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Cleaner synthesis of amines remains a key challenge in organic chemistry because of their prevalence in pharmaceuticals, agrochemicals and synthetic building blocks. Here, we report a different paradigm for chemoselective hydrogenation of nitro compounds to amines, under mild, aqueous conditions. The hydrogenase enzyme releases electrons from H 2 to a carbon black support which facilitates nitro-group reduction. For 30 nitroarenes we demonstrate full conversion (isolated yields 78 – 96%), with products including pharmaceuticals benzocaine, procainamide and mesalazine, and 4-aminophenol – precursor to paracetamol (acetaminophen). We also showcase gram-scale synthesis of procainamide with 90% isolated yield. We demonstrate potential for extension to aliphatic substrates. The catalyst is highly selective for reduction of the nitro group over other unsaturated bonds, tolerant to a wide range of functional groups, and exhibits excellent stability in reactions lasting up to 72 hours and full reusability over 5 cycles with a total turnover number over 1 million, indicating scope for direct translation to fine chemical manufacturing. The reduction of nitro-groups is a common synthetic route to amines, but biocatalytic strategies for such reactions are still being developed. In this study, the authors repurposed the hydrogenase enzyme by immobilisation on carbon black to yield a heterogeneous chemobiocatalyst for selective production of amines.

Stiffening of the aorta is an important independent risk factor for myocardial infarction and stroke. Yet its genetics is complex and little is known about its molecular drivers. We have identified for the first time, tagSNPs in the genes for extracellular matrix proteins, aggrecan and fibulin-1, that modulate stiffness in young healthy adults. We confirmed SNP associations with ex vivo stiffness measurements and expression studies in human donor aortic tissues. Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan reflecting loss of chondroitin-sulphate binding domains. These differences were age-dependent but the striking finding was the acceleration of this process in stiff versus elastic young aortas. These findings suggest that aggrecan and fibulin-1 have critical roles in determining the biomechanics of the aorta and their modification with age could underpin age-related aortic stiffening.

Deletion of exon 9 from Cullin‐3 (CUL3, residues 403–459: CUL3 Δ403–459 ) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin‐RING‐ubiquitin‐ligase complexes. Bound to KLHL3, CUL3‐RBX1 ubiquitylates WNK kinases, promoting their ubiquitin‐mediated proteasomal degradation. Since WNK kinases activate Na/Cl co‐transporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting Cullin‐RING‐ligase formation. We report here that the PHA2E mutant, CUL3 Δ403–459 , is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3 Δ403–459 auto‐ubiquitylates and loses interaction with two important Cullin regulators: the COP9‐signalosome and CAND1. A novel knock‐in mouse model of CUL3 WT /Δ403–459 closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases. Synopsis Molecular defects observed in a mutant form of the ubiquitin E3 protein CUL3 causing a severe form of familial hypertension (PHA2E) result in E3 ligase loss of function. A novel mouse model with the same CUL3 disease mutation was generated, and it closely recapitulates the human PHA2E phenotype. Mutations in CUL3 that cause hereditary hypertension prevent the ubiquitylation and degradation of WNK kinases probably due to increased flexibility of the cullin backbone. The mutant CUL3 Δ403–459 protein shows marked auto‐ubiquitylation and loss of binding to the critical cullin regulators, CSN and CAND1. The phenotype of knock‐in mice carrying the CUL3 Δ403–459 mutation closely recapitulates PHA2E; kidney DCTs contain striking accumulation of WNK and SPAK proteins. The mice expressing CUL3 Δ403–459 have a vascular phenotype suggesting increased vascular tone that may contribute to the severity of the hypertension seen in PHA2E compared to other forms (PHA2A‐D). Graphical Abstract Molecular defects observed in a mutant form of the ubiquitin E3 protein CUL3 causing a severe form of familial hypertension (PHA2E) result in E3 ligase loss of function. A novel mouse model with the same CUL3 disease mutation was generated, and it closely recapitulates the human PHA2E phenotype.

Background Although arterial stiffness is of clinical interest, data on the elastic modulus of the human aortic wall are scarce. The aim of this work is to directly measure the elastic modulus of human aorta ex vivo. Methods Using a standard tensiometer, we measured the elastic modulus (E) of human aortic rings (n = 205). Wall thickness and diameter were measured, and the pulse wave velocity (PWV) for each aorta was calculated using Moens-Kortweg equations. The results were analysed based on age, gender and aortic site, then compared with data obtained in living subjects using MRI (n = 160). Results At 100mmHg pressure, E of aortic rings increased with age, with a commiserate increase in PWV: under 30 years = 3.73±0.49; 30–39 years = 3.32±0.58; 40–49 years = 3.32±0.49; 50–59 years = 3.55±1.00; 60–69 years = 4.05±1.21; 70–79 years = 4.52±1.26; 80–89 years = 5.59±0.39 m/s. There was no significant difference in either E or PWV between genders. There was also no significant difference in E or PWV based on aortic site, likely due to under-representation of most sites. PWV measured in vivo using MRI was higher every age: under 30 years = 3.96±0.51; 30–39 years = 4.47±0.61; 40–49 years = 4.85±0.75; 50–59 years = 5.97±1.14; 60–69 years = 6.64±1,16; 70–79 years = 9.40±4.24 m/s. The difference between in vivo and ex vivo measurements increased with age. Conclusions PWV calculated from ex vivo E measurements reflect established physiological patterns, suggesting that direct elastic modulus measurement may be an acceptable method for analysing stiffness in aortic tissue.

