In vivo evaluation of recombinant Vaccinia virus MVA delivering ancestral H9 hemagglutinin antigen of Avian Influenza virus

Avian Influenza (AI) viruses pose a threat to human and animal health and are responsible for potential economic losses. From the waterfowl reservoir, these RNA viruses can be transmitted to domestic poultry and humans, causing illness and death among people as well as mass culling of farm birds worldwide. This study contributes to increasing the knowledge by evaluating a promising poxvirus-based vector vaccine that carries and expresses an artificial, computationally derived hemagglutinin sequence in order to induce immunity against low pathogenic avian influenza H9N2. Modified Vaccinia virus Ankara (MVA) based vaccines have been tested in multiple human and animal trials and proved to be a safe and reliable vector system. The ancestral strategy uses a hemagglutinin sequence located at the node of a phylogenetic tree which arranges virus strains according to their evolutionary relationship. Inactivated whole virus vaccines engineered this way have conferred cross-clade protection in the ferret model of influenza A virus infections. In the present study, we aimed at testing the ancestral H9N2 MVA vaccine in the chicken model. Hereby, we tried to find answers to the following questions: What levels of H9 specific antibody responses are induced in chicken? Do the antibodies elicited by the ancestral H9 antigen cross-react with H9 antigens from other virus strains? Do the induced antibodies confer protection

In vivo evaluation of recombinant Vaccinia virus MVA delivering ancestral H9 hemagglutinin antigen of Avian Influenza virus

Avian Influenza (AI) viruses pose a threat to human and animal health and are responsible for potential economic losses. From the waterfowl reservoir, these RNA viruses can be transmitted to domestic poultry and humans, causing illness and death among people as well as mass culling of farm birds worldwide. This study contributes to increasing the knowledge by evaluating a promising poxvirus-based vector vaccine that carries and expresses an artificial, computationally derived hemagglutinin sequence in order to induce immunity against low pathogenic avian influenza H9N2. Modified Vaccinia virus Ankara (MVA) based vaccines have been tested in multiple human and animal trials and proved to be a safe and reliable vector system. The ancestral strategy uses a hemagglutinin sequence located at the node of a phylogenetic tree which arranges virus strains according to their evolutionary relationship. Inactivated whole virus vaccines engineered this way have conferred cross-clade protection in the ferret model of influenza A virus infections. In the present study, we aimed at testing the ancestral H9N2 MVA vaccine in the chicken model. Hereby, we tried to find answers to the following questions: What levels of H9 specific antibody responses are induced in chicken? Do the antibodies elicited by the ancestral H9 antigen cross-react with H9 antigens from other virus strains? Do the induced antibodies confer protection

Change of Muscle Activity as Well as Kinematic and Kinetic Parameters during Headers after Core Muscle Fatigue

In soccer, headers are a tactical measure and influenced by numerous factors. The goal of this study was to identify whether changes in kinematics and muscular activity, especially of the head-stabilizing muscles, occur during headers when the core musculature is fatigued. In two subgroups, muscular activity (12 amateur players, age 23.6 ± 4.2 years) and kinematics and dynamics (29 amateur players, age 23.7 ± 2.8 years) were examined during straight headers on a pendulum header. Data were collected before and after the core muscles were fatigued by an exercise program. Telemetric surface EMG, 3D acceleration sensor, force plate, and video recordings were used. Under fatigue, the activity of M. erector spinae and M. rectus abdominis was significantly reduced in the preparation phase of the header. The activity of M. sternocleidomastoideus was significantly increased during the jump phase, and the hip extension angle during maximum arched body tension was significantly reduced under fatigue. Jumping height, acceleration force impulse, and linear head acceleration were also significantly reduced. We conclude that fatigue of the core muscles affects the motion technique of the header and the activity of the muscle groups stabilizing the head. Therefore, the necessity of specific training in soccer should be emphasized from a medical-preventive point of view

Cost-optimal adaptive iterative linearized FEM for semilinear elliptic PDEs

We consider scalar semilinear elliptic PDEs where the nonlinearity is strongly monotone, but only locally Lipschitz continuous. We formulate an adaptive iterative linearized finite element method (AILFEM) which steers the local mesh refinement as well as the iterative linearization of the arising nonlinear discrete equations. To this end, we employ a damped Zarantonello iteration so that, in each step of the algorithm, only a linear Poisson-type equation has to be solved. We prove that the proposed AILFEM strategy guarantees convergence with optimal rates, where rates are understood with respect to the overall computational complexity (i.e., the computational time). Moreover, we formulate and test an adaptive algorithm where also the damping parameter of the Zarantonello iteration is adaptively adjusted. Numerical experiments underline the theoretical findings

