Supramolecular helix of an oligomeric azapeptide building block containing four ß-turn structures.

Oligomers of benzoylalanine-based amidothioureas containing four ß-turn structures spaced by meta-substituted benzenes were shown to undergo assembly in dilute CH3CN solution into supramolecular helices of enhanced supramolecular helicity, whereas those spaced by para-substituted benzene spacer(s) or those spaced by meta-substituted benzenes but with one or two ß-turns exhibit a substantially decreased tendency of assembling.

Noncovalent interaction network of chalcogen, halogen and hydrogen bonds for supramolecular ß-sheet organization.

An alanine-based bilateral building block, linked by 2,5-thiophenediamide motifs and equipped with C-terminal 4-iodoaniline groups, was designed, allowing a noncovalent interaction network consisting of intramolecular chalcogen bonds and intermolecular halogen/hydrogen bonds, which cooperatively maintain a supramolecular ß-sheet organization in the solid state, as well as in dilute CH3CN solution with a high g factor of -0.017.

Artificial intelligence for automatic surgical phase recognition of laparoscopic gastrectomy in gastric cancer.

PURPOSE: This study aimed to classify laparoscopic gastric cancer phases. We also aimed to develop a transformer-based artificial intelligence (AI) model for automatic surgical phase recognition and to evaluate the model's performance using laparoscopic gastric cancer surgical videos. METHODS: One hundred patients who underwent laparoscopic surgery for gastric cancer were included in this study. All surgical videos were labeled and classified into eight phases (P0. Preparation. P1. Separate the greater gastric curvature. P2. Separate the distal stomach. P3. Separate lesser gastric curvature. P4. Dissect the superior margin of the pancreas. P5. Separation of the proximal stomach. P6. Digestive tract reconstruction. P7. End of operation). This study proposed an AI phase recognition model consisting of a convolutional neural network-based visual feature extractor and temporal relational transformer. RESULTS: A visual and temporal relationship network was proposed to automatically perform accurate surgical phase prediction. The average time for all surgical videos in the video set was 9114 ± 2571 s. The longest phase was at P1 (3388 s). The final research accuracy, F1, recall, and precision were 90.128, 87.04, 87.04, and 87.32%, respectively. The phase with the highest recognition accuracy was P1, and that with the lowest accuracy was P2. CONCLUSION: An AI model based on neural and transformer networks was developed in this study. This model can identify the phases of laparoscopic surgery for gastric cancer accurately. AI can be used as an analytical tool for gastric cancer surgical videos.

Non-Covalently Stapled H+ /Cl- Ion Channels Activatable by Visible Light for Targeted Anticancer Therapy.

The development of stimuli-responsive artificial H+ /Cl- ion channels, capable of specifically disturbing the intracellular ion homeostasis of cancer cells, presents an intriguing opportunity for achieving high selectivity in cancer therapy. Herein, we describe a novel family of non-covalently stapled self-assembled artificial channels activatable by biocompatible visible light at 442 nm, which enables the co-transport of H+ /Cl- across the membrane with H+ /Cl- transport selectivity of 6.0. Upon photoirradiation of the caged C4F-L for 10 min, 90 % of ion transport efficiency can be restored, giving rise to a 10.5-fold enhancement in cytotoxicity against human colorectal cancer cells (IC50 =8.5 µM). The mechanism underlying cancer cell death mediated by the H+ /Cl- channels involves the activation of the caspase 9 apoptosis pathway as well as the scarcely reported disruption of the autophagic processes. In the absence of photoirradiation, C4F-L exhibits minimal toxicity towards normal intestine cells, even at a concentration of 200 µM.

One-Pot Cyclization to Large Peptidomimetic Macrocycles by In Situ-Generated ß-Turn-Enforced Folding.

