The genetic architecture of local adaptation in a cline

Local adaptation is pervasive. It occurs whenever selection favors different phenotypes in different environments, provided that there is genetic variation for the corresponding traits and that the effect of selection is greater than the effect of drift and migration. In many cases, ecologically relevant traits are quantitative and controlled by many genes. It has been repeatedly proposed that the localization of these genes in the genome may not be random, but could be an evolved feature. In particular, the clustering of local adaptation genes may be theoretically expected and has been observed in several situations. Previous theory has focused on two-patch or continent-island models to investigate this phenomenon, reaching the conclusion that such clustering could evolve, but in relatively limited conditions. In particular, it required that migration rate was neither too low nor too large and that the full optimization of trait values could not be eventually achieved by a mutation at a single locus. Here, we investigate this question in a spatially-explicit model, considering two contiguous habitats with distinct trait optima on a circular stepping-stone. We find that clustering of local-adaptation genes is pervasive within clines during both the establishment phase of local adaptation and the subsequent “reconfiguration” phase where different genetic architectures compete with each other. We also show that changing the fitness function relating trait to fitness has a strong impact on the overall evolutionary dynamics and resulting architecture

Strontium ranelate and alendronate have differing effects on distal tibia bone microstructure in women with osteoporosis

The structural basis of the antifracture efficacy of strontium ranelate and alendronate is incompletely understood. We compared the effects of strontium ranelate and alendronate on distal tibia microstructure over 2years using HR-pQCT. In this pre-planned, interim, intention-to-treat analysis at 12months, 88 osteoporotic postmenopausal women (mean age 63.7±7.4) were randomized to strontium ranelate 2g/day or alendronate 70mg/week in a double-placebo design. Primary endpoints were changes in microstructure. Secondary endpoints included lumbar and hip areal bone mineral density (aBMD), and bone turnover markers. This trial is registered with http://www.controlled-trials.com, number ISRCTN82719233. Baseline characteristics of the two groups were similar. Treatment with strontium ranelate was associated with increases in mean cortical thickness (CTh, 5.3%), cortical area (4.9%) and trabecular density (2.1%) (all P<0.001, except cortical area P=0.013). No significant changes were observed with alendronate. Between-group differences in favor of strontium ranelate were observed for CTh, cortical area, BV/TV and trabecular density (P=0.045, 0.041, 0.048 and 0.035, respectively). aBMD increased to a similar extent with strontium ranelate and alendronate at the spine (5.7% versus 5.1%, respectively) and total hip (3.3% versus 2.2%, respectively). No significant changes were observed in remodeling markers with strontium ranelate, while suppression was observed with alendronate. Within the methodological constraints of HR-pQCT through its possible sensitivity to X-ray attenuation of different minerals, strontium ranelate had greater effects than alendronate on distal tibia cortical thickness and trabecular volumetric densit

Hexagons, Kinks and Disorder in Oscillated Granular Layers

Experiments on vertically oscillated granular layers in an evacuated container reveal a sequence of well-defined pattern bifurcations as the container acceleration is increased. Period doublings of the layer center of mass motion and a parametric wave instability interact to produce hexagons and more complicated patterns composed of distinct spatial domains of different relative phase separated by kinks (phase discontinuities). Above a critical acceleration, the layer becomes disordered in both space and time.Comment: 4 pages. The RevTeX file has a macro allowing various styles. The appropriate style is "myprint" which is the defaul

Locoregional and systemic therapy for hepatocellular carcinoma

The management of hepatocellular carcinoma (HCC) remains challenging due to late presentation and the presence of accompanying liver dysfunction. As such, most patients are not eligible for curative resection and liver transplant. Management in this scenario depends on a number of factors including hepatic function, tumor burden, patency of hepatic vasculature and patients' functional status. Based on these, patients can be offered catheter based intra-arterial therapy for intermediate stage disease and in more advanced disease, sorafenib. Given recent data, regorafenib is now an option following failure of sorafenib. Catheter directed intra-arterial therapy takes advantage of tumor hypervascularity and the unique dual blood supply of the liver, as hepatic tumors receive arterial perfusion via the hepatic artery while the rest of the liver is supplied by the portal vein. This allows selective embolization and delivery of chemotherapeutic agents to the tumor. Compared to best supportive care, intra-arterial therapy offers a survival benefit in intermediate stage HCC and is the recommended approach for treatment. None of the catheter based approaches; including bland embolization, conventional trans-arterial chemoembolization (cTACE), drug eluting bead trans-arterial chemoembolization (DEB-TACE) or trans-arterial radioembolization (TARE) offers a clear advantage over the other, although DEB-TACE may be characterized by less systemic toxicity. All of these approaches are contraindicated in patients with portal vein thrombosis (PVT). On the other hand, intra-arterial, radio embolization, with Yttrium-90 (Y90) can be offered to patients with PVT. The place of this modality in management of HCC is still being investigated. The role of sorafenib in advanced HCC is not in doubt, as until recently, it was the only systemic therapy approved for the management in this setting. This is despite multiple trials evaluating other agents. The addition of sorafenib to catheter-based therapy in intermediate stage disease has also failed to show any benefit. The modest survival benefit with sorafenib and the failure of other targeted agents suggest that it is important to look beyond inhibition of angiogenesis in advanced HCC. Identification of key drivers and mediators of HCC remains paramount for successful drug development. In line with this, it is refreshing that the excitement that has followed developments in cancer immunotherapy is finding its way to HCC with early trials of anti-PD1 monoclonal antibodies showing sufficient activity that phase III trials are now ongoing for Pembrolizumab and Nivolumab in advanced HCC. Future drug development efforts will focus on defining the feasibility of combining different treatment approaches targeting multiple important modulators of HCC

