Stimulation of microglial metabotropic glutamate receptor mGlu2 triggers tumor necrosis factor alpha-induced neurotoxicity in concert with microglial-derived fas ligand

Activated microglia may be detrimental to neuronal survival in a number of neurodegenerative diseases. Thus, strategies that reduce microglial neurotoxicity may have therapeutic benefit. Stimulation of group II metabotropic glutamate (mGlu) receptors on rat primary microglia with the specific group II agonist 2S, 2 ' R, 3 ' R- 2-(2 ', 3 '-dicarboxy-cyclopropyl) glycine for 24 h induced microglial activation and resulted in a neurotoxic microglial phenotype. These effects were attributable to preferential mGlu2 stimulation, because N-acetyl-L-aspartyl-L-glutamate, a specific mGlu3 agonist, did not induce microglial activation or neurotoxicity. Stimulation of microglial mGlu2 but not mGlu3 induced caspase-3 activation in cerebellar granule neurons in culture, using microglial-conditioned media as well as cocultures. Stimulation of microglial mGlu2 induced tumor necrosis factor-alpha(TNF alpha) release, which contributed to microglial neurotoxicity mediated via neuronal TNF receptor 1 and caspase-3 activation. Stimulation of microglial group I or III mGlu receptors did not induce TNF alpha release. TNF alpha was only neurotoxic in the presence of microglia or microglial-conditioned medium. The toxicity of TNF alpha could be prevented by coexposure of neurons to conditioned medium from microglia stimulated by the specific group III agonist L-2-amino-4-phosphono-butyric acid. The neurotoxicity of TNF alpha derived from mGlu2-stimulated microglia was potentiated by microglial-derived Fas ligand (FasL), the death receptor ligand. FasL was constitutively expressed in microglia and shed after mGlu2 stimulation. Our data suggest that selective and inverse modulation of microglial mGlu2 and mGlu3 may prove a therapeutic target in neuroinflammatory diseases such as Alzheimer's disease and multiple sclerosis

Impaired clearance of ceftizoxime and cefotaxime after orthotopic liver transplantation.

The pharmacokinetics of ceftizoxime (CZX) and of cefotaxime (CTX) were studied in five children and five adults after orthotopic liver transplantation (OLT). Delayed clearance of CZX (clearance of 0.21 to 1.26 ml/min per kg [body weight]) and CTX (clearance of 0.40 to 1.49 ml/min per kg) occurred in 7 of the 10 OLT patients. We conclude that abnormal CZX and CTX clearance is common after OLT and may be associated with minimal change in serum creatinine

Trump-induced anxiety among Latina/os

During the 2016 election, Donald Trump castigated unauthorized immigrants as “murderers and rapists.” During his presidency, he continued the use of this rhetoric, explicitly linking unauthorized migrants to threatening narratives. Here, we consider three questions: Did Donald Trump and his immigration positions serve as an “anxiety trigger” for Latina/os? Are individuals with contextually stigmatized attributes especially sensitive to Trump and his policy proposals? Is Spanish language itself, an attribute negatively stigmatized in the context of the immigration issue, sufficient to increase deportation anxiety? Utilizing survey experiments of Latina/os, we demonstrate that exposure to a Trump immigration cue is sufficient to increase anxiety about deportation. We also demonstrate that stigmatized attributes predict anxiety, but do not moderate the effect of the Trump cue. Lastly, we provide evidence that survey language affects anxiety among Latina/os. In Studies 1 (n = 736) and 2 (n = 1,040), we show that exposure to information about Trump’s immigration agenda significantly increases reports about deportation anxiety. In Study 3 (n = 1,734), we show that the Trump exposure condition induces heightened anxiety but that Latina/o attributes (language proficiency and use, immigration status, assessed phenotype) and identity strength have an independent effect on deportation anxiety. In Study 4 (n = 775), we randomized bilingual respondents into Spanish or English language survey protocols and found that comparable bilinguals exposed to Spanish language report higher levels of anxiety compared to English-language survey takers

Robust Buchwald-Hartwig amination enabled by ball-milling

An operationally simple mechanochemical method for the Pd catalysed Buchwald–Hartwig amination of arylhalides with secondary amines has been developed using a Pd PEPPSI catalyst system. The system is demonstrated on 30 substrates and applied in the context of a target synthesis. Furthermore, the performance of the reaction under aerobic conditions has been probed under traditional solution and mechanochemical conditions, the observations are discussed herein

A Robust Pd-Catalyzed C-S Cross-Coupling Process Enabled by Ball-Milling

An operationally simple mechanochemical C–S coupling of aryl halides with thiols has been developed. The reaction process operates under benchtop conditions without the requirement for a (dry) solvent, an inert atmosphere, or catalyst preactivation. The reaction is finished within 3 h. The reaction is demonstrated across a broad range of substrates; the inclusion of zinc metal has been found to be critical in some instances, especially for coupling of alkyl thiols

A Ball-Milling-Enabled Cross-Electrophile Coupling

The nickel-catalyzed cross-electrophile coupling of aryl halides and alkyl halides enabled by ball-milling is herein described. Under a mechanochemical manifold, the reductive C–C bond formation was achieved in the absence of bulk solvent and air/moisture sensitive setups, in reaction times of 2 h. The mechanical action provided by ball milling permits the use of a range of zinc sources to turnover the nickel catalytic cycle, enabling the synthesis of 28 cross-electrophile coupled products

Predetermined time constant approximation method for optimising search space boundary by standard genetic algorithm