Macrocycles have been targets of extensive synthetic efforts for decades because of their potent molecular recognition and self-assembly capabilities. Yet, efficient syntheses of macrocyclic molecules via irreversible covalent bonds remain challenging. Here, we report an efficient approach to large peptidomimetic macrocycles by using the in situ-generated ß-turn structural motifs afforded in the amidothiourea moieties from the early steps of the reaction of 2 molecules of bilateral amino acid-based acylhydrazine with 2 molecules of diisothiocyanate. Four chiral and achiral peptidomimetic large macrocycles were successfully synthesized in high yields of 45-63% in a feasible one-pot reaction under sub-molar concentration conditions and were purified by simple filtration. X-ray crystallographic characterization of three macrocycles reveals an important feature that their four ß-turn structures, each maintained by four 10-membered intramolecular hydrogen bonds, alternatively network the four aromatic arms. This affords an interesting conformation switching mode upon anion binding. Binding of SO42- to 1L or 1D that contains 4 alanine residues (with the lowest steric hinderance among the macrocycles) leads to an inside-out structural change of the host macrocycle, as confirmed by the X-ray crystal structure of 1L-SO42- and 1D-SO42- complexes, accompanied by an inversion of the CD signals. On the basis of the strong sulfate affinity of the macrocycles, we succeeded in the removal of sulfate anions from water via a macrocycle-mediated liquid-liquid extraction method. Our synthetic protocol can be easily extended to other macrocycles of varying arms and/or chiral amino acid residues; thus, a variety of structurally and functionally diverse macrocycles are expected to be readily made.

Synthetic approaches to metal-coordination-directed macrocyclic complexes.

Metal-coordination-directed macrocyclic complexes, in which macrocyclic architectures are formed by metal-ligand coordination interactions, have emerged as attractive supramolecular scaffolds for the creation of materials for applications in biosensing and therapeutics. Despite recent progress, uncontrolled multicyclic cages and linear oligomers/polymers is the most likely outcome from metal-ligands assembly, representing a challenge to current synthetic methods. Herein we outlined the state-of-art synthetic approaches to the metal-coordination-directed macrocyclic complexes by using foldable ligands or through assembly of amphiphilic ligands. This mini-review offers a guideline for the efficient preparation of metal-coordination-directed macrocyclic complexes with predictable and controllable structures, which may find applications in many biology-related areas.

Ubiquitin specific peptidase 38 promotes the progression of gastric cancer through upregulation of fatty acid synthase.

Gastric cancer (GC) is a malignant tumor with an adverse health effect worldwide, whereas the underlying mechanism of GC development remains controversial. Identification of biomarkers is critical for the treatment of GC. Increasing evidence demonstrates that protein modification plays a pivotal role in carcinogenesis. USP38 is a member of the ubiquitin-specific protease (USP) family, which promotes protein stability by deubiquitinating the target proteins. In this study, we focused on the effect of USP38 on the GC and explored its underlying mechanism. The Cancer Genome Atlas (TCGA) database was used to evaluate the expression of USP38. AGS and HGC27 cells were treated with siRNA targeting USP38 or plasmids overexpressing USP38 to disturb levels of USP38. Immumohistochemical staining was performed to detect the level of USP38 and FASN. RT-qPCR and Western blotting (WB) were used to analyze the expression of mRNA and protein respectively. CCK8 assay, colony formation, cell migration assay, and cell apoptosis and cell cycle were performed to assess cell proliferation and migration ability. A subcutaneous tumor mice model was carried to verify the effect of USP38 on the GC in vivo. In this research, we found that USP38 was overexpressed in GC tissues, and USP38 contributed to GC cell proliferation, migration and tumorigenesis. Cell cycle and apoptosis were also regulated by USP38. Mechanistically, USP38 interacted with FASN, which resulted in enhanced protein stability of FASN and increased triglyceride production. Furthermore, FASN was critical for GC cell growth, migration and tumor development triggered by USP38 overexpression because its inhibitor orilistat reversed phenotypes in USP38 overexpressed GC cells. Collectively, USP38 overexpression is critical for GC cell growth, migration and tumorigenesis. Targeting FASN with inhibitors could be used as a potential treatment for GC patients with highly expressed USP38.

Spontaneous Resolution of Helical Building Blocks through the Formation of Homochiral Helices in Two Dimensions.

Spontaneous resolution leading to conglomerate crystals remains a significant challenge. Here we propose the formation of orthogonal homochiral supramolecular helices in at least two dimensions to allow spontaneous resolution. We suggest the design rationale that the chiral species is made into helical building blocks to allow the helix formation. As a proof-of-concept, acetylalanine was made into a helical short azapeptide, its N-amidothiourea derivative containing a ß-turn structure, to which a halogen atom was further introduced at the phenylthiourea aromatic ring. The resultant folded species undergoes both intermolecular hydrogen and halogen bonding across the turn structure to form orthogonal intermolecular hydrogen-bonded and halogen-bonded supramolecular helices in two dimensions, and undergoes chiral resolution upon crystallization. Meanwhile, counterparts containing either an F-substituent with weak halogen bonding or no halogen atom crystallize as racemic compounds.

