An interactive online educational environment to reduce anxiety, improve emotional well-being, and critical thinking for college students.

Interactive education can reduce anxiety among students by creating a supportive and supportive learning environment. This approach can also stimulate critical thinking, as it requires active student participation in debates, analysis, and discussions. The purpose of this study is to determine the impact of interactive learning on Zoom on the anxiety, emotional well-being, and critical thinking of college students. The experiment involved 80 college students between 18 and 21 years of age. The research was performed by scientists from the [Zhengzhou University of Technology] University. To analyze the impact of the proposed strategy on emotional and cognitive well-being, the study used a set of questionnaires, namely Taylor Manifest Anxiety Scale, WAM (Well-being Assessment Measure), and Subjective Questionnaire for assessing critical thinking. The obtained results confirm the effectiveness of the interactive learning methodology, which significantly reduced anxiety and increased the level of critical thinking among students. Anxiety decreased by 14 points, and critical thinking improved by 2.5 points, indicating positive dynamics of psychological and cognitive development. Despite the positive results, some contextual factors such as the level of the learning environment, cultural characteristics, and the personalities of students can influence the generalization of the findings. These findings can have practical application in the pedagogical practice of creating a favorable learning environment. Future research may focus on improving the methodology of interactive learning, studying its impact on other aspects of learning and development. It is also necessary to explore the use of interactive learning in various cultural and educational contexts.

Human-mouse chimeric brain models constructed from iPSC-derived brain cells: Applications and challenges.

The establishment of reliable human brain models is pivotal for elucidating specific disease mechanisms and facilitating the discovery of novel therapeutic strategies for human brain disorders. Human induced pluripotent stem cell (iPSC) exhibit remarkable self-renewal capabilities and can differentiate into specialized cell types. This makes them a valuable cell source for xenogeneic or allogeneic transplantation. Human-mouse chimeric brain models constructed from iPSC-derived brain cells have emerged as valuable tools for modeling human brain diseases and exploring potential therapeutic strategies for brain disorders. Moreover, the integration and functionality of grafted stem cells has been effectively assessed using these models. Therefore, this review provides a comprehensive overview of recent progress in differentiating human iPSC into various highly specialized types of brain cells. This review evaluates the characteristics and functions of the human-mouse chimeric brain model. We highlight its potential roles in brain function and its ability to reconstruct neural circuitry in vivo. Additionally, we elucidate factors that influence the integration and differentiation of human iPSC-derived brain cells in vivo. This review further sought to provide suitable research models for cell transplantation therapy. These research models provide new insights into neuropsychiatric disorders, infectious diseases, and brain injuries, thereby advancing related clinical and academic research.

Hypo-connectivity of the primary somatosensory cortex in Parkinson's disease: a resting-state functional MRI study.

Background: Parkinson's disease (PD) is characterized by a range of motor symptoms as well as documented sensory dysfunction. This sensory dysfunction can present itself either as a "pure" sensory disturbance or as a consequence of sensory-motor integration within the central nervous system. This study aims to investigate changes in the functional connectivity of the primary somatosensory cortex (S1) and its clinical significance in Parkinson's disease (PD), an area that has received limited attention in previous neuroimaging studies. Methods: This study included thirty-three patients with PD and thirty-four healthy controls (HCs). Clinical evaluations were conducted to assess the clinical manifestations, severity, and functional capacity of all the patients. Resting-state functional MRI (fMRI) was employed to evaluate the functional connectivity of six paired S1 subregions in the participants. Seed-based correlation (SBC) analysis was utilized to construct the correlation matrix among the subregions and to generate connectivity maps between the subregions and the remaining brain voxels. Finally, the study employed partial least-squares (PLS) correlation analysis to investigate the association between modified functional connectivity and clinical characteristics in PD patients. Results: In the correlation matrix, patients with PD demonstrated a notable decrease in functional connectivity across various S1 subregions in comparison to HCs (p < 0.001, corrected using network-based methods). In connectivity maps, hypo-connectivity was primarily observed in the sensorimotor network as common patterns (p < 0.001, corrected for false discovery rate) and in the default mode network (DMN) as distinct patterns. Moreover, this study identified a negative association between the correlation matrix within S1 subregions and the scores for axial symptoms and postural instability/gait difficulty (PIGD) in PD patients. Nevertheless, a direct relationship between the connectivity maps of S1 subregions and clinical assessment scales was not established. Conclusion: This study offers novel insights into the neurobiological mechanisms that contribute to S1 dysfunction in PD, highlighting the significant involvement of S1 hypo-connectivity in the motor disturbances observed in PD patients.

