Trade-offs constrain the success of glyphosate-free farming.

Glyphosate, the most widely used herbicide, is linked with environmental harm and there is a drive to replace it in agricultural systems. We model the impacts of discontinuing glyphosate use and replacing it with cultural control methods. We simulate winter wheat arable systems reliant on glyphosate and typical in northwest Europe. Removing glyphosate was projected to increase weed abundance, herbicide risk to the environment, and arable plant diversity and decrease food production. Weed communities with evolved resistance to non-glyphosate herbicides were not projected to be disproportionately affected by removing glyphosate, despite the lack of alternative herbicidal control options. Crop rotations with more spring cereals or grass leys for weed control increased arable plant diversity. Stale seedbed techniques such as delayed drilling and choosing ploughing instead of minimum tillage had varying effects on weed abundance, food production, and profitability. Ploughing was the most effective alternative to glyphosate for long-term weed control while maintaining production and profit. Our findings emphasize the need for careful consideration of trade-offs arising in scenarios where glyphosate is removed. Integrated Weed Management (IWM) with more use of cultural control methods offers the potential to reduce chemical use but is sensitive to seasonal variability and can incur negative environmental and economic impacts.

An in vitro biofilm model system to facilitate study of microbial communities of the human oral cavity.

The human oral cavity is host to a diverse microbiota. Much of what is known about the behaviour of oral microbes derives from studies of individual or several cultivated species, situations which do not totally reflect the function of organisms within more complex microbiota or multispecies biofilms. The number of validated models that allow examination of the role that biofilms play during oral cavity colonization is also limited. The CDC biofilm reactor is a standard method that has been deployed to study interactions between members of human microbiotas allowing studies to be completed during an extended period under conditions where nutrient availability, and washout of waste products are controlled. The objective of this work was to develop a robust in vitro biofilm-model system from a pooled saliva inoculum to study the development, reproducibility and stability of the oral microbiota. By employing deep sequencing of the variable regions of the 16S rRNA gene, we found that the CDC biofilm reactor could be used to efficiently cultivate microbiota containing all six major phyla previously identified as the core saliva microbiota. After an acclimatisation period, communities in each reactor stabilised. Replicate reactors were predominately populated by a shared core microbiota; variation between replicate reactors was primarily driven by shifts in abundance of shared operational taxonomic units. We conclude that the CDC biofilm reactor can be used to cultivate communities that replicate key features of the human oral cavity and is a useful tool to facilitate studies of the dynamics of these communities.

Making marinas bivalve friendly for enhanced biodiversity outcomes.

Natural coastlines are being replaced by artificial structures (pilings, pontoons, breakwaters), with negative environmental impacts, particularly in marinas. Ropes seeded with mussels (Mytilus galloprovincialis) were added to artificial structures in a marina, using aquaculture techniques, to reduce the colonisation of invasive taxa. After 6-months, droplines beneath pontoons had the highest seeded mussel survival and growth, richness of native and invasive taxa, and proportion of invasive to native taxa, compared with the other interventions. Mussel ropes on the intertidal structures (pilings and breakwaters) supported higher biomass of native taxa, whereas mussel ropes on subtidal structures (pontoons and breakwaters) had reduced biomass of invasive taxa, relative to the unseeded ropes. Droplines had the greater biomass of mussels, while mussel ropes placed under pontoons, and in subtidal gabion baskets limited the biomass but not the diversity of invasive species. Further study is required to determine whether these interventions can be upscaled to improve both the native biodiversity and functioning of marinas.

Characterization and application of nonlinear plastic materials for post-CPA pulse compression.

We demonstrate the three-fold post-chirped-pulse-amplification (post-CPA) pulse compression of a high peak power laser pulse using allyl diglycol carbonate (CR39), which was selected as the optimal material for near-field self-phase modulation out of a set of various nonlinear plastic materials, each characterized with respect to its nonlinear refractive index and optical transmission. The investigated materials could be applied for further pulse compression at high peak powers, as well as for gain narrowing compensation within millijoule-class amplifiers. The post-CPA pulse compression technique was tested directly after the first CPA stage within the POLARIS laser system, with the compact setup containing a single 1 mm thick plastic sample and a chirped mirror pair, which enabled a substantial shortening of the compressed pulse duration and, hence, a significant increase in the laser peak power without any additional modifications to the existing CPA chain.

Addressing identity-related barriers to collaboration for conservation through self-affirmation theory and moral foundations theory.

