Aggregation-Induced Emission (AIE), Life and Health

Light has profoundly impacted modern medicine and healthcare, with numerous luminescent agents and imaging techniques currently being used to assess health and treat diseases. As an emerging concept in luminescence, aggregation-induced emission (AIE) has shown great potential in biological applications due to its advantages in terms of brightness, biocompatibility, photostability, and positive correlation with concentration. This review provides a comprehensive summary of AIE luminogens applied in imaging of biological structure and dynamic physiological processes, disease diagnosis and treatment, and detection and monitoring of specific analytes, followed by representative works. Discussions on critical issues and perspectives on future directions are also included. This review aims to stimulate the interest of researchers from different fields, including chemistry, biology, materials science, medicine, etc., thus promoting the development of AIE in the fields of life and health

Analysis of the π-Electronic Structure of Infinitely Large Networks

In order to expand the Coulson and Longuet-Higgins' integral method to infinitely large conjugated π-electronic networks, such as branched polyenes and periodic polyacenes, two new efficient techniques are proposed. The analytical solutions of bond orders and π-electronic energy of these two kinds of networks with various modes of bond alternation are derived, which are expressd in terms of the three kinds of the elliptic integrals. The benzene characters for polycyclic aromatics are also obtained. The dependency of these results on the bond alternation parameter can explicitly be discussed

Functional Mapping of the Transient Receptor Potential Vanilloid 1 Intracellular Binding Site

Capsaicin (vanilloid) sensitivity has long served as the functional signature of a subset of nociceptive sensory neurons. Mutagenesis studies have revealed seemingly distinct regions involved in mediating ligand binding and channel activation at the capsaicin binding site. Residue 547 (transmembrane region 4) mediates significant species differences in resiniferatoxin (RTX) sensitivity, and the Ser512 residue is critical in discriminating between pH and capsaicin gating. In the present study, the pharmacological profiles of a variety of ligands were studied to investigate cross-talk between these two regions. Exchange of residue 547 between species mediated a difference in capsaicin and RTX-dependent gating. Likewise, the potency of iodoresiniferatoxin (I-RTX) and a novel transient receptor potential vanilloid 1 antagonist were also altered. Experiments using the S512Y mutant channel have confirmed the importance of residue 512 for functional interaction of capsaicin and our novel antagonist. In this study, we were surprised to find that the mutation S512Y converted the activity of the antagonist I-RTX into an intrinsic agonist, albeit with a lower potency than its parent compound, RTX. Recent studies have proposed a novel model for the receptor, based on the X-ray crystal structure of the voltage-dependent potassium channel, in which both the 512 and 547 amino acid residues are in close proximity. Our data support the model whereby intracellular ligand interaction occurs within an S3-S4 “sensor” domain, enabling binding of ligands to be transduced to functional gating of the channel. The binding pocket also seems to be exquisitely sensitive to residue-specific interaction with ligands, because subtle changes in either ligand or channel structure can have profound effects on channel activity

Conduction system pacing improves the outcomes on patients with high percentage of ventricular pacing and heart failure with mildly reduced ejection fraction

AimsThis study aimed to investigate the efficacy and safety of CSP in patients with a high percentage of ventricular pacing and heart failure with HFmrEF.MethodsPatients who underwent CSP for HFmrEF and ventricular pacing >40% were consecutively enrolled from January 2018 to May 2021. All participants were followed up at least 12 months. Clinical data including cardiac performance and lead outcomes were compared before and after the procedure. Left ventricular ejection fraction (LVEF) was measured using the biplane Simpson's method. HFmrEF was defined as heart failure with the LVEF ranging from 41%–49%.ResultsCSP was successfully performed in 64 cases (96.97%), which included 16 cases of left bundle branch pacing (LBBP) and 48 cases of His bundle pacing (HBP). After a mean of 23.12 ± 8.17 months follow-up, NYHA classification (P < 0.001), LVEF (42.45 ± 1.84% vs. 49.97 ± 3.57%, P < 0.001) and left ventricular end diastolic diameter (LVEDD) (55.59 ± 6.17 mm vs. 51.66 ± 3.48 mm, P < 0.001) improved significantly. During follow-up, more than half (39/64,60.9%) of patients returned to normal LVEF and LVEDD with complete reverse remodeling. The pacing threshold in LBBP was lower (0.90 ± 0.27 [email protected] ms vs. 1.61 ± 0.71 [email protected] ms, P < 0.001) than that in HBP. No perforation, electrode dislodging, thrombosis or infection was observed during follow-up.ConclusionsCSP could improve the clinical outcomes in patients with HFmrEF and a high percentage of ventricular pacing. LBBP might be a better choice because of its feasibility and safety, especially in patients with infranodal atrioventricular block