BRAF testing in metastatic colorectal carcinoma and novel, chemotherapy-free therapeutic options

In the past 25 years, treatment of metastatic colorectal cancer (mCRC) has undergone profound changes. The approval of newer chemotherapeutics such as irinotecan and oxaliplatin was followed in 2005 by the first targeted therapies, for example, monoclonal antibodies directed against the epidermal growth factor receptor (EGFR), as cetuximab and panitumumab, or the angiogenesis inhibitors bevacizumab, ramucirumab, and aflibercept. With the rapidly progressing molecular characterization of mCRC in the last 10 years and the classification of the disease in four consensus subtypes, further changes are emerging, which will promote, among other things, the introduction of protein-kinase inhibitors developed for specific molecular aberrations as well as immune checkpoint inhibitors into the treatment algorithm. Thorough molecular pathologic testing is indispensable today for guideline-compliant treatment of mCRC patients. In addition to RAS testing as a precondition for the therapy decision with regard to cetuximab and panitumumab, BRAF testing is of considerable relevance to allow decision making with regard to the newly approved chemotherapy-free combination of the BRAF inhibitor encorafenib and cetuximab in cases where a BRAF-V600E mutation is detected. Additional diagnostic tests should also include genome instability (microsatellite instability). Overall, more and more molecular alterations need to be investigated simultaneously, so that the use of focused next-generation sequencing is increasingly recommended. This overview describes the prognostic relevance of BRAF testing in the context of molecular pathologic diagnostics of mCRC, presents new treatment options for BRAF-mutated mCRC patients, and explains which modern DNA analytical and immunohistochemical methods are available to detect BRAF mutations in mCRC patients

High magnitude and rapid incision from river capture: Rhine River, Switzerland

Landscape evolution is controlled by the development and organization of drainage basins. As a landscape evolves, drainage reorganization events can occur via river capture or piracy, whereby one river basin grows at the expense of another. The river downstream of a capture location will generate a transient topographic response as the added water discharge increases sediment transport and erosion efficiency. This erosional response will propagate upstream through both the captured and original river basins. Here we focus on quantifying the impact of drainage reorganization along the Rhine/Aare River system (~45,000 km 2 ) during the late Pliocene/early Pleistocene, where gravel remnants indicate total incision of ~650 m during the last ~4.2 Myr in the region of the recent Aare‐Rhine confluence. We develop a numerical model of drainage capture to quantify the range of possible magnitudes of erosion and the transient river response resulting from the reorganization of the Rhine River. The model accounts for both fluvial incision and sediment transport. Our model estimates 400–800 m of river elevation change (lowering profiles) during the last ~4 Myr due to river capture events, providing an important component to the recent exhumation budget of the Swiss Alpine Foreland. The model indicates a rapid response to capture events (re‐equilibration timescale of ~1 Myr). The predicted incision magnitudes are consistent with incision measured from the elevation of Pliocene and early Pleistocene river gravels, suggesting that across northern Switzerland, a significant amount of incision can be explained by drainage reorganization. Key Points Drainage capture has caused significant erosion along the Rhine River The transient erosional wave propagates quickly through the landscape The incision is a significant fraction of Plio‐Pleistocene erosion in the regionPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99064/1/jgrf20056.pd

In vivo immunomodulation of IL6 signaling in a murine multiple trauma model

A significant number of trauma patients die during the ICU phase of care because of a severe immune response. Interleukin-6 (IL6) plays a central role within that immune response, signaling through a membrane-bound (IL6-R) and a soluble IL6 receptor (sIL6-R). IL6 and the sIL6-R can form an agonistic IL6/sIL6-R-complex, activating numerous cells that are usually not IL6 responsive, a process called trans-signaling. We attempted to demonstrate that modulation of the IL6 signaling (classic signaling and trans-signaling) can attenuate the devastating immune response after trauma in a murine multiple trauma model. Mice were allocated to three study arms: sham, fracture or polytrauma. Half of the animals had the application of an IL6-R antibody following an intervention. After a pre-set time, blood samples were analysed for IL6 and sIL6-R serum levels, organs were analysed for neutrophil infiltration and end organ damage was evaluated. IL6 and sIL6-R showed a rapid peak after fracture, and much more markedly after polytrauma. These parameters were reduced significantly by globally blocking IL6 signaling via IL6-R antibody (Mab) application. Shock organ analysis also illustrated significant neutrophil infiltration following polytrauma, which was also abated via IL6-R Mab application. Furthermore, end organ damage was reduced by IL6-R Mab application. The study results prove the regulatory role of IL6 signaling pathways in polytrauma, with haemorrhagic shock being a major trigger of inflammatory response. Modulation of IL6 signaling shows promise in the prevention of adverse events like organ failure following major trauma and might be a target for in vivo immunomodulation to reduce mortality in severely injured patients, but further evaluation regarding classic IL6 signaling and IL6 trans-signaling is needed

