Yun Wang’s research while affiliated with Shanghai Jiao Tong University and other places

Mutations in mitochondrial DNA (mtDNA) contribute to a variety of serious multi-organ human diseases, which are strictly inherited from the maternal germline. However, there is currently no curative treatment. Attention has been focused on preventing the transmission of mitochondrial diseases through mitochondrial replacement (MR) therapy, but levels of mutant mtDNA can often unexpectedly undergo significant changes known as mitochondrial genetic drift. Here, we proposed a novel strategy to perform spindle-chromosomal complex transfer (SCCT) with maximal residue removal (MRR) in metaphase II (MII) oocytes, thus hopefully eliminated the transmission of mtDNA diseases. With the MRR procedure, we initially investigated the proportions of mtDNA copy numbers in isolated karyoplasts to those of individual oocytes. Spindle-chromosomal morphology and copy number variation (CNV) analysis also confirmed the safety of this method. Then, we reconstructed oocytes by MRR-SCCT, which well developed to blastocysts with minimal mtDNA residue and normal chromosomal copy numbers. Meanwhile, we optimized the manipulation order between intracytoplasmic sperm injection (ICSI) and SCC transfer and concluded that ICSI-then-transfer was conducive to avoid premature activation of reconstructed oocytes in favor of normal fertilization. Offspring of mice generated by embryos transplantation in vivo and embryonic stem cells derivation further presented evidences for competitive development competence and stable mtDNA carryover without genetic drift. Importantly, we also successfully accomplished SCCT in human MII oocytes resulting in tiny mtDNA residue and excellent embryo development through MRR manipulation. Taken together, our preclinical mouse and human models of the MRR-SCCT strategy not only demonstrated efficient residue removal but also high compatibility with normal embryo development, thus could potentially be served as a feasible clinical treatment to prevent the transmission of inherited mtDNA diseases.

Decidual natural killer cells (dNK cells) are an essential component of the immune cells present at the maternal–foetal interface during early pregnancy, and they play a vital role in various physiological processes. Abnormalities in the ratio or function of dNK cells have been linked to recurrent miscarriages. CD96 has been previously shown to regulate NK cell function in the tumour microenvironment; however, its role and mechanism at the maternal–foetal interface remains unclear. The present study aimed to investigate the immunomodulatory role of CD96 in dNK cells and its function at the maternal–foetal interface. Immunofluorescence staining and flow cytometry were used to detect the expression of cellular markers such as CD96. Furthermore, the secretory function, adhesion-function-related molecules, and cell proliferation markers of CD96+ and CD96− dNK cells were detected using flow cytometry. In addition, we performed cell culture experiments via the magnetic bead sorting of NK cells to detect changes in the expression of the aforementioned functional molecules in dNK cells after the CD96 blockade. Furthermore, we examined the functional characteristics of dNK cells after palmitic acid treatment at a concentration of 10 μM. We also examined the changes in dNK cell function when subjected to the combined effect of palmitic acid and CD96 antagonists. The results indicated that CD96, TIGIT, CD155, and CD112 were highly expressed at the maternal–foetal interface, with dNK cells predominantly expressing CD96, whereas TIGIT was mainly expressed on T cells, and CD155 and CD112 were mainly present in metaphase stromal and trophoblast cells. CD96+ dNK cells displayed low cytotoxic activity and a high adhesion phenotype, which mediated the immunosuppressive effect on dNK cells at the maternal–foetal interface. Palmitic acid upregulated CD96 expression on the surface of dNK cells in the coculture system, inhibiting dNK cell activity and increasing their adhesion molecule expression. CD96 antagonist treatment blocked the inhibitory effect of trophoblasts on dNK cells, resulting in enhanced cytokine secretion and reduced adhesion. The results of this study provide valuable insight into the immunomodulatory role of CD96 in dNK cells and its mechanism at the maternal–foetal interface, particularly in metaphase NK cells. This study sheds light on the mechanisms of immune regulation at the maternal–foetal interface and their implications for the study of recurrent miscarriages of unknown origin.

Urban blue spaces (UBSs) hold significant value in terms of public health, tourism economy, and residents’ well-being. The Huangpu River in Shanghai, renowned as a global urban blue space, currently faces challenges such as unequal service capacity across sections and varying levels of spatial vitality. This study incorporates the concept of “service effectiveness” into public space evaluation. Drawing inspiration from the 4E (economics, efficiency, equity, and effectiveness) principles of effectiveness evaluation, a social service effectiveness evaluation system is constructed to measure service efficiency and effect. Through the literature research, 6 primary indicators and 12 secondary indicators are set to investigate the utilization rate and realization effect of the UBS. The evaluation system utilizes field surveys, text analysis, and remote-sensing techniques to collect relevant data. Through standardized calculations, different aspects of the indicators are integrated into a single evaluation criterion. The “overall effectiveness index” and the “efficiency–effect balance index” is introduced to quantitatively analyze the overall effectiveness characteristics, including spatial characteristics and time-varying characteristics, as well as efficiency–effect balance and imbalances. The evaluation located three low-effectiveness sections and three imbalanced sections at the north and south ends of the core section of the Huangpu River. The influence factors of effectiveness are analyzed through correlation test and literature studies, mainly including the urban hinterland, service facilities, environmental quality, and management publicity factors. This study aims to provide research ideas and methods for waterfront area planning and city-refined management.

