Electrophilic aminating reagents have seen a renaissance in recent years as effective nitrogen sources for the synthesis of unprotected amino functionalities. Based on their reactivity, several noble ...and non-noble transition metal catalysed amination reactions have been developed. These include the aziridination and difunctionalisation of alkenes, the amination of arenes as well as the synthesis of aminated sulfur compounds. In particular, the use of hydroxylamine-derived (N-O) reagents, such as PONT (PivONH
3
OTf), has enabled the introduction of unprotected amino groups on various different feedstock compounds, such as alkenes, arenes and thiols. This strategy obviates undesired protecting-group manipulations and thus improves step efficiency and atom economy. Overall, this feature article gives a recent update on several reactions that have been unlocked by employing versatile hydroxylamine-derived aminating reagents, which facilitate the generation of unprotected primary, secondary and tertiary amino groups.
Electrophilic aminating reagents have seen a renaissance in recent years as effective nitrogen sources for the synthesis of unprotected amino functionalities.
We report both an intermolecular C–H amination of arenes to access N-methylanilines and an intramolecular variant for the synthesis of tetrahydroquinolines. A newly developed, highly electrophilic ...aminating reagent was key for the direct synthesis of unprotected N-methylanilines from simple arenes. The reactions display a broad functional group tolerance and employ catalytic amounts of a benign iron salt under mild reaction conditions.
Abstract
Classical metalation reactions such as the metal-halogen exchange have had a transformative impact on organic synthesis owing to their broad applicability in building carbon-carbon bonds ...from carbon-halogen bonds. Extending the metal-halogen exchange logic to a metal-carbon exchange would enable the direct modification of carbon frameworks with new implications in retrosynthetic analysis. However, such a transformation requires the selective cleavage of highly inert chemical bonds and formation of stable intermediates amenable to further synthetic elaborations, hence its development has remained considerably challenging. Here we introduce a skeletal metalation strategy that allows lactams, a prevalent motif in bioactive molecules, to be readily converted into well-defined, synthetically useful organonickel reagents. The reaction features a selective activation of unstrained amide C–N bonds mediated by an easily prepared Ni(0) reagent, followed by CO deinsertion and dissociation under mild room temperature conditions in a formal carbonyl-to-nickel-exchange process. The underlying principles of this unique reactivity are rationalized by organometallic and computational studies. The skeletal metalation is further applied to a direct CO excision reaction and a carbon isotope exchange reaction of lactams, underscoring the broad potential of metal-carbon exchange logic in organic synthesis.
Streptococcus thermophilus is a bacterium widely used in the production of yogurts and cheeses, where it efficiently ferments lactose, the saccharide naturally present in milk. It is also employed as ...a starter in dairy- or plant-based fermented foods that contain saccharides other than lactose (e.g., sucrose, glucose). However, little is known about how saccharide use is regulated, in particular when saccharides are mixed. Here, we determine the effect of the 5 sugars that S. thermophilus is able to use, at different concentration and when they are mixed on the promoter activities of the C-metabolism genes.
Using a transcriptional fusion approach, we discovered that lactose and glucose modulated the activity of the lacS and scrA promoters in a concentration-dependent manner. When mixed with lactose, glucose also repressed the two promoter activities; when mixed with sucrose, lactose still repressed scrA promoter activity. We determined that catabolite control protein A (CcpA) played a key role in these dynamics. We also showed that promoter activity was linked with glycolytic flux, which varied depending on saccharide type and concentration. Overall, this study identified key mechanisms in carbohydrate metabolism - autoregulation and partial hierarchical control - and demonstrated that they are partly mediated by CcpA.
•Glucose repressed promoter activity for transporter-encoding genes lacS and scrA.•Sucrose concentration did not affect promoter activity for carbon metabolism genes.•Catabolite control protein A (CcpA) repressed lacS promoter activity.•Promoter activity of lacS and scrA genes was linked to the glycolytic flux.•Carbohydrate use was partially hierarchical controlled in mixed-saccharide media.
