Effects of paternal ionizing radiation exposure on fertility and offspring's health.

Purpose: The intergenerational effects of ionizing radiation remain controversial. Extensive insights have been revealed for DNA mutations and cancer incidence in progeny, yet many of these results were obtained by immediate post-radiation mating. However, conception at short times after radiation exposure is likely to be avoided. After a long period of fertility recovery, whether unexposed sperm derived from exposed spermatogonia would challenge the health of the offspring is not yet clearly demonstrated. Methods: Ten-week-old C57BL/6J males underwent whole-body acute γ irradiation at 0 and 6.4 Gy. Testes and sperm were collected at different times after radiation to examine reproductive changes. The reproductive, metabolic, and neurodevelopmental parameters were measured in the offspring of controls and the offspring derived from irradiated undifferentiated spermatogonia. Results: Paternal fertility was lost after acute 6.4 Gy γ radiation and recovered at 10-11 weeks post irradiation in mice. The reproductive, metabolic, and neurodevelopmental health of offspring born to irradiated undifferentiated spermatogonia were comparable to those of controls. Conclusion: The male mice could have healthy offspring after recovery from the damage caused by ionizing radiation.

BNC1 deficiency induces mitochondrial dysfunction-triggered spermatogonia apoptosis through the CREB/SIRT1/FOXO3 pathway: the therapeutic potential of nicotinamide riboside and metformin†.

Male infertility is a global health problem that disturbs numerous couples worldwide. Basonuclin 1 (BNC1) is a transcription factor mainly expressed in proliferative keratinocytes and germ cells. A frameshift mutation of BNC1 was identified in a large Chinese primary ovarian insufficiency pedigree. The expression of BNC1 was significantly decreased in the testis biopsies of infertile patients with nonobstructive azoospermia. Previous studies have revealed that mice with BNC1 deficiency are generally subfertile and undergo gradual spermatogenic failure. We observed that apoptosis of spermatogonia is tightly related to spermatogenic failure in mice with a Bnc1 truncation mutation. Such impairment is related to mitochondrial dysfunction causing lower mitochondrial membrane potential and higher reactive oxygen species. We showed that downregulation of CREB/SIRT1/FOXO3 signaling participates in the above impairment. Administration of nicotinamide riboside or metformin reversed mitochondrial dysfunction and inhibited apoptosis in Bnc1-knockdown spermatogonia by stimulating CREB/SIRT1/FOXO3 signaling. Dietary supplementation with nicotinamide riboside or metformin in mutated mice increased SIRT1 signaling, improved the architecture of spermatogenic tubules, inhibited apoptosis of the testis, and improved the fertility of mice with a Bnc1 truncation mutation. Our data establish that oral nicotinamide riboside or metformin can be useful for the treatment of spermatogenic failure induced by Bnc1 mutation.

Nanoscale multi-beam lithography of photonic crystals with ultrafast laser.

Photonic crystals are utilized in many noteworthy applications like optical communications, light flow control, and quantum optics. Photonic crystal with nanoscale structure is important for the manipulation of light propagation in visible and near-infrared range. Herein, we propose a novel multi beam lithography method to fabricate photonic crystal with nanoscale structure without cracking. Using multi-beam ultrafast laser processing and etching, parallel channels with subwavelength gap are obtained in yttrium aluminum garnet crystal. Combining optical simulation based on Debye diffraction, we experimentally show the gap width of parallel channels can be controlled at nanoscale by changing phase holograms. With the superimposed phase hologram designing, functional structures of complicated channel arrays distribution can be created in crystal. Optical gratings of different periods are fabricated, which can diffract incident light in particular ways. This approach can efficiently manufacture nanostructures with controllable gap, and offer an alternative to the fabrication of complex photonic crystal for integrated photonics applications.

Selective binding of retrotransposons by ZFP352 facilitates the timely dissolution of totipotency network.

