Live Birth with or without Preimplantation Genetic Testing for Aneuploidy.

BACKGROUND: Embryo selection with preimplantation genetic testing for aneuploidy (PGT-A) may improve pregnancy outcomes after initial embryo transfer. However, it remains uncertain whether PGT-A improves the cumulative live-birth rate as compared with conventional in vitro fertilization (IVF). METHODS: In this multicenter, randomized, controlled trial, we randomly assigned subfertile women with three or more good-quality blastocysts to undergo either PGT-A or conventional IVF; all the women were between 20 and 37 years of age. Three blastocysts were screened by next-generation sequencing in the PGT-A group or were chosen by morphologic criteria in the conventional-IVF group and then were successively transferred one by one. The primary outcome was the cumulative live-birth rate after up to three embryo-transfer procedures within 1 year after randomization. We hypothesized that the use of PGT-A would result in a cumulative live-birth rate that was no more than 7 percentage points higher than the rate after conventional IVF, which would constitute the noninferiority margin for conventional IVF as compared with PGT-A. RESULTS: A total of 1212 patients underwent randomization, and 606 were assigned to each trial group. Live births occurred in 468 women (77.2%) in the PGT-A group and in 496 (81.8%) in the conventional-IVF group (absolute difference, -4.6 percentage points; 95% confidence interval [CI], -9.2 to -0.0; P<0.001). The cumulative frequency of clinical pregnancy loss was 8.7% and 12.6%, respectively (absolute difference, -3.9 percentage points; 95% CI, -7.5 to -0.2). The incidences of obstetrical or neonatal complications and other adverse events were similar in the two groups. CONCLUSIONS: Among women with three or more good-quality blastocysts, conventional IVF resulted in a cumulative live-birth rate that was noninferior to the rate with PGT-A. (Funded by the National Natural Science Foundation of China and others; ClinicalTrials.gov number, NCT03118141.).

Preimplantation genetic testing for human blastocysts with potential parental contamination using a quantitative parental contamination test (qPCT): an evidence-based study.

RESEARCH QUESTION: Is it possible to develop a quantitative method for detecting parental DNA contamination in conventional IVF using preimplantation genetic testing for aneuploidy (PGT-A)? DESIGN: In this study, a quantification method was established for the parental contamination test (qPCT), which ensured more reliable results, and then verified its effectiveness for vitrified conventional IVF embryos. A total of 120 surplus vitrified blastocysts from patients who underwent prior routine IVF cycles were available for study. RESULTS: The results of the prospective clinical study of qPCT-PGT-A showed that the maternal contamination rate was 0.83% (1/120) and that the risk of paternal contamination was negligible. The 24 frozen embryo transfer cycles resulted in 16 clinical pregnancies, including 13 live births, one late inevitable miscarriage and two ongoing pregnancies. CONCLUSIONS: The risk of PGT in embryos with potential parental contamination is relatively low, and PGT-A is applicable for vitrified conventional IVF embryos.

Analytical ray tracing based on Hamilton principal function and conjugate variable pairs.

A transformation method based on optical Hamilton equations is proposed for 3D ray tracing in axially inhomogeneous gradient-index (GRIN) media with cylindrical symmetry. For a given GRIN field, the optical conjugate variable pairs of physical space can be transformed into a virtual space by applying canonical transformation. The virtual trace can be simply solved as a uniform expression regardless of what the GRIN field is, and one can inversely transform it into the physical space. The transformation is intimately related to a Hamilton principal function, called the S function, which simultaneously gives the real ray trace and its conjugate. The "conjugate trace" displays the direction cosines of the ray trace and thus shows the information about propagation direction at every point, and it can be independently derived from the S function without knowing the real trace. In addition, as two special dimension-reduction cases, the S function is also applicable for 2D structures with only axial inhomogeneity or cylindrical symmetry.

Retrospective cohort study of neonatal blood transfusion in China.

