Acoustic function of sound hole design in musical instruments

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 69-70).Sound-hole, an essential component of stringed musical instruments, enhances the sound radiation in the lower octave by introducing a natural vibration mode called air resonance. Many musical instruments, including those from the violin, lute and oud families have evolved complex sound-hole geometries through centuries of trail and error. However, due to the inability of current theories to analyze complex sound-holes, the design knowledge in such sound-holes accumulated by time is still uncovered. Here we present the potential physical principles behind the historical development of complex sound-holes such as rosettes in lute, f-hole in violin and multiple sound-holes in oud families based on a newly developed unified approach to analyze general sound-holes. We showed that the majority of the air flow passes through the near-the-edge area of the opening, which has potentially led to the emergence of rosettes in lute family. Consequently, we showed that the variation in resonance frequency and bandwidth of different traditional rosettes with fixed outer diameter is less than a semitone, while the methods based on the total void area predicts variations of many semitones. Investigating the evolution of sound-holes in violin family from circular geometry in at least 10th century to the present-day f-hole geometry, we found that the evolution is consistent with a drive toward decreasing the void area and increasing the resonance bandwidth for a fixed resonance frequency. We anticipate this approach to be a starting point in discovering the concepts behind the geometrical design of the existing sound-hole geometries, and helping the musicians, instrument makers and scientists utilize this knowledge to design consistently better instruments.by Hadi Tavakoli Nia.S.M

Nanomechanics of cartilage at the matrix and molecular levels

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2013.Cataloged from PDF version of thesis.Includes bibliographical references.Cartilage, as well as many soft connective tissues, functions mechanically across a wide spectrum of daily loading frequencies (time scales), from <1 Hz in slow activities such as walking, to 1000 Hz for high-rate activities such as jumping and impact sports. A major mechanism underlying the macroscale mechanical functions of cartilage is known to be poroelasticity, based on previous theoretical and experimental studies. Poroelasticity manifests itself via fluid-solid frictional dissipation and intra-tissue fluid pressurization that underlie important mechanical functions of cartilage, especially frequency-dependent self-stiffening, load-bearing, energy dissipation, solute and fluid transport, lubrication and mechanotransduction. More recently, nanoscale methodologies have been employed to study cartilage function under quasi-static and low frequency loadings. However, the nanoscale full-frequency spectrum of poroelastic behavior, which is critically important to the understanding of molecular level fluid-solid interactions in dynamic loading, has not been well-studied. How does the molecular structure of cartilage provide optimal tissue-level function over the wide spectrum of daily joint motions, what are the molecular mechanisms underlying this optimal function, and how does impact loading induce molecular-level degradation of the extracellular matrix (ECM) that occurs at the earliest stages of post-traumatic osteoarthritis? In this thesis, atomic force microscopy (AFM)-based oscillatory loading was employed in conjunction with finite element modeling to quantify and predict the frequency-dependent mechanical properties of articular cartilage at deformation amplitudes [delta] ~ 2 - 15 nm; i.e., at length scales less than the dimension of single collagen or aggrecan molecules. The magnitude lE*l and the phase angle p of the dynamic complex indentation modulus were first measured in the frequency range, f ~ 0.2-130 Hz. For fresh, normal cartilage, the experimental frequency and length-scale dependence of lE*l and [pi], corresponded well with that predicted by a fibril-reinforced poroelastic model over a 3-decade frequency range. Hence, these results suggest that poroelasticity is the dominant mechanism underlying the frequency-dependent mechanical behavior observed, even for these nanoscale deformations. Second, a new AFM-based wide-frequency rheology system was developed to extend the typical frequency range of commercial AFMs (i.e., 0.1 - 300 Hz) to the much wider frequency range of 0.1 Hz to 10 kHz. The dynamic nanomechanical behavior of normal and glycosaminoglycan (GAG)-depleted cartilage (the latter representing matrix degradation that occurs at the earliest stages of osteoarthritis) were measured. The dynamic modulus of cartilage was found to undergo a dramatic alteration after GAG loss even with the collagen network still intact: while the magnitude of the dynamic modulus decreased 2-3-fold at higher frequencies, the hydraulic permeability increased up to 25-fold, suggesting that early osteoarthritic cartilage is more vulnerable to higher loading rates than to the conventionally studied 'loading magnitude'. Third, a key ECM macromolecule, the GAG-rich proteoglycan, aggrecan, was isolated from native cartilage. Dense brush layers of aggrecan having the same packing density as that in normal cartilage, were end-grafted onto gold-coated substrates for AFM-based nanomechanical studies. The dynamic mechanical behavior of these 3-D aggrecan layers, including fluid-solid interactions over a wide range of frequencies was quantified using the high frequency AFMbased rheology system. For the first time, the hydraulic permeability of aggrecan layers was measured at the molecular level and was quantified to be k = 4.8 x 10 -¹⁵ +/- 2.8 x 10 -¹⁵ m4/N-s, which closely matched both the nanoscale and macroscale hydraulic permeability of native cartilage. These results confirmed that aggrecan is primarily responsible for the resistance to fluid flow in cartilage at the molecular scale, and thereby primarily responsible for tissue-level poroelastic behavior. The mechanisms underlying the poroelasticity of aggrecan layers were also investigated and found to be dominated by the electrostatic interaction between the GAG chains of aggrecan.by Hadi Tavakoli Nia.Ph.D

