Photochemical Modification of the Extracellular Matrix to Alter the Vascular Remodeling Process.

Therapeutic interventions for vascular diseases aim at achieving long-term patency by controlling vascular remodeling. The extracellular matrix (ECM) of the vessel wall plays a crucial role in regulating this process. This study introduces a novel photochemical treatment known as Natural Vascular Scaffolding, utilizing a 4-amino substituted 1,8-naphthimide (10-8-10 Dimer) and 450 nm light. This treatment induces structural changes in the ECM by forming covalent bonds between amino acids in ECM fibers without harming vascular cell survival, as evidenced by our results. To further investigate the mechanism of this treatment, porcine carotid artery segments were exposed to 10-8-10 Dimer and light activation. Subsequent experiments subjected these segments to enzymatic degradation through elastase or collagenase treatment and were analyzed using digital image analysis software (MIPAR) after histological processing. The results demonstrated significant preservation of collagen and elastin structures in the photochemically treated vascular wall, compared to controls. This suggests that photochemical treatment can effectively modulate vascular remodeling by enhancing the resistance of the ECM scaffold to degradation. This approach shows promise in scenarios where vascular segments experience significant hemodynamic fluctuations as it reinforces vascular wall integrity and preserves lumen patency. This can be valuable in treating veins prior to fistula creation and grafting or managing arterial aneurysm expansion.

Direct imaging and astrometric detection of a gas giant planet orbiting an accelerating star.

Direct imaging of gas giant exoplanets provides information on their atmospheres and the architectures of planetary systems. However, few planets have been detected in blind surveys with direct imaging. Using astrometry from the Gaia and Hipparcos spacecraft, we identified dynamical evidence for a gas giant planet around the nearby star HIP 99770. We confirmed the detection of this planet with direct imaging using the Subaru Coronagraphic Extreme Adaptive Optics instrument. The planet, HIP 99770 b, orbits 17 astronomical units from its host star, receiving an amount of light similar to that reaching Jupiter. Its dynamical mass is 13.9 to 16.1 Jupiter masses. The planet-to-star mass ratio [(7 to 8) × 10-3] is similar to that of other directly imaged planets. The planet's atmospheric spectrum indicates an older, less cloudy analog of the previously imaged exoplanets around HR 8799.

Survey of Vital Pulp Therapy Treatment in Permanent Dentition Being Taught at U.S. Dental Schools.

INTRODUCTION: In May 2021, the American Association of Endodontists released a Position Statement on Vital Pulp Therapy (VPT) as a conservative means by which to treat inflamed vital pulps in permanent dentition. The objective of this study was to conduct a survey to understand how U.S. dental schools are educating their students regarding VPT. METHODS: This survey was administered through Qualtrics. Participation was voluntary and anonymous. RESULTS: 43 of 66 (65%) of the dental schools in the United States completed the survey. All schools (n = 43) indicated that students receive a didactic lecture about VPT on permanent teeth. In contrast, 14 of 43 (33%) schools teach VPT on permanent teeth as a technique exercise in the simulation/pre-clinic; 29 of 43 (67%) do not. Fifty percent of newer dental schools (0-15 years) teach VPT on permanent teeth as a simulation/pre-clinic technique exercise compared with 30% of older dental schools (16 years or older). In older schools, VPT is taught by endodontists 59% of the time, whereas the percentage of endodontists teaching in newer schools is roughly half of that (33%). CONCLUSION: A paradigm shift in endodontics has occurred due to the development and use of bioceramic dental materials. The standard of dental care is shifting in favor of more conservative treatment options. The results of the study indicate that there is a deficiency in the number of U.S. dental schools teaching VPT on permanent teeth as a simulation/pre-clinic technique exercise.

Perception of the plant hormone ethylene: known-knowns and known-unknowns.

The gaseous phytohormone ethylene is implicated in virtually all phases of plant growth and development and thus has a major impact on crop production. This agronomic impact makes understanding ethylene signaling the Philosopher's Stone of the plant biotechnology world in applications including post-harvest transport of foodstuffs, consistency of foodstuff maturity pre-harvest, decorative flower freshness and longevity, and biomass production for biofuel applications. Ethylene is biosynthesized by plants in response to environmental factors and plant life-cycle events, and triggers a signaling cascade that modulates over 1000 genes. The key components in the perception of ethylene are a family of copper dependent receptors, the bioinorganic chemistry of which has been largely ignored by the chemical community. Since identification of these receptors two decades ago, there has been tremendous growth in knowledge in the biological community on the signal transduction pathways and mechanisms of ethylene signaling. In this review, we highlight these advances and key chemical voids in knowledge that are overdue for exploration, and which are required to ultimately regulate and control ethylene signaling.

Structure-Based Design of 1,4-Dibenzoylpiperazines as ß-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction Inhibitors.