The natural resource management literature documents many reasons for pursuing collaborative processes, offering useful insights on how to manage conflict and facilitate productive deliberation in complex multistakeholder collaborative efforts. Moral foundations theory and self-affirmation theory can further help collaborative efforts mitigate conflicts caused by identity threats and the identity-protective reasoning these threats provoke. Moral foundations theory suggests an approach to increase collaboration by minimizing triggering language and helping people appreciate opposing viewpoints. Self-affirmation theory suggests a practical intervention that could be used to increase collaboration by desensitizing people to identity threats and reducing defensiveness. Taken together, these theories can contribute substantially to the understanding and practice of collaboration and conflict management for conservation.

Consideración de las Barreras Relacionadas con la Identidad que Enfrenta la Colaboración para la Conservación a través de la Teoría de Autoafirmación y la Teoría de Fundamentos Morales Resumen La literatura sobre el manejo de recursos naturales documenta muchas razones por las que es necesario buscar procesos colaborativos, los cuales ofrecen conocimiento útil sobre cómo manejar el conflicto. Estos procesos también facilitan la deliberación productiva dentro de los esfuerzos colaborativos complejos en los cuales participan múltiples actores. La teoría de fundamentos morales puede ayudar a que los esfuerzos colaborativos mitiguen los conflictos causados por las amenazas a la identidad y el razonamiento de protección de identidad que estas amenazas provocan. La teoría de fundamentos morales propone una estrategia para incrementar la colaboración al minimizar el lenguaje detonante y ayudar a que las personas aprecien los puntos de vista contrarios. La teoría de autoafirmación sugiere una intervención práctica que podría usarse para incrementar la colaboración al desensibilizar a las personas a tal grado que identifiquen amenazas y reduzcan la actitud defensiva. En conjunto, estas teorías pueden contribuir sustancialmente al entendimiento y la práctica de la colaboración y el manejo de conflictos para la conservación.

A kinetic Monte Carlo approach to study fluid transport in pore networks.

The mechanism of fluid migration in porous networks continues to attract great interest. Darcy's law (phenomenological continuum theory), which is often used to describe macroscopically fluid flow through a porous material, is thought to fail in nano-channels. Transport through heterogeneous and anisotropic systems, characterized by a broad distribution of pores, occurs via a contribution of different transport mechanisms, all of which need to be accounted for. The situation is likely more complicated when immiscible fluid mixtures are present. To generalize the study of fluid transport through a porous network, we developed a stochastic kinetic Monte Carlo (KMC) model. In our lattice model, the pore network is represented as a set of connected finite volumes (voxels), and transport is simulated as a random walk of molecules, which "hop" from voxel to voxel. We simulated fluid transport along an effectively 1D pore and we compared the results to those expected by solving analytically the diffusion equation. The KMC model was then implemented to quantify the transport of methane through hydrated micropores, in which case atomistic molecular dynamic simulation results were reproduced. The model was then used to study flow through pore networks, where it was able to quantify the effect of the pore length and the effect of the network's connectivity. The results are consistent with experiments but also provide additional physical insights. Extension of the model will be useful to better understand fluid transport in shale rocks.

Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis.

Essentials Anticoagulants prevent venous thromboembolism but may be associated with greater bleeding risks. Bivariate analysis assumes a non-linear relationship between efficacy and safety outcomes. Extended full-dose betrixaban is favorable over standard enoxaparin in bivariate endpoint. Clinicians must weigh efficacy and safety outcomes in decision-making on thromboprophylaxis. SUMMARY: Background Among acutely ill hospitalized medical patients, extended-duration thromboprophylaxis reduces the risk of venous thromboembolism (VTE), but some pharmacologic strategies have been associated with greater risks of major bleeding, thereby offsetting the net clinical benefit (NCB). Methods To assess the risk-benefit profile of anticoagulation regimens, a previously described bivariate method that does not assume a linear risk-benefit tradeoff and can accommodate different margins for efficacy and safety was performed to simultaneously assess efficacy (symptomatic VTE) and safety (major bleeding) on the basis of data from four randomized controlled trials of extended-duration (30-46 days) versus standard-duration (6-14 days) thromboprophylaxis among 28 227 patients (EXCLAIM, ADOPT, MAGELLAN and APEX trials). Results Extended thromboprophylaxis with full-dose betrixaban (80 mg once daily) was superior in efficacy and non-inferior in safety to standard-duration enoxaparin, and showed a significantly favorable NCB, with a risk difference of - 0.51% (- 0.89% to - 0.10%) in the bivariate outcome. Extended enoxaparin was superior in efficacy and inferior in safety (bivariate outcome: 0.03% [- 0.37% to 0.43%]), whereas apixaban and rivaroxaban were non-inferior in efficacy and inferior in safety (- 0.20% [- 0.49% to 0.17%] and 0.23% [- 0.16% to 0.69%], respectively). Reduced-dose betrixaban did not show a significant difference in either efficacy or safety (0.41% [- 0.85% to 1.94%]). Conclusions In a bivariate analysis that assumes non-linear risk-benefit tradeoffs, extended prophylaxis with full-dose betrixaban was superior to standard-duration enoxaparin, whereas other regimens failed to simultaneously achieve both superiority and non-inferiority with respect to symptomatic VTE and major bleeding in the management of acutely ill hospitalized medical patients.

