Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double-blind, pilot study.

The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain

Role of adiponectin and inflammation in insulin resistance of Mc3r and Mc4r knockout mice

Objective: To investigate the involvement of hypoadiponectinemia and inflammation in coupling obesity to insulin resistance in melanocortin-3 receptor and melanocortin-4 receptor knockout (KO) mice (Mc3/4rKO). Research Methods and Procedures: Sera and tissue were collected from 6-month-old Mc3rKO, Mc4rKO, and wild-type C57BL6J litter mates maintained on low-fat diet or exposed to high-fat diet (HFD) for 1 or 3 months. Inflammation was assessed by both real-time polymerase chain reaction analysis of macrophage-specific gene expression and immunohistochemistry. Results: Mc4rKO exhibited hypoadiponectinemia, exacerbated by HFD and obesity, previously reported in murine models of obesity. Mc4r deficiency was also associated with high levels of macrophage infiltration of adipose tissue, again exacerbated by HFD. In contrast, Mc3rKO exhibited normal serum adiponectin levels, irrespective of diet or obesity, and a delayed inflammatory response to HFD relative to Mc4rKO. Discussion: Our findings suggest that severe insulin resistance of Mc4rKO fed a HFD, as reported in other models of obesity such as leptin-deficient (Lep ob/Lepob) and KK-Ay mice, is linked to reduced serum adiponectin and high levels of inflammation in adipose tissue. Conversely, maintenance of normal serum adiponectin may be a factor in the relatively mild insulin-resistant phenotype of severely obese Mc3rKO. Mc3rKO are, thus, a unique mouse model where obesity is not associated with reduced serum adiponectin levels. A delay in macrophage infiltration of adipose tissue of Mc3rKO during exposure to HFD may also be a factor contributing to the mild insulin resistance in this model. Copyright © 2007 NAASO

The impact of salinity perturbations on the future uptake of heat by the Atlantic Ocean

Anthropogenic ocean heat uptake is a key factor in determining climate change and sea-level rise. There is considerable uncertainty in projections of freshwater forcing of the ocean, with the potential to influence ocean heat uptake. We investigatethis by adding either -0.1 Sv or +0.1 Sv freshwater to the Atlantic in global climate model simulations, simultaneously imposing an atmospheric CO2 increase. The resulting changes in the Atlantic meridional overturning circulation are roughly equal and opposite (±2Sv). The impact of the perturbation on ocean heat content is more complex, although it is relatively small (~5%) compared to the total anthropogenic heat uptake. Several competing processes either accelerate or retard warming at different depths. Whilst positive freshwater perturbations cause an overall heating of the Atlantic, negative perturbations produce insignificant net changes in heat content. The processes active in our model appear robust, although their net result is likely model- and experiment-dependent

Jumping without slipping: leafhoppers (Hemiptera: Cicadellidae) possess special tarsal structures for jumping from smooth surfaces.

Many hemipteran bugs can jump explosively from plant substrates, which can be very smooth. We therefore analysed the jumping performance of froghoppers (Philaenus spumarius, Aphrophoridae) and leafhoppers (Aphrodes bicinctus/makarovi, Cicadellidae) taking off from smooth (glass) and rough (sandpaper, 30 µm asperity size) surfaces. On glass, the propulsive hind legs of Philaenus froghoppers slipped, resulting in uncontrolled jumps with a fast forward spin, a steeper angle and only a quarter of the velocity compared with jumps from rough surfaces. By contrast, Aphrodes leafhoppers took off without their propulsive hind legs slipping, and reached low take-off angles and high velocities on both substrates. This difference in jumping ability from smooth surfaces can be explained not only by the lower acceleration of the long-legged leafhoppers, but also by the presence of 2-9 soft pad-like structures (platellae) on their hind tarsi, which are absent in froghoppers. High-speed videos of jumping showed that platellae contact the surface briefly (approx. 3 ms) during the acceleration phase. Friction force measurements on individual hind tarsi on glass revealed that at low sliding speeds, both pushing and pulling forces were small, and insufficient to explain the recorded jumps. Only when the tarsi were pushed with higher velocities did the contact area of the platellae increase markedly, and high friction forces were produced, consistent with the observed jumps. Our findings show that leafhoppers have special adhesive footpads for jumping from smooth surfaces, which achieve firm grip and rapid control of attachment/detachment by combining anisotropic friction with velocity dependence