BACKGROUND: Blood transfusion therapy is extremely important for certain neonatal diseases, but the threshold for neonatal blood transfusion is not the same in different countries. Until now, clinical studies to determine the suitable threshold for newborns in China are lacking. Therefore, it is of high importance to establish a multi-center cohort study to explore appropriate transfusion thresholds for newborns in China. METHODS: This retrospective cohort study investigated neonatal blood transfusion therapy administered from January 1, 2017 to June 30, 2018, with the aim of evaluating the effect of restricted and nonrestricted blood transfusion on neonatal health. The subjects were enrolled in 46 hospitals in China. A total of 5669 neonatal cases were included in the study. Clinical diagnosis and transfusion treatment of these neonates were collected and the data were retrospectively analyzed. The neonates were followed up 1 week and 1 month after leaving the hospital. The newborns' and their mothers' data were collected containing 280 variables in the database. The primary outcome of the study was mortality, and the secondary outcomes were complications, hospital stays, NICU hospital stays and hospital costs. RESULTS: Results from the < 1500 g group showed that there was a higher mortality rate in the restricted transfusion group (11.41%) when compared with the non-restricted transfusion group (5.12%) (P = 0.000). Among the secondary outcomes, the restricted transfusion group had fewer costs. Results from the 1500-2500 g group showed that the mortality rates of the restricted and non-restricted transfusion groups were 3.53% and 4.71%, respectively, however there was no statistical significance between the two groups (P = 0.345). Among the secondary outcomes, the restricted transfusion group had fewer hospital stays, NICU hospital stays and hospital costs. The incidence of necrotizing enterocolitis was lower in the restricted transfusion group (OR, 2.626; 95% confidence interval [CI], 1.445 to 4.773; P = 0.003). The results from the ≥ 2500 g restricted transfusion group suggested that the mortality rate of (3.02%) was significantly lower than that of non-restricted transfusion group (9.55%) (P = 0.000). Among the secondary outcomes, the restricted transfusion group had fewer hospital stays and hospital costs. The incidence of retinopathy of prematurity was lower in the restricted transfusion group (OR, 4.624; 95% confidence interval [CI], 2.32 to 9.216; P = 0.000). CONCLUSIONS: Current transfusion protocols for newborns weighing less than 1500 g may be inappropriate and lead to higher mortality. The current transfusion threshold performed better for the other two weight groups.

Artificial Small Molecules as Cofactors and Biomacromolecular Building Blocks in Synthetic Biology: Design, Synthesis, Applications, and Challenges.

Enzymes are essential catalysts for various chemical reactions in biological systems and often rely on metal ions or cofactors to stabilize their structure or perform functions. Improving enzyme performance has always been an important direction of protein engineering. In recent years, various artificial small molecules have been successfully used in enzyme engineering. The types of enzymatic reactions and metabolic pathways in cells can be expanded by the incorporation of these artificial small molecules either as cofactors or as building blocks of proteins and nucleic acids, which greatly promotes the development and application of biotechnology. In this review, we summarized research on artificial small molecules including biological metal cluster mimics, coenzyme analogs (mNADs), designer cofactors, non-natural nucleotides (XNAs), and non-natural amino acids (nnAAs), focusing on their design, synthesis, and applications as well as the current challenges in synthetic biology.

New biopsy after antibiotic treatment: effect on outcomes of assisted reproduction in patients with infertility and chronic endometritis.

RESEARCH QUESTION: What is the effect of chronic endometritis on patients with infertility, the necessity of endometrial re-examination and the effect of improving chronic endometritis after one cycle of antibiotic treatment on pregnancy outcomes? DESIGN: Infertile patients (n = 4003) who underwent IVF and intracytoplasmic sperm injection treatment were included. Pregnancy outcomes of groups positive for chronic endometritis were compared with groups that were negative (group 1). Patients that were positive were divided into the chronic endometritis new biopsy group (group 2) and chronic endometritis non-re-examination group (group 3). After doxycycline treatment and re-examination, the chronic endometritis new biopsy group was divided into improved chronic endometritis group (ICE) and not-improved chronic endometritis group (NICE), and their general indicators and reproductive outcomes were compared. RESULTS: No significant difference was observed in embryo implantation, early or late pregnancy loss, ectopic pregnancy, clinical pregnancy and live birth rates between groups 2 and 3. The clinical pregnancy and live birth rates in the NICE group were significantly lower than those in the ICE group (P = 0.008 and P = 0.001, respectively). After controlling for potential confounding factors, age, average number of high-quality embryos, endometrial thickness on the day of embryo transfer and number and type of embryo transfer were factors associated with live birth rates. CONCLUSIONS: Endometrial re-examination of women with chronic endometritis treated with doxycycline had no effect on pregnancy outcomes. The first cycle of doxycycline treatment could effectively improve reproductive outcomes of women with five or more CD138+ cells/high-power field.