D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial.

BACKGROUND: D-dimer concentrations have not been evaluated extensively as a predictor of increased venous thromboembolism (VTE) risk in acutely ill, hospitalized medical patients. OBJECTIVES: To analyze the relationships between D-dimer concentration, VTE and bleeding in the MAGELLAN trial (NCT00571649). PATIENTS/METHODS: This was a multicenter, randomized, controlled trial. Patients aged ≥ 40 years, hospitalized for acute medical illnesses with risk factors for VTE received subcutaneous enoxaparin 40 mg once daily for 10 ± 4 days then placebo up to day 35, or oral rivaroxaban 10 mg once daily for 35 ± 4 days. Patients (n = 7581) were grouped by baseline D-dimer ≤ 2 × or > 2 × the upper limit of normal. VTE and major plus non-major clinically relevant bleeding were recorded at day 10, day 35, and between days 11 and 35. RESULTS: The frequency of VTE was 3.5-fold greater in patients with high D-dimer concentrations. Multivariate analysis showed that D-dimer was an independent predictor of the risk of VTE (odds ratio 2.29 [95% confidence interval 1.75-2.98]), and had a similar association to established risk factors for VTE, for example cancer and advanced age. In the high D-dimer group, rivaroxaban was non-inferior to enoxaparin at day 10 and, unlike the low D-dimer group, superior to placebo at day 35 (P < 0.001) and days 11-35 (P < 0.001). In both groups, bleeding outcomes favored enoxaparin/placebo. CONCLUSIONS: Elevated baseline D-dimer concentrations may identify acutely ill, hospitalized medical patients at high risk of VTE for whom extended anticoagulant prophylaxis may provide greater benefit than for those with low D-dimer concentrations.

Loss of coupling between calcium influx, energy consumption and insulin secretion associated with development of hyperglycaemia in the UCD-T2DM rat model of type 2 diabetes.

AIMS/HYPOTHESIS: Previous studies on isolated islets have demonstrated tight coupling between calcium (Ca(2+)) influx and oxygen consumption rate (OCR) that is correlated with insulin secretion rate (ISR). To explain these observations, we have proposed a mechanism whereby the activation of a highly energetic process (Ca(2+)/metabolic coupling process [CMCP]) by Ca(2+) mediates the stimulation of ISR. The aim of the study was to test whether impairment of the CMCP could play a role in the development of type 2 diabetes. METHODS: Glucose- and Ca(2+)-mediated changes in OCR and ISR in isolated islets were compared with the time course of changes of plasma insulin concentrations observed during the progression to hyperglycaemia in a rat model of type-2 diabetes (the University of California at Davis type 2 diabetes mellitus [UCD-T2DM] rat). Islets were isolated from UCD-T2DM rats before, 1 week, and 3 weeks after the onset of hyperglycaemia. RESULTS: Glucose stimulation of cytosolic Ca(2+) and OCR was similar for islets harvested before and 1 week after the onset of hyperglycaemia. In contrast, a loss of decrement in islet OCR and ISR in response to Ca(2+) channel blockade coincided with decreased fasting plasma insulin concentrations observed in rats 3 weeks after the onset of hyperglycaemia. CONCLUSIONS/INTERPRETATION: These results suggest that phenotypic impairment of diabetic islets in the UCD-T2DM rat is downstream of Ca(2+) influx and involves unregulated stimulation of the CMCP. The continuously elevated levels of CMCP induced by chronic hyperglycaemia in these islets may mediate the loss of islet function.

Prevention and treatment of venous thromboembolism--International Consensus Statement.

The aim of this document is to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage venous thromboembolism (VTE).

Rosiglitazone treatment does not decrease amyloid deposition in transplanted islets from transgenic mice expressing human islet amyloid polypeptide.