A small-molecule inhibitor with a 1,4-dibenzoylpiperazine scaffold was designed to match the critical binding elements in the ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction interface. Inhibitor optimization led to a potent inhibitor that can disrupt the ß-catenin/BCL9 interaction and exhibit 98-fold selectivity over the ß-catenin/cadherin interaction. The binding mode of new inhibitors was characterized by structure-activity relationships and site-directed mutagenesis studies. Cell-based studies demonstrated that this series of inhibitors can selectively suppress canonical Wnt signaling and inhibit growth of Wnt/ß-catenin-dependent cancer cells.

Two N-(2-phenylethyl)nitroaniline derivatives as precursors for slow and sustained nitric oxide release agents.

Notwithstanding its simple structure, the chemistry of nitric oxide (NO) is complex. As a radical, NO is highly reactive. NO also has profound effects on the cardiovascular system. In order to regulate NO levels, direct therapeutic interventions include the development of numerous NO donors. Most of these donors release NO in a single high-concentration burst, which is deleterious. N-Nitrosated secondary amines release NO in a slow, sustained, and rate-tunable manner. Two new precursors to sustained NO-releasing materials have been characterized. N-[2-(3,4-Dimethoxyphenyl)ethyl]-2,4-dinitroaniline, C16H17N3O6, (I), crystallizes with one independent molecule in the asymmetric unit. The adjacent amine and nitro groups form an intramolecular N-H...O hydrogen bond. The anti conformation about the phenylethyl-to-aniline C-N bond leads to the planes of the arene and aniline rings being approximately perpendicular. Molecules are linked into dimers by weak intermolecular N-H...O hydrogen bonds such that each amine H atom participates in a three-center interaction with two nitro O atoms. The dimers pack so that the arene rings of adjacent molecules are not parallel and π-π interactions do not appear to be favored. N-(4-Methylsulfonyl-2-nitrophenyl)-L-phenylalanine, C16H16N2O6S, (II), with an optically active center, also crystallizes with one unique molecule in the asymmetric unit. The L enantiomer was established via the configuration of the starting material and was confirmed by refinement of the Flack parameter. As in (I), there is an intramolecular N-H...O hydrogen bond between adjacent amine and nitro groups. The conformation of the molecule is such that the arene rings display a dihedral angle of ca 60°. Unlike (I), molecules are not linked via intermolecular N-H...O hydrogen bonds. Rather, the carboxylic acid H atom forms a classic, approximately linear, O-H...O hydrogen bond with a sulfone O atom. Pairs of molecules related by twofold rotation axes are linked into dimers by two such interactions. The packing pattern features a zigzag arrangement of the arene rings without apparent π-π interactions. These structures are compared with reported analogues, revealing significant differences in molecular conformation, intermolecular interactions, and packing that result from modest changes in functional groups. The structures are discussed in terms of potential NO-release capability.

Near-infrared imaging polarimetry of LkCa 15: A possible warped inner disk.

We present high-contrast H-band polarized intensity images of the transitional disk around the young solar-like star LkCa 15. By utilizing Subaru/HiCIAO for polarimetric differential imaging, the angular resolution and the inner working angle reach 0.07 and r = 0″.1, respectively. We obtained a clearly resolved gap (width ≲ 27 au) at ~48 au from the central star. This gap is consistent with images reported in previous studies. We also confirmed the existence of a bright inner disk with a misaligned position angle of 13° ±4° with respect to that of the outer disk, i.e., the inner disk is possibly warped. The large gap and the warped inner disk both point to the existence of a multiple planetary system with a mass of ≲ 1 M Jup.

Fast-moving features in the debris disk around AU Microscopii.

In the 1980s, excess infrared emission was discovered around main-sequence stars; subsequent direct-imaging observations revealed orbiting disks of cold dust to be the source. These 'debris disks' were thought to be by-products of planet formation because they often exhibited morphological and brightness asymmetries that may result from gravitational perturbation by planets. This was proved to be true for the ß Pictoris system, in which the known planet generates an observable warp in the disk. The nearby, young, unusually active late-type star AU Microscopii hosts a well-studied edge-on debris disk; earlier observations in the visible and near-infrared found asymmetric localized structures in the form of intensity variations along the midplane of the disk beyond a distance of 20 astronomical units. Here we report high-contrast imaging that reveals a series of five large-scale features in the southeast side of the disk, at projected separations of 10-60 astronomical units, persisting over intervals of 1-4 years. All these features appear to move away from the star at projected speeds of 4-10 kilometres per second, suggesting highly eccentric or unbound trajectories if they are associated with physical entities. The origin, localization, morphology and rapid evolution of these features are difficult to reconcile with current theories.

Rational design of selective small-molecule inhibitors for ß-catenin/B-cell lymphoma 9 protein-protein interactions.

