Ynamide Coupling Reagents: Origin and Advances.

Since the pioneering work of Curtius and Fischer, chemical peptide synthesis has witnessed a century's development and evolved into a routine technology. However, it is far from perfect. In particular, it is challenged by sustainable development because the state-of-the-art of peptide synthesis heavily relies on legacy reagents and technologies developed before the establishment of green chemistry. Over the past three decades, a broad range of efforts have been made for greening peptide synthesis, among which peptide synthesis using unprotected amino acid represents an ideal and promising strategy because it does not require protection and deprotection steps. Unfortunately, C → N peptide synthesis employing unprotected amino acids has been plagued by undesired polymerization, while N → C inverse peptide synthesis with unprotected amino acids is retarded by severe racemization/epimerization owing to the iterative activation and aminolysis of high racemization/epimerization susceptible peptidyl acids. Consequently, there is an urgent need to develop innovative coupling reagents and strategies with novel mechanisms that can address the long-standing notorious racemization/epimerization issue of peptide synthesis.This Account will describe our efforts in discovery of ynamide coupling reagents and their application in greening peptide synthesis. Over an eight-year journey, ynamide coupling reagents have evolved into a class of general coupling reagents for both amide and ester bond formation. In particular, the superiority of ynamide coupling reagents in suppressing racemization/epimerization enabled them to be effective for peptide fragment condensation, and head-to-tail cyclization, as well as precise incorporation of thioamide substitutions into peptide backbones. The first practical inverse peptide synthesis using unprotected amino acids was successfully accomplished by harnessing such features and taking advantage of a transient protection strategy. Ynamide coupling reagent-mediated ester bond formation enabled efficient intermolecular esterification and macrolactonization with preservation of α-chirality and the configuration of the conjugated α,ß-C-C double bond. To make ynamide coupling reagents readily available with reasonable cost and convenience, we have developed a scalable one-step synthetic method from cheap starting materials. Furthermore, a water-removable ynamide coupling reagent was developed, offering a column-free purification of the target coupling product. In addition, the recycle of ynamide coupling reagent was accomplished, thereby paving the way for their sustainable industrial application.As such, this Account presents the whole story of the origin, mechanistic insights, preparation, synthetic applications, and recycle of ynamide coupling reagents with a perspective that highlights their future impact on peptide synthesis.

Inverse Peptide Synthesis Using Transient Protected Amino Acids.

Peptide therapeutics have experienced a rapid resurgence over the past three decades. While a few peptide drugs are biologically produced, most are manufactured via chemical synthesis. The cycle of prior protection of the amino group of an α-amino acid, activation of its carboxyl group, aminolysis with the free amino group of a growing peptide chain, and deprotection of the N-terminus constitutes the principle of conventional C → N peptide chemical synthesis. The mandatory use of the Nα-protecting group invokes two additional operations for incorporating each amino acid, resulting in poor step- and atom-economy. The burgeoning demand in the peptide therapeutic market necessitates cost-effective and environmentally friendly peptide manufacturing strategies. Inverse peptide chemical synthesis using unprotected amino acids has been proposed as an ideal and appealing strategy. However, it has remained unsuccessful for over 60 years due to severe racemization/epimerization during N → C peptide chain elongation. Herein, this challenge has been successfully addressed by ynamide coupling reagent employing a transient protection strategy. The activation, transient protection, aminolysis, and in situ deprotection were performed in one pot, thus offering a practical peptide chemical synthesis strategy formally using unprotected amino acids as the starting material. Its robustness was exemplified by syntheses of peptide active pharmaceutical ingredients. It is also amenable to fragment condensation and inverse solid-phase peptide synthesis. The compatibility to green solvents further enhances its application potential in large-scale peptide production. This study offered a cost-effective, operational convenient, and environmentally benign approach to peptides.

Working memory impairment in children orphaned by parental HIV/AIDS: An event-related potentials study.

