What is the source level of pile-driving noise in water?

To meet the growing demand for carbon-free energy sources, the European Union (EU) has ambitious plans to increase its capacity for generation of offshore wind power. The United Kingdom and The Netherlands, for example, plan to increase their offshore power-generating capacity to 33 and 6 GW, respectively, by the year 2020. Assuming that this power is generated entirely by wind and that a single wind turbine can generate up to 10 MW, at least 3,900 offshore turbines would be required by these two states alone to achieve this goal. A popular turbine construction method known as “pile driving” involves the use of hammering a steel cylinder (a “monopile”) into the seabed. A concern has arisen for the possible effect on mammals (Southall et al. 2007) and fish (Popper and Hastings 2009) of the sound produced by the succession of hammer impacts required to sink the pile to its required depth (tens of meters)

Saquinavir Loaded Acetalated Dextran Microconfetti – a Long Acting Protease Inhibitor Injectable

Since the adoption of highly active antiretroviral therapy, HIV disease progression has slowed across the world; however, patients are often required to take multiple medications daily of poorly bioavailable drugs via the oral route, leading to gastrointestinal irritation. Recently, long acting antiretroviral injectables that deliver drug for months at a time have moved into late phase clinical trials. Unfortunately, these solid phase crystal formulations have inherent drawbacks in potential dose dumping and a greater likelihood for burst release of drug compared to polymeric formulations

Impaired myocardial function does not explain reduced left ventricular filling and stroke volume at rest or during exercise at high altitude

Impaired myocardial systolic contraction and diastolic relaxation have been suggested as possible mechanisms contributing to the decreased stroke volume (SV) observed at high altitude (HA). To determine whether intrinsic myocardial performance is a limiting factor in the generation of SV at HA, we assessed left ventricular (LV) systolic and diastolic mechanics and volumes in 10 healthy participants (aged 32 ± 7; mean ± SD) at rest and during exercise at sea level (SL; 344 m) and after 10 days at 5,050 m. In contrast to SL, LV end-diastolic volume was ∼19% lower at rest (P = 0.004) and did not increase during exercise despite a greater untwisting velocity. Furthermore, resting SV was lower at HA (∼17%; 60 ± 10 vs. 70 ± 8 ml) despite higher LV twist (43%), apical rotation (115%), and circumferential strain (17%). With exercise at HA, the increase in SV was limited (12 vs. 22 ml at SL), and LV apical rotation failed to augment. For the first time, we have demonstrated that EDV does not increase upon exercise at high altitude despite enhanced in vivo diastolic relaxation. The increase in LV mechanics at rest may represent a mechanism by which SV is defended in the presence of a reduced EDV. However, likely because of the higher LV mechanics at rest, no further increase was observed up to 50% peak power. Consequently, although hypoxia does not suppress systolic function per se, the capacity to increase SV through greater deformation during submaximal exercise at HA is restricted. during initial exposure to hypobaric hypoxia at high altitude (HA), cardiac output for a given absolute workload is increased to compensate for a lower arterial oxygen content before returning to baseline levels with acclimatization (8). However, after 2-5 days of acclimatization, the required cardiac output is generated through a lower stroke volume (SV) and higher heart rate (38). The reduced SV is suggestive of either lower ventricular filling, potentially caused in part by an impaired myocardial relaxation, or impaired ejection secondary to systolic contractile dysfunction. There is, however, a paucity of data in humans supporting a direct effect of hypoxia on myocardial function at HA (25, 41). The suggestion that hypoxia may impair myocardial systolic function during exercise was proposed nearly 50 years ago (3) and has been revisited more recently (27–29). Negative inotropic effects of hypoxia (arterial oxygen tension of 44 mmHg) have been shown in intact animal models (39) and isolated myocardial fibers under severe hypoxia (1% O2) (33). Exercise training under hypobaric hypoxia is also associated with altered mechanical properties at a cellular level in rodents (9), although chronic hypoxia alone did not decrease myofilament sensitivity to calcium. However, in contrast to animal studies, data in humans indicate that systolic function is maintained or enhanced at HA. For example, Suarez et al. (37) reported the maintenance of systolic function after gradual decompression to a barometric pressure of 282 mmHg, a finding that was subsequently confirmed by numerous investigations during acute and prolonged hypoxic exposure (6, 10, 12, 23, 31). However, of these studies, only Suarez et al. (37) investigated systolic function during light exercise (60 W), where function appeared to be maintained. It is not known whether systolic function is maintained at higher exercise intensities. It has also been speculated that reduced oxygen availability may impair diastolic relaxation at HA (15, 18) and thus explain the decreased left ventricular (LV) end-diastolic volume (EDV) commonly observed (2, 6, 18). However, despite numerous studies reporting a decrease in plasma volume and altered transmitral filling patterns (2, 6, 20), myocardial relaxation was only previously investigated during hypoxia in dogs (15), and no data exist examining LV relaxation during exercise at high altitude. By using sensitive, noninvasive imaging techniques (two-dimensional speckle tracking), it is now possible to examine the LV deformation mechanics (strain, twist, and untwist velocity) that underpin LV systolic and diastolic function. LV strain and twist have been shown to be sensitive measures of global and regional myocardial function, and reveal subclinical dysfunction in patients where ejection fraction is unchanged (16, 22). In addition, diastolic LV untwist velocity correlates well with invasive measures of LV stiffness and provides a temporal link between relaxation and the development of intraventricular pressure gradients (30, 43). Therefore, examination of LV mechanics at HA may determine whether the decreased SV observed at HA is dependent on impaired myocardial relaxation and/or myocardial contractile dysfunction or confirm previous findings of preserved ventricular function during exercise (37). We therefore assessed systolic and diastolic ventricular mechanics during incremental exercise at sea level and HA to examine whether impaired myocardial relaxation or systolic dysfunction explains the previously reported reduction in SV at HA. We hypothesized that at HA, 1) ventricular filling would be lower at rest and during exercise and would be accompanied by a reduction in untwist velocity and 2) systolic mechanics would be impaired during exercise at HA