Field Validation of a Non-carcinogenic and Eco-Friendly Disinfectant in a Stand-In Footbath for Treatment of Footrot Associated With aprV2-Positive Strains of Dichelobacter nodosus in Swiss Sheep Flocks.

A national control program for virulent footrot is currently planned in Switzerland. Since commonly used disinfectants either contain heavy metals or are carcinogenic, the aim of this study was to verify the effectiveness of an eco-friendly and non-carcinogenic candidate disinfectant against aprV2-positive strains of Dichelobacter nodosus. Additionally, the effect of the selective use of long-acting oxytetracyclines was evaluated. A total of 18 farms with confirmed footrot infection, randomly allocated to two treatment groups: (1) with antibiotics (AB; n = 9) and, (2) no antibiotics (NAB; n = 9), were included. Claws were carefully trimmed and scored using a scale from 0 (clinically healthy) to 5 (complete loss of the horn capsule) and a prewash waterbath was implemented on 11 farms. Twice-weekly, repeated whole-flock stand-in footbaths with the candidate disinfectant (6%) were performed. Additionally, animals of group AB with a score ≥ 3 were administered oxytetracyclines by injection. On all farms, 10 days after last treatment, aprV2-positive strains could not be detected by risk-based sampling for real-time PCR analysis after 7-21 (median = 12) footbaths with a minimal culling rate of non-responders on nine farms. Farms without contact to other sheep remained without clinical signs of footrot for a minimum of 245 days (mean ± standard deviation: 293.6 ± 23.6). Antibiotic treatment did not reduce the number of footbaths needed. In contrast, a mean of 3.3 disinfecting footbaths could be saved by implementing a prewash waterbath. At animal level, individual and selective use of oxytetracyclines lead to a higher chance (odds ratio = 9.95; 95% CI: 3.54-27.95; p < 0.001) for a lesion score ≥ 3 to improve to a lesion score < 3 within 2 weeks compared to treatment without antibiotics. The test disinfectant is an effective and eco-friendly alternative for the planned Swiss footrot control program and selective use of oxytetracycline has a beneficial impact on the recovery of animals with lesion scores ≥ 3

Lithologic Effects on Landscape Response to Base Level Changes: A Modeling Study in the Context of the Eastern Jura Mountains, Switzerland

Landscape evolution is a product of the forces that drive geomorphic processes (e.g., tectonics and climate) and the resistance to those processes. The underlying lithology and structural setting in many landscapes set the resistance to erosion. This study uses a modified version of the Channel‐Hillslope Integrated Landscape Development (CHILD) landscape evolution model to determine the effect of a spatially and temporally changing erodibility in a terrain with a complex base level history. Specifically, our focus is to quantify how the effects of variable lithology influence transient base level signals. We set up a series of numerical landscape evolution models with increasing levels of complexity based on the lithologic variability and base level history of the Jura Mountains of northern Switzerland. The models are consistent with lithology (and therewith erodibility) playing an important role in the transient evolution of the landscape. The results show that the erosion rate history at a location depends on the rock uplift and base level history, the range of erodibilities of the different lithologies, and the history of the surface geology downstream from the analyzed location. Near the model boundary, the history of erosion is dominated by the base level history. The transient wave of incision, however, is quite variable in the different model runs and depends on the geometric structure of lithology used. It is thus important to constrain the spatiotemporal erodibility patterns downstream of any given point of interest to understand the evolution of a landscape subject to variable base level in a quantitative framework.Key PointsA landscape evolution model is used to show how topographic history is influenced by regional geologyExhumation of different lithologies modulates the transient response to base level changes over millions of yearsSignificantly different erosion and topographic histories result depending on the stratigraphic architecture, even over a small range in erodibilityPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141336/1/jgrf20766_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141336/2/jgrf20766.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141336/3/jgrf20766-sup-0001-Data_S1.pd