In human islet transplantation, insulin independence decreases over time. We previously showed that amyloid deposition following transplantation of islets from human islet amyloid polypeptide (hIAPP) transgenic mice resulted in ß-cell loss and that rosiglitazone treatment decreased islet amyloid deposition and preserved ß-cell area in the endogenous pancreas of hIAPP transgenic mice. Thus, we sought to determine if rosiglitazone treatment decreases islet amyloid deposition and the associated ß-cell loss after islet transplantation. Streptozocin-diabetic mice were transplanted with 100 islets from hIAPP transgenic (T) mice or nontransgenic (NT) littermates under the kidney capsule and received either rosiglitazone (R) in drinking water or plain drinking water (C). The resultant groups (NTC [n = 11], NTR [n = 9], TC [n = 14], and TR [n = 10]) were followed for 12 weeks after which the graft was removed and processed for histology. Amyloid was detected in nearly all T islet grafts (TC = 13/14, TR = 10/10) but not in NT grafts. Rosiglitazone did not alter amyloid deposition (% graft area occupied by amyloid; TC: 2.15 ± 0.7, TR: 1.72 ± 0.66; P = .86). % ß-cell/graft area was decreased in the TC grafts compared to NTC (56.2 ± 3.1 vs 73.8 ± 1.4; P < .0001) but was not different between TC and TR groups (56.2 ± 3.1 vs 61.0 ± 2.9; P = .34). Plasma glucose levels before and after transplantation did not differ between NTC and TC groups and rosiglitazone did not affect plasma glucose levels post-islet transplantation. Rosiglitazone did not decrease amyloid deposition in hIAPP transgenic islet grafts. Therefore, rosiglitazone treatment of recipients of amyloid forming islets may not improve transplantation outcomes.

cJUN N-terminal kinase (JNK) activation mediates islet amyloid-induced beta cell apoptosis in cultured human islet amyloid polypeptide transgenic mouse islets.

AIMS/HYPOTHESIS: Aggregation of human islet amyloid polypeptide (hIAPP) as islet amyloid is associated with increased beta cell apoptosis and reduced beta cell mass in type 2 diabetes. Islet amyloid formation induces oxidative stress, which contributes to beta cell apoptosis. The cJUN N-terminal kinase (JNK) pathway is a critical mediator of beta cell apoptosis in response to stress stimuli including oxidative stress and exogenous application of hIAPP. We determined whether amyloid formation by endogenous hIAPP mediates beta cell apoptosis through JNK activation and downstream signalling pathways. METHODS: hIAPP transgenic and non-transgenic mouse islets were cultured for up to 144 h in 16.7 mmol/l glucose to induce islet amyloid in the presence or absence of the amyloid inhibitor Congo Red or a cell-permeable JNK inhibitor. Amyloid, beta cell apoptosis, JNK signalling and activation of downstream targets in the intrinsic and extrinsic apoptotic pathways were measured. RESULTS: JNK activation occurred with islet amyloid formation in hIAPP transgenic islets after 48 and 144 h in culture. Neither high glucose nor the hIAPP transgene alone was sufficient to activate JNK independent of islet amyloid. Inhibition of islet amyloid formation with Congo Red reduced beta cell apoptosis and partially decreased JNK activation. JNK inhibitor treatment reduced beta cell apoptosis without affecting islet amyloid. Islet amyloid increased mRNA levels of markers of the extrinsic (Fas, Fadd) and intrinsic (Bim [also known as Bcl2l11]) apoptotic pathways, caspase 3 and the anti-apoptotic molecule Bclxl (also known as Bcl2l1) in a JNK-dependent manner. CONCLUSIONS/INTERPRETATION: Islet amyloid formation induces JNK activation, which upregulates predominantly pro-apoptotic signals in both extrinsic and intrinsic pathways, resulting in beta cell apoptosis.

Prophylaxis of venous thromboembolism: low molecular weight heparin compared to the selective anticoagulants rivaroxaban, dabigatran and fondaparinux.