How effectively do horizontal and vertical response strategies of long-finned pilot whales reduce sound exposure from naval sonar?

PJW was supported with studentships of The Netherlands Ministry of Defence (grant number 032.30370/01.02) and the VSB Foundation (grant number VSB.08/228-E) and Ren e Dekeling is acknowledged for making funding possible. The 3S project was supported by the US Office of Naval Research, The Netherlands Ministry of Defence, Royal Norwegian Navy and Norwegian Ministry of Defence, and by World Wildlife Fund Norway. PLT received funding from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland) and their support is gratefully acknowledged.The behaviour of a marine mammal near a noise source can modulate the sound exposure it receives. We demonstrate that two long-finned pilot whales both surfaced in synchrony with consecutive arrivals of multiple sonar pulses. We then assess the effect of surfacing and other behavioural response strategies on the received cumulative sound exposure levels and maximum sound pressure levels (SPLs) by modelling realistic spatiotemporal interactions of a pilot whale with an approaching source. Under the propagation conditions of our model, some response strategies observed in the wild were effective in reducing received levels (e.g. movement perpendicular to the source's line of approach), but others were not (e.g. switching from deep to shallow diving; synchronous surfacing after maximum SPLs). Our study exemplifies how simulations of source-whale interactions guided by detailed observational data can improve our understanding about motivations behind behaviour responses observed in the wild (e.g., reducing sound exposure, prey movement).PostprintPeer reviewe

Needle-Free Delivery of Acetalated Dextran-Encapsulated AR-12 Protects Mice from Francisella tularensis Lethal Challenge

ABSTRACT Francisella tularensis causes tularemia and is a potential biothreat. Given the limited antibiotics for treating tularemia and the possible use of antibiotic-resistant strains as a biowarfare agent, new antibacterial agents are needed. AR-12 is an FDA-approved investigational new drug (IND) compound that induces autophagy and has shown host-directed, broad-spectrum activity in vitro against Salmonella enterica serovar Typhimurium and F. tularensis . We have shown that AR-12 encapsulated within acetalated dextran (Ace-DEX) microparticles (AR-12/MPs) significantly reduces host cell cytotoxicity compared to that with free AR-12, while retaining the ability to control S. Typhimurium within infected human macrophages. In the present study, the toxicity and efficacy of AR-12/MPs in controlling virulent type A F. tularensis SchuS4 infection were examined in vitro and in vivo . No significant toxicity of blank MPs or AR-12/MPs was observed in lung histology sections when the formulations were given intranasally to uninfected mice. In histology sections from the lungs of intranasally infected mice treated with the formulations, increased macrophage infiltration was observed for AR-12/MPs, with or without suboptimal gentamicin treatment, but not for blank MPs, soluble AR-12, or suboptimal gentamicin alone. AR-12/MPs dramatically reduced the burden of F. tularensis in infected human macrophages, in a manner similar to that of free AR-12. However, in vivo , AR-12/MPs significantly enhanced the survival of F. tularensis SchuS4-infected mice compared to that seen with free AR-12. In combination with suboptimal gentamicin treatment, AR-12/MPs further improved the survival of F. tularensis SchuS4-infected mice. These studies provide support for Ace-DEX-encapsulated AR-12 as a promising new therapeutic agent for tularemia