A large body of literature has established that children orphaned by HIV/AIDS ('AIDS orphans') face numerous challenges, such as parental death, poverty, disrupted school attendance and stigma. All of these early life adversities can have long-lasting effects on brain function, especially the executive functions. Working memory, as one of the most studied aspects of executive functions, is also reported to be impaired in children with early adversity. However, limited data are available regarding how early life adverse events affect the neural dynamic associated with working memory processing in AIDS orphans. This study applied the electroencephalogram (EEG) technique to investigate the working memory process in 81 AIDS orphans and 62 non-orphan controls with n-back tasks. Results from EEG analysis and time-frequency analysis showed that AIDS orphans displayed smaller N2 and larger P2, P3 activation as well as enhanced theta and attenuated alpha band oscillations compared to the controls. The present findings indicated a deficit in working memory process in AIDS orphans and suggested that this deficit might be due to the impairments in attention allocation, detection and classification of stimuli and updating process in working memory.

Association of Genetic Polymorphisms of TERT with Telomere Length in Coke Oven Emissions-Exposed Workers.

We explored the association between variations in the telomere maintenance genes and change in telomere length (TL) in workers. The TL of peripheral blood leukocytes from 544 coke oven workers and 238 controls were detected using the Real-time PCR method. Variations in four genes were then detected using the PCR based restriction fragment length polymorphism. The effects of environmental and genetic factors on TL were subsequently analyzed through covariance analysis and a generalized linear model .The TL of subjects with GG genotypes were longer than those with AG genotype in the TERT rs2736098 locus amongst the controls (P = .032). The combined effect of COEs exposure and AG+AA genotypes had a significant effect on TL (P < .001). The interaction between the COEs exposure factor and the rs2736098AG+AA genotypes had a significant effect on the TL (P < .05). The TL in coke oven workers is associated with the interactions between TERT rs2736098 AG+AA and COEs exposure.

Ynamide-Mediated Thioamide and Primary Thioamide Syntheses.

Environmentally friendly ynamide-mediated thioamidation of monothiocarboxylic acids with amines or ammonium hydroxide for the syntheses of thioamides and primary thioamides is described. Simple and mild reaction conditions enable the reaction to tolerate a wide variety of functional groups such as hydroxyl group, ester, tertiary amine, ketone, and amide moieties. Readily available NaSH served as the sulfur source, avoiding the use of toxic, expensive, and malodorous organic sulfur reagents and making this strategy environmentally friendly and practical. Importantly, the stereochemical integrity of α-chiral monothiocarboxylic acids was maintained during the activation step and subsequent aminolysis process, thus offering a racemization-free strategy for peptide C-terminal modification. Furthermore, a number of thioamide-modified drugs were prepared in good yields by using this protocol and the synthesized primary thioamides were transformed into backbone thiazolyl modified peptides.

Synthesis of (Z)-ß-Chloro-enamides via a Base-Promoted trans-Hydroamidation of Alkynyl Chlorides Using 1,1-Dichloroalkenes as Precursor.

An efficient and general base-promoted reaction of 1,1-dichloroalkenes with secondary sulfonamides and amides for the synthesis of (Z)-ß-chloro-enamides has been described. This reaction exhibits functional group tolerance under simple and mild conditions. Mechanistic study indicated that a stereoselective trans-hydroamidation of alkynyl chlorides generated in situ from 1,1-dichloroalkenes was the key step.

Long-Term Trajectories of Depressive Symptoms Among Children Affected by Parental HIV: A 12-Year Follow-Up Study.

The present study explored the trajectories of depressive symptoms over 12 years spanning from childhood to emerging adulthood and the between-trajectory differences in psychosocial adjustment among Chinese children (N = 492, 52.8% boys, aged 6 to 18 years at baseline) affected by parental HIV. Rebounding (12.6%), resilient (64.8%), and improving  (22.6%) trajectories were identified. Individuals in the rebounding trajectory reported the highest levels of psychological distress and the lowest levels of subjective well-being, positive self-regard, and personal strengths in adulthood. Individuals in the resilient trajectory reported lower levels of psychological distress and negative affect than those in the improving trajectory. The findings support the development of programs by policymakers and practitioners to improve the psychosocial adjustment of children who have been affected by parental HIV while considering individual differences in the trajectories of depressive symptoms.

