science Foundation (Grant AST79-25075)National Science Foundation (Grant AST79-20984)National Science Foundation (Grant AST79-19553)U.S. Navy - Office of Naval Research (Contract N00014-80-C-0348)National Aeronautics and Space Administration (Grant NAG2-50)MIT Sloan Fund for Basic ResearchJoint Services Electronics Program(Contract DAAG80-C-0104)Lockheed Aircraft Corporation (Contract LS90B4860F)National Aeronautics and Space Administration (Grant NAG5-10)National Aeronautics and Space Administration (Contract NAS5-22929)U.S. Department of Commerce, National Oceanic and Atmospheric Administration (Grant 04-8-MO1-1)California Institute of Technology Jet Propulsion Laboratory (Contract LZ-727891)California Institute of Technology Jet Propulsion Laboratory Subcontract 956059California Institute of Technology Jet Propulsion Laboratory Task Order RD-15

Radio Astronomy

Contains reports on sixteen research projects.National Science Foundation (Grant AST81-21416)National Science Foundation (Grant AST80-22864)National Aeronautics and Space Administration (Contract S-10665-C)National Aeronautics and Space Administration (Contract NAGW373)National Science Foundation (Grant AST79-19553)National Oceanic and Atmospheric Administration (Grant 04-8-M01-1)National Aeronautics and Space Administration (Grant NAG5-10)National Aeronautics and Space Administration (Contract NAS5-22929)Defense Advanced Research Projects Agency (Contract MDA 903-82-K-0521)Intelsat (Contract Intel-188)Joint Services Electronics Program (Contract DAAG29-80-C-0104)Lockheed Missiles and Space Company (Contract LS90B4860F

Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

BACKGROUND: In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown. METHODS: Common and rare genetic variants in the GPR146 gene locus were used as research instruments in the UK-Biobank. The Lifelines, and The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare GPR146 variants. RESULTS: In the UK-Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease (P=0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between GPR146 gene expression and plasma lipid and liver enzyme levels. CONCLUSIONS: This study shows that carriers of new genetic GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans

Randomized Clinical Trials and Observational Tribulations: Providing Clinical Evidence for Personalized Surgical Pain Management Care Models

Proving clinical superiority of personalized care models in interventional and surgical pain management is challenging. The apparent difficulties may arise from the inability to standardize complex surgical procedures that often involve multiple steps. Ensuring the surgery is performed the same way every time is nearly impossible. Confounding factors, such as the variability of the patient population and selection bias regarding comorbidities and anatomical variations are also difficult to control for. Small sample sizes in study groups comparing iterations of a surgical protocol may amplify bias. It is essentially impossible to conceal the surgical treatment from the surgeon and the operating team. Restrictive inclusion and exclusion criteria may distort the study population to no longer reflect patients seen in daily practice. Hindsight bias is introduced by the inability to effectively blind patient group allocation, which affects clinical result interpretation, particularly if the outcome is already known to the investigators when the outcome analysis is performed (often a long time after the intervention). Randomization is equally problematic, as many patients want to avoid being randomly assigned to a study group, particularly if they perceive their surgeon to be unsure of which treatment will likely render the best clinical outcome for them. Ethical concerns may also exist if the study involves additional and unnecessary risks. Lastly, surgical trials are costly, especially if the tested interventions are complex and require long-term follow-up to assess their benefit. Traditional clinical testing of personalized surgical pain management treatments may be more challenging because individualized solutions tailored to each patient’s pain generator can vary extensively. However, high-grade evidence is needed to prompt a protocol change and break with traditional image-based criteria for treatment. In this article, the authors review issues in surgical trials and offer practical solutions

The Changing Environment in Postgraduate Education in Orthopedic Surgery and Neurosurgery and Its Impact on Technology-Driven Targeted Interventional and Surgical Pain Management : Perspectives from Europe, Latin America, Asia, and The United States

Personalized care models are dominating modern medicine. These models are rooted in teaching future physicians the skill set to keep up with innovation. In orthopedic surgery and neurosurgery, education is increasingly influenced by augmented reality, simulation, navigation, robotics, and in some cases, artificial intelligence. The postpandemic learning environment has also changed, emphasizing online learning and skill- and competency-based teaching models incorporating clinical and bench-top research. Attempts to improve work–life balance and minimize physician burnout have led to work-hour restrictions in postgraduate training programs. These restrictions have made it particularly challenging for orthopedic and neurosurgery residents to acquire the knowledge and skill set to meet the requirements for certification. The fast-paced flow of information and the rapid implementation of innovation require higher efficiencies in the modern postgraduate training environment. However, what is taught typically lags several years behind. Examples include minimally invasive tissue-sparing techniques through tubular small-bladed retractor systems, robotic and navigation, endoscopic, patient-specific implants made possible by advances in imaging technology and 3D printing, and regenerative strategies. Currently, the traditional roles of mentee and mentor are being redefined. The future orthopedic surgeons and neurosurgeons involved in personalized surgical pain management will need to be versed in several disciplines ranging from bioengineering, basic research, computer, social and health sciences, clinical study, trial design, public health policy development, and economic accountability. Solutions to the fast-paced innovation cycle in orthopedic surgery and neurosurgery include adaptive learning skills to seize opportunities for innovation with execution and implementation by facilitating translational research and clinical program development across traditional boundaries between clinical and nonclinical specialties. Preparing the future generation of surgeons to have the aptitude to keep up with the rapid technological advances is challenging for postgraduate residency programs and accreditation agencies. However, implementing clinical protocol change when the entrepreneur–investigator surgeon substantiates it with high-grade clinical evidence is at the heart of personalized surgical pain management