Poroelasticity is the dominant energy dissipation mechanism in cartilage at the nano-scale

Recent studies of micro- and nano-scale mechanics of cartilage and chondrocyte pericellular matrix have begun to relate matrix molecular structure to its mechanical response. AFM-based indentation has revealed rate-dependent stiffness at the micro-scale. While multi-scale elastic behavior has been studied, and poro-viscoelastic properties have been extensively documented at the tissue-level, time-dependent behavior and energy dissipation mechanisms of cartilage matrix at the nano-scale are not well understood. Here, we used AFM-based dynamic compression in conjunction with poroelastic finite element modeling to study the frequency-dependent behavior of cartilage using nano-scale oscillatory displacement amplitudes. We introduce the characteristic frequency f[subscript peak] at which the maximum energy dissipation occurs as an important parameter to characterize matrix time-dependent behavior. Use of micron-sized AFM probe tips with nano-scale oscillatory displacements over a 3-decade frequency range enabled clear identification of this characteristic frequency f[subscript peak]. The length-scale dependence of poroelastic behavior combined with judicious choice of probe tip geometry revealed flow-dependent and flow-independent behavior during matrix displacement amplitudes on the order of macromolecular dimensions and intermolecular pore-sizes.National Science Foundation (U.S.) (Grant CMMI-0758651)National Institutes of Health (U.S.) (National Institute of Arthritis and Musculoskeletal and Skin Diseases (U.S.) Grant AR33236

High-bandwidth AFM-based rheology is a sensitive indicator of early cartilage aggrecan degradation relevant to mouse models of osteoarthritis

Murine models of osteoarthritis (OA) and post-traumatic OA have been widely used to study the development and progression of these diseases using genetically engineered mouse strains along with surgical or biochemical interventions. However, due to the small size and thickness of murine cartilage, the relationship between mechanical properties, molecular structure and cartilage composition has not been well studied. We adapted a recently developed AFM-based nano-rheology system to probe the dynamic nanomechanical properties of murine cartilage over a wide frequency range of 1 Hz to 10 kHz, and studied the role of glycosaminoglycan (GAG) on the dynamic modulus and poroelastic properties of murine femoral cartilage. We showed that poroelastic properties, highlighting fluid–solid interactions, are more sensitive indicators of loss of mechanical function compared to equilibrium properties in which fluid flow is negligible. These fluid-flow-dependent properties include the hydraulic permeability (an indicator of the resistance of matrix to fluid flow) and the high frequency modulus, obtained at high rates of loading relevant to jumping and impact injury in vivo. Utilizing a fibril-reinforced finite element model, we estimated the poroelastic properties of mouse cartilage over a wide range of loading rates for the first time, and show that the hydraulic permeability increased by a factor ~16 from k[subscript normal] = 7.80 × 10[superscript −16] ± 1.3 × 10[superscript −16] m[superscript 4]/N s to k[subscript GAG-depleted] = 1.26 × 10[superscript −14] ± 6.73 × 10[superscript −15] m[superscript 4]/N s after GAG depletion. The high-frequency modulus, which is related to fluid pressurization and the fibrillar network, decreased significantly after GAG depletion. In contrast, the equilibrium modulus, which is fluid-flow independent, did not show a statistically significant alteration following GAG depletion.National Institutes of Health (U.S.) (Grant 060331)Whitaker Foundation (Health Sciences Fund Fellowship)Arthritis Australi