Retrospective analysis of ultrasound-guided minimally invasive treatment of various thyroid cysts.

PURPOSE: The aim of this article was to determine the efficacy and safety of the combined use of ethanol and microwave (MWA) to thyroid cysts and explore the differences of various cysts. MATERIALS AND METHODS: A total of 136 patients and 142 thyroid cystic nodules and predominantly cystic nodules received combination therapy of ethanol and MWA between January 2016 and December 2019 in BeiJing Friendship Hospital. They were divided into different groups according to the size, and the characteristics of fluid aspirated. We compared the Initial size, treatment procedure, postoperative complications, and follow-up results to analyze the characteristics of different groups. RESULTS: The combination treatments reduced the size of cysts by more than 93% with less complications at the end of follow-up. The treatment duration was longest in the colloid cysts (difference from the clear-fluid group, p < 0.01), the absolute volume of the clear-fluid group at the end of follow-up was the smallest (difference from the other two groups: P < 0.01).There were the similar mean volume reduction rate (VRR) between the large cysts and the small cysts (p > 0.05). CONCLUSION: The combination treatments were applicable to all types of cysts. Understanding the characteristics of different cystic nodules and adopting different methods are helpful for us to carry out the minimally invasive treatment of cysts better.

Affective Profiles and Psychosocial Adjustment among Chinese Adolescents and Adults with Adverse Childhood Experiences: A Person-Centered Approach.

Purpose: Two studies were conducted to explore the patterns of positive affect (PA) and negative affect (NA) while considering collectivist cultural specificity (dialecticism) and to examine the associations of affective profiles with psychosocial adjustment. Methods: We used two Chinese samples, one comprising adults with adverse childhood experiences (N = 488) and one comprising ordinary adolescents (N = 635). The participants completed scales on PA, NA, and psychosocial adjustment, including mental health problems (depressive symptoms, anxiety), personal strengths (self-esteem, gratitude, resilience), and life satisfaction. Results: Three profiles were identified through latent profile analysis: well-adjusted (high PA, low NA), low affective (low PA, low NA), and moderate affective (moderate PA, moderate NA). Participants in the well-adjusted profile had the fewest mental health problems (depressive symptoms, anxiety) and scored highest on personal strengths (self-esteem, gratitude, resilience) and life satisfaction. Participants in the low affective profile had fewer mental health problems than those in the moderate affective profile. Conclusion: Individual differences and cultural variations should be considered when exploring affective profiles. Future interventions aimed at promoting affective well-being should accommodate dialecticism and individual differences in the target population. Supplementary Information: The online version contains supplementary material available at 10.1007/s10902-022-00566-7.

Long-term effects of a resilience-based intervention on mental health of children affected by parental HIV in China: Testing the mediation effects of emotion regulation and coping.

Resilience-based interventions have been suggested to improve mental health among children affected by parental HIV. Very few studies, however, have explicitly tested the mechanisms of change underlying the effects of resilience-based interventions on mental health among this group of children. The present study utilized a cluster randomized controlled trial to determine the effects of the Child-Caregiver-Advocacy Resilience (ChildCARE) intervention on mental health for children affected by parental HIV. Specifically, we examined the effects of the intervention on three mental health outcomes (i.e., depressive symptoms, school anxiety, loneliness) and whether emotion regulation and coping played mediating roles in the intervention's effectiveness. Child-caregiver dyads (N = 790) were randomly assigned by clusters to three intervention groups and a control group. Children reported on mental health outcomes for 36 months at 6-month intervals. Latent growth curve models showed that there were no direct impacts of the ChildCARE intervention on changes in mental health outcomes beyond 18-month follow-up. Mediation analyses showed that the ChildCARE intervention yielded significant improvements in positive coping, but not negative coping or emotion regulation at 18 months. Emotion regulation, positive coping, and negative coping were consistently associated with the intercepts (i.e., mean at 18 months) of mental health outcomes. Negative coping also significantly predicted the rates of change of mental health outcomes over time. Findings provide important implications for future resilience-based intervention development and highlight the promise of interventions that aim to strengthen emotion regulation and coping skills to improve mental health for children affected by parental HIV.