Correlations of Inflammatory Cytokines in the Intestinal Mucosa, Serum Inflammation, Oxidative Stresses and Immune Changes with Vitamin Deficiency in Ulcerative Colitis Patients.

Ulcerative colitis (UC) is a chronic inflammatory disease. Studies in China and foreign countries have shown that vitamins have anti-inflammation and immunoregulation functions in patients with UC, but the specific mechanism is not yet clear. In this study, the levels of inflammatory cytokines in the intestinal mucosa, serum inflammatory indexes, oxidative stress indexes and immune-related indexes were detected, and their correlations with vitamin deficiency and clinical significance were discussed. Enzyme-linked immunosorbent assay (ELISA) was adopted to detect the serum level of 25-hydroxyvitamin D3, immunohistochemistry was applied to examine the expression of inflammatory cytokines in the intestinal mucosa, serum inflammatory indexes, oxidative stress indexes and immune-related indexes were measured, and their correlations were analyzed. Inflammatory and oxidative stress indexes in the UC group were notably higher than in the control group. The Vitamin deficiency group had more inflammatory cytokines than the normal vitamin group. Oxidative stress indexes such as superoxide dismutase (SOD) and malondialdehyde (MDA) in the vitamin deficiency group were significantly different from those in the normal vitamin group, but no difference was found in myeloperoxidase (MPO). Immune-related indexes, complement 3 (C3) and interferon-gamma (IFN-γ), in the normal vitamin group were higher than those in the vitamin deficiency group. Besides, interleukin-4 (IL-4) (r=-0.37, p=0.04) and IL-1ß (r=-0.31, p=0.04) had significant correlations with vitamins. Vitamins in patients with UC have significant correlations with inflammatory responses in vivo, which can be used to predict inflammatory responses in vivo and have strong clinical significance. Vitamins are also related to oxidative stresses to some extent but have little effect on immune-related indexes.

Effects of increasing serum luteinizing hormone levels during early phase of the gonadotropin-releasing hormone antagonist protocol on clinical outcomes of the in vitro fertilization cycle.

OBJECTIVE: To determine the effects of changes in serum luteinizing hormone (LH) levels in the early stages of the gonadotropin-releasing hormone antagonist (GnRH-A) protocol on in vitro fertilization and embryo transfer/intracytoplasmic sperm injection clinical outcomes. METHODS: Data from 2116 fresh embryo transfer cycles with the GnRH-A protocol were retrospectively analyzed. Patients were divided into two groups, ΔLH-increased and ΔLH-decreased, according to changes in serum LH levels on the day of GnRH-A addition compared with that on the start day of ovarian stimulation. Patients in whom ΔLH increased were categorized according to early-onset LH increases (serum LH level ≥10 mIU/mL or twice the baseline). RESULTS: ΔLH increased and decreased in 14.9% and 85.1% of patients, respectively. The fertilization rate was lower, and fewer oocytes were retrieved in patients with increased ΔLH compared to those with decreased ΔLH (p < .05). The number of AFC, oocytes retrieved, and AMH in patients with early-onset ΔLH increase was lower between the subgroups (p < .05). There were no significant differences in clinical pregnancy, early abortion, biochemical pregnancy, and live birth rates between the groups and subgroups (p > .05). CONCLUSIONS: Early increases in LH levels during GnRH-A protocol might affect the number of oocytes retrieved, but not the clinical outcomes.

Clinical efficacy analysis of oocyte cryopreservation: A propensity score matched study.