Public open space (POS) confers numerous physical and mental health benefits to people throughout life. The study applies POI and other multi-dimensional methods to examine the intergenerational equity of POS within a 15-min living circle of old communities in high-density cities. Firstly, an evaluation system for the comprehensive POS supply level in the community is constructed from the perspective of the quantity, quality, and spatial distribution of POS. Secondly, based on the idea of all-age sharing, the population in the community is divided into children, young and middle-aged, and elderly, and the factor “adaptation space share” is introduced to supplement the intergenerational equity evaluation system. The study takes Caoyang New Village in Shanghai as an example and the districts of the community committee as the basic evaluation units. The results show that the comprehensive supply of POS in Caoyang New Village is relatively high but there is still a mismatch between supply and demand; the intergenerational equity level is medium, and spatial alienation exists between POS supply and intergenerational equity; and the adaptation space share for children is much higher than that for the elderly, young and middle-aged people. Furthermore, young and middle-aged people are found to form a marginal group in spatial sharing and resource allocation. Finally, it is proposed that in community POS planning, attention should be focused on the differences in population age structure and on spatial cultural attributes and functional compounding on the basis of ensuring the comprehensive service of POS, so as to promote all-age sharing in community POS.

Objective To investigate whether Day 3 (D3) embryo status matter to reproductive outcomes of blastocyst transfer cycles. Design Retrospective cohort study. Setting Assisted Reproduction Department of Shanghai Ninth People's Hospital, Shanghai, China. Population A total of 6906 vitrified–thawed single blastocyst transfer cycles in 6502 women were included. Methods Generalised estimated equation regression models were used to calculate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the associations between embryo status and pregnancy outcomes. Main outcome measures Biochemical pregnancy, miscarriage, live birth. Results High‐quality blastocysts derived from poor‐grade D3 embryos had comparable pregnancy outcomes to those derived from high‐grade D3 embryos (40.0% versus 43.2%, aOR 1.00, 95% CI 0.85–1.17 for live birth rate; 8.3% versus 9.5%, aOR 0.82, 95% CI 0.63–1.07 for miscarriage rate). Cycles with low D3 cell number (five cells or fewer) had significantly higher miscarriage rate (9.2% versus 7.6%, aOR 1.33, 95% CI 1.02–1.75) compared with cycles with eight cells on D3. Conclusions Poor‐quality cleavage embryos should be cultivated to the blastocyst stage because high‐quality blastocysts derived from poor‐grade D3 embryos had acceptable pregnancy outcomes. When the blastocyst grade is identical, choosing embryos with higher D3 cell number (eight or more cells) for transfer could reduce the risk of early miscarriage.

The second polar body (PB2) transfer in assisted reproductive technology is regarded as the most promising mitochondrial replacement scheme for preventing the mitochondrial disease inheritance owing to its less mitochondrial carryover and stronger operability. However, the mitochondrial carryover was still detectable in the reconstructed oocyte in conventional second polar body transfer scheme. Moreover, the delayed operating time would increase the second polar body DNA damage. In this study, we established a spindle-protrusion-retained second polar body separation technique, which allowed us to perform earlier second polar body transfer to avoid DNA damage accumulation. We could also locate the fusion site after the transfer through the spindle protrusion. Then, we further eliminated the mitochondrial carryover in the reconstructed oocytes through a physically based residue removal method. The results showed that our scheme could produce a nearly normal proportion of normal-karyotype blastocysts with further reduced mitochondrial carryover, both in mice and humans. Additionally, we also obtained mouse embryonic stem cells and healthy live-born mice with almost undetectable mitochondrial carryover. These findings indicate that our improvement in the second polar body transfer is conducive to the development and further mitochondria carryover elimination of reconstructed embryos, which provides a valuable choice for future clinical applications of mitochondrial replacement.