Yin Yang 1 regulates cohesin complex protein SMC3 in mouse hematopoietic stem cells.

ABSTRACT: Yin Yang 1 (YY1) and structural maintenance of chromosomes 3 (SMC3) are 2 critical chromatin structural factors that mediate long-distance enhancer-promoter interactions and promote developmentally regulated changes in chromatin architecture in hematopoietic stem/progenitor cells (HSPCs). Although YY1 has critical functions in promoting hematopoietic stem cell (HSC) self-renewal and maintaining HSC quiescence, SMC3 is required for proper myeloid lineage differentiation. However, many questions remain unanswered regarding how YY1 and SMC3 interact with each other and affect hematopoiesis. We found that YY1 physically interacts with SMC3 and cooccupies with SMC3 at a large cohort of promoters genome wide, and YY1 deficiency deregulates the genetic network governing cell metabolism. YY1 occupies the Smc3 promoter and represses SMC3 expression in HSPCs. Although deletion of 1 Smc3 allele partially restores HSC numbers and quiescence in YY1 knockout mice, Yy1-/-Smc3+/- HSCs fail to reconstitute blood after bone marrow transplant. YY1 regulates HSC metabolic pathways and maintains proper intracellular reactive oxygen species levels in HSCs, and this regulation is independent of the YY1-SMC3 axis. Our results establish a distinct YY1-SMC3 axis and its impact on HSC quiescence and metabolism.

Neurotrophins and neural stem cells in posttraumatic brain injury repair.

Traumatic brain injury (TBI) is the main cause of disability, mental health disorder, and even death, with its incidence and social costs rising steadily. Although different treatment strategies have been developed and tested to mitigate neurological decline, a definitive cure for these conditions remains elusive. Studies have revealed that various neurotrophins represented by the brain-derived neurotrophic factor are the key regulators of neuroinflammation, apoptosis, blood-brain barrier permeability, neurite regeneration, and memory function. These factors are instrumental in alleviating neuroinflammation and promoting neuroregeneration. In addition, neural stem cells (NSC) contribute to nerve repair through inherent neuroprotective and immunomodulatory properties, the release of neurotrophins, the activation of endogenous NSCs, and intercellular signaling. Notably, innovative research proposals are emerging to combine BDNF and NSCs, enabling them to synergistically complement and promote each other in facilitating injury repair and improving neuron differentiation after TBI. In this review, we summarize the mechanism of neurotrophins in promoting neurogenesis and restoring neural function after TBI, comprehensively explore the potential therapeutic effects of various neurotrophins in basic research on TBI, and investigate their interaction with NSCs. This endeavor aims to provide a valuable insight into the clinical treatment and transformation of neurotrophins in TBI, thereby promoting the progress of TBI therapeutics.

Corrigendum: Association between endometrial blood and clinical outcome in frozen single blastocyst transfer cycles.

[This corrects the article DOI: 10.3389/fphys.2023.1113853.].

Airy-Gaussian vector beam and its application in generating flexible optical chains.

In recent years, the manipulation of structured optical beam has become an attractive and promising area. The Gaussian beam is the most common beam as the output beam of the laser, and the Airy beam is recently proposed with fascinating properties and applications. In this paper, for the first time to our knowledge, the polarization is used as a tool to design a new kind of Airy-Gaussian vector beam by connecting the Gaussian and Airy functions, which opens a new avenue in designing new beams based on the existed beams. We realize the Airy-Gaussian vector beam with space-variant polarization distribution in theory and experiment, and find that the vector beam can autofocus twice during propagation. The optical chains with flexible intensity peaks are achieved with the Airy-Gaussian vector beam, which can be applied in trapping and delivering particles including biological cells and Rydberg atoms. Such optical chains can significantly improve the trapping efficiency, reduce the heat accumulation, and sweep away the impurity particles.

The research on the impact of distance learning on students' mental health.