Ynamide-Mediated Peptide Bond Formation: Mechanistic Study and Synthetic Applications.

Ynamides, a class of novel coupling reagents for peptide synthesis, facilitated peptide bond formation in a one-pot, two-step manner with α-acyloxyenamide active esters of amino acids as stable intermediates. Ynamide-mediated peptide synthesis proceeded by a reaction mechanism that is completely different from that of conventional coupling reagents and exhibited superiority in addressing the issue of racemization/epimerization during peptide bond formation. Herein, we present a systematic mechanistic analysis, including kinetics and Brønsted-type structure-reactivity studies and density functional theory calculations, providing unprecedented mechanistic insight into ynamide-mediated peptide bond formation. Based on these mechanistic studies, significant improvements were made, and the applicability of ynamide-mediated peptide bond formation was successfully expanded to peptide fragment condensation, head-to-tail cyclization and solid-phase peptide synthesis.

Current Status of Endovascular Treatment for Acute Large Vessel Occlusion in China: A Real-World Nationwide Registry.

BACKGROUND AND PURPOSE: The benefit of endovascular treatment (EVT) for large vessel occlusion in clinical practice in developing countries like China needs to be confirmed. The aim of the study was to determine whether the benefit of EVT for acute ischemic stroke in randomized trials could be generalized to clinical practice in Chinese population. METHODS: We conducted a prospective registry of EVT at 111 centers in China. Patients with acute ischemic stroke caused by imaging-confirmed intracranial large vessel occlusion and receiving EVT were included. The primary outcome was functional independence at 90 days defined as a modified Rankin Scale score of 0 to 2. Outcomes of specific subgroups in the anterior circulation were reported and logistic regression was performed to predict the primary outcome. RESULTS: Among the 1793 enrolled patients, 1396 (77.9%) had anterior circulation large vessel occlusion (median age, 66 [56-73] years) and 397 (22.1%) had posterior circulation large vessel occlusion (median age, 64 [55-72] years). Functional independence at 90 days was reached in 45% and 44% in anterior and posterior circulation groups, respectively. For anterior circulation population, underlying intracranial atherosclerotic disease was identified in 29% of patients, with higher functional independence at 90 days (52% versus 44%; P=0.0122) than patients without intracranial atherosclerotic disease. In the anterior circulation population, after adjusting for baseline characteristics, procedure details, and early outcomes, the independent predictors for functional independence at 90 days were age <66 years (odds ratio [OR], 1.733 [95% CI, 1.213-2.476]), time from onset to puncture >6 hours (OR, 1.536 [95% CI, 1.065-2.216]), local anesthesia (OR, 2.194 [95% CI, 1.325-3.633]), final modified Thrombolysis in Cerebral Infarction 2b/3 (OR, 2.052 [95% CI, 1.085-3.878]), puncture-to-reperfusion time ≤1.5 hours (OR, 1.628 [95% CI, 1.098-2.413]), and National Institutes of Health Stroke Scale score 24 hours after the procedure <11 (OR, 9.126 [95% CI, 6.222-13.385]). CONCLUSIONS: Despite distinct characteristics in the Chinese population, favorable outcome of EVT can be achieved in clinical practice in China. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03370939.

Allenone-Mediated Racemization/Epimerization-Free Peptide Bond Formation and Its Application in Peptide Synthesis.