Intramolecular chalcogen bonding to tune the molecular conformation of helical building blocks for a supramolecular helix.

We propose to employ intramolecular chalcogen bonding to make a helical building block take its otherwise unfavorable cis-conformation. The 2,5-thiophenediamide motif was taken to bridge two ß-turn structures to lead to an azapeptide that exists in cis-conformation and forms a halogen-bonded single-strand helix that exhibits a much stronger supramolecular helicity and a higher thermal stability.

Supramolecular helices from helical building blocks via head-to-tail intermolecular interactions.

Supramolecular helices from helical building blocks represent an emerging analogue of the α-helix. In cases where the helicity of the helical building block is well propagated, the head-to-tail intermolecular interactions that lead to the helix could be enhanced to promote the formation and the stability of the supramolecular helix, wherein homochiral elongation dominates and functional helical channel structures could also be generated. This feature article outlines the supramolecular helices built from helical building blocks, i.e., helical aromatic foldamers and helical short peptides that are held together by intermolecular π-π stacking, hydrogen/halogen/chalcogen bonding, metal coordination, dynamic covalent bonding and solvophobic interactions, with emphasis on the influence of efficient propagation of helicity during assembly, favouring homochirality and channel functions.

Current Advancement on the Dynamic Mechanism of Gastroesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) is a common clinical disease associated with upper gastrointestinal motility disorders. Recently, with improvements in living standards and changes in lifestyle and dietary habits, the incidence of GERD has been increasing yearly. However, the mechanism of GERD has not been fully elucidated due to its complex pathogenesis, and this had led to unsatisfactory therapeutic outcomes. Currently, the occurrence and development of GERD involve multiple factors. Its pathogenesis is mainly thought to be related to factors, such as lower esophageal sphincter pressure, transient lower esophageal sphincter relaxation, crural diaphragmatic dysfunction, hiatus hernia, and impaired esophageal clearance. Therefore, explaining the pathogenesis of GERD more clearly and systematically, exploring potential and effective therapeutic targets, and choosing the best treatment methods have gradually become the focus of scholars' attention. Herein, we reviewed current advancements in the dynamic mechanism of GERD to better counsel patients on possible treatment options.

Chalcogen bonding mediates the formation of supramolecular helices of azapeptides in crystals.

To explore whether chalcogen bonding was able to drive the formation of supramolecular helices, alanine-based azapeptides containing a ß-turn structure, with a thiophene group, respectively, incorporated in the N- or C-terminus, were employed as helical building blocks. While the former derivative formed a supramolecular M-helix via intermolecular SS chalcogen bonding in crystals, the latter formed P-helix via intermolecular SO chalcogen bonding.

Current indications for endoscopic submucosal dissection of early gastric cancer.

The development of endoscopic treatment technology has further promoted the minimally invasive treatment of early gastric cancer (EGC). Endoscopic treatment has achieved better therapeutic effects in terms of safety and prognosis and is the preferred treatment method for patients who meet the indications for endoscopic treatment. However, the consequent problem is that some patients receiving endoscopic treatment may undergo non-curative resection, and the principle of follow-up management for non-curative resection patients deserves further attention. In addition, there are still debates on how to improve the accuracy of clinical staging, select a reasonable treatment method for patients who meet the expanded indications for endoscopic treatment, manage patients with positive endoscopic surgical margins, conduct research on function-preserving surgery, and manage the treatment of EGC under the current situation in China. Consequently, we aim to review current indications for endoscopic submucosal dissection of EGC in order to better inform treatment options.

Nanosphere [Ag(SR)]n: coordination polymers of Ag+ with a combination of hydrophilic and hydrophobic thiols.

We propose to create nanospheres in aqueous solutions from coordination polymers of Ag+ with a combination of a hydrophilic and a hydrophobic thiol, of diameter ca. 2.7 nm in the case of using cysteine and n-butanethiol. A spectral probe for the formation of the nanospheres is a reversal of the CD signal at 253 nm from negative in the case of cysteine alone to positive when cysteine and n-BuSH are both employed, together with an amplification.