The mental health of students learning online is a critical task for many countries around the globe. The research purpose was to analyse the factors affecting the quality of mental health of young individuals who learnt under conditions of not total lockdowns but adaptive quarantine restrictions. The research involved 186 volunteers from Zhengzhou University of Technology, 94 were first-year students, and 92 were fourth-year students. The experimental group involved first-year students, and the control group involved fourth-year students. An average age of the participants in the experimental group was 18.3 years, and in the control group, the average age was 22.4 years. The scholars conducted the research after four months of distance learning under the adaptive quarantine. The students could be involved in their usual entertainment activities and interpersonal communication outside the home. The Behavioural Health Measure, better known as BHM-20, was the core psychometric tool. The research finds that distance learning is less effective for first-year students than for fourth-year students because the former cannot effectively adapt and communicate in a new social environment, and develop trusting interpersonal relationships with fellow students and teachers. The research results coincide with other research on this issue and demonstrate a low degree of mental resilience during and after the pandemic. Previous research is not suitable for the analysis of the mental health of students under adaptive quarantine, including the freshmen, considered the most vulnerable group. The article will be useful for professionals interested in distance education in higher educational institutions, workers of socio-psychological services at universities or individuals involved in adapting curriculum materials for distance learning.

Long-term follow up and comparison between conservative and interventional therapy in postoperative bronchopleural fistula-a cohort study.

Background: Bronchopleural fistula (BPF) is a relatively rare postoperative complication with high mortality. The management is tough and controversial. The aim of this study was to compare the short and long-term outcomes between the conservative and the interventional therapy in postoperative BPF. We also concluded our own strategy and experience of treatment in postoperative BPF. Methods: Postoperative BPF patients with malignancies, aged from 18 to 80 years old who had undergone thoracic surgery between June 2011 and June 2020, were included in this study and followed up from 20 months to 10 years. They were retrospectively reviewed and analyzed. Results: Ninety-two BPF patients were included in this study, 39 of whom underwent interventional treatment. Significant differences were found in the 28-day and the 90-day survival rates between the conservative and the interventional therapy (P=0.001, 43.40% vs. 76.92%; P=0.006, 35.85% vs. 66.67%). Simple conservative therapy was independently associated with 90-day mortality between the groups in postoperative BPF [P=0.002, hazards ratio (HR) =2.913, 95% confidence interval (CI): 1.480-5.731]. Conclusions: Postoperative BPF is notorious for its high mortality. Surgical and bronchoscopic interventions are recommendable in postoperative BPF as they guarantee better short and long-term outcomes compared with the conservative therapy.

Comparative Expedited Regulatory Programs of U.S Food & Drug Administration and Project Orbis Partners.

Project Orbis was initiated in May 2019 by the Oncology Center of Excellence to facilitate faster patient access to innovative cancer therapies by providing a framework for concurrent submissions and review of oncology products among international partners. Since its inception, Australia's Therapeutic Goods Administration (TGA), Canada's Health Canada (HC), Singapore's Health Sciences Authority (HSA), Switzerland's Swissmedic (SMC), Brazil's National Health Surveillance Agency (ANVISA), United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA), and most recently Israel's Ministry of Health (IMoH) Medical Technologies, Health Information, Innovation and Research (MTIIR) Directorate, have joined Project Orbis. While each country has its own expedited review pathways to bring promising therapies to patients, there are some similarities and differences in pathways and timelines. FDA's fast-track designation and MHRA's marketing authorization under exceptional circumstances (MAEC) allow non-clinical and limited clinical evidence to support approval under these programs. HC's Extraordinary Use New Drug (EUND) pathway allows granting exceptional use authorization with limited clinical evidence. ANVISA, HSA, MTIIR, and TGA do not have standard pathways that allow non-clinical evidence and limited clinical evidence. While there is no definite regulatory pathway for HSA, the current framework for approval does allow flexibility in the type of data (non-clinical or clinical) required to demonstrate the benefit-risk profile of a product. HSA may register a product if the agency is satisfied that the overall benefit outweighs the risk. All Project Orbis Partner (POP) countries have similar programs to the FDA accelerated approval program except ANVISA. Although HSA and MTIIR do not have defined pathways for accelerated approval programs, there are opportunities to request accelerated approval per these agencies. All POP countries have pathways like the FDA priority review except MHRA. Priority review timelines for new drugs range from 120 to 264 calendar days (cd). Standard review timelines for new drugs range from 180 to 365 cd.

Association between endometrial blood and clinical outcome in frozen single blastocyst transfer cycles.