Bayesian detection of unmodeled bursts of gravitational waves

The data analysis problem of coherently searching for unmodeled gravitational-wave bursts in the data generated by a global network of gravitational-wave observatories has been at the center of research for almost two decades. As data from these detectors is starting to be analyzed, a renewed interest in this problem has been sparked. A Bayesian approach to the problem of coherently searching for gravitational wave bursts with a network of ground-based interferometers is here presented. We demonstrate how to systematically incorporate prior information on the burst signal and its source into the analysis. This information may range from the very minimal, such as best-guess durations, bandwidths, or polarization content, to complete prior knowledge of the signal waveforms and the distribution of sources through spacetime. We show that this comprehensive Bayesian formulation contains several previously proposed detection statistics as special limiting cases, and demonstrate that it outperforms them.Comment: 18 pages, 3 figures, revisions based on referee comment

A review of predictability studies of the Atlantic sector climate on decadal time-scales

This review paper discusses the physical basis and the potential for decadal climate predictability over the Atlantic and its adjacent land areas. Many observational and modeling studies describe pronounced decadal and multidecadal variability in the Atlantic Ocean. However, it still needs to be quantified to which extent the variations in the ocean drive variations in the atmosphere and over land. In particular, although a clear impact of the Tropics on the midlatitudes has been demonstrated, it is unclear if and how the extratropical atmosphere responds to midlatitudinal sea surface temperature anomalies. Although the mechanisms behind the decadal to multidecadal variability in the Atlantic sector are still controversial, there is some consensus that some of the longer-term multidecadal variability is driven by variations in the thermohaline circulation. The variations in the North Atlantic thermohaline circulation appear to be predictable one to two decades ahead, as shown by a number of perfect model predictability experiments. The next few decades will be dominated by these multidecadal variations, although the effects of anthropogenic climate change are likely to introduce trends. Some impact of the variations of the thermohaline circulation on the atmosphere has been demonstrated in some studies so that useful decadal predictions with economic benefit may be possible

Jumping in lantern bugs (Hemiptera, Fulgoridae)

Lantern bugs are amongst the largest of the jumping hemipteran bugs with body lengths reaching 44 mm and their masses 0.7 g. They are up to 600 times heavier than smaller hemipterans that jump powerfully using catapult mechanisms to store energy. Does a similar mechanism also propel jumping in these much larger insects? The jumping performance of two species of lantern bugs (Hemiptera, Auchenorrhyncha, family Fulgoridae) from India and Malaysia was therefore analysed from high-speed videos. The kinematics showed that jumps were propelled by rapid and synchronous movements of both hind legs with their trochantera moving first. The hind legs were 20-40% longer than the front legs, which was attributable to longer tibiae. It took 5-6 ms to accelerate to take-off velocities reaching 4.65 m s-1 in the best jumps by female Kalidasa lanata. During these jumps, adults experienced an acceleration of 77 g, required an energy expenditure of 4800 μJ, a power output of 900 mW and exerted a force of 400 mN. The required power output of the thoracic jumping muscles was 21,000 W kg−1, 40 times greater than the maximum active contractile limit of muscle. Such a jumping performance therefore required a power amplification mechanism with energy storage in advance of the movement as in their smaller relatives. These large lantern bugs are near isometrically scaled up versions of their smaller relatives, still achieve comparable, if not higher, take-off velocities, and outperform other large jumping insects such as grasshoppers

Understanding how Victoria, Australia gained control of its second COVID-19 wave

During 2020, Victoria was the Australian state hardest hit by COVID-19, but was successful in controlling its second wave through aggressive policy interventions. We calibrated a detailed compartmental model of Victoria's second wave to multiple geographically-structured epidemic time-series indicators. We achieved a good fit overall and for individual health services through a combination of time-varying processes, including case detection, population mobility, school closures, physical distancing and face covering usage. Estimates of the risk of death in those aged ≥75 and of hospitalisation were higher than international estimates, reflecting concentration of cases in high-risk settings. We estimated significant effects for each of the calibrated time-varying processes, with estimates for the individual-level effect of physical distancing of 37.4% (95%CrI 7.2-56.4%) and of face coverings of 45.9% (95%CrI 32.9-55.6%). That the multi-faceted interventions led to the dramatic reversal in the epidemic trajectory is supported by our results, with face coverings likely particularly important