Coupling of crop and livestock production can reduce the agricultural GHG emission from smallholder farms.

Ensuring global food security and environmental sustainability is dependent upon the contribution of the world's hundred million smallholder farms, but the contributions of smallholder farms to global agricultural greenhouse gas (GHG) emissions have been understudied. We developed a localized agricultural life cycle assessment (LCA) database to calculate GHG emissions and made the first extensive assessment of the smallholder farms' GHG emission reduction potentials by coupling crop and livestock production (CCLP), a redesign of current practices toward sustainable agriculture in China. CCLP can reduce the GHG emission intensity by 17.67%, with its own feed and manure returning to the field as an essential path. Scenario analysis verified that greater GHG emission reduction (28.09%-41.32%) will be achieved by restructuring CCLP. Therefore, this mixed farming is a mode with broader benefits to provide sustainable agricultural practices for reducing GHG emissions fairly.

Racial Equity and U.S. Law.

History and experience teach us that our Constitution and laws can be instruments of racial discrimination and oppression as well as tools for advancing freedom and equality. The substance of our laws matters, and there is much to be learned from innovative policies and legal strategies around the country. In addition to laws promoting health equity and racial justice at the state, tribal, and local levels, a new federal Executive Order has the potential to drive major positive change if fully and properly implemented. Just as important, however, is linking legal advocacy with dynamic social movements, shrewd communication strategies, and courageous civic leadership that insists on transformative change. In this article, I briefly recount the turbulent relationship between law and equity in our nation; discuss the elements that can lead to major progress through law; and recommend specific steps that different actors can take to move an equity and opportunity agenda forward.

Incorporation of Hydrophilic Macrocycles Into Drug-Linker Reagents Produces Antibody-Drug Conjugates With Enhanced in vivo Performance.

Antibody-drug conjugates (ADCs) have begun to fulfil their promise as targeted cancer therapeutics with ten clinical approvals to date. As the field matures, much attention has focused upon the key factors required to produce safe and efficacious ADCs. Recently the role that linker-payload reagent design has on the properties of ADCs has been highlighted as an important consideration for developers. We have investigated the effect of incorporating hydrophilic macrocycles into reagent structures on the in vitro and in vivo behavior of ADCs. Bis-sulfone based disulfide rebridging reagents bearing Val-Cit-PABC-MMAE linker-payloads were synthesized with a panel of cyclodextrins and crown ethers integrated into their structures via a glutamic acid branching point. Brentuximab was selected as a model antibody and ten ADCs with a drug-to-antibody ratio (DAR) of 4 were prepared for biological evaluation. In vitro, the ADCs prepared showed broadly similar potency (range: 16-34 pM) and were comparable to Adcetris® (16 pM). In vivo, the cyclodextrin containing ADCs showed greater efficacy than Adcetris® and the most efficacious variant (incorporating a 3'-amino-α-cyclodextrin component) matched a 24-unit poly(ethylene glycol) (PEG) containing comparator. The ADCs bearing crown ethers also displayed enhanced in vivo efficacy compared to Adcetris®, the most active variant (containing a 1-aza-42-crown-14 macrocycle) was superior to an analogous ADC with a larger 24-unit PEG chain. In summary, we have demonstrated that hydrophilic macrocycles can be effectively incorporated into ADC reagent design and offer the potential for enhanced alternatives to established drug-linker architectures.

Managing health risks of perfluoroalkyl acids in aquatic food from a river-estuary-sea environment affected by fluorochemical industry.

Substantial perfluoroalkyl acids (PFAAs) production still occurs in China, and the consumption of aquatic products is a critical exposure pathway of PFAAs in humans. In this study, specimens of 16 freshwater and 40 marine species were collected in the river-estuary-sea environment affected by a mega fluorochemical industry park in China in 2015, and the edible tissues of these organisms were analyzed for PFAA levels. Perfluorooctanoic acid (PFOA) was the dominating contaminant with an overall contribution of more than 90%, and concentrations as high as 2161 ng/g wet weight (measured in the freshwater winkle). All species with the greatest PFOA levels were benthic. The trophic magnification factor (TMF) of PFOA was 1.10 for freshwater species and 1.28 for marine species, indicating that PFOA was slightly magnifying. Analysis of carbon source indicated that freshwater species were more benthic feeding, while marine species were more pelagic feeding. Aquatic food consumption screening values of PFOA were modified according to estimated daily intake (EDI) values, which generated recommendations for limited meal categories and the do-not-eat category. Thus, this study provides recommendations for mitigating the health risks of PFAA-contaminated aquatic food, ranging from food selection to consumption frequency and proper food processing.

The potential role of sediment organic phosphorus in algal growth in a low nutrient lake.

The role of sediment-bound organic phosphorus (Po) as an additional nutrient source is a component of internal P budgets in lake system that is usually neglected. Here we examined the relative importance of sediment Po to internal P load and the role of bioavailable Po in algal growth in Lake Erhai, China. Lake Erhai sediment extractable Po accounted for 11-43% (27% average) of extractable total P, and bioavailable Po accounted for 21-66% (40%) of Po. The massive storage of bioavailable Po represents an important form of available P, essential to internal loads. The bioavailable Po includes mainnly labile monoester P and diester P was identified in the sequential extractions by H2O, NaHCO3, NaOH, and HCl. 40% of H2O-Po, 39% of NaHCO3-Po, 43% of NaOH-Po, and 56% of HCl-Po can be hydrolyzed to labile monoester and diester P, suggesting that the bioavailability of Po fractions was in decreasing order as follows: HCl-Po > NaOH-Po > H2O-Po > NaHCO3-Po. It is implied that traditional sequential fractionation of Po might overestimate the availability of labile Po in sediments. Furthermore, analysis of the environmental processes of bioavailable Po showed that the stabler structure of dissloved organic matter (DOM) alleviated the degradation and release of diester P, abundant alkaline phosphatase due to higher algal biomass promoted the degradation of diester P. The stability of DOM structure and the degradation of diester P might responsible for the spatial differences of labile monoester P. The biogeochemical cycle of bioavailable Po replenishs available P pools in overlying water and further facilitate algal growth during the algal blooms. Therefore, to control the algal blooms in Lake Erhai, an effective action is urgently required to reduce the accumulation of Po in sediments and interrupt the supply cycle of bioavailable Po to algal growth.

Forty years of reform and opening up: China's progress toward a sustainable path.

After 40 years of reform and "opening up," China has made remarkable economic progress. Such economic prosperity, however, has been coupled with environmental degradation. We analyze diverse long-term data to determine whether China is experiencing a decoupling of economic growth and environmental impacts, and where China stands with respect to the Sustainable Development Goals (SDGs) in terms of reducing regional division, urban-rural gap, social inequality, and land-based impacts on oceans. The results highlight that China's desire to achieve "ecological civilization" has resulted in a decoupling trend for major pollutants since 2015, while strong coupling remains with CO2 emissions. Progress has been made in health care provision, poverty reduction, and gender equity in education, while income disparity continues between regions and with rural-urban populations. There is a considerable way to go toward achieving delivery of the SDGs; however, China's progress toward economic prosperity and concomitant sustainability provides important insights for other countries.

Potential effects of changes in climate and emissions on distribution and fate of perfluorooctane sulfonate in the Bohai Rim, China.

Climate change and emissions rates of contaminants are expected to affect distribution and fate of Persistent Organic Pollutants (POPs) in the environment, however, studies on these combined factors are rare. In this study, Perfluorooctane Sulfonate (PFOS) is used as an example to assess how those two factors synthetically affect fate and disposition of POPs in the Bohai Rim of China by using the Berkeley-Trent-Urban-Rural (BETR-Urban-Rural) model. We set up three climate change scenarios and four emission scenarios to conduct the simulations. The results show that climate change could have significant effects on the transport and fate of PFOS mainly including advection, inter-compartmental transfer under the "worst case" emission scenario. For most grids, a remarkable decrease in concentrations of PFOS are predicted for fresh water and urban soil in the future, with precipitation and temperature being predominant factors, whilst for coastal water and rural soil, an increasing trend is predicted. Additionally, predicted sum of sources to the Bohai Sea increases greater than removals from the Bohai Sea in the future, adding evidence that concentrations of PFOS in coastal water will increase more in the future. Under scenarios of reduced emissions and climate change, concentrations of PFOS in each compartment decreased more rapidly over time. We suggest that assessment of future climate change impacts on fate of PFOS could take emission reductions into consideration.

Response of the phytoplankton community to water quality in a local alpine glacial lake of Xinjiang Tianchi, China: potential drivers and management implications.

Eutrophication has become one of the most serious threats to aquatic ecosystems in the world. With the combined drivers of climate change and human activities, eutrophication has expanded from warm shallow lakes to cold-water lakes in relatively high latitude regions and has raised greater concerns over lake aquatic ecosystem health. A two-year field study was carried out to investigate water quality, phytoplankton characteristics and eutrophication status in a typical alpine glacial lake of Tianchi, a scenic area and an important drinking water source in the Xinjiang Autonomous Region of China, in 2014 and 2015. Clear seasonal and annual variations of nutrients and organic pollutants were found especially during rainy seasons. For the phytoplankton community, Bacillariophyta held the dominant position in terms of both species and biomass throughout the year, suggesting the dominant characteristics of diatoms in the phytoplankton structure in such a high-altitude cold-water lake. This was quite different from plain and warm lakes troubled with cyanobacterial blooming. Moreover, the dominant abundance of Cyclotella sp. in Tianchi might suggest regional warming caused by climate change, which might have profound effects on the local ecosystems and hydrological cycle. Based on water quality parameters, a comprehensive trophic level index TLI (Σ) was calculated to estimate the current status of eutrophication, and the results inferred emerging eutrophication in Tianchi. Results from Canonical Correspondence Analysis (CCA) and correlation analysis of phytoplankton genera and physico-chemical variables of water indicated that abiotic factors significantly influenced the phytoplankton community and its succession in Tianchi Lake. These abiotic factors could explain 77.82% of the total variance, and ammonium was identified as the most discriminant variable, which could explain 41% of the total variance followed by TP (29%). An estimation of annual nutrient loadings to Tianchi was made, and the results indicated that about 212.97 t of total nitrogen and 32.14 t of total phosphorus were transported into Tianchi Lake annually. Human socio-economic activities (runoff caused by historical overgrazing and increasing tourism) were identified as the most important contributors to Tianchi nutrient loadings.

Sex differences in mouse Transient Receptor Potential Cation Channel, Subfamily M, Member 8 expressing trigeminal ganglion neurons.

The detection of cool temperatures is thought to be mediated by primary afferent neurons that express the cool temperature sensing protein Transient Receptor Potential Cation Channel, Subfamily M, Member 8 (TRPM8). Using mice, this study tested the hypothesis that sex differences in sensitivity to cool temperatures were mediated by differences in neurons that express TRPM8. Ion currents from TRPM8 expressing trigeminal ganglion (TRG) neurons in females demonstrated larger hyperpolarization-activated cyclic nucleotide-gated currents (Ih) than male neurons at both 30° and 18°C. Additionally, female neurons' voltage gated potassium currents (Ik) were suppressed by cooling, whereas male Ik was not significantly affected. At the holding potential tested (-60mV) TRPM8 currents were not visibly activated in either sex by cooling. Modeling the effect of Ih and Ik on membrane potentials demonstrated that at 30° the membrane potential in both sexes is unstable. At 18°, female TRPM8 TRG neurons develop a large oscillating pattern in their membrane potential, whereas male neurons become highly stable. These findings suggest that the differences in Ih and Ik in the TRPM8 TRG neurons of male and female mice likely leads to greater sensitivity of female mice to the cool temperature. This hypothesis was confirmed in an operant reward/conflict assay. Female mice contacted an 18°C surface for approximately half the time that males contacted the cool surface. At 33° and 10°C male and female mice contacted the stimulus for similar amounts of time. These data suggest that sex differences in the functioning of Ih and Ik in TRPM8 expressing primary afferent neurons leads to differences in cool temperature sensitivity.