Background: The success of embryo transfer cycle depends mainly on the quality of embryo and endometrial receptivity. Ultrasound examination is still the most widely used non-invasive evaluation method for its advantages of convenience, non-invasiveness and repeatability. Ultrasound-measured endometrial blood flow is one of the important evaluation indicators of morphology. Aims: To investigate the effect of the number of endometrial blood flow branches on pregnancy outcome of frozen-thawed embryo transfer cycles which have undergoing hormone replacement therapy (HRT-FET). Material and methods: A retrospective cohort study was performed looking at a total of 1390 HRT-FET cycles from our reproductive medicine center between January 2017 to December 2021, which transferred one blastocyst frozen on day 5 with good quality in morphology. Associations between endometrial blood flow branches and pregnancy outcomes were evaluated with multivariable linear regression analysis. Results: The number of endometrial blood flow branches was independently associated with clinical pregnancy (OR 1.10; 95% CI 1.02-1.20). After adjusting for potential confounders, the effect size (odds ratio) was 1.09 (95% CI 1.00-1.19), and the results showed that the clinical pregnancy rate and live birth rate of T2 and T3 groups were significantly higher than those in group T1 (p < 0.05). Subgroup analysis showed that a consistent association between the endometrial blood flow branches and clinical pregnancy in all subgroups. Conclusion: Our study provided evidence for the influence of endometrial blood flow on pregnancy outcomes. There may be an independent association between the number of endometrial blood flow branches and pregnancy outcomes in frozen-thawed single blastocyst transfer cycles.

Predictive value of 3D ultrasound assessment of endometrial receptivity for PGD/PGS for transfer pregnancy outcome.

OBJECTIVE: To investigate the predictive value of three-dimensional ultrasound assessment of endometrial receptivity in PGD/PGS transplantation patients on pregnancy outcome. METHODS: 280 patients undergoing PGD/PGS transplantation were enrolled and divided into group A and group B according to the patients' pregnancy outcomes. The general conditions, endometrial receptivity indexes of the two groups were compared. Multifactorial logistic regression analysis was used to determine the factors influencing pregnancy outcome in PGD/PGS transplant patients. ROC curves were plotted to analyze the predictive value of 3D ultrasound parameters on pregnancy outcome. The results of the study were validated with patients who underwent FET transplantation, and the patients in the validation group were treated with the same 3D ultrasound examination method and treatment plan as the observation group. RESULTS: The differences in basic situations between two groups were not statistically significant (P > 0.05). The percentage of endometrial thickness, endometrial blood flow, and endometrial blood flow classification type II + II were higher in group A than in group B (P < 0.05). Multifactorial logistic regression analysis showed that endometrial thickness, endometrial blood flow and endometrial blood flow classification were influencing factors of pregnancy outcome in PGD/PGS patients. The sensitivity of predicting pregnancy outcome based on the results of transcatheter 3D ultrasound was 91.18%, the specificity was 82.35%, and the accuracy was 90.00%, which has a high predictive value. CONCLUSION: 3D ultrasound can predict pregnancy outcome by assessing the endometrial receptivity of PGD/PGS transplantation, in which endometrial thickness and endometrial blood flow have a good predictive value.

Perioperative outcomes of robotic versus laparoscopic distal gastrectomy for gastric cancer: a meta-analysis of propensity score-matched studies and randomized controlled trials.

BACKGROUND: Da Vinci robotic surgery system, a novel type of surgery, was widespread in surgical field. However, the perioperative outcomes of robotic distal gastrectomy (RDG) are still controversy, despite several observational studies and randomized controlled trials (RCT) had been reported. Therefore, we performed a meta-analysis of propensity score-matched (PSM) and RCT studies to evaluated the perioperative feasibility and safety of RDG. METHODS: Studies were systematically searched in PubMed, Web of Science, Cochrane Library, and Embase database, and screened according to the defined limitations. The quality of PSM studies and RCT studies were respectively assessed by ROBINS-I and Cochrane risk-of-bias tool. Extracted data were analyzed by Review Manager 5.4. RESULTS: 7 PSM studies and 1 RCT with a total of 2763 patients were included in this analysis. The longer operative time (MD = 31.42, 95% CI [22.88, 39.96], p < 0.00001), less blood loss (MD = - 25.89, 95% CI [- 36.18, - 15.6], p < 0.00001), more retrieved lymph nodes (MD = 3.46, 95% CI [2.94, 3.98], p < 0.00001), shorter time to first flatus (MD = - 0.08, 95% CI [- 0.13, - 0.02], p = 0.006) and liquid intake (MD = - 0.13, 95% CI [- 0.22, - 0.05], p = 0.002) were observed in RDG group compared with LDG group. There are no statistically significant in time to start soft diet, postoperative hospital stays, overall complications, complications Grade I-II, complications Grade ≥ III, anastomotic leakage, bleeding, intra-abdominal bleeding, intraluminal bleeding, ileus, abdominal infection, delayed gastric emptying and wound complications. CONCLUSIONS: RDG showed less blood loss and more retrieved lymph nodes, revealed less time to first flatus and liquid intake after operation. But the operative time was longer in RDG group than in LDG. The incidence rate of postoperative complications was comparable between RDG and LDG.