OBJECTIVE: To investigate the effectiveness of oocyte thawing cycles in the clinical application of assisted reproductive technology (ART). STUDY DESIGN: The clinical data of 78 cases who underwent oocyte thawing cycles in our center were retrospectively analyzed. All patients in this study received oocyte cryopreservation for the husband reason. According to patient age at egg freezing, patients were divided into three observation groups (Group A, <30 years old; Group B, 30-34 years old; Group C, ≥35 years old), and the control groups were selected by propensity score matching with fresh cycles. The clinical outcomes of each group were compared, and the clinical efficacy of oocyte thawing cycles was analyzed. RESULTS: Clinical pregnancy outcomes of oocyte thawing cycles were not significantly different from that of fresh oocytes, but vitrification affected the number of two pronuclei zygotes developing to cleavage stage and the number of high-quality embryos, and the normal fertilization rate after thawing. The cycle cumulative live birth rate in Group C was significantly lower than those in Groups A and B. The live birth rates per egg of Groups A, B, C were 5.03%, 5.61%, and 3.57%, respectively, and the numbers of eggs per live birth were 13.72, 14.43, and 21.0, respectively. CONCLUSIONS: The overall clinical outcomes of oocyte vitrification were similar to that of fresh oocytes, but the cleavage rate and embryo quality of frozen oocytes were slightly reduced. Freezing of oocytes in women over 35 years of age affects the clinical efficacy of ART.

A comparison of the clinical effects of thinning and drilling on laser-assisted hatching.

To systematically investigate the effects of two methods used for laser-assisted hatching (LAH) on clinical outcomes after day 4 (D4) on frozen-embryo-transfer (FET) cycles. Data from 11471 infertile patients who underwent FET cycles between January 2014 and October 2018 was retrospectively analyzed. The 1410 patients who met the inclusion criteria were further categorized into two groups based on the hatching procedure used: the thinning laser-assisted hatching group (T-LAH, 716 patients), and the drilling laser-assisted hatching group (D-LAH, 694 patients). The baseline characteristics of the patients were consistent between the two groups. However, the rates of implantation and clinical pregnancy were significantly higher in the T-LAH group compared to the D-LAH group (32.73% vs. 29.09%, P < 0.01, and 50.98% vs. 43.95%, P < 0.01). The proportion of live birth was also higher in the T-LAH group, but the difference was insignificant (39.11% vs. 36.89%, P > 0.05). Moreover, there were no significant differences in rates of miscarriages, multiple pregnancies, ectopic pregnancies, preterm births, and congenital disabilities between the two groups. Nonetheless, significantly higher rates of implantation and pregnancy were reported in the T-LAH group compared to the D-LAH group among patients aged <35 years, patients with at least one previously failed cycle, and patients with an endometrial thickness of 8-10 mm. T-LAH is superior to D-LAH in improving clinical implantation and pregnancy outcomes in D4 FET, particularly in patients aged <35 years with at least one previously failed cycle or an endometrial thickness of 8-10 mm. The findings of this study provide theoretical support for clinical individualized diagnosis and treatment of patients with infertility.

Transfer of Fresh versus Frozen Embryos in Ovulatory Women.

BACKGROUND: Elective frozen-embryo transfer has been shown to result in a higher live-birth rate than fresh-embryo transfer among anovulatory women with the polycystic ovary syndrome. It is uncertain whether frozen-embryo transfer increases live-birth rates among ovulatory women with infertility. METHODS: In this multicenter, randomized trial, we randomly assigned 2157 women who were undergoing their first in vitro fertilization cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. Up to two cleavage-stage embryos were transferred in each participant. The primary outcome was a live birth after the first embryo transfer. RESULTS: The live-birth rate did not differ significantly between the frozen-embryo group and the fresh-embryo group (48.7% and 50.2%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.89 to 1.06; P=0.50). There were also no significant between-group differences in the rates of implantation, clinical pregnancy, overall pregnancy loss, and ongoing pregnancy. Frozen-embryo transfer resulted in a significantly lower risk of the ovarian hyperstimulation syndrome than fresh-embryo transfer (0.6% vs. 2.0%; relative risk, 0.32; 95% CI, 0.14 to 0.74; P=0.005). The risks of obstetrical and neonatal complications and other adverse outcomes did not differ significantly between the two groups. CONCLUSIONS: The live-birth rate did not differ significantly between fresh-embryo transfer and frozen-embryo transfer among ovulatory women with infertility, but frozen-embryo transfer resulted in a lower risk of the ovarian hyperstimulation syndrome. (Funded by the National Key Research and Development Program of China and the National Natural Science Foundation of China; Chinese Clinical Trial Registry number, ChiCTR-IOR-14005406 .).