We conducted this retrospective cohort study aiming to compare the different pregnancy outcomes of endometrial preparation regimens on ischemic placental disease in a frozen embryo transfer cycle. The study included a total of 9351 women who had undergone therapy at our single tertiary hospital from January 2015 to July 2020. The women were divided into three groups depending on their endometrial regimens: natural cycle, stimulation cycle, hormone replacement therapy cycle. The data were analyzed after propensity score matching, then we used multiple linear regression to study the relationship between ischemic placental disease and endometrial regimens, adjusted by confounding factors including age, body mass index, and score of propensity score matching. We performed univariate logistic regression, as well as multivariate logistic regression for ischemic placental disease, small for gestational age infant, placental abruption. and pre-eclampsia, respectively, listing the odds ratio and p-values in the table. As a result, risk of ischemic placental disease and small for gestational age infant were detected as higher in stimulation cycles compared to natural cycles before or after adjustment. Hormone replacement therapy cycles conferred a higher risk of pre-eclampsia and preterm delivery compared to natural cycles. No difference was found between stimulation cycles and hormone replacement therapy cycles, regardless of whether they are adjusted or not. In summary, more pharmacological intervention in endometrial preparation was associated with a higher risk of ischemic placental disease related symptoms than natural cycles for endometrial preparation in women undergoing frozen embryo transfer. Our findings supported that minimizing pharmacological interventions during endometrial preparation when conditions permit has positive implications for improving pregnancy outcomes.

Background: The potential correlation between progestin-primed ovarian stimulation (PPOS) and the risk of compromised embryo competence still lacks sound evidence. Methods: A large retrospective cohort study was used to compare the incidence of pregnancy loss and neonatal birthweights in frozen embryo transfer (FET) cycles using embryos from PPOS and GnRH analogue protocols. Propensity matched scores were used to balance the baseline confounders. Results: A total of 5744 matched cycles with positive hCG test were included to compare the pregnancy outcomes. The incidence of pregnancy loss was similar between PPOS and GnRH analogue groups (19.2% vs. 18.4%, RR 1.02 (0.97, 1.06), p > 0.05). The neonatal birthweights were comparable between two groups, respectively, for singleton births (3337.0 ± 494.4 g vs. 3346.0 ± 515.5 g) and in twin births (2496.8 ± 429.2 g vs. 2533.2 ± 424.2 g) (p > 0.05). Conclusions: The similar incidence of pregnancy loss and neonatal birthweights in FET cycles using embryos from PPOS provided us with a more complete picture about the safety of PPOS.

BACKGROUND Recurrent pregnancy loss negatively affects the reproductive outcomes of natural conception. Preimplantation genetic testing for aneuploidies has been the focus of interventions in women with recurrent pregnancy loss. However, the risk of no embryos being available, high costs, and uncertainties surrounding its effectiveness limit its use. Factors beyond euploidy, such as an appropriate intrauterine environment, are also important for improving the reproductive outcomes in women with recurrent pregnancy loss. It remains unknown whether a history of recurrent pregnancy loss can affect the reproductive outcomes after fertility treatment. OBJECTIVE This study aimed to investigate the impact of history of recurrent pregnancy loss on the reproductive outcomes of women undergoing fertility treatment. STUDY DESIGN This was a retrospective cohort study of women who underwent their first frozen embryo transfer cycle or intrauterine insemination cycle between January 2014 and July 2020 in Shanghai, China. We excluded couples with known karyotypic abnormalities (e.g. balanced translocation) or uterine malformation. We performed multivariate binary logistic regressions for biochemical pregnancy, miscarriage, and live birth rates to investigate the associations between recurrent pregnancy loss history and reproductive outcomes. RESULTS A total of 29,825 women who underwent frozen embryo transfer cycles, and 5,476 women who underwent intrauterine insemination cycles were included in this study. In those who underwent frozen embryo transfer, history of recurrent pregnancy loss was not significantly associated with biochemical pregnancy (adjusted odds ratio [aOR]: 1.19 [95% confidence interval {CI}: 0.87, 1.63]), miscarriage (aOR: 0.99 [95% CI: 0.78, 1.26]) or live birth rates (aOR: 0.91 [95% CI: 0.79, 1.06]). Similarly, in frozen embryo transfer cycles that led to clinical pregnancy, recurrent pregnancy loss history was not significantly associated with live birth (aOR: 0.99 [95% CI: 0.76, 1.28]) or miscarriage rates (aOR: 1.04 [95% CI: 0.81, 1.35]). In women with intrauterine insemination, history of recurrent pregnancy loss showed no significant associations with fertility outcomes in all cycles (aOR: 1.36 [95% CI: 0.88, 2.10] for live birth rate, aOR: 1.74 [95% CI: 0.75, 4.01] for miscarriage rate) and in cycles that led to clinical pregnancy (aOR: 0.70 [95% CI: 0.31, 1.63] for live birth rate, aOR: 1.45 [95% CI: 0.58, 3.63] for miscarriage rate). ONCLUSION In women without obvious chromosome abnormality and uterine malformation who undergo fertility treatment, recurrent pregnancy loss history was not significantly associated with miscarriage and live birth rates, suggesting that it has little or no prognostic value in predicting the reproductive outcomes of frozen embryo transfer or intrauterine insemination cycles.