The Preventive Effect of Dexmedetomidine Against Delirium in Patients with Aortic Dissection: A Retrospective Cohort Study.

BACKGROUND: Dexmedetomidine (DEX) is often used to reduce the incidence of delirium in intensive care unit (ICU) patients. However, it was found in our clinical practice that the incidence of delirium in some patients with aortic dissection (AD) remained high even after using DEX. The aim of the present study was to clarify whether the protective effects of DEX against delirium were different between Stanford type A and B AD patients during ICU stay. METHODS: Data of patients with Stanford type A or B AD who were treated in the ICU of our hospital between 2015 and 2018 retrospectively were reviewed. They were divided into four groups: A1 group (Stanford type A AD patients using DEX), A2 group (Stanford type A AD patients without using DEX), B1 group (Stanford type B AD patients using DEX), and B2 group (Stanford type B AD patients without using DEX). Patients in A1 and B1 groups received intravenous administration of DEX within 1 h admission to the ICU and after surgery or stent implantation at a loading dose of 1 µg/kg, followed by continuous infusion of 0.2-0.7 µg/(kg·h) for >24 h. The mortality rate, delirium incidence, length of ICU stay, and drug administration were compared between the four groups. RESULTS: After intravenous administration of DEX, the delirium incidence in B1 group was reduced significantly compared with that in B2 group (2.8% vs. 17.8%, P = 0.04), while there was no significant difference between A1 and A2 group (20.8% vs. 24.3%, P = 0.7). However, DEX administration significantly reduced the use of anti-hypertensive drugs (P = 0.04) and morphine (P = 0.02) in Stanford type A AD patients. CONCLUSION: The use of DEX reduced the incidence of delirium in Stanford type B AD patients during ICU stay, therefore reducing the risk of medical accidents and risk of rupture of the aortic dissecting aneurysm. The preventive effect of DEX against delirium in Stanford type A AD patients was not obvious, and whether increasing the dosage of DEX could enhance the therapeutic efficacy in this group of patients needs to be further observed in future studies.

Complete chloroplast genome sequence of Pithecellobium clypearia (Jack) Benth.

Pithecellobium clypearia (Jack) Benth. 1844 belongs to the genus Pithecellobium in the family Fabaceae. The complete chloroplast genome of P. clypearia was sequenced and analyzed by Illumina sequencing in this study. The full length of the complete chloroplast genome is 176,770 bp, containing a pair of inverted repeat regions of 39,693 bp (IRa and IRb) separated by a large single-copy (LSC) region of 92,500 bp and a small single-copy (SSC) region of 4,884 bp. The P. clypearia chloroplast genome encodes 137 genes, comprising 92 protein-coding genes, 37 tRNA genes, and 8 rRNA genes. Phylogenetic analysis based on complete chloroplast genomes revealed that P. clypearia is closely related to Archidendron lucyi and Pithecellobium flexicaule. This study provides useful resources for further study and development of this species.

Normothermic ex vivo lung perfusion outperforms conventional cold preservation in a deceased rat lung.