Association between endogenous LH level prior to progesterone administration and live birth rate in artificial frozen-thawed blastocyst transfer cycles of ovulatory women.

STUDY QUESTION: Is there an association between serum LH levels prior to progesterone administration and live birth rate (LBR) in artificial frozen-thawed embryo transfer (FET) cycles? SUMMARY ANSWER: : Low serum LH levels on the day before progesterone initiation in artificial frozen-thawed blastocyst transfer cycles of ovulatory women are associated with a lower LBR. WHAT IS KNOWN ALREADY: In artificial FET cycles, exogenous oestrogen and progesterone are administered sequentially to mimic the serum hormone pattern similar to the natural cycle. In oestrogen-only phase, the supplemental oestrogen causes thickening of the endometrium and is sometimes accompanied by a rise in serum LH. However, whether the endogenous LH level in artificial FET cycles is related to clinical outcomes remains unclear. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study including 3469 artificial frozen-thawed blastocyst transfer cycles was conducted at a tertiary-care academic medical centre between February 2014 and January 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 3469 frozen blastocyst transfer cycles were stratified into four groups based on the quartiles of serum LH level before progesterone initiation: <25th percentile (LH < 8.79 mIU/ml), 25-50th percentile (8.79 ≤ LH ≤ 13.91 mIU/ml), 51-75th percentile (13.91 < LH ≤ 20.75 mIU/ml) and >75th percentile (LH > 20.75 mIU/ml). The serum LH level >75th percentile group was considered as the reference group. Patients with polycystic ovarian syndrome or other ovulatory disorders were excluded from the study. We also excluded cycles with an endometrial thickness <7 mm before progesterone initiation and patients with intrauterine adhesions and uterine abnormalities. In order to avoid the interference of BMI, all patients were divided into two categories based on the overweight threshold: BMI <25 kg/m2 and ≥25 kg/m2, and the impacts of serum LH levels on LBR were investigated separately. Univariable and multivariable logistic regression analysis were performed to adjust for potential confounders. EmpowerStats software and R-project were used to build smooth curve fitting models. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with the reference group, the implantation rate significantly decreased with low LH levels (<25th percentile) on the day before progesterone initiation (odds ratio [OR] = 0.74; 95% CI, 0.64-0.86; P = 0.001). Accounting for major covariates, low LH levels were associated with a relatively lower LBR (adjusted OR = 0.649; 95% CI, 0.531-0.794; P < 0.001), mainly due to a lower implantation rate, lower clinical pregnancy rate and higher pregnancy loss rate. Moreover, in the patients with BMI <25 kg/m2, low LH was associated with a lower LBR (P < 0.001); while in the overweight subgroup, LBR and LH were not correlated (P = 0.823). LIMITATIONS, REASONS FOR CAUTION: The main limitation of this study is its retrospective design. Owing to the relatively small number in the overweight group, the results of the overweight subgroup should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The evidence provided in this study shows the importance of serum LH levels on the day before progesterone initiation in patients undergoing artificial FET cycles. Hypothalamic dysfunction may be one of the important causes of a relatively low LH, which is related to impaired pregnancy outcomes. Serum LH levels may be used as one of the clinical indicators to predict pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S): No funding and no competing interest were involved in this study. TRIAL REGISTRATION NUMBER: NA.

Successful birth after preimplantation genetic testing for a couple with two different reciprocal translocations and review of the literature.