Modulation of drug-linker design to enhance in vivo potency of homogeneous antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are a promising class of anticancer agents which have undergone substantial development over the past decade and are now achieving clinical success. The development of novel site-specific conjugation technologies enables the systematic study of architectural features within the antibody conjugated drug linker that may affect overall therapeutic indices. Here we describe the results of a systematic study investigating the impact of drug-linker design on the in vivo properties of a series of homogeneous ADCs with a conserved site of conjugation, a monodisperse drug loading, a lysosomal release functionality and monomethyl auristatin E as a cytotoxic payload. The ADCs, which differed only in the relative position of certain drug-linker elements within the reagent, were first evaluated in vitro using anti-proliferation assays and in vivo using mouse pharmacokinetics (PK). Regardless of the position of a discrete polymer unit, the ADCs showed comparable in vitro potencies, but the in vivo PK properties varied widely. The best performing drug-linker design was further used to prepare ADCs with different drug loadings of 4, 6 and 8 drugs per antibody and compared to Adcetris® in a Karpas-299 mouse xenograft model. The most efficacious ADC showed complete tumor regression and 10/10 tumor free survivors at a single 0.5mg/kg dose. This study revealed drug-linker design as a critical parameter in ADC development, with the potential to enhance ADC in vivo potency for producing more efficacious ADCs.

Addressing China's grand challenge of achieving food security while ensuring environmental sustainability.

China's increasingly urbanized and wealthy population is driving a growing and changing demand for food, which might not be met without significant increase in agricultural productivity and sustainable use of natural resources. Given the past relationship between lack of access to affordable food and political instability, food security has to be given a high priority on national political agendas in the context of globalization. The drive for increased food production has had a significant impact on the environment, and the deterioration in ecosystem quality due to historic and current levels of pollution will potentially compromise the food production system in China. We discuss the grand challenges of not only producing more food but also producing it sustainably and without environmental degradation. In addressing these challenges, food production should be considered as part of an environmental system (soil, air, water, and biodiversity) and not independent from it. It is imperative that new ways of meeting the demand for food are developed while safeguarding the natural resources upon which food production is based. We present a holistic approach to both science and policy to ensure future food security while embracing the ambition of achieving environmental sustainability in China. It is a unique opportunity for China to be a role model as a new global player, especially for other emerging economies.

The Pivotal Role of Phosphorus in a Resilient Water-Energy-Food Security Nexus.

We make the case that phosphorus (P) is inextricably linked to an increasingly fragile, interconnected, and interdependent nexus of water, energy, and food security and should be managed accordingly. Although there are many other drivers that influence water, energy, and food security, P plays a unique and under-recognized role within the nexus. The P paradox derives from fundamental challenges in meeting water, energy, and food security for a growing global population. We face simultaneous dilemmas of overcoming scarcity of P to sustain terrestrial food and biofuel production and addressing overabundance of P entering aquatic systems, which impairs water quality and aquatic ecosystems and threatens water security. Historical success in redistributing rock phosphate as fertilizer to enable modern feed and food production systems is a grand societal achievement in overcoming inequality. However, using the United States as the main example, we demonstrate how successes in redistribution of P and reorganization of farming systems have broken local P cycles and have inadvertently created instability that threatens resilience within the nexus. Furthermore, recent expansion of the biofuels sector is placing further pressure on P distribution and availability. Despite these challenges, opportunities exist to intensify and expand food and biofuel production through recycling and better management of land and water resources. Ultimately, a strategic approach to sustainable P management can help address the P paradox, minimize tradeoffs, and catalyze synergies to improve resilience among components of the water, energy, and food security nexus.

Impacts of soil and water pollution on food safety and health risks in China.

Environmental pollution and food safety are two of the most important issues of our time. Soil and water pollution, in particular, have historically impacted on food safety which represents an important threat to human health. Nowhere has that situation been more complex and challenging than in China, where a combination of pollution and an increasing food safety risk have affected a large part of the population. Water scarcity, pesticide over-application, and chemical pollutants are considered to be the most important factors impacting on food safety in China. Inadequate quantity and quality of surface water resources in China have led to the long-term use of waste-water irrigation to fulfill the water requirements for agricultural production. In some regions this has caused serious agricultural land and food pollution, especially for heavy metals. It is important, therefore, that issues threatening food safety such as combined pesticide residues and heavy metal pollution are addressed to reduce risks to human health. The increasing negative effects on food safety from water and soil pollution have put more people at risk of carcinogenic diseases, potentially contributing to 'cancer villages' which appear to correlate strongly with the main food producing areas. Currently in China, food safety policies are not integrated with soil and water pollution management policies. Here, a comprehensive map of both soil and water pollution threats to food safety in China is presented and integrated policies addressing soil and water pollution for achieving food safety are suggested to provide a holistic approach.