Time resolved particle dynamics in granular convection

We present an experimental study of the movement of individual particles in a layer of vertically shaken granular material. High-speed imaging allows us to investigate the motion of beads within one vibration period. This motion consists mainly of vertical jumps, and a global ordered drift. The analysis of the system movement as a whole reveals that the observed bifurcation in the flight time is not adequately described by the Inelastic Bouncing Ball Model. Near the bifurcation point, friction plays and important role, and the branches of the bifurcation do not diverge as the control parameter is increased. We quantify the friction of the beads against the walls, showing that this interaction is the underlying mechanism responsible for the dynamics of the flow observed near the lateral wall

Principles of Faithful Execution in the implementation of trusted objects.

We begin with the following definitions: Definition: A trusted volume is the computing machinery (including communication lines) within which data is assumed to be physically protected from an adversary. A trusted volume provides both integrity and privacy. Definition: Program integrity consists of the protection necessary to enable the detection of changes in the bits comprising a program as specified by the developer, for the entire time that the program is outside a trusted volume. For ease of discussion we consider program integrity to be the aggregation of two elements: instruction integrity (detection of changes in the bits within an instruction or block of instructions), and sequence integrity (detection of changes in the locations of instructions within a program). Definition: Faithful Execution (FE) is a type of software protection that begins when the software leaves the control of the developer and ends within the trusted volume of a target processor. That is, FE provides program integrity, even while the program is in execution. (As we will show below, FE schemes are a function of trusted volume size.) FE is a necessary quality for computing. Without it we cannot trust computations. In the early days of computing FE came for free since the software never left a trusted volume. At that time the execution environment was the same as the development environment. In some circles that environment was referred to as a ''closed shop:'' all of the software that was used there was developed there. When an organization bought a large computer from a vendor the organization would run its own operating system on that computer, use only its own editors, only its own compilers, only its own debuggers, and so on. However, with the continuing maturity of computing technology, FE becomes increasingly difficult to achiev

A novel approach for treating type II endoleaks utilizing contrast-enhanced ultrasound

Endoleaks are a frequent and well-known complication after endovascular repair of aortic aneurysms. An endoleak can lead to increased intrasac pressure, sac enlargement, and potential aneurysm rupture. Type II endoleaks result from retrograde filling of aortic branch vessels and can be treated with surgical, endovascular, or direct percutaneous approaches. Direct percutaneous treatment typically involves embolization of the perfused endoleak cavity typically using a translumbar approach with fluoroscopic guidance. We illustrate a novel image-guided approach for percutaneous transabdominal endoleak treatment using contrast-enhanced ultrasound in combination with fluoroscopy

Scaling Behavior of Granular Particles in a Vibrating Box

Using numerical and analytic methods, we study the behavior of granular particles contained in a vibrating box. We measure, by molecular dynamics (MD) simulation, several quantities which characterize the system. These quantities--the density and the granular temperature fields, and the vertical expansion--obey scaling in the variable $x = Af$. Here, $A$ and $f$ are the amplitude and the frequency of the vibration. The behavior of these quantities is qualitatively different for small and large values of $x$. We also study the system using Navier-Stokes type equations developed by Haff. We develop a boundary condition for moving boundaries, and solve for the density and the temperature fields of the steady state in the quasi-incompressible limit, where the average separation between the particles is much smaller than the average diameter of the particles. The fields obtained from Haff's equations show the same scaling as those from the simulations. The origin of the scaling can be easily understood. The behavior of the fields from the theory is consistent with the simulation data for small $x$, but they deviate significantly for large $x$. We argue that the deviation is due to the breakdown of the quasi-incompressibility condition for large $x$.Comment: LaTeX, 26 pages, 9 figures available upon reques