Tortuous arteries are often associated with aging, hypertension, atherosclerosis, and degenerative vascular diseases, but the mechanisms are poorly understood. Our recent theoretical analysis suggested that mechanical instability (buckling) may lead to tortuous blood vessels. The objectives of this study were to determine the critical pressure of artery buckling and the effects of elastin degradation and surrounding matrix support on the mechanical stability of arteries. The mechanical properties and critical buckling pressures, at which arteries become unstable and deform into tortuous shapes, were determined for a group of five normal arteries using pressurized inflation and buckling tests. Another group of nine porcine arteries were treated with elastase (8 U/ml), and the mechanical stiffness and critical pressure were obtained before and after treatment. The effect of surrounding tissue support was simulated using a gelatin gel. The critical pressures of the five normal arteries were 9.52 kPa (SD 1.53) and 17.10 kPa (SD 5.11) at axial stretch ratios of 1.3 and 1.5, respectively, while model predicted critical pressures were 10.11 kPa (SD 3.12) and 17.86 kPa (SD 5.21), respectively. Elastase treatment significantly reduced the critical buckling pressure (P < 0.01). Arteries with surrounding matrix support buckled into multiple waves at a higher critical pressure. We concluded that artery buckling under luminal pressure can be predicted by a buckling equation. Elastin degradation weakens the arterial wall and reduces the critical pressure, which thus leads to tortuous vessels. These results shed light on the mechanisms of the development of tortuous vessels due to elastin deficiency.

Cyclic peptides have provided one of the most important platforms for exploration of biorelevant chemical space between small molecules and biologics. However, in comparison with the design and synthesis of small molecules, chemists' ability to fine-tune the three-dimensional structures and properties of cyclic peptides lag far behind. Intrigued by cyclophane peptide natural products, we wondered whether the rigid, planar, and hydrophobic cyclophane motif could provide a new design element for the synthesis of cyclic peptides with well-behaved 3D structures. Herein, we report a generally applicable method for synthesis of natural-product-like cyclophane-braced peptide macrocycles via Pd-catalyzed intramolecular C(sp 3 )−H arylation with aryl iodides at the remote γ position of various N-terminal aliphatic amino acid units using a simple picolinamide directing group. Products of high structural and stereochemical complexity were quickly assembled from easily accessible peptide precursors prepared by standard solid phase peptide synthesis. Many of these peptide macrocycles show highly ordered structures as revealed by X-ray crystallography. Remarkably, the PA-directed C(sp 3 )−H cyclization reaction of unprotected peptide substrates carrying various free polar side chains proceeded with high efficiency and selectivity in aqueous media. This demonstrates not only the synthetic utility of Pd-catalyzed C(sp 3 )−H functionalization reactions, but also offers a valuable new orthogonal reactivity for peptide chemistry.

A versatile method for the construction of C(sp 2 )-linked cyclophane peptide macrocycles via Pd-catalyzed picolinamide-directed intramolecular arylation of aryl and alkenyl C−H bonds of amino acid side chains with aryl iodides is developed. This method provides simple and efficient access to a variety of cyclophane-braced structures from readily accessible linear peptide precursors.

Genetic encoding of noncanonical amino acid (ncAA) for site-specific protein modification has been widely applied for many biological and therapeutic applications. To efficiently prepare homogeneous protein multiconjugates, we design two encodable noncanonical amino acids (ncAAs), 4-(6-(3-azidopropyl)-s-tetrazin-3-yl) phenylalanine (pTAF) and 3-(6-(3-azidopropyl)-s-tetrazin-3-yl) phenylalanine (mTAF), containing mutually orthogonal and bioorthogonal azide and tetrazine reaction handles. Recombinant proteins and antibody fragments containing the TAFs can easily be functionalized in one-pot reactions with combinations of commercially available fluorophores, radioisotopes, PEGs, and drugs in a plug-and-play manner to afford protein dual conjugates to assess combinations of tumor diagnosis, image-guided surgery, and targeted therapy in mouse models. Furthermore, we demonstrate that simultaneously incorporating mTAF and a ketone-containing ncAA into one protein via two non-sense codons allows preparation of a site-specific protein triconjugate. Our results demonstrate that TAFs are doubly bio-orthogonal handles for efficient and scalable preparation of homogeneous protein multiconjugates.

Incorporation of structurally novel noncanonical amino acids (ncAAs) into proteins is valuable for both scientific and biomedical applications.Toexpand the structural diversity of available ncAAs and to reduce the burden of chemically synthesizing them, we have developed ageneral and simple biosynthetic method for genetically encoding novel ncAAs into recombinant proteins by feeding cells with economical commercially available or synthetically accessible aromatic thiols.W ed emonstrate that nearly 50 ncAAs with ad iverse arrayo fs tructures can be biosynthesized from these simple small-molecule precursors by hijacking the cysteine biosynthetic enzymes,a nd the resulting ncAAs can subsequently be incorporated into proteins via an expanded genetic code.M oreover,w ed emonstrate that bioorthogonal reactive groups such as aromatic azides and aromatic ketones can be incorporated into green fluorescent protein or at herapeutic antibody with high yields,a llowing for subsequent chemical conjugation.

Incorporation of structurally novel noncanonical amino acids (ncAAs) into proteins is valuable for both scientific and biomedical applications.Toexpand the structural diversity of available ncAAs and to reduce the burden of chemically synthesizing them, we have developed ageneral and simple biosynthetic method for genetically encoding novel ncAAs into recombinant proteins by feeding cells with economical commercially available or synthetically accessible aromatic thiols.W ed emonstrate that nearly 50 ncAAs with ad iverse arrayo fs tructures can be biosynthesized from these simple small-molecule precursors by hijacking the cysteine biosynthetic enzymes,a nd the resulting ncAAs can subsequently be incorporated into proteins via an expanded genetic code.M oreover,w ed emonstrate that bioorthogonal reactive groups such as aromatic azides and aromatic ketones can be incorporated into green fluorescent protein or at herapeutic antibody with high yields,a llowing for subsequent chemical conjugation.

No abstract

Pressure-induced surface-enhanced Raman spectroscopy (PI-SERS) is among the foremost achievements of high-pressure fields, benefiting from the advantage that pressure-modulated interactions between substrates and molecules overcome the weakness of individual substrates or molecules. However, the pressure corresponding to PI-SERS enhancement is currently still at a low-pressure stage within 8 GPa. Therefore, how to realize PI-SERS enhancement under higher or ultrahigh pressure remains a huge challenge. Here, we applied few-layer WS2 (FL-WS2) nanosheets as PI-SERS substrates and selected 4-mercaptobenzoic acid (4-MBA) molecules with a big energy gap as probes to explore PI-SERS enhancement in more depth. The experimental results indicate that the PI-SERS signals increase gradually as pressure increases and reaches a maximum at 18 GPa, which has set a pressure record for the PI-SERS field so far. Different from the C exciton resonance-induced SERS intensities at ambient conditions, the charge-transfer transition between FL-WS2 and 4-MBA is strengthened via the pressure-induced increase in the band gap of FL-WS2 and decrease in the highest-occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) energy gap of 4-MBA, thus enhancing PI-SERS signals accordingly. Therefore, this strategy will be beneficial for practical applications in the field of optoelectronics and for the design of other PI-SERS sensors for trace detection in complex and extreme environments.