Acquisition of new stem cell fates relies on the dissolution of the prior regulatory network sustaining the existing cell fates. Currently, extensive insights have been revealed for the totipotency regulatory network around the zygotic genome activation (ZGA) period. However, how the dissolution of the totipotency network is triggered to ensure the timely embryonic development following ZGA is largely unknown. In this study, we identify the unexpected role of a highly expressed 2-cell (2C) embryo specific transcription factor, ZFP352, in facilitating the dissolution of the totipotency network. We find that ZFP352 has selective binding towards two different retrotransposon sub-families. ZFP352 coordinates with DUX to bind the 2C specific MT2_Mm sub-family. On the other hand, without DUX, ZFP352 switches affinity to bind extensively onto SINE_B1/Alu sub-family. This leads to the activation of later developmental programs like ubiquitination pathways, to facilitate the dissolution of the 2C state. Correspondingly, depleting ZFP352 in mouse embryos delays the 2C to morula transition process. Thus, through a shift of binding from MT2_Mm to SINE_B1/Alu, ZFP352 can trigger spontaneous dissolution of the totipotency network. Our study highlights the importance of different retrotransposons sub-families in facilitating the timely and programmed cell fates transition during early embryogenesis.

Fluorescence enhancement of organic dyes by femtosecond laser-induced cavitation bubbles for crystal imaging.

Fluorescence from organic dyes can be applied in many research fields such as imaging, bio-sensing and diagnosis. One shortcoming of fluorescence imaging is the limitation in emission intensity. Amplification of fluorescence signals can be achieved by the enhancement of localized electromagnetic fields. Metallic nanoparticles are widely applied to produce plasmon resonance, but they cause thermal damage to fragile bio-materials. In this study, we propose a method for nanoparticle-free fluorescence enhancement by ultrafast laser-induced cavitation bubbles in organic dye solutions. Fluorescence enhancement without the use of nanoparticles prevents potential hazards including thermal effects and biotoxicity. In order to achieve fluorescence enhancement in neat dye solution, cavitation bubbles were induced by focusing an 800 nm ultrafast laser beam. Another 400 nm laser beam was used to pump the gain medium. Fluorescence enhancement was observed in various dye solutions. The intensity and spectra of the fluorescence emission can be controlled by changing the power and focus of the excitation laser. According to time-resolved microscopy and simulation results, the cavity formed by the laser-induced bubbles results in the enhancement of the localized electromagnetic field and induces the amplification of the fluorescence signal. The bubble-enhanced fluorescence emission was used for imaging of protein crystals without causing thermal damage to the samples. This study provides an effective method for bio-compatible fluorescence enhancement and has application prospects in fields such as bio-imaging.

Exosome-Based Regimen Rescues Endometrial Fibrosis in Intrauterine Adhesions Via Targeting Clinical Fibrosis Biomarkers.

Intrauterine adhesions (IUA), which is characterized by endometrial fibrosis, continue to be the most common cause of uterine infertility globally. Our work revealed that 3 fibrotic progression markers (Vimentin, COL5A2, and COL1A1) were significantly increased in the endometrium of IUA patients. Mesenchymal stem cell-derived exosomes (EXOs) have been recently revealed as a cell-free therapy for fibrosis diseases. Nevertheless, the application of EXOs is restricted by the short residency duration in the target tissue. To overcome this limitation, herein, we reported an exosome-based regimen (EXOs-HP) that thermosensitive poloxamer hydrogel possessed the ability to efficiently promote the residency duration of EXOs in the uterine cavity. By downregulating fibrotic progression markers (Vimentin, COL5A2, and COL1A1), EXOs-HP could significantly restore the function and structure of the injured endometrium in the IUA model. Our work provides the theoretical and experimental foundation of EXOs-HP in treating IUA, highlighting the clinical potential of topical EXOs-HP delivery system in IUA patients.

A Machine Learning-Combined Flexible Sensor for Tactile Detection and Voice Recognition.

Intelligent sensors have attracted substantial attention for various applications, including wearable electronics, artificial intelligence, healthcare monitoring, and human-machine interactions. However, there still remains a critical challenge in developing a multifunctional sensing system for complex signal detection and analysis in practical applications. Here, we develop a machine learning-combined flexible sensor for real-time tactile sensing and voice recognition through laser-induced graphitization. The intelligent sensor with a triboelectric layer can convert local pressure to an electrical signal through a contact electrification effect without external bias, which has a characteristic response behavior when exposed to various mechanical stimuli. With the special patterning design, a smart human-machine interaction controlling system composed of a digital arrayed touch panel is constructed to control electronic devices. Based on machine learning, the real-time monitoring and recognition of the changes of voice are achieved with high accuracy. The machine learning-empowered flexible sensor provides a promising platform for the development of flexible tactile sensing, real-time health detection, human-machine interaction, and intelligent wearable devices.