Assessing recovery from acidification of European surface waters in the year 2010: evaluation of projections made with the MAGIC model in 1995.

In 1999 we used the MAGIC (Model of Acidification of Groundwater In Catchments) model to project acidification of acid-sensitive European surface waters in the year 2010, given implementation of the Gothenburg Protocol to the Convention on Long-Range Transboundary Air Pollution (LRTAP). A total of 202 sites in 10 regions in Europe were studied. These forecasts can now be compared with measurements for the year 2010, to give a "ground truth" evaluation of the model. The prerequisite for this test is that the actual sulfur and nitrogen deposition decreased from 1995 to 2010 by the same amount as that used to drive the model forecasts; this was largely the case for sulfur, but less so for nitrogen, and the simulated surface water [NO3(-)] reflected this difference. For most of the sites, predicted surface water recovery from acidification for the year 2010 is very close to the actual recovery observed from measured data, as recovery is predominantly driven by reductions in sulfur deposition. Overall these results show that MAGIC successfully predicts future water chemistry given known changes in acid deposition.

Simeprevir (TMC435) with pegylated interferon/ribavirin in patients coinfected with HCV genotype 1 and HIV-1: a phase 3 study.

BACKGROUND: Simeprevir is an oral, once-daily, hepatitis C virus (HCV) NS3/4A protease inhibitor for the treatment of chronic HCV genotype 1 infection. Human immunodeficiency virus (HIV) coinfection accelerates progression of liver disease. This uncontrolled, open-label trial explored the safety and efficacy of simeprevir in patients with HCV genotype 1/HIV type 1 (HIV-1) coinfection. METHODS: Patients received simeprevir (150 mg once daily) with pegylated interferon alfa-2a/ribavirin (peg-IFN/RBV) for 12 weeks. Noncirrhotic HCV treatment-naive patients and prior relapsers received response-guided therapy (RGT) with peg-IFN/RBV for 24 or 48 weeks. Prior null responders, prior partial responders, and patients with cirrhosis received peg-IFN/RBV for 48 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). RESULTS: One hundred and six patients (93 on antiretroviral therapy) were enrolled and treated. SVR12 rates were 79.2% in HCV treatment-naive patients, 57.1% in prior null responders, 86.7% in prior relapsers, and 70.0% in prior partial responders. Fifty-four of 61 eligible patients (88.5%) met RGT criteria for 24 weeks of peg-IFN/RBV, of whom 87.0% (47/54) achieved SVR12. SVR12 rates were 80.0% (36/45) and 63.6% (14/22) for patients with METAVIR scores of F0-F2 and F3-F4, respectively. Common adverse event (AE) rates were consistent with peg-IFN/RBV therapy (fatigue, headache, nausea, neutropenia). Most AEs were grade 1/2; serious AEs occurred in 5.7% of patients, none of which were fatal. CONCLUSIONS: Simeprevir was generally well tolerated with safety similar to that observed in HCV-monoinfected patients and high SVR12 rates in HCV treatment-naive patients, prior relapsers, prior partial responders, and prior null responders with HIV-1 coinfection. CLINICAL TRIALS REGISTRATION: NCT01479868.

The effects of a co-application of menthol and capsaicin on nociceptive behaviors of the rat on the operant orofacial pain assessment device.