Background: Utilization rate of donor lungs in China is constrained by the inefficiency of conventional cold preservation (COLD) in lung transplantation. We assessed the performance of normothermic ex vivo lung perfusion (EVLP) in lung donors following cardiac death (DCD) with fresh EVLP perfusate. Methods: A total of 24 adult Sprague-Dawley (SD) rats were randomized into three groups (EVLP, COLD, and control groups) with 8 rats each. Fresh EVLP perfusate was prepared for lung perfusion. The pH, electrolyte concentration, perfusate penetration pressure during irrigation, physiological function, integrity of barrier function, pathological changes, and expressions of inflammation-related cytokines of donor lungs were examined. Results: The pH, electrolyte concentration, osmotic pressure of the perfusate were kept stable for 4 hours after EVLP was administered. Pulmonary arterial pressure (PAP), pulmonary venous pressure (PVP), pulmonary venous oxygenation index (PaO2/FiO2), and end carbon dioxide partial pressure (PCO2) in the EVLP group were all within acceptable limits. After 4 hours, the oxygenation index was significantly higher in the EVLP group compared with that of the COLD group (P=0.0032). The EVLP group had a decreased wet/dry weight ratio (P=0.0155) and Evans blue dye content (P=0.0075) compared to that of the COLD group. Pathological examination showed more obvious lung damage in the COLD group than in the EVLP group. However, there was no difference in protein expression of high mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4) between the EVLP group and the COLD group. Conclusions: Fresh lung perfusate could be used for EVLP to protect and repair donor lungs. Normothermic EVLP performed better than conventional cold preservation. EVLP might be powerful for lung quality maintenance and may have potential for anti-inflammation.

The relationship and optimal threshold of endometrial thickness with early clinical pregnancy in frozen embryo transfer cycles.

OBJECTIVE: To investigate the associations of endometrial thickness with pregnancy outcome in frozen embryo transfer (FET) cycles. METHODS: A retrospective cohort study was performed looking at 1627 FET cycles from the Reproductive Medicine Center of the study hospital between January 2017 and July 2018. Endometrial ultrasonographic characteristics were recorded on the embryo transfer day in FET cycles. RESULTS: A total of 1627 FET cycles were included. The endometrial thickness was independently associated with clinical pregnancy outcomes after adjusting for potential confounders (odds ratio 1.06; 95% confidence interval [CI] 1.01-1.12). A non-linear relationship was detected between endometrial thickness and pregnancy outcomes, whose point was 10.9 mm. The effect size of the left and right sides of the inflection point were 1.16 (95% CI 1.07-1.25) and 0.89 (95% CI 0.78-1.01), respectively. Subgroup analysis showed that the correlation between endometrial thickness and pregnancy outcome was consistent in all subgroups. CONCLUSION: The relationship between endometrial thickness and pregnancy outcome was non-linear and there is an inflection point. When endometrial thickness was less than 9.5 mm, it was positively related to clinical pregnancy rate. If it was beyond the inflection point, the pregnancy rate does not increase significantly.

Total Synthesis of Euonymine and Euonyminol Octaacetate.

Euonymine (1) and euonyminol octaacetate (2) share the core structure of euonyminol (3), the most hydroxylated member of the dihydro-ß-agarofuran family. In 2, eight of the nine hydroxy groups of 3 are acetylated, and 1 has six acetyl groups and a 14-membered bislactone comprising a pyridine dicarboxylic acid with two methyl groups. The different acylation patterns provide distinct biological activities: 1 and 2 display anti-HIV and P-glycoprotein inhibitory effects, respectively. The 11 contiguous stereocenters and 9 oxygen functionalities of the ABC-ring system of 1 and 2 represent a formidable challenge, which is further heightened by the macrocyclic structure of 1. Here we disclose an efficient synthetic strategy for enantioselective total synthesis of 1 and 2. Starting from (R)-glycerol acetonide, we constructed the B-ring by an Et3N-accelerated Diels-Alder reaction, the C-ring by intramolecular iodoetherification, and the A-ring by ring-closing olefin metathesis. The 10 stereocenters were installed through a series of substrate-controlled stereoselective C-C and C-O bond formations by exploiting the three-dimensional structures of judiciously designed substrates. These newly developed reaction sequences led to protected euonyminol 5, which served as a common intermediate for assembling 1 and 2. Global deprotection of 5 and subsequent acetylation produced 2. Alternatively, the discriminative protective groups of 5 allowed for site-selective bis-esterification to generate bislactone. Combining [3 + 2]-cycloaddition and reductive desulfurization introduced the last remaining stereocenters of the two methyl groups on the macrocycle. Finally, deprotection and acetylation gave rise to fully synthetic 1 for the first time.