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

Poroelasticity of Cartilage at the Nanoscale

Atomic-force-microscopy-based oscillatory loading was used in conjunction with finite element modeling to quantify and predict the frequency-dependent mechanical properties of the superficial zone of young bovine articular cartilage at deformation amplitudes, δ, of ∼15 nm; i.e., at macromolecular length scales. Using a spherical probe tip (R ∼ 12.5 μm), the magnitude of the dynamic complex indentation modulus, |E*|, and phase angle, φ, between the force and tip displacement sinusoids, were measured in the frequency range f ∼ 0.2–130 Hz at an offset indentation depth of δ[subscript 0] ∼ 3 μm. The experimentally measured |E*| and φ corresponded well with that predicted by a fibril-reinforced poroelastic model over a three-decade frequency range. The peak frequency of phase angle, f[subscript peak], was observed to scale linearly with the inverse square of the contact distance between probe tip and cartilage, [1 over d[superscript 2]], as predicted by linear poroelasticity theory. The dynamic mechanical properties were observed to be independent of the deformation amplitude in the range δ = 7–50 nm. Hence, these results suggest that poroelasticity was the dominant mechanism underlying the frequency-dependent mechanical behavior observed at these nanoscale deformations. These findings enable ongoing investigations of the nanoscale progression of matrix pathology in tissue-level disease.National Science Foundation (U.S.) (Grant CMMI-0758651)National Institutes of Health (U.S.) (Grant AR033236

Roles of Integrin and Its Application for Anti-viral Drug Development

Integrins are a large family of adhesion molecules under cellular control that could act bilabially in different situations; on the other hand, they play a significant role in adsorption and entry of immune system cells or other helper cells. Furthermore, they could be good targets for entry, localization and replication of infectious viruses into cells. As viruses apply various strategies for entry and infiltration to cells, comparison of these ways (especially integrin mediated), elucidates effective mechanisms in the inception of viral infection and the host cells interactions. At this point, the present study reviewed the relationships between common viruses such as Adenovirus, Papillomavirus, Herpesvirus, Hantavirus, Rotavirus, Echovirus, foot-and-mouth disease virus, Coxsackievirus type 9, Parechovirus type 1 and Human immunodeficiency virus type 1 with integrins and their viable interactions for therapeutical issues and better recognition of the commencement process of the infection by these viruses

Laser Speckle Rheology for evaluating the viscoelastic properties of hydrogel scaffolds

Natural and synthetic hydrogel scaffolds exhibit distinct viscoelastic properties at various length scales and deformation rates. Laser Speckle Rheology (LSR) offers a novel, non-contact optical approach for evaluating the frequency-dependent viscoelastic properties of hydrogels. In LSR, a coherent laser beam illuminates the specimen and a high-speed camera acquires the time-varying speckle images. Cross-correlation analysis of frames returns the speckle intensity autocorrelation function, g2(t), from which the frequency-dependent viscoelastic modulus, G*(ω), is deduced. Here, we establish the capability of LSR for evaluating the viscoelastic properties of hydrogels over a large range of moduli, using conventional mechanical rheometry and atomic force microscopy (AFM)-based indentation as reference-standards. Results demonstrate a strong correlation between |G*(ω)| values measured by LSR and mechanical rheometry (r = 0.95, p 0.08) over a large range (47 Pa – 36 kPa). In addition, |G*(ω)| values measured by LSR correlate well with indentation moduli, E, reported by AFM (r = 0.92, p < 10−7). Further, spatially-resolved moduli measurements in micro-patterned substrates demonstrate that LSR combines the strengths of conventional rheology and micro-indentation in assessing hydrogel viscoelastic properties at multiple frequencies and small length-scales

Nanoscale Poroelasticity of the Tectorial Membrane Determines Hair Bundle Deflections

Stereociliary imprints in the tectorial membrane (TM) have been taken as evidence that outer hair cells are sensitive to shearing displacements of the TM, which plays a key role in shaping cochlear sensitivity and frequency selectivity via resonance and traveling wave mechanisms. However, the TM is highly hydrated (97% water by weight), suggesting that the TM may be flexible even at the level of single hair cells. Here we show that nanoscale oscillatory displacements of microscale spherical probes in contact with the TM are resisted by frequency-dependent forces that are in phase with TM displacement at low and high frequencies, but are in phase with TM velocity at transition frequencies. The phase lead can be as much as a quarter of a cycle, thereby contributing to frequency selectivity and stability of cochlear amplification.National Institutes of Health (U.S.) (Grant R01-DC000238)National Science Foundation (U.S.) (Grant CMMI-1536233)National Science Foundation (Grant 1122374