In this paper, a new predetermined time constant approximation (Tsp) method for optimising the search space boundaries to improve SGAs convergence is proposed. This method is demonstrated on parameter identification of higher order models. Using the dynamic response period and desired settling time of the transfer function coefficients offered a better suggestion for initial Tsp values. Furthermore, an extension on boundaries derived from the initial Tsp values and the consecutive execution, brought the elite groups within feasible boundary regions for better exploration. This enhanced the process of locating of the optimal values of coefficients for the transfer function. The Tsp method is investigated on two processes; excess oxygen and a third order continuous model with and without random disturbance. The simulation results assured the Tsp method's effectiveness and flexibility in assisting SGAs to locate optimal transfer function coefficients. Copyright © 2015 ACM

The Relationship between Daily Physical Activity and Pain in Individuals with Knee Osteoarthritis

Objective. Investigate the association between physical activity and pain severity in individuals with knee osteoarthritis. Design. Cross-sectional; systematic review with meta-analyses. Methods. Thirty-one participants with knee osteoarthritis underwent assessment of symptoms via self-report questionnaires and quantitative sensory testing. Following testing, physical activity and symptoms were monitored for seven days using accelerometers and logbooks. Cross-correlation analyses were performed on fluctuations in symptoms and physical activity across the week to detect the relative timing of the strongest association between pain and activity. These data were complemented by meta-analyses of studies that examined correlations between pain from knee osteoarthritis and physical activity or fitness. Results. Pain severity at baseline correlated with moderate to vigorous physical activity (r2 = 0.161–0.212, P < 0.05), whereby participants who were more physically active had less pain. Conversely, the peak of the cross-correlation analyses was most often positive and lagging, which indicated that pain was increased subsequent to periods of increased activity. These superficially discrepant findings were supported by the results of a meta-analysis of 13 studies and 9,363 participants, which identified significant heterogeneity for associations between physical activity and pain (I2 = 91%). Stronger inverse associations were found between fitness and pain. Conclusions. Associations between physical activity and pain in people with knee osteoarthritis are variable and dynamic. These results reflect the beneficial impact of an active lifestyle and accompanying higher fitness. Yet, the side effect of acute periods of physical activity to transiently exacerbate pain may influence the behavior of some people to avoid activity because of pain

Soil microbial populations in deep floodplain soils are adapted to infrequent but regular carbon substrate addition

This is the final version of the article. Available from Elsevier via the DOI in this record.Floodplain soils provide an important link in the land-ocean aquatic continuum. Understanding microbial activity in these soils, which can be many metres deep, is a key component in our understanding of the role of floodplains in the carbon (C) cycle. We sampled the mineral soil profile to 3 m depth from two floodplain sites under long-term pasture adjacent to the river Culm in SW England, UK. Soil chemistry (C, nitrogen (N), phosphorus (P), soil microbial biomass (SMB), moisture content) and soil solution (pH, dissolved organic C (DOC) and N, nitrate, ammonium, water extractable P) were analysed over the 3 m depth in 6 increments: 0.0–0.2, 0.2–0.7, 1.0–1.5, 1.5–2.0, 2.0–2.5, and 2.5–3.0 m. 14 C-glucose was added to the soil and the evolution of 14 CO 2 measured during a 29 d incubation. From soil properties and 14 C-glucose mineralisation, three depth groups emerged, with distinct turnover times extrapolated from initial k 1 mineralisation rate constants of 2 h (topsoil 0.0–0.2 m), 4 h (subsoil 0.2–0.7 m), and 11 h (deep subsoil 1.0–3.0 m). However, when normalised by SMB, k 1 rate constants had no significant differences across all depths. Deep subsoil had a 2 h lag to reach maximal 14 CO 2 production whereas the topsoil and subsoil (0.2–0.7 m) achieved maximum mineralisation rates immediately. SMB decreased with depth, but only to half of the surface population, with the proportion of SMB-C to total C increasing from 1% in topsoil to 15% in deep subsoil ( > 1.0 m). The relatively large SMB concentration and rapid mineralisation of 14 C-glucose suggests that DOC turnover in deep soil horizons in floodplains is limited by access to biologically available C and not the size of the microbial population.Natural Environment Research Council (NERC)Biotechnology and Biological Sciences Research Council (BBSRC

HIV knowledge, disclosure and sexual risk among pregnant women and their partners in rural South Africa

Partner involvement has been deemed fundamental for the prevention of mother-to-child transmission (PMTCT) of HIV, although it remains difficult to achieve. This study aimed to explore the attitudes and behaviours of pregnant women and their partners who participated in a behavioural risk reduction intervention in six community health centres in the Mpumalanga province of South Africa. Qualitative methods only were used in this study. Women and their partners took part in four gender-concordant groups that addressed HIV, PMTCT, disclosure of HIV status and safer sex practices. The results indicate that men value and understand the importance of being involved in women’s reproductive health, although some components of the PMTCT programme such as condom use were still met with some resistance. Participants demonstrated high levels of HIV- and sexually transmitted infection-related knowledge. Men lacked knowledge about PMTCT but were interested in acquiring information so that they could support their partners. All groups highlighted the emotional and physical benefits of disclosing one’s HIV status. The involvement of men in antenatal care has the potential to prevent women from becoming infected with HIV both during pregnancy and post-partum when they are more vulnerable to infection and have a high risk of transmission to the infant. There is a need for interventions that focus on both increasing male involvement and promoting condom use during pregnancy.Keywords: HIV, PMTCT, disclosure, partners, risk reduction intervention, Mpumalang