Chiral Recognition by Flexible Coordination Polymers of Ag+ with a Cysteine-Based Chiral Thiol Ligand That Bears a Binding Site.

We report a new scheme for chiral recognition using coordination polymers of Ag+ with a chiral thiol ligand that contains a binding group. N-Benzoyl-l-cysteine ethyl ester equipped with a boronic acid group at the para position of the phenyl ring forms coordination polymers with Ag+ in alkaline aqueous solutions that exhibit excellent selectivity toward a d-glucose enantiomer over l-glucose, while the coordination polymers from the d-cysteine-based thiol ligand are specific for l-glucose. It is assumed that a conformation change occurs upon interaction of a saccharide molecule with the polymeric chain receptor, for which the next binding is promoted, leading to the highly effective chiral recognition, despite the flexible nature of the polymeric receptor.

Solvophobic interaction promoted supramolecular helical assembly of building blocks of weak intermolecular halogen bonding.

We report supramolecular helical assembly in water of ß-turn structured bis(N-amidothioureas) containing Br-substitutes of moderate halogen bonding ability, promoted by stronger hydrophobic interaction. The helical polymers show an unusual negative nonlinear CD-ee dependence.

Helical nanofibers of N-(perfluorooctanoyl)cysteine ethyl ester in coordination polymers of Ag.

We propose using the formation of coordination polymers of Ag+ to probe differences between the perfluorinated alkyl chain and the alkyl chain by deriving a thiol ligand, N-(perfluoroalkanoyl)cysteine. Rapid formation in EtOH of P-/M-helical nanofibrils of high thermostability was found for N-(perfluorooctanoyl)-l-/d-cysteine ethyl esters at the µM level upon mixing with Ag+, but not for the octanoyl counterpart. This difference was also observed in terms of circular dichroism-enantiomeric excess dependence.

Supramolecular Chiral Aggregates Exhibiting Nonlinear CD-ee Dependence.

Although a linear relationship between the optical activity (normally the CD signal) and the enantiomeric excess (ee) of chiral auxiliaries has been the most commonly observed dependence in dynamic supramolecular helical aggregates, positive nonlinear CD-ee dependence, known as the "majority-rules effect" (MRE), indicative of chiral amplification, has also been well documented and to some extent understood. In sharp contrast, the negative nonlinear CD-ee dependence has been much less reported and is not well understood. Here, the state of the art of both the positive and negative nonlinear CD-ee dependence in noncovalently bound supramolecular helical aggregates is summarized, with the hope that the vast examples of supramolecular aggregates showing positive nonlinear dependence, in terms of the methods of investigations, variations in the structure of the building block (single species or multiple species), and theoretical modeling using the mismatch penalty energy and helix reversal penalty energy, would help to guide the design of building blocks to form aggregates showing negative nonlinear dependence, and thus to understand the mechanisms. The potential applications of those functional supramolecular aggregates are also discussed.

Balancing interactions in proline-based receptors for chiral recognition of l-/d-DOPA.

Proline based receptors (1-14) attached with phenylboronic acid and benzaldehyde binding groups at the N-/C- or C-/N-termini of the proline residue were created for chiral recognition of l-/d-DOPA, in an attempt to examine if balancing the two binding events would influence the recognition. By changing the positions of boronic acid and aldehyde groups substituted on the phenyl rings (1-4, 5-8) and the site at which phenylboronic acid and benzaldehyde moieties attached respectively to the N- and C-termini or C- and N-termini of the proline residue (1-4vs.5-8), and by introducing an electron-withdrawing fluorine atom in the phenyl ring of the weaker binder the benzaldehyde moiety (11vs.1, 14vs.5), we were able to show that a better balance of the two binding events does improve the chiral recognition. This finding can only be made with the current version of receptors that were equipped with two different binding groups. Together with the finding that the chiral recognition performance in mixed organic-aqueous solutions is tunable by varying the solvent composition, we have now arrived at a protocol for designing proline based receptors for extended applications in chiral recognition.

Turn Conformation of ß-Amino Acid-Based Short Peptides Promoted by an Amidothiourea Moiety at C-Terminus.

A C-terminal amidothiourea motif is shown to promote a ß-turn-like folded conformation in a series of ß-amino acid-based short peptides in both the solid state and solution phase by an intramolecular 11-membered ring hydrogen bond.