Embryo morphologic quality in relation to the metabolic and cognitive development of singletons conceived by in vitro fertilization and intracytoplasmic sperm injection: a matched cohort study.

BACKGROUND: Embryos with higher morphologic quality grading may have a greater potential to achieve clinical pregnancy that leads to a live birth regardless of the type of cleavage-stage embryos or blastocysts. Few studies have investigated the impacts of embryo grading on the long-term health of the offspring. OBJECTIVE: This pilot study aimed to examine the associations between embryo morphologic quality and the physical, metabolic, and cognitive development of singletons conceived by in vitro fertilization and intracytoplasmic sperm injection at preschool age. STUDY DESIGN: This matched cohort study included singletons born to infertile couples who underwent fresh cleavage-stage embryo transfer cycles with good- or poor-quality embryos from 2014 to 2016 at the reproductive center of the Women's Hospital, School of Medicine, Zhejiang University. A total of 144 children, aged 4 to 6 years, participated in the follow-up assessment from 2020 to 2021, and the response rate of poor-quality embryo offspring was 39%. Singletons in the good-quality embryo group were matched with singletons in the poor-quality embryo group at a 2:1 ratio according to the fertilization method and the children's age (±1 year). We measured the offspring's height, weight, body mass index, blood pressure, thyroid hormone levels, and metabolic indicators. Neurodevelopmental assessments were performed using the Chinese version of the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition, and the Adaptive Behavior Assessment System, Second Edition. We also collected data from the medical records. A linear regression model was used to analyze the association between embryo morphologic quality and offspring health outcomes. RESULTS: A total of 48 singletons conceived with poor-quality embryo transfer and 96 matched singletons conceived with good-quality embryo transfer were included in the final analysis. Age, sex, height, weight, body mass index, blood pressure, thyroid function, and metabolic indicators were comparable between the 2 groups. After adjustment for potential risk factors by linear regression model 1 and model 2, poor-quality embryo offspring exhibited a tendency toward higher free thyroxine levels than offspring of good-quality embryo transfers (beta, 0.22; 95% confidence interval, 0.09-0.90; beta, 0.22; 95% confidence interval, 0.09-0.91, respectively), but this difference was not clinically significant. Regarding neurodevelopmental assessments, there was no difference in the full-scale intelligence quotient based on the Wechsler Preschool and Primary Scale of Intelligence (109.96±12.42 vs 109.60±14.46; P=.88) or the general adaptive index based on the Adaptive Behavior Assessment System (108.26±11.70 vs 108.08±13.44; P=.94) between the 2 groups. The subindices of the 2 tests were also comparable. These findings remained after linear regression analysis. CONCLUSION: At 4 to 6 years of age, singletons born from poor-quality embryo transfers have comparable metabolic and cognitive development as those born from good-quality embryo transfers using fresh cleavage-stage embryos. The results of this pilot study indicate that poor-quality embryos that can survive implantation and end in live birth are likely to have a developmental potential comparable to that of good-quality embryos.

Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels.