BACKGROUND: Transient receptor potential (TRP) cation channels are involved in the perception of hot and cold pain and are targets for pain relief in humans. We hypothesized that agonists of TRPV1 and TRPM8/TRPA1, capsaicin and menthol, would alter nociceptive behaviors in the rat, but their opposite effects on temperature detection would attenuate one another if combined. METHODS: Rats were tested on the Orofacial Pain Assessment Device (OPAD, Stoelting Co.) at three temperatures within a 17 min behavioral session (33°C, 21°C, 45°C). RESULTS: The lick/face ratio (L/F: reward licking events divided by the number of stimulus contacts. Each time there is a licking event a contact is being made.) is a measure of nociception on the OPAD and this was equally reduced at 45°C and 21°C suggesting they are both nociceptive and/or aversive to rats. However, rats consumed (licks) equal amounts at 33°C and 21°C but less at 45°C suggesting that heat is more nociceptive than cold at these temperatures in the orofacial pain model. When menthol and capsaicin were applied alone they both induced nociceptive behaviors like lower L/F ratios and licks. When applied together though, the licks at 21°C were equal to those at 33°C and both were significantly higher than at 45°C. CONCLUSIONS: This suggests that the cool temperature is less nociceptive when TRPM8/TRPA1 and TRPV1 are co-activated. These results suggest that co-activation of TRP channels can reduce certain nociceptive behaviors. These data demonstrate that the motivational aspects of nociception can be influenced selectively by TRP channel modulation and that certain aspects of pain can be dissociated and therefore targeted selectively in the clinic.

Use of the Operant Orofacial Pain Assessment Device (OPAD) to measure changes in nociceptive behavior.

We present an operant system for the detection of pain in awake, conscious rodents. The Orofacial Pain Assessment Device (OPAD) assesses pain behaviors in a more clinically relevant way by not relying on reflex-based measures of nociception. Food fasted, hairless (or shaved) rodents are placed into a Plexiglas chamber which has two Peltier-based thermodes that can be programmed to any temperature between 7 °C and 60 °C. The rodent is trained to make contact with these in order to access a reward bottle. During a session, a number of behavioral pain outcomes are automatically recorded and saved. These measures include the number of reward bottle activations (licks) and facial contact stimuli (face contacts), but custom measures like the lick/face ratio (total number of licks per session/total number of contacts) can also be created. The stimulus temperature can be set to a single temperature or multiple temperatures within a session. The OPAD is a high-throughput, easy to use operant assay which will lead to better translation of pain research in the future as it includes cortical input instead of relying on spinal reflex-based nociceptive assays.

The global nitrogen cycle in the twenty-first century.

Global nitrogen fixation contributes 413 Tg of reactive nitrogen (Nr) to terrestrial and marine ecosystems annually of which anthropogenic activities are responsible for half, 210 Tg N. The majority of the transformations of anthropogenic Nr are on land (240 Tg N yr(-1)) within soils and vegetation where reduced Nr contributes most of the input through the use of fertilizer nitrogen in agriculture. Leakages from the use of fertilizer Nr contribute to nitrate (NO3(-)) in drainage waters from agricultural land and emissions of trace Nr compounds to the atmosphere. Emissions, mainly of ammonia (NH3) from land together with combustion related emissions of nitrogen oxides (NOx), contribute 100 Tg N yr(-1) to the atmosphere, which are transported between countries and processed within the atmosphere, generating secondary pollutants, including ozone and other photochemical oxidants and aerosols, especially ammonium nitrate (NH4NO3) and ammonium sulfate (NH4)2SO4. Leaching and riverine transport of NO3 contribute 40-70 Tg N yr(-1) to coastal waters and the open ocean, which together with the 30 Tg input to oceans from atmospheric deposition combine with marine biological nitrogen fixation (140 Tg N yr(-1)) to double the ocean processing of Nr. Some of the marine Nr is buried in sediments, the remainder being denitrified back to the atmosphere as N2 or N2O. The marine processing is of a similar magnitude to that in terrestrial soils and vegetation, but has a larger fraction of natural origin. The lifetime of Nr in the atmosphere, with the exception of N2O, is only a few weeks, while in terrestrial ecosystems, with the exception of peatlands (where it can be 10(2)-10(3) years), the lifetime is a few decades. In the ocean, the lifetime of Nr is less well known but seems to be longer than in terrestrial ecosystems and may represent an important long-term source of N2O that will respond very slowly to control measures on the sources of Nr from which it is produced.