Tapping into primal and animalistic instincts, the representation of murder draws upon a sense that the human condition is to be fundamentally flawed, and suggests that such universal emotions as greed, jealousy, lust, and pride motivate a significant number of murders. The Old Testament figure of Cain, supposedly the first murderer (of his brother Abel), was forever cursed to 'be a fugitive and a wanderer of the earth' for all eternity.1 Cain's story of fraternal betrayal and antagonism is one commonly represented in films such as Bloodline (2005), Before the Devil Knows You're Dead (2007), We Own the Night (2007), and the Broadway musical Blood Brothers (1983-present).

[...]of these experiments at the hands of a maniacal dancing scientist, and set to the dulcet notes of KC and the Sunshine Band's 'Get Down Tonight', Brooke is dramatically transformed from victim to victor through quite an unusual innovation, thus providing a refreshing twist to what is often considered a genre at the edge of exhaustion. An apocalyptic harbinger, according to The Book of Revelations, 'Wormwood' is a disease-carrying star which will wipe out mankind, carrying the souls of the good to heaven and the bad to hell, and condemning those left behind on earth to endure a trial by fire. When Old-Testament warnings have materialised, and family members who once loved and cherished you are now clutching at your throat in order to rip it open and eat the contents, all bets are pretty much off. [...]within the world of a zombie apocalypse, you can pretty much get away with murder, which is essentially what Brooke and Barry manage to do.

[...]it could be argued that DVDs, downloads and so on happen through us, whereas television happens to us. In spite of this, TV Horror wishes to challenge the assumption \"that graphic depictions of gore are intrinsic to horror by asserting instead that the aesthetics of horror are characterized by the spectacle, with visual and aural excess encompassing both terror and horror\" (p.132).

The recent genome-wide analysis of carotid–femoral pulse wave velocity (PWV) identified a significant locus within the 14q32.2 gene desert. Gene regulatory elements for the transcriptional regulator B-cell CLL/lymphoma 11B (BCL11B) are within this locus and an attractive target for the gene association. We investigated the functional impact of these gene desert SNPs on BCL11B transcript in human aorta to characterize further its role in aortic stiffness. To do this, we used a large repository of aortic tissues (n = 185) from an organ transplant program and assessed ex vivo stiffness of the aortic rings. We tested association of three lead SNPs from the GWAS meta-analysis with ex vivo aortic stiffness and BCL11B aortic mRNA expression: rs1381289 and rs10782490 SNPs associated significantly with PWV and showed allele-specific differences in BCL11B mRNA. The risk alleles associated with lower BCL11B expression, suggesting a protective role for BCL11B. Despite strong association, we could not detect BCL11B protein in the human aorta. However, qPCR for CD markers showed that BCL11B transcript correlated strongly with markers for activated lymphocytes. Our data confirm the significance of the 14q32.2 region as a risk locus for aortic stiffness and an upstream regulator of BCL11B. The BCL11B transcript detected in the human aorta may reflect lymphocyte infiltration, suggesting that immune mechanisms contribute to the observed association of BCL11B with aortic stiffness.

Many commercialized medicinal compounds are analogs of chemicals isolated from sources found in nature (also called natural products). However, the natural sources of these chemicals, such as plants, fungi, or insects, only offer small quantities of these bioactive agents. Thus, it is typically desirable to find ways to synthesize these products and their analogs in large quantities using cost-effective methods that also minimize the impact on the environment. It is also important to develop strategies that expedite the process of modifying the natural products, which allows medicinal chemists to determine which functional groups are enhancing or deleterious to the bioactivity. In the Brewer lab, I have investigated organic reactions and methodologies with this aim—to find ways to efficiently break and form carbon-carbon bonds, and to utilize these reactions in the total synthesis of structurally related natural products. The total synthesis of natural products is often used to showcase a methodology's utility by applying it in a more complex structure. The Lewis acid-promoted fragmentation of γ-silyloxy-β-hydroxy-α-diazo esters to provide tethered aldehyde ynoates was discovered and developed in the Brewer lab. This methodology was extended to bicyclic systems, in which the ring-fusion bond fragmented as a way to afford 10-membered ring ynones and ynolides, which are traditionally challenging to synthesize. This work will exhibit how the fragmentation reaction that provided 10-membered ynolides has the potential to lend itself to the synthesis of several structurally related, bioactive natural products via a divergent total synthesis strategy. In addition, this dissertation will describe our discovery that modifying the diazo carbonyl precursor to a β-hydroxy-α-diazo ketone changes the course of the Lewis acid-promoted reaction. Rather than a fragmentation sequence, the compound is converted to a vinyl cation, which undergoes a rearrangement then a C-H insertion of a second vinyl cation intermediate. This transition metal-free rearrangement/C-H insertion reaction provided cyclopentenone products. The migratory aptitudes of non-equivalent substituents in the cationic rearrangement step will also be discussed. Finally, the disparate reactivities of vinyl cations derived from diazo ketone, diazo ester, and diazo amide precursors will be detailed from an experimental and computational perspective. The results underscore the fact that this rearrangement and C-H insertion reaction may eventually be an effective way to prepare complex cyclopentyl-containing structures, which are common motifs in biologically active natural products.