Newer therapeutic options available in the prevention of postoperative thromboembolism, currently focused on fondaparinux, rivaroxaban and dabigatran warrant an overall therapeutic assessment. The constitutive comparisons with enoxaparin are based on a combined outcome measure solely driven by the incidence of "asymptomatic deep vein thrombosis". Its validity as a clinically relevant endpoint is missing if antithrombotics of different classes are compared. This is because they target different phases of thrombogenesis i. e. ahead and beyond the asymptomatic stage of thrombosis. Additional concerns refer to the dosing-regimens and their practical administration: Fondaparinux, rivaroxaban and dabigatran are dosed to achieve maximum effects very close to their limits of tolerance whereas wide dosing spectra for the low molecular weight herparin (LMWH)'s indicate the potential for dose adaptation and increase. The other disadvantage to the control-heparin originates in the timing for the 1st administration which doesn't fit in with the "just-in-time" principle. So the enoxaparin-regimen is lacking in benchmark-quality - with the consequence that the meaning of the Phase III-trials does'nt go beyond a mere technical demarcation from the marketed variant of the product as defined by the stipulations in the package insert. As to tolerance the selective anticoagulants exhibit an increased risk of major and other clinically relevant bleeding, exceeding that of enoxaparin by 30% (P<0.001). The outcome of the meta-analyses on fondaparinux, rivaroxaban and dabigatran is supported by product-specific calculations and assessments of the European Medicine Equivalence Agency (EMEA). Rivaroxaban and dabigatran show significant age-dependent renal accumulation. Because the dose-finding studies were restricted to patients over 60 year old the regimens definitely established are not applicable to younger patients. The reason for the limited therapeutic index of the selective anticoagulants originates in their monovalent activity as such not adequately matching the complexity of thrombogenesis and early thrombus extension. Their class-specific limitations are compensated through more intensive dosage-regimens which result in accentuated bleeding complications. Connotatively the hypothesis emerged that antiXa- and IIa-effects interact synergistically which translates into enhanced efficacy and tolerance. Experimental studies on hirudin with pentasaccharide and hirudin with "lower low molecular weight heparin" (3KDA) support such rationale.

Exendin-4 increases islet amyloid deposition but offsets the resultant beta cell toxicity in human islet amyloid polypeptide transgenic mouse islets.

AIMS/HYPOTHESIS: In type 2 diabetes, aggregation of islet amyloid polypeptide (IAPP) into amyloid is associated with beta cell loss. As IAPP is co-secreted with insulin, we hypothesised that IAPP secretion is necessary for amyloid formation and that treatments that increase insulin (and IAPP) secretion would thereby increase amyloid formation and toxicity. We also hypothesised that the unique properties of the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 to maintain or increase beta cell mass would offset the amyloid-induced toxicity. METHODS: Islets from amyloid-forming human IAPP transgenic and control non-transgenic mice were cultured for 48 h in 16.7 mmol/l glucose alone (control) or with exendin-4, potassium chloride (KCl), diazoxide or somatostatin. Human IAPP and insulin release, amyloid deposition, beta cell area/islet area, apoptosis and AKT phosphorylation levels were determined. RESULTS: In control human IAPP transgenic islets, amyloid formation was associated with increased beta cell apoptosis and beta cell loss. Increasing human IAPP release with exendin-4 or KCl increased amyloid deposition. However, while KCl further increased beta cell apoptosis and beta cell loss, exendin-4 did not. Conversely, decreasing human IAPP release with diazoxide or somatostatin limited amyloid formation and its toxic effects. Treatment with exendin-4 was associated with an increase in AKT phosphorylation compared with control and KCl-treated islets. CONCLUSIONS/INTERPRETATION: IAPP release is necessary for islet amyloid formation and its toxic effects. Thus, use of insulin secretagogues to treat type 2 diabetes may result in increased islet amyloidogenesis and beta cell death. However, the AKT-associated anti-apoptotic effects of GLP-1 receptor agonists such as exendin-4 may limit the toxic effects of increased islet amyloid.

Levels of phosphorylated axonal neurofilament subunit H (pNfH) are increased in acute ischemic stroke.

For the study of stroke outcomes, there is the need for measurements of severity of stroke damage. Phosphorylated neurofilament heavy protein (pNfH) levels are elevated in axonal injury. We have measured levels of pNfH in stroke and correlated these levels with measures of stroke severity. Blood samples were collected from 54 ischaemic stroke patients at day 1, week 1 (days 7-10) and weeks 3-6, and an ELISA was used to measure pNfH levels in each patient at each time-point. Serum pNfH levels were significantly elevated in stroke patients compared to healthy controls. The levels were low at day 1, higher at day 7 and reached a peak at week 3, the latest day that we assessed. Significant associations were found between the pNfH levels at week 3 and early and stroke severity, size and outcome. Blood pNfH levels that reflect the severity of ischaemic stroke, are correlated with outcome and rise during the weeks after stroke. This may be a useful measure of tissue damage in stroke.

Coupled effects of ion beam chemistry and morphology on directed self-assembly of epitaxial semiconductor nanostructures.

We study the coupled effects of ion beam chemistry and morphology on the assembly of templated epitaxial nanostructures. Using a focused ion beam (FIB) system equipped with a mass-selecting filter, we pattern Si substrates with local ion doses of Si, Ge and Ga to control subsequent Ge(x)Si(1 - x) epitaxial nanostructure assembly. This capability to employ different templating species allows us to study how different incorporated ion species in the near surface region affect the ability to localize nucleation during subsequent epitaxial growth. Our results indicate that FIB-directed self-assembly is a complex process, dependent on dose-induced morphology in addition to ion-specific chemical effects.