Allenone has been identified as a highly effective peptide coupling reagent for the first time. The peptide bond was formed with an α-carbonyl vinyl ester as the key intermediate, the formation and subsequent aminolysis of which proceed spontaneously in a racemization-/epimerization-free manner. The allenone coupling reagent not only is effective for the synthesis of simple amides and dipeptides but is also amenable to peptide fragment condensation and solid-phase peptide synthesis (SPPS). The robustness of the allenone-mediated peptide bond formation was showcased incisively by the synthesis of carfilzomib, which involved a rare racemization-/epimerization-free N to C peptide elongation strategy. Furthermore, the successful synthesis of the model difficult peptide ACP (65-74) on a solid support suggested that this method was compatible with SPPS. This method combines the advantages of conventional active esters and coupling reagents, while overcoming the disadvantages of both strategies. Thus, this allenone-mediated peptide bond formation strategy represents a disruptive innovation in peptide synthesis.

Recent Advances in the Pd-Catalyzed Coupling of Arylhydrazines and Ammonium Salts via C-N Bond Cleavage.

Both arylhydrazines and quaternary ammonium salts are readily accessible or commercially available chemicals that show versatile reactivity in Pd-catalyzed coupling reactions via C-N bond cleavage. A tremendous array of coupling reactions involving reaction partners such as organoborons, aryl silanes, alkenes, alkynes, arylation or alkylation reagents in C-H functionalization and carbonylation reactions are summarized, in which arylhydrazines or quaternary ammonium salts function as aryl or alkyl donors. This account mainly focuses on recent advances in Pd-catalyzed coupling reactions with arylhydrazines or quaternary ammonium salts via C-N bond cleavage, including mechanistic elucidations.

Dissection of the Glycosylation in the Biosynthesis of the Heptadecaglycoside Antibiotic Saccharomicin A.

Oligosaccharide natural products have diverse biological activities and represent a potentially important source for drug development. In this study, we focus on the glycosylation pathway in the biosynthesis of saccharomicin A (SA-A), an oligosaccharide antibiotic containing 17 sugar moieties. By extensive gene-knockout studies with comparative metabolic profile analysis, we established a complete pathway in assembling the heptadecasaccharide chain of SA-A, the longest saccharide chain found in natural products.

Ynamide-Mediated Thioester Synthesis.

A novel ynamide-mediated thioester synthesis strategy was developed. Importantly, no detectable racemization was observed for the thioesterifications of carboxylic acids containing an α-chiral center, enabling it to be useful for the synthesis of peptide thioester, which is the key component of native chemical ligation. It is worth mentioning that amino acid side chain functional groups such as -OH and indole -NH are compatible with the reaction conditions, rendering their protection unnecessary. Moreover, this method was also amenable to selenoesters.

Behavioural intention of receiving COVID-19 vaccination, social media exposures and peer discussions in China.

The study aimed to investigate behavioural intentions to receive free and self-paid COVID-19 vaccinations (BICV-F and BICV-SP) among Chinese university students if the vaccine was 80% effective with rare mild side effects, to examine their associations with social media exposures and peer discussions regarding COVID-19 vaccination, and to explore the mediational role of perceived information sufficiency about COVID-19 vaccination. An online anonymous survey (N = 6922) was conducted in November 2020 in five Chinese provinces. Logistic regression and path analysis were adopted. The prevalence of BICV-F and BICV-SP were 78.1% and 57.7%. BICV-F was positively associated with the frequencies of passive social media exposure (adjusted odds ratio (AOR) = 1.32, P < 0.001), active social media interaction (AOR = 1.13, P < 0.001) and peer discussions (AOR = 1.17, P < 0.001). Indirect effects of the three factors on BICV-F via perceived information sufficiency were all significant (P < 0.001). The direct effect of active social media interaction on BICV-F was significantly negative (P < 0.001). Similar associations/mediations were observed for BICV-SP. The COVID-19 vaccination intention of Chinese university students needs improvement. Boosting social media exposures and peer discussions may raise students' perceived information sufficiency and subsequently increase their vaccination intention. Considering the potential negative effect of active social media interaction, caution is needed when using social media to promote COVID-19 vaccination.

A long-term retrospective study of ultrasound-guided microwave ablation of thyroid benign solid nodules.