BACKGROUND: Preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) is widely applied in couples with single reciprocal translocation to increase the chance for a healthy live birth. However, limited knowledge is known on the data of PGT-SR when both parents have a reciprocal translocation. Here, we for the first time present a rare instance of PGT-SR for a non-consanguineous couple in which both parents carried an independent balanced reciprocal translocation and show how relevant genetic counseling data can be generated. METHODS: The precise translocation breakpoints were identified by whole genome low-coverage sequencing (WGLCS) and Sanger sequencing. Next-generation sequencing (NGS) combining with breakpoint-specific polymerase chain reaction (PCR) was used to define 24-chromosome and the carrier status of the euploid embryos. RESULTS: Surprisingly, 2 out of 3 day-5 blastocysts were found to be balanced for maternal reciprocal translocation while being normal for paternal translocation and thus transferable. The transferable embryo rate was significantly higher than that which would be expected theoretically. Transfer of one balanced embryo resulted in the birth of a healthy boy. CONCLUSION(S): Our data of PGT-SR together with a systematic review of the literature should help in providing couples carrying two different reciprocal translocations undergoing PGT-SR with more appropriate genetic counseling.

Aquaporin 3 promotes human extravillous trophoblast migration and invasion.

PROBLEM: Does aquaporin 3 (AQP3) affect the migration and invasion of human extravillous trophoblast (HTR8/Svneo) cells? METHOD OF STUDY: A lentivirus infection system was used to construct stable cell lines with either AQP3 knockdown or overexpression. RT-PCR and western blotting were used to verify the efficiencies of AQP3 knockdown or overexpression in HTR8/Svneo cells at mRNA and protein levels, respectively. Cell Counting Kit-8 and flow cytometry assays were used to detect the influence of AQP3 knockdown or overexpression on proliferation and apoptosis of HTR8/Svneo cells. In addition, wound healing and Transwell invasion assays were used to detect the effects of AQP3 knockdown or overexpression on migration and invasion capabilities of HTR8/Svneo cells. An Agilent gene chip was used to screen for significant differentially expressed genes after AQP3 knockdown. Finally, mechanisms by which AQP3 influences the migration and invasion of HTR8/Svneo cells were explored using bioinformatic analysis. RESULTS: Compared with controls, migration and invasion capabilities of HTR8/Svneo cells were significantly reduced after AQP3 knockdown, and significantly increased after AQP3 overexpression. Subsequent bioinformatic analysis of gene chip expression profiles indicated downregulation of genes related to adhesion such as PDGF-B, as well as signaling pathways (such as PIK3/AKT, NF-κB, and TNF) after AQP3 knockdown. CONCLUSIONS: AQP3 could significantly promote migration and invasion capabilities of human extravillous trophoblasts, it may mediate embryo invasion and adhesion to endometrium by regulating PDGF-B, PIK3/AKT signaling pathways, although this requires further verification.

miR-124-3p Ameliorates Isoflurane-Induced Learning and Memory Impairment via Targeting STAT3 and Inhibiting Neuroinflammation.

INTRODUCTION: Substantial evidence has indicated that isoflurane leads to learning and memory impairment. This study was designed to investigate the potential role of microRNA-124-3p (miR-124-3p) in isoflurane-induced learning and memory impairment in rats. METHODS: Spatial learning and memory of rats were estimated by the Morris water maze (MWM) test after the construction of isoflurane-treated models. qRT-PCR was performed to assess the expression levels of miR-124-3p. The levels of interleukin-1ß, interleukin-6, and tumor necrosis factor-α in the hippocampal tissues were determined by enzyme-linked immunosorbent assay. The luciferase activity was determined by using a dual-luciferase reporter assay system. RESULTS: The higher escape latency and lower time spent in the original quadrant were shown in isoflurane-treated rats compared with the control rats. Moreover, treatment with isoflurane could induce neuroinflammation, and miR-124-3p was poorly expressed in the hippocampal tissue of isoflurane-treated rats. Furthermore, STAT3 is a functional target of miR-124-3p, and inflammatory cytokine level was downregulated by miR-124-3p. DISCUSSION/CONCLUSION: Combining the results of the current study demonstrates that miR-124-3p may have pivotal roles in improving isoflurane-induced learning and memory impairment via targeting STAT3 and inhibiting neuroinflammation.

NIR-II-activated biocompatible hollow nanocarbons for cancer photothermal therapy.