Abstract Objective Investigation of the predictability of finite element (FE) models regarding rupture risk assessment of abdominal aortic aneurysms (AAAs). Materials and materials Peak wall stress ...(PWS) and peak wall rupture risk (PWRR) of ruptured ( n = 20) and non-ruptured ( n = 30) AAAs were predicted by four FE models of different complexities derived from computed tomography (CT) data. Two matching sub-groups of ruptured and non-ruptured aneurysms were used to investigate the usability of different FE models to discriminate amongst them. Results All FE models exhibited a strong positive correlation between PWS and PWRR with the maximum diameter. FE models, which excluded the intra-luminal thrombus (ILT) failed to discriminate between ruptured and non-ruptured aneurysms. The predictability of all applied FE models was strengthened by including wall strength data, that is, computing the PWRR. The most sophisticated FE model applied in this study predicted PWS and PWRR 1.17 ( p = 0.021) and 1.43 ( p = 0.016) times higher in ruptured than diameter-matched non-ruptured aneurysms, respectively. Conclusions PWRR reinforces PWS as a biomechanical rupture risk index. The ILT has a major impact on AAA biomechanics and rupture risk, and hence, needs to be considered in meaningful FE simulations. The applied FE models, however, could not explain rupture in all analysed aneurysms.
The identification as cooperating targets of Proviral Integrations of Moloney virus in murine lymphomas suggested early on that PIM serine/threonine kinases play an important role in cancer biology. ...Whereas elevated levels of PIM1 and PIM2 were mostly found in hematologic malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumors. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumor cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the protein structure facilitated identification of an increasing number of potent small molecule PIM kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we highlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials.
Background
Abdominal aortic aneurysm (AAA) is an important cause of sudden death; however, there are currently incomplete means to predict the risk of AAA rupture. AAA peak wall stress (PWS) can be ...estimated using finite element analysis (FEA) methods from computed tomography (CT) scans. The question is whether AAA PWS can predict AAA rupture. The aim of this systematic review was to compare PWS in patients with ruptured and intact AAA.
Methods
The MEDLINE database was searched on 25 May 2013. Case–control studies assessing PWS in asymptomatic intact, and acutely symptomatic or ruptured AAA from CT scans using FEA were included. Data were extracted independently. A random‐effects model was used to calculate standard mean differences (SMDs) for PWS measurements.
Results
Nine studies assessing 348 individuals were identified and used in the meta‐analysis. Results from 204 asymptomatic intact and 144 symptomatic or ruptured AAAs showed that PWS was significantly greater in the symptomatic/ ruptured AAAs compared with the asymptomatic intact AAAs (SMD 0·95, 95 per cent confidence interval 0·71 to 1·18; P < 0·001). The findings remained significant after adjustment for mean systolic blood pressure, standardized at 120 mmHg (SMD 0·68, 0·39 to 0·96; P < 0·001). Minimal heterogeneity between studies was noted (I2 = 0 per cent).
Conclusion
This study suggests that PWS is greater in symptomatic or ruptured AAA than in asymptomatic intact AAA.
Possible marker of impending rupture
Many important changes occur throughout reproductive development in beef heifers, including during the prenatal, early postnatal, and peripubertal periods. Wave-like patterns of follicular ...development have been observed in heifer calves as early as 2 wk of age. Some dramatic changes occur from about 2 to 5 mo of age, most notably the transient increase in LH secretion. Most components of the hypothalamic-pituitary-ovarian axis are fully competent by approximately 5 to 6 mo of age. Peripubertal changes include increases in LH secretion, estradiol production, follicular development, and reproductive tract size. Eventually, the process reaches the point that the initial ovulation is achieved. Heifers that reach puberty and experience multiple estrous cycles before the onset of their initial breeding season have a greater probability for early conception and optimal lifetime productivity. Attainment of puberty typically occurs at around 12 to 14 mo of age in beef heifers but varies greatly. Genetic differences and environmental factors contribute to this variation. In typical U.S. cow-calf operations, calves are generally weaned at approximately 200 d of age. The impact of postweaning management on age at puberty in heifers has been demonstrated, and there is considerable flexibility in the timing of gain from weaning to breeding. However, even when heifers are grown to the desired BW before the start of breeding, there remains a pronounced variation in the timing of puberty, which impacts pregnancy rates. Less attention has been focused on the impact of preweaning management on age at puberty. Heifer calves with increased growth rates from birth to weaning have reached puberty at earlier ages. Precocious puberty has also been induced in a majority of heifers with early weaning and feeding a high-concentrate diet. Nutritional control during early maturation in heifers exerts a substantial influence on the timing of puberty. Understanding the mechanisms involved in reproductive development increases our ability to effectively manage replacement beef heifers for optimal reproductive performance.
Enzymes immobilization is a useful way to allow enzyme reuse and increase their stability. A high redox potential laccase from Trametes versicolor (TvL) and a low redox potential, but commercially ...available low-cost laccase from Myceliophthora thermophila (MtL), were successfully immobilized and co-immobilized onto fumed silica nanoparticles (fsNP). Enzyme loads of 1.78 ± 0.07, 0.69 ± 0.03, and 1.10 ± 0.01 U/mg fsNP were attained for the optimal doses of TvL, MtL, and co-immobilized laccases, respectively. In general, the laccase-fsNP conjugates showed a higher resistance against an acidic pH value (i.e., pH 3), and a higher storage stability than free enzymes. In addition, immobilized enzymes exhibited a superior long-term stability than free laccases when incubated in a secondary effluent from a municipal wastewater treatment plant (WWTP). For instance, the residual activity after 2 weeks for the co-immobilized laccases and the mixture of free laccases were 40.2 ± 2.5 % and 16.8 ± 1.0 %, respectively. The ability of the laccase-fsNP to remove a mixture of ¹⁴C-bisphenol A (BPA) and ¹⁴C-sodium diclofenac (DCF) from spiked secondary effluents was assessed in batch experiments. The catalytic efficiency was highly dependent on both the microbial source and state of the biocatalyst. The high redox potential TvL in free form attained a four-fold higher percentage of BPA transformation than the free MtL. Compared to free laccases, immobilized enzymes led to much slower rates of BPA transformation. For instance, after 24 h, the percentages of BPA transformation by 1000 U/L of a mixture of free laccases or co-immobilized enzymes were 67.8 ± 5.2 and 27.0 ± 3.9 %, respectively. Nevertheless, the use of 8000 U/L of co-immobilized laccase led to a nearly complete removal of BPA, despite the unfavorable conditions for laccase catalysis (pH ~ 8.4). DCF transformation was not observed for any of the enzymatic systems, showing that this compound is highly recalcitrant toward laccase oxidation under realistic conditions.
This paper presents a viscoelastic model for the fully three-dimensional stress and deformation response of fiber-reinforced composites that experience finite strains. The composites are thought to ...be (soft) matrix materials which are reinforced by two families of fibers so that the mechanical properties of the composites depend on two fiber directions. The relaxation and/or creep response of each compound of the composite is modeled separately and the global response is obtained by an assembly of all contributions. We develop novel closed-form expressions for the fourth-order elasticity tensor (tangent moduli) in full generality. Constitutive models for orthotropic, transversely isotropic and isotropic hyperelastic materials at finite strains with or without dissipation are included as special cases. In order to clearly show the good performance of the constitutive model, we present 3D and 2D numerical simulations of a pressurized laminated circular tube which shows an interesting `stretch inversion phenomenon' in the low pressure domain. Numerical results are in good qualitative agreement with experimental data and approximate the observed strongly anisotropic physical response with satisfying accuracy. A third numerical example is designed to illustrate the anisotropic stretching process of a fiber-reinforced rubber bar and the subsequent relaxation behavior at finite strains. The material parameters are chosen so that thermodynamic equilibrium is associated with the known homogeneous deformation state.
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