Degradation of acetalated dextran can be broadly tuned based on cyclic acetal coverage and molecular weight

Microparticles (MPs) derived from acid-sensitive biopolymers enable rapid degradation and cargo release under acidic conditions, such as at tumor microenvironments, within lysosomal/phagosomal compartments inside phagocytic cells, or at sites of inflammation. One such acid-sensitive biopolymer, acetalated dextran (Ace-DEX), has tunable degradation rates and pH-neutral degradation byproducts consisting of dextran, acetone, and ethanol. By studying the degradation profiles of Ace-DEX MPs with varying cyclic acetal coverage (CAC) and dextran molecular weight (MW), we concluded that MPs composed of low CAC or high MW polymer degraded the fastest at both pH 7.4 and 5.0. To further understand the properties of this unique polymer, we encapsulated a model drug resiquimod, which is a toll-like receptor (TLR) 7/8 agonist, into Ace-DEX MPs of different polymer CAC and dextran MW. It was observed that resiquimod was released faster from MPs of lower CAC or higher MW. By evaluating the activation of RAW macrophages cultured with different types of resiquimod-loaded Ace-DEX MPs, we found that MPs of lower CAC or higher MW promoted greater nitrite production and resulted in more robust cell activation. Our results indicate we can precisely control the degradation profile, release kinetics, and bioactivity of encapsulated cargos by altering CAC and MW, furthering Ace-DEX MPs' novelty as a drug carrier

Morning exercise mitigates the impact of prolonged sitting on cerebral blood flow in older adults

Preventing declines in cerebral blood flow is important for maintaining optimal brain health with aging. We compared the effects of a morning bout of moderate-intensity exercise, with and without subsequent light-intensity walking breaks from sitting, on cerebral blood velocity over 8 h in older adults. In a randomized crossover trial, overweight/obese older adults (n = 12, 70 ± 7 yr; 30.4 ± 4.3 kg/m2), completed three acute conditions (6-day washout); SIT: prolonged sitting (8 h, control); EX+SIT: sitting (1 h), moderate-intensity walking (30 min), followed by uninterrupted sitting (6.5 h); and EX + BR: sitting (1 h), moderate-intensity walking (30 min), followed by sitting (6.5 h) interrupted with 3 min of light-intensity walking every 30 min. Bilateral middle cerebral artery velocities (MCAv) were determined using transcranial Doppler at 13 time points across the day. The temporal pattern and average MCAv over 8 h was determined. The pattern of MCAv over 8 h was a negative linear trend in SIT (P < 0.001), but a positive quadratic trend in EX + SIT (P < 0.001) and EX + BR (P < 0.01). Afternoon time points in SIT were lower than baseline within condition (P ≤ 0.001 for all). A morning dip in MCAv was observed in EX + SIT and EX + BR (P < 0.05 relative to baseline), but afternoon time points were not significantly lower than baseline. The average MCAv over 8 h was higher in EX + SIT than SIT (P = 0.007) or EX + BR (P = 0.024). Uninterrupted sitting should be avoided, and moderate-intensity exercise should be encouraged for the daily maintenance of cerebral blood flow in older adults. The clinical implications of maintaining adequate cerebral blood flow include the delivery of vital oxygen and nutrients to the brain

Modelling the broadband propagation of marine mammal echolocation clicks for click-based population density estimates

Funding: U.S. Office of Naval Research (ONR Grant No. N00014-14-1-0409); P.L.T. acknowledges funding received from the MASTS pooling initiative (The Marine Alliance for Science and Technology for Scotland). MASTS is funded by the Scottish Funding Council (Grant No. HR09011) and contributing institutions.Passive acoustic monitoring with widely-dispersed hydrophones has been suggested as a cost-effective method to monitor population densities of echolocating marine mammals. This requires an estimate of the area around each receiver over which vocalizations are detected—the “effective detection area” (EDA). In the absence of auxiliary measurements enabling estimation of the EDA, it can be modelled instead. Common simplifying model assumptions include approximating the spectrum of clicks by flat energy spectra, and neglecting the frequency-dependence of sound absorption within the click bandwidth (narrowband assumption), rendering the problem amenable to solution using the sonar equation. Here, it is investigated how these approximations affect the estimated EDA and their potential for biasing the estimated density. EDA was estimated using the passive sonar equation, and by applying detectors to simulated clicks injected into measurements of background noise. By comparing model predictions made using these two approaches for different spectral energy distributions of echolocation clicks, but identical click source energy level and detector settings, EDA differed by up to a factor of 2 for Blainville's beaked whales. Both methods predicted relative density bias due to narrowband assumptions ranged from 5% to more than 100%, depending on the species, detector settings, and noise conditions.Publisher PDFPeer reviewe