Photothermal therapy has attracted extensive attentions in cancer treatment due to its precise spatial-temporal controllability, minimal invasiveness, and negligible side effects. However, two major deficiencies, unsatisfactory heat conversion efficiency and limited tissue penetration depth, hugely impeded its clinical application. In this work, hollow carbon nanosphere modified with polyethylene glycol-graft-polyethylenimine (HPP) was elaborately synthesized. The synthesized HPP owns outstanding physical properties as a photothermal agent, such as uniform core-shell structure, good biocompatibility and excellent heat conversion efficiency. Upon NIR-II laser irradiation, the intracellular HPP shows excellent photothermal activity towards cancer cell killing. In addition, depending on the large internal cavity of HPP, the extended biomedical application as drug carrier was also demonstrated. In general, the synthesized HPP holds a great potential in NIR-II laser-activated cancer photothermal therapy.

Up-regulation of matrix metalloproteinases-9 in the kidneys of diabetic rats and the association with neutrophil gelatinase-associated lipocalin.

BACKGROUND: Matrix metalloproteinases-9 (MMP-9) can regulate extracellular matrix deposition in diabetic glomerular injury. However, it remains unknown whether MMP-9 is involved in the renal tubular injury. Meanwhile, neutrophil gelatinase-associated lipocalin (NGAL), defined as a biomarker of proximal tubular injury, may influence MMP-9 by forming the MMP-9/NGAL complex. The aim of this study was to investigate MMP-9 expression in proximal renal tubules and the relationship of MMP-9 and NGAL in diabetic rat model treated with Valsartan. METHODS: Sprague Dawley rats were randomly divided into three groups: Diabetic group, Control group, and Treated group. The diabetic rat model was established by injection of streptozotocin. Related indexes were measured at the end of the 2nd, 4th, 8th and 12th week post-modeling. RESULTS: In diabetic groups, the concentrations of MMP-9 markedly increased in the serum and urine of rats in the early stage, even before the appearance of pathological albuminuria. Markedly elevated MMP-9/NGAL complex concentrations were also tested in diabetic groups. Western blot and qPCR tests confirmed that MMP-9 expression levels in the proximal renal tubular epithelial cells of diabetic rats were significantly higher than in control groups (P < 0.05). Correlation analysis showed that MMP-9 was positively correlated with NGAL at both protein and gene expression levels. In addition, Valsartan observably reduced tubular injury as well as MMP-9 expression in diabetic rats. CONCLUSIONS: In diabetic kidney injury, the expression of MMP-9 in the proximal renal tubular epithelial cells was significantly increased. Besides, a positive correlation was found between MMP-9 and NGAL expression, along with high levels of MMP-9/NGAL complex, which indicated that NGAL might participate in the regulation of MMP-9 expression. The administration of Valsartan may reduce this effect.

Fabrication of fish gelatin / sodium alginate double network gels for encapsulation of probiotics.

BACKGROUND: To improve the environmental resistance of probiotics, and particularly their survival in the gastrointestinal environment, a fish gelatin (FG) / sodium alginate (SA) double network gelation (FSDN) was developed to encapsulate them. Thermal treatment and calcium ion inducement were adopted to fabricate fish gelatin and sodium alginate gels. It was feasible to scale up this process. The effects of FG concentration (0-60 g/L) on FSDN properties, including morphology, water-holding capacity, and encapsulation efficiency were evaluated. RESULTS: The results indicated that the addition of FG could improve the transparency, rehydration, and water-holding capacity of FSDN. Scanning electronic microscope (SEM) images revealed that FSDN had a denser and more complete structure than SA. Encapsulation efficiency improved from 15.85% to 91.91% as the FG concentration ranged from 0 to 50 g/L. Bifidobacterium longum embedded by FSDN showed better thermal stability than when it was free. Compared with bare probiotics (1.7%), the encapsulated ones exhibited higher viability (above 15%) in simulated gastric fluid. CONCLUSION: In conclusion, interpenetrating FSDN is an effective barrier constituent and could achieve the targeted delivery of probiotics. It is a potential new delivery carrier for the oral administration of probiotics. © 2021 Society of Chemical Industry.

Glucose-Sensitive Myokine/Cardiokine MG53 Regulates Systemic Insulin Response and Metabolic Homeostasis.

BACKGROUND: Mitsugumin 53 (MG53 or TRIM72), a striated muscle-specific E3 ligase, promotes ubiquitin-dependent degradation of the insulin receptor and insulin receptor substrate-1 and subsequently induces insulin resistance, resulting in metabolic syndrome and type 2 diabetes mellitus (T2DM). However, it is unknown how MG53 from muscle regulates systemic insulin response and energy metabolism. Increasing evidence demonstrates that muscle secretes proteins as myokines or cardiokines that regulate systemic metabolic processes. We hypothesize that MG53 may act as a myokine/cardiokine, contributing to interorgan regulation of insulin sensitivity and metabolic homeostasis. METHODS: Using perfused rodent hearts or skeletal muscle, we investigated whether high glucose, high insulin, or their combination (conditions mimicking metabolic syndrome or T2DM) alters MG53 protein concentration in the perfusate. We also measured serum MG53 levels in rodents and humans in the presence or absence of metabolic diseases, particularly T2DM. The effects of circulating MG53 on multiorgan insulin response were evaluated by systemic delivery of recombinant MG53 protein to mice. Furthermore, the potential involvement of circulating MG53 in the pathogenesis of T2DM was assessed by neutralizing blood MG53 with monoclonal antibodies in diabetic db/db mice. Finally, to delineate the mechanism underlying the action of extracellular MG53 on insulin signaling, we analyzed the potential interaction of MG53 with extracellular domain of insulin receptor using coimmunoprecipitation and surface plasmon resonance assays. RESULTS: Here, we demonstrate that MG53 is a glucose-sensitive myokine/cardiokine that governs the interorgan regulation of insulin sensitivity. First, high glucose or high insulin induces MG53 secretion from isolated rodent hearts and skeletal muscle. Second, hyperglycemia is accompanied by increased circulating MG53 in humans and rodents with diabetes mellitus. Third, systemic delivery of recombinant MG53 or cardiac-specific overexpression of MG53 causes systemic insulin resistance and metabolic syndrome in mice, whereas neutralizing circulating MG53 with monoclonal antibodies has therapeutic effects in T2DM db/db mice. Mechanistically, MG53 binds to the extracellular domain of the insulin receptor and acts as an allosteric blocker. CONCLUSIONS: Thus, MG53 has dual actions as a myokine/cardiokine and an E3 ligase, synergistically inhibiting the insulin signaling pathway. Targeting circulating MG53 opens a new therapeutic avenue for T2DM and its complications.

The best execution of the DuoStim strategy (double stimulation in the follicular and luteal phase of the same ovarian cycle) in patients who are poor ovarian responders.

BACKGROUND: Patients found to be poor ovarian responders (POR) are a challenging patient population for any assisted reproduction technology. Despite attempts at various controlled ovarian stimulation schemes, reproductive outcomes in this patient population have not improved. In recent years, the DuoStim protocol (both follicular and luteal phase stimulation during the same menstrual cycle) has shown a potential for use in patients with POR. METHODS: This retrospective study reviewed the medical records of 304 women who were diagnosed as POR and underwent the DuoStim protocol. We compared follicular phase stimulation (FPS) data and luteal phase stimulation (LPS) data of the same patients. We also compared the effects of different trigger drugs including urine human chorionic gonadotropin (uHCG; 10,000 IU), recombinant human chorionic gonadotropin (rHCG; 250 µg), and gonadotropin-releasing hormone agonist (GnRH-a; 0.2 mg) at the FPS and LPS stages. RESULTS: POR undergoing the DuoStim protocol resulted in a significantly higher number of oocytes retrieved, normal fertilised oocytes, cleaved embryos, cryopreserved embryos, and good quality embryos at the LPS stage than at the FPS stage. Trigger drugs at the FPS stage did not affect the FPS stage data. Regardless of the stage, rHCG and GnRH-a yielded significantly more cryopreserved embryos and good quality embryos than uHCG. CONCLUSION: The use of GnRH-a or rHCG as the trigger drug may be better than uHCG in both the FPS and LPS stages for POR undergoing the DuoStim protocol. This will increase the number of good quality embryos at the LPS stage. We found that the LPS stage results in more oocytes (and therefore more embryos) than the FPS stage.