PURPOSE: To explore the clinical outcomes and safety of ultrasound-guided microwave ablation (MWA) for treating thyroid benign solid nodules during a three-year follow-up. METHODS: A total of 53 patients with thyroid benign solid nodules with the largest diameter exceeding 2 cm were treated with US-guided MWA between January 2015 and December 2017. Nodule volume, the cosmetic score, and the symptom scores were evaluated before ablation and 1, 2, and 3 years after the operation. The characteristics of MWA and complications were also evaluated. RESULTS: The thyroid nodule volume at each time point after ablation was significantly smaller than that before ablation (p < .05). The Symptom and Cosmetics score were significantly improved (p < .05). Hoarseness was the major complication, with an incidence of 1.89%. The original nodules volume was 7.28 ± 11.42 mL; the isolating fluid was 34.36 ± 13.35 mL; the ablation time was 188.77 ± 89.13s. CONCLUSIONS: MMA is an effective and safe approach for reducing nodule volume and symptoms in patients with benign thyroid solid nodules.

A cohort study of microwave ablation and surgery for low-risk papillary thyroid microcarcinoma.

BACKGROUND: The optimal treatment method for papillary thyroid microcarcinoma (PTMC) is lacking consensus. Here we aimed to compare the efficacy and safety of surgery and microwave ablation (MWA) for PTMC. METHODS: The clinical data of 644 patients with PTMC treated between July 2013 and June 2020 were retrospectively analyzed. A total of 320 and 324 patients underwent MWA and surgery, respectively. We observed lesion changes in the MWA group and compared the recurrence, metastasis, complications, and other health economic indicators between the 2 groups. RESULTS: The mean follow-up time was 890.7 ± 532.9 (187.9-2679.0) days in the MWA group and 910.9 ± 568.4 (193.8-2821.5) days in the surgery group. In the MWA group, lesion volume increased significantly after ablation and then gradually decreased. The final lesion volume reduction rate was 90.73% ± 7.94%, and 193 lesions (60.3%) disappeared completely. There were no significant intergroup differences in recurrence or metastasis. The incidence of main complications (temporary hypothyroidism, hypoparathyroidism, and temporary hoarseness) was significantly lower in the MWA group than in the surgery group (p < 0.001). The treatment time, intraoperative blood loss, and hospital stay were significantly lower in the MWA group than in the surgery group (p < 0.001). CONCLUSIONS: MWA is effective for treating PTMC, with a low incidence of complications and less trauma. The rates of post-treatment recurrence and metastasis are similar to those of surgery, indicating that MWA is a suitable alternative to surgery.

A short-term non-randomized controlled study of ultrasound-guided microwave ablation and parathyroidectomy for secondary hyperparathyroidism.

BACKGROUND: To compare the short-term clinical outcomes of ultrasound-guided microwave ablation (MWA) and parathyroidectomy (PTX) for severe secondary hyperparathyroidism(SHPT). METHODS: In a prospective multi-center study, we compared the outcomes of MWA and PTX for severe SHPT. The outcome measures were case rate of successful treatment, improvement of clinical symptoms, incidence of complications, and differences in treatment parameters and costs between the two groups. RESULTS: A total of 167 eligible patients were included in the study, of which 79 underwent MWA and 88 underwent PTX. There was no significant difference in rate of successful treatment between the MWA and PTX groups (χ2=2.299, p = 0.125). However, the MWA group showed significantly lower range of intact parathyroid hormone (iPTH) decrease than the PTX group (t=-2.352, p = 0.023). Postoperative clinical symptoms improved in both groups, with no significant difference between the two groups (p > 0.05). Postoperative hypocalcemia was significantly more common in the PTX group (p < 0.05). The operative time, incision and postoperative pain of the MWA group were significantly better than those of the PTX group (p < 0.05), while postoperative recurrent laryngeal nerve injury and hematoma showed no significant difference between the two groups (p > 0.05). The cost of MWA was significantly less than PTX (p = 0.000). CONCLUSIONS: Both MWA and PTX are effective and safe for severe secondary hyperparathyroidism. PTX is more thorough and traumatic, while MWA is minimally invasive and postoperative iPTH is more consistent with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendation.