The use of temperature‐controlled mechanochemistry to enable the mechanochemical nickel‐catalyzed Suzuki–Miyaura coupling is herein described. Transitioning from a capricious room‐temperature ...protocol, through to a heated, PID‐controlled programmable jar heater manifold was required to deliver an efficient method for the coupling of aryl sulfamates (derived from ubiquitous phenols) and aryl boronic acid species. Furthermore, this process is conducted using a base‐metal nickel catalyst, in the absence of bulk solvent, and in the absence of air/moisture sensitive reaction set‐ups. This methodology is showcased through translation to large‐scale twin‐screw extrusion methodology enabling 200‐fold scale increase, producing decagram quantities of C−C coupled material.
The nickel catalyzed Suzuki–Miyaura‐type coupling of aryl sulfamates and boronic acid derivatives enabled by temperature‐controlled mechanochemistry via the development of a programmable PID‐controlled jar heater is reported. This base‐metal‐catalyzed, solvent‐free, all‐under‐air protocol was also scaled 200‐fold using twin‐screw extrusion technology affording decagram quantities of material.
Ball‐Milling‐Enabled Reactivity of Manganese Metal Nicholson, William I.; Howard, Joseph L.; Magri, Giuseppina ...
Angewandte Chemie (International ed.),
October 18, 2021, Letnik:
60, Številka:
43
Journal Article
Recenzirano
Odprti dostop
Efforts to generate organomanganese reagents under ball‐milling conditions have led to the serendipitous discovery that manganese metal can mediate the reductive dimerization of arylidene malonates. ...The newly uncovered process has been optimized and its mechanism explored using CV measurements, radical trapping experiments, EPR spectroscopy, and solution control reactions. This unique reactivity can also be translated to solution whereupon pre‐milling of the manganese is required.
A manganese‐mediated reductive dimerization of arylidene malonates by ball milling is reported. The process has been optimised and its mechanism explored by CV measurements, radical trapping, and EPR spectroscopy. Control experiments identify the action of ball milling rather than mortar and pestle is necessary to realise the effective activation of manganese, which can then be used in either solution or a ball mill for subsequent reactions.
We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal ...nocturnal hemoglobinuria (PNH).
We conducted a double-blind, randomized, placebo-controlled, multicenter, phase 3 trial. Patients received either placebo or eculizumab intravenously; eculizumab was given at a dose of 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26. The two primary end points were the stabilization of hemoglobin levels and the number of units of packed red cells transfused. Biochemical indicators of intravascular hemolysis and the patients' quality of life were also assessed.
Eighty-seven patients underwent randomization. Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% (21 of 43) of the patients assigned to eculizumab and none (0 of 44) of those assigned to placebo (P<0.001). During the study, a median of 0 units of packed red cells was administered in the eculizumab group, as compared with 10 units in the placebo group (P<0.001). Eculizumab reduced intravascular hemolysis, as shown by the 85.8% lower median area under the curve for lactate dehydrogenase plotted against time (in days) in the eculizumab group, as compared with the placebo group (58,587 vs. 411,822 U per liter; P<0.001). Clinically significant improvements were also found in the quality of life, as measured by scores on the Functional Assessment of Chronic Illness Therapy-Fatigue instrument (P<0.001) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Of the 87 patients, 4 in the eculizumab group and 9 in the placebo group had serious adverse events, none of which were considered to be treatment-related; all these patients recovered without sequelae.
Eculizumab is an effective therapy for PNH.
Summary
Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, ...dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events (TEs) and chronic kidney disease (CKD). The long‐term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3‐year survival estimate of 97·6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86·9% at 36 months), reflecting inhibition of chronic haemolysis. TEs decreased by 81·8%, with 96·4% of patients remaining free of TEs. Patients also showed a time‐dependent improvement in renal function: 93·1% of patients exhibited improvement or stabilization in CKD score at 36 months. Transfusion independence increased by 90·0% from baseline, with the number of red blood cell units transfused decreasing by 54·7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival.
Efforts to generate organomanganese reagents under ball‐milling conditions have led to the serendipitous discovery that manganese metal can mediate the reductive dimerization of arylidene malonates. ...The newly uncovered process has been optimized and its mechanism explored using CV measurements, radical trapping experiments, EPR spectroscopy, and solution control reactions. This unique reactivity can also be translated to solution whereupon pre‐milling of the manganese is required.
A manganese‐mediated reductive dimerization of arylidene malonates by ball milling is reported. The process has been optimised and its mechanism explored by CV measurements, radical trapping, and EPR spectroscopy. Control experiments identify the action of ball milling rather than mortar and pestle is necessary to realise the effective activation of manganese, which can then be used in either solution or a ball mill for subsequent reactions.
Covalent kinase inhibitors, which typically target cysteine residues, represent an important class of clinically relevant compounds. Approximately 215 kinases are known to have potentially targetable ...cysteines distributed across 18 spatially distinct locations proximal to the ATP-binding pocket. However, only 40 kinases have been covalently targeted, with certain cysteine sites being the primary focus. To address this disparity, we have developed a strategy that combines the use of a multi-targeted acrylamide-modified inhibitor, SM1-71, with a suite of complementary chemoproteomic and cellular approaches to identify additional targetable cysteines. Using this single multi-targeted compound, we successfully identified 23 kinases that are amenable to covalent inhibition including MKNK2, MAP2K1/2/3/4/6/7, GAK, AAK1, BMP2K, MAP3K7, MAPKAPK5, GSK3A/B, MAPK1/3, SRC, YES1, FGFR1, ZAK (MLTK), MAP3K1, LIMK1, and RSK2. The identification of nine of these kinases previously not targeted by a covalent inhibitor increases the number of targetable kinases and highlights opportunities for covalent kinase inhibitor development.
