Towards energetically viable asymmetric deprotonations : selectivity at more elevated temperatures with C2-symmetric magnesium bisamides

A novel chiral magnesium bisamide has enabled the development of effective asymmetric deprotonation protocols at substantially more elevated temperatures. This new, structurally simple, C2-symmetric magnesium complex displays excellent levels of asymmetric efficiency and energy reduction in the synthesis of enantioenriched enol silane

West Nile Virus Infections Projected from Blood Donor Screening Data, United States, 2003

Routine donor nucleic acid amplification testing is a valuable surveillance screening tool

Arginase impairs hypoxic pulmonary vasoconstriction in murine endotoxemia

Background: Hypoxic pulmonary vasoconstriction (HPV) optimizes the match between ventilation and perfusion in the lung by reducing blood flow to poorly ventilated regions. Sepsis and endotoxemia impair HPV. We previously showed that nitric oxide synthase 2 (NOS2) is required, but not sufficient, for the effect of endotoxin on HPV. The aim of the current study was to identify additional factors that might contribute to the impairment of HPV during endotoxemia. Methods: Gene expression profiling was determined using pulmonary tissues from NOS2-deficient (NOS2−/−) and wild-type mice subjected to endotoxin or saline challenge (control). HPV was accessed as the percentage increase in left pulmonary vascular resistance (LPVR) in response to left main bronchus occlusion (LMBO) in wild-type mice. Results: Among the 22,690 genes analyzed, endotoxin induced a greater than three-fold increase in 59 and 154 genes in the lungs of wild-type and NOS2−/− mice, respectively. Of all the genes induced by endotoxin in wild-type mice, arginase 1 (Arg1) showed the greatest increase (16.3-fold compared to saline treated wild-type mice). In contrast, endotoxin did not increase expression of Arg1 in NOS2−/− mice. There was no difference in the endotoxin-induced expression of Arg2 between wild-type and NOS2-deficient mice. We investigated the role of arginase in HPV by treating the mice with normal saline or the arginase inhibitor Nω-hydroxy-nor-L-arginine (norNOHA). In control mice (in the absence of endotoxin) treated with normal saline, HPV was intact as determined by profound LMBO-induced increase in LPVR (121 ± 22% from baseline). During endotoxemia and treatment with normal saline, HPV was impaired compared to normal saline treated control mice (33 ± 9% vs. 121 ± 22%, P < 0.05). HPV was restored in endotoxin-exposed mice after treatment with the arginase inhibitor norNOHA as shown by the comparison to endotoxemic mice treated with normal saline (113 ± 29% vs, 33 ± 9%, P < 0.05) and to control mice treated with normal saline (113 ± 29% vs, 121 ± 22%, P = 0.97). Conclusions: The results of this study suggest that endotoxemia induces Arg1 and that arginase contributes to the endotoxin-induced impairment of HPV in mice

Comparison of deferral rates using a computerized versus written blood donor questionnaire: a randomized, cross-over study [ISRCTN84429599]

BACKGROUND: Self-administered computer-assisted blood donor screening strategies may elicit more accurate responses and improve the screening process. METHODS: Randomized crossover trial comparing responses to questions on a computerized hand-held tool (HealthQuiz, or HQ), to responses on the standard written instrument (Donor Health Assessment Questionnaire, or DHAQ). Randomly selected donors at 133 blood donation clinics in the area of Hamilton, Canada participated from 1995 to 1996. Donors were randomized to complete either the HQ or the DHAQ first, followed by the other instrument. In addition to responses of 'yes' and 'no' on both questionnaires, the HQ provided a response option of 'not sure'. The primary outcome was the number of additional donors deferred by the HQ. RESULTS: A total of 1239 donors participated. Seventy-one potential donors were deferred as a result of responses to the questionnaires; 56.3% (40/71) were deferred by the DHAQ, and an additional 43.7% (31/71) were deferred due to risks identified by the HQ but not by the DHAQ. Fourteen donors self-deferred; 11 indicated on the HQ that they should not donate blood on that day but did not use the confidential self-exclusion option on the DHAQ, and three used the self-exclusion option on the DHAQ but did not indicate that they should not donate blood on the HQ. The HQ identified a blood contact or risk factor for HIV/AIDS or sexually transmitted infection that was not identified by the DHAQ in 0.1% to 2.7% of donors. CONCLUSION: A self-administered computerized questionnaire may increase risk reporting by blood donors

Quantum Mechanics from Focusing and Symmetry

A foundation of quantum mechanics based on the concepts of focusing and symmetry is proposed. Focusing is connected to c-variables - inaccessible conceptually derived variables; several examples of such variables are given. The focus is then on a maximal accessible parameter, a function of the common c-variable. Symmetry is introduced via a group acting on the c-variable. From this, the Hilbert space is constructed and state vectors and operators are given a clear interpretation. The Born formula is proved from weak assumptions, and from this the usual rules of quantum mechanics are derived. Several paradoxes and other issues of quantum theory are discussed.Comment: 26 page