Selective inhibition of α-helix-mediated protein-protein interactions (PPIs) with small organic molecules provides great potential for the discovery of chemical probes and therapeutic agents. Protein Data Bank data mining using the HippDB database indicated that (1) the side chains of hydrophobic projecting hot spots at positions i, i + 3, and i + 7 of an α-helix had few orientations when interacting with the second protein and (2) the hot spot pockets of PPI complexes had different sizes, shapes, and chemical groups when interacting with the same hydrophobic projecting hot spots of α-helix. On the basis of these observations, a small organic molecule, 4'-fluoro-N-phenyl-[1,1'-biphenyl]-3-carboxamide, was designed as a generic scaffold that itself directly mimics the binding mode of the side chains of hydrophobic projecting hot spots at positions i, i + 3, and i + 7 of an α-helix. Convenient decoration of this generic scaffold led to the selective disruption of α-helix-mediated PPIs. A series of small-molecule inhibitors selective for ß-catenin/B-cell lymphoma 9 (BCL9) over ß-catenin/cadherin PPIs was designed and synthesized. The binding mode of new inhibitors was characterized by site-directed mutagenesis and structure-activity relationship studies. This new class of inhibitors can selectively disrupt ß-catenin/BCL9 over ß-catenin/cadherin PPIs, suppress the transactivation of canonical Wnt signaling, downregulate the expression of Wnt target genes, and inhibit the growth of Wnt/ß-catenin-dependent cancer cells.

AlphaScreen selectivity assay for ß-catenin/B-cell lymphoma 9 inhibitors.

The aberrant formation of the ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein complex is the driving force for many diseases, including cancer. Crystallographic analyses demonstrate that the surface area in ß-catenin for interacting with BCL9 is overlapped with that for the ß-catenin/E-cadherin interaction. In this study, a robust AlphaScreen selectivity assay was developed to quantify inhibitor potency for the ß-catenin/BCL9 interaction and selectivity for ß-catenin/BCL9 over ß-catenin/E-cadherin interactions. A pilot screen was performed to demonstrat the feasibility of this assay. This selectivity assay is highly sensitive and suitable for adaptation to high-throughput screening. The establishment of this assay lays the foundation for the discovery of selective inhibitors specific for ß-catenin/BCL9 interactions.

Hot spot-based design of small-molecule inhibitors for protein-protein interactions.

Protein-protein interactions (PPIs) are important targets for the development of chemical probes and therapeutic agents. From the initial discovery of the existence of hot spots at PPI interfaces, it has been proposed that hot spots might provide the key for developing small-molecule PPI inhibitors. However, there has been no review on the ways in which the knowledge of hot spots can be used to achieve inhibitor design, nor critical examination of successful examples. This Digest discusses the characteristics of hot spots and the identification of druggable hot spot pockets. An analysis of four examples of hot spot-based design reveals the importance of this strategy in discovering potent and selective PPI inhibitors. A general procedure for hot spot-based design of PPI inhibitors is outlined.

Incidence of cerebral concussions associated with type of mouthguard used in college football.

Controversy exists among sports dentists as to whether or not a 'custom made' mouthguard is more effective in reducing the incidence of cerebral concussion than the boil-and-bite 'non-custom made' mouthguard. While members on each side remain steadfast in their opinion, not a single epidemiological study has been conducted to investigate the effect of type of mouthguard worn on the incidence of cerebral concussion. The aim of this study was to determine if there was a difference between the type of mouthguard worn and the incidence of cerebral concussions among National Collegiate Athletic Association (NCAA) Division I-A football players. During the 15-week 2001 college football season, trainers entered, via an interactive web site, weekly data for each game and practice sessions for the preceding week. Eighty-seven (76%) out of a possible 114 Division I teams participated. A total of 506 297 athletic exposures were recorded; 369 brain concussions were reported. The incidence of cerebral concussions per 1000 exposures was 0.73. Utilizing a risk ratio with a 95% confidence interval, no statistical difference occurred in the incidence of cerebral concussions between football players wearing custom made versus non-custom made mouthguards (0.990,1.750). In this study, there was no advantage of wearing a custom made mouthguard over a boil-and-bite mouthguard to reduce the risk of cerebral concussion in football players.

Comparison of reporting systems to determine concussion incidence in NCAA Division I collegiate football.

OBJECTIVE: To determine the incidence of concussion during the 2001 Division I-A college football season through utilization of the Internet. DESIGN: Prospective Internet survey. SETTING: Internet Web site. PARTICIPANTS: Head athletic trainers from Division I-A collegiate football programs. MAIN OUTCOME MEASURES: During the 2001-2002 football season, head athletic trainers from 87 Division I-A football programs agreed to use an Internet Web site to submit weekly data on the number of athlete exposures and concussions. RESULTS: A total of 373 concussions were reported over the course of a season in both practices and games combined. Of these concussions, 256 (68.6%) occurred during games, and 117 (31.4%) occurred during practice. The injury rate per 1,000 athletic exposures was 5.56 in games and 0.25 in practices. There were 230 grade 1 (61.7%), 134 grade 2 (35.9%), and 9 grade 3 (2.4%) concussions reported. There was a significant (p < 0.01) difference found between the total concussion injury rate and game concussion injury rate when comparing the Internet and the NCAA injury data collection methods. CONCLUSIONS: The results of this study suggest an underreporting of concussions using the NCAA Injury Surveillance System and demonstrate that the Internet is a simple and effective tool for data collection.