Urban development is the most common form of land conversion in the United States. Using a before-after control-impact study design, we investigated the effects of urbanization on larval and adult ...stages of southern two-lined salamanders (Eurycea cirrigera) and northern dusky salamanders (Desmognathus fuscus). Over 5 years, we estimated changes in occupancy and probabilities of colonization and survival in 13 stream catchments after urbanization and in 17 catchments that were not urbanized. We also examined effects of proportion of urbanized area in a catchment and distance of the salamander population to the nearest stream on probabilities of colonization and survival. Before urbanization, adult and larval stages of the two salamander species occupied nearly all surveyed streams, with occupancy estimates ranging from 1.0 to 0.78. Four years after urbanization mean occupancy of larval and adult two-lined salamanders had decreased from 0.87 and 0.78 to 0.57 and 0.39, respectively. Estimates of mean occupancy of larval northern dusky salamanders decreased from 1.0 to 0.57 in urban streams 4 years after urbanization; however, adult northern dusky salamander occupancy remained close to 1.0 in urban streams over 5 years. Occupancy estimates in control streams were similar for each species and stage over 5 years. Urbanization was associated with decreases in survival probabilities of adult and larval two-lined salamanders and decreases in colonization probabilities of larval dusky salamanders. Nevertheless, proportion of impervious surface and distance to nearest stream had little effect on probabilities of survival and colonization. Our results imply that in the evaluation of the effects of urbanization on species, such as amphibians, with complex life cycles, consideration of the effects of urbanization on both adult and larval stages is required. El desarrollo urbano es la forma más común de conversión de suelo en los Estados Unidos. Mediante el diseño de un estudio previo y posterior del impacto del control, investigamos los efectos de la urbanización sobre la fase larvaria y adulta de dos especies de salamandras (Eurycea cirrigera y Desmognathus fuscus). A lo largo de 5 años estimamos los cambios en ocupación y las probabilidades de colonización y supervivencia en el área de influencia de 13 arroyos después de la urbanización y en 17 que no fueron urbanizados. También examinamos los efectos de la proporción de superficie impermeable en cada área de influencia y de la distancia de la población de salamandras al arroyo más cercano sobre las probabilidades de colonización y supervivencia. Previo a la urbanización, la fase adulta y larvaria de las dos especies de salamandras ocuparon casi todos los arroyos muestreados, las estimaciones de ocupación variaron entre 1.0 y 0.78. Cuatro años después de la urbanización, la ocupación media de larvas y adultos de E. cirrigera disminuyó de 0.87 a 0.78 a 0.57 y 0.39, respectivamente. Las estimaciones de la ocupación media de larvas de D. fuscus disminuyó de 1.0 a 0.57 en arroyos urbanos 4 años después de la urbanización; sin embargo, la ocupación de adultos de D. fuscus permaneció cercana a 1.0 en arroyos urbanos durante los 5 años. Las estimaciones de ocupación en los arroyos control fueron similares para cada especie y fase a lo largo de los 5 años. La urbanización fue asociada con la disminución en las probabilidades de supervivencia de adultos y larvas de E. cirrigera y con la disminución en las probabilidades de colonización de D. fuscus. Sin embargo, la proporción de superficie impermeable y la distancia al arroyo más cercano tuvo poco efecto sobre las probabilidades de supervivencia y colonización. Nuestros resultados implican, que en la evaluación de los efectos de la urbanización sobre especies, como los anfibios, que es necesario de considerar los efectos de la urbanización tanto sobre la fase adulta y como la larvaria.
Although tropical regions harbor the greatest arthropod diversity on Earth, the majority of species are taxonomically and scientifically unknown. Furthermore, how they are organized into functional ...communities and distributed among habitats is mostly unstudied. Here we examine species richness, diversity, and community composition of carabid beetles (Coleoptera: Carabidae) and compare them between flooded (FP) and non-flooded terra firme (TF) forests in the Yasuní area of Ecuador. The forest understory was sampled using flight intercept traps (FITs) and systematic hand collections at night in June and July 2011 and 2012, and FITs in October and November 2011. A total of 1,255 Carabidae representing 20 tribes, 54 genera, and 143 morphospecies was collected. Mean number of individuals and mean species richness did not differ significantly between FP and TF; however, numbers of Cicindelini (tiger beetles) and Pentagonicini were higher in TF forest while numbers of Lachnophorini and Scaritini were higher in FP forest. Overall, FP had significantly higher rarefied richness but extrapolation of rarefaction curves using the Chao1 nonparametric diversity estimator show that this difference may decrease with additional sampling. The inverse Simpson index was significantly higher for FP than TF forest. Nonmetric multidimensional scaling (NMDS) ordination and dissimilarity coefficient values show that FP and TF forests maintain unique assemblages with minimal overlap in community composition. Given ongoing anthropogenic pressures, particularly petroleum extraction, and those resulting from climate change, a greater understanding of the richness, diversity and community assemblages of Yasuní rainforest are needed to better conserve the fauna of this megadiverse area of Amazonia.
The National Ecological Observatory Network (NEON) will monitor ground beetle populations across a network of broadly distributed sites because beetles are prevalent in food webs, are sensitive to ...abiotic factors, and have an established role as indicator species of habitat and climatic shifts. We describe the design of ground beetle population sampling in the context of NEON's long‐term, continental‐scale monitoring program, emphasizing the sampling design, priorities, and collection methods. Freely available NEON ground beetle data and associated field and laboratory samples will increase scientific understanding of how biological communities are responding to land‐use and climate change.
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