Mutant Prourokinase with Adjunctive C1-Inhibitor Is an Effective and Safer Alternative to tPA in Rat Stroke

A single-site mutant (M5) of native urokinase plasminogen activator (prouPA) induces effective thrombolysis in dogs with venous or arterial thrombosis with a reduction in bleeding complications compared to tPA. This effect, related to inhibition of two-chain M5 (tcM5) by plasma C1-inhibitor (C1I), thereby preventing non-specific plasmin generation, was augmented by the addition of exogenous C1I to plasma in vitro. In the present study, tPA, M5 or placebo +/− C1I were administered in two rat stroke models. In Part-I, permanent MCA occlusion was used to evaluate intracranial hemorrhage (ICH) by the thrombolytic regimens. In Part II, thromboembolic occlusion was used with thrombolysis administered 2 h later. Infarct and edema volumes, and ICH were determined at 24 h, and neuroscore pre (2 h) and post (24 h) treatment. In Part I, fatal ICH occurred in 57% of tPA and 75% of M5 rats. Adjunctive C1I reduced this to 25% and 17% respectively. Similarly, semiquantitation of ICH by neuropathological examination showed significantly less ICH in rats given adjunctive C1I compared with tPA or M5 alone. In Part-II, tPA, M5, and M5+C1I induced comparable ischemic volume reductions (>55%) compared with the saline or C1I controls, indicating the three treatments had a similar fibrinolytic effect. ICH was seen in 40% of tPA and 50% of M5 rats, with 1 death in the latter. Only 17% of the M5+C1I rats showed ICH, and the bleeding score in this group was significantly less than that in either the tPA or M5 group. The M5+C1I group had the best Benefit Index, calculated by dividing percent brain salvaged by the ICH visual score in each group. In conclusion, adjunctive C1I inhibited bleeding by M5, induced significant neuroscore improvement and had the best Benefit Index. The C1I did not compromise fibrinolysis by M5 in contrast with tPA, consistent with previous in vitro findings

Securing the climate benefits of stable forests

Stable forests – those not already significantly disturbed nor facing predictable near-future risks of anthropogenic disturbance – may play a large role in the climate solution, due to their carbon sequestration and storage capabilities. Their importance is recognized by the Paris Agreement, but stable forests have received comparatively little attention through existing forest protection mechanisms and finance. Instead, emphasis has been placed on targeting locations where deforestation and forest degradation are happening actively. Yet stopping deforestation and forest degradation does not guarantee durable success, especially outside the geographic scope of targeted efforts. As a result, today's stable forests may be at risk without additional efforts to secure their long-term conservation. We synthesize the gaps in existing policy efforts that could address the climate-related benefits derived from stable forests, noting several barriers to action, such as uncertainty around the level of climate services that stable forests provide and difficulties describing the real level of threat posed. We argue that resource and finance allocation for stable forests should be incorporated into countries’ and donors’ comprehensive portfolios aimed at tackling deforestation and forest degradation as well as resulting emissions. A holistic and forward-looking approach will be particularly important, given that success in tackling deforestation and forest degradation where it is currently happening will need to be sustained in the long term

Transfusion-transmitted infections

Although the risk of transfusion-transmitted infections today is lower than ever, the supply of safe blood products remains subject to contamination with known and yet to be identified human pathogens. Only continuous improvement and implementation of donor selection, sensitive screening tests and effective inactivation procedures can ensure the elimination, or at least reduction, of the risk of acquiring transfusion transmitted infections. In addition, ongoing education and up-to-date information regarding infectious agents that are potentially transmitted via blood components is necessary to promote the reporting of adverse events, an important component of transfusion transmitted disease surveillance. Thus, the collaboration of all parties involved in transfusion medicine, including national haemovigilance systems, is crucial for protecting a secure blood product supply from known and emerging blood-borne pathogens

Examining the Interactome of Huperzine A by Magnetic Biopanning

Huperzine A is a bioactive compound derived from traditional Chinese medicine plant Qian Ceng Ta (Huperzia serrata), and was found to have multiple neuroprotective effects. In addition to being a potent acetylcholinesterase inhibitor, it was thought to act through other mechanisms such as antioxidation, antiapoptosis, etc. However, the molecular targets involved with these mechanisms were not identified. In this study, we attempted to exam the interactome of Huperzine A using a cDNA phage display library and also mammalian brain tissue extracts. The drugs were chemically linked on the surface of magnetic particles and the interactive phages or proteins were collected and analyzed. Among the various cDNA expressing phages selected, one was identified to encode the mitochondria NADH dehydrogenase subunit 1. Specific bindings between the drug and the target phages and target proteins were confirmed. Another enriched phage clone was identified as mitochondria ATP synthase, which was also panned out from the proteome of mouse brain tissue lysate. These data indicated the possible involvement of mitochondrial respiratory chain matrix enzymes in Huperzine A's pharmacological effects. Such involvement had been suggested by previous studies based on enzyme activity changes. Our data supported the new mechanism. Overall we demonstrated the feasibility of using magnetic biopanning as a simple and viable method for investigating the complex molecular mechanisms of bioactive molecules