Long-term persistence in protection and response to a hepatitis B vaccine booster among adolescents immunized in infancy in the western region of China

Objectives: To evaluate the persistence of protection from hepatitis B (HB) vaccination among adolescents immunized with a primary series of HB vaccine as infants, and the immune response to booster doses. Methods: Healthy adolescents aged 15–17 y vaccinated with HB vaccine only at birth were enrolled. Baseline serum hepatitis B surface antigen (HBsAg), antibody against hepatitis B surface antigen (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) were detected by Enzyme-Linked Immunosorbent Assay (ELISA) and anti-HBs level was measured using Chemiluminescent Microparticle Immunoassay (CMIA). The rate of HBV infection was calculated. The seroprotection rate of anti-HBs (≥ 10 mIU/ml) and GMC level were used to evaluate the persistence of immunity from HB vaccination. Those with anti-HBs < 10 mIU/ml were immunized with booster doses of HB vaccine and the anamnestic response was assessed. Results: Of 180 adolescents who received a primary series of HB vaccinations as infants, 3 (1.7%) had HBV infection and 74 (41.1%) had anti-HBs ≥ 10 mIU/ml with a GMC of 145.11 mIU/ml. The remaining 103 (57.2%) with anti-HBs < 10 mIU/ml received a booster dose of 20 μg HB vaccine and achieved the seroprotection rate of 84% (84/100) and a GMC of 875.19 mIU/ml at one month post-booster. An additional dose of 60 μg HB vaccine was administered to the 16 adolescents with anti-HBs < 10 mIU/ml after the first booster. All of them obtained anti-HBs seroprotection with a GMC of 271.02 mIU/ml at 1.5 months after an additional dose. Conclusions: Vaccine-induced immunity persisted for up to 15–17 y in 89.3% (158/177) of participants after a primary HB vaccination in infancy. Administering a booster dose of 20μg HB vaccine elicited an anamnestic immune responses in the majority of individuals with baseline anti-HBs <10 mIU/ml

D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II

Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and characterization of catechol-based inhibitors including L-DOPA, D-DOPA, and caffeic acid, with sub-micromolar potencies. Of these, D-DOPA emerged as the most promising compound, with good metabolic stability, and excellent PK properties. Orally administered D-DOPA yielded high plasma exposures (AUCplasma = 72.7 nmol&middot;h/mL) and an absolute oral bioavailability of 47.7%. Unfortunately, D-DOPA brain exposures were low with AUCbrain = 2.42 nmol/g and AUCbrain/plasma ratio of 0.03. Given reports of isomeric inversion of D-DOPA to L-DOPA via D-amino acid oxidase (DAAO), we evaluated D-DOPA PK in combination with the DAAO inhibitor sodium benzoate and observed a &gt;200% enhancement in both plasma and brain exposures (AUCplasma = 185 nmol&middot;h/mL; AUCbrain = 5.48 nmol&middot;h/g). Further, we demonstrated GCPII target engagement; orally administered D-DOPA with or without sodium benzoate caused significant inhibition of GCPII activity. Lastly, mode of inhibition studies revealed D-DOPA to be a noncompetitive, allosteric inhibitor of GCPII. To our knowledge, this is the first report of D-DOPA as a distinct scaffold for GCPII inhibition, laying the groundwork for future optimization to obtain clinically viable candidates