BACKGROUND: Thin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage. Much effort has been devoted toward regenerating thin endometrium by stem cell-based therapies. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs with various advantages. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms. METHODS: Ethanol was injected into the mice uterus to establish the endometrium-injured model. The retention time of HP-MSCs and HA hydrogel was detected by in vivo imaging, while the distribution of HP-MSCs was detected by immunofluorescence staining. Functional restoration of the uterus was assessed by testing embryo implantation rates. The endometrial morphological alteration was observed by H&E staining, Masson staining, and immunohistochemistry. In vitro studies were further conducted using EdU, transwell, tube formation, and western blot assays. RESULTS: Instilled HP-MSCs with HA hydrogel (HP-MSCs-HA) exhibited a prolonged retention time in mouse uteri than normal HP-MSCs. In vivo studies showed that the HP-MSCs-HA could significantly increase the gland number and endometrial thickness (P < 0.001, P < 0.05), decrease fibrous area (P < 0.0001), and promote the proliferation and angiogenesis of endometrial cells (as indicated by Ki67 and VEGF, P < 0.05, P < 0.05, respectively) in mice injured endometrium. HP-MSCs-HA could also significantly improve the embryo implantation rate (P < 0.01) compared with the ethanol group. Further mechanistic study showed the paracrine effects of HP-MSCs. They could not only promote the proliferation and migration of human endometrial stromal cells via the JNK/Erk1/2-Stat3-VEGF pathway but also facilitate the proliferation of glandular cells via Jak2-Stat5 and c-Fos-VEGF pathway. In turn, the increased VEGF in the endometrium promoted the angiogenesis of endothelial cells. CONCLUSION: Our study suggested the potential therapeutic effects and the underlying mechanisms of HP-MSCs-HA on treating thin endometrium. HA hydrogel could be a preferable delivery method for HP-MSCs, and the strategy represents a promising therapeutic approach against endometrial injury in clinical settings.

How Is the Sexual Function of Premenopausal Chinese Women Without Hyperlipidemia?

INTRODUCTION: Most premenopausal women in China have normal lipid profiles while the sexual function among them was scarcely demonstrated. AIM: To find out the characteristics of the sexual function in premenopausal Chinese women without hyperlipidemia using the Female Sexual Function Index (FSFI) and the Golombok Rust Inventory of Sexual Satisfaction (GRISS). METHODS: This cross-sectional study was performed to find out the characteristics of sexual function in premenopausal Chinese women without hyperlipidemia. Between January 2019 and March 2019, we recruited 216 women, 25-49 years of age. Data from questionnaires and health checkups were collected and analyzed. MAIN OUTCOME MEASURE: We report the prevalence of and factors related to female sexual dysfunction (FSD) in premenopausal Chinese women without hyperlipidemia in accordance with the FSFI and the GRISS. RESULTS: The prevalence of FSD in our study was 46.2%. The mean age was 38.07 ± 6.94 years. More highly educated women suffered from FSD than those in the control group (61.1% vs 35.2%, P < .05). Binge eating was significantly different between the groups (P = .023). Multiple logistic regression analyses demonstrated that total cholesterol level was positively associated with low desire (OR, 2.13; 95% CI, 1.10-4.13; P = .025) and so was the low-density lipoprotein level (OR, 2.18; 95% CI, 1.03-4.62; P = .0.041). The high-density lipoprotein level was inversely associated with infrequency (OR, 0.18; 95% CI, 0.06-0.59; P = .004). More women with FSD had orgasm disorder than those in the control group, for 83.3% vs 35.2% in the FSFI (P < .001), 88.9% vs 54.3% in the GRISS (P < .001), respectively. Dissatisfaction remained the most common issue for the control group in both the FSFI and the GRISS (90.50% and 58.10%, respectively). CONCLUSIONS: FSD is frequent in premenopausal Chinese women without hyperlipidemia. Dissatisfaction as the common problem influenced over half of them and orgasm disorder is a severe sexual issue for women with FSD. Xiang Y, Tang Y, Li J, et al. How Is the Sexual Function of Premenopausal Chinese Women Without Hyperlipidemia. J Sex Med 2019;8:65-75.

Cisplatin induced apoptosis of ovarian cancer A2780s cells by activation of ERK/p53/PUMA signals.

Cisplatin (CDDP) is one of the most effective anticancer agents widely used in the treatment of solid tumors, including ovarian cancer. It is generally considered as a cytotoxic drug which kills cancer cells by causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, the underlying mechanisms leading to cell apoptosis remain obscure. In this study, the signaling pathways involved in CDDP-induced apoptosis were examined using CDDP-sensitive ovarian cancer A2780s cells. A2780s cells were treated with CDDP (1.5-3 µg/ml) for 6h, 12h and 24h. Using siRNA targeting P53 and PUMA, and a selective MEK inhibitor, PD98059 to examine the relation between ERK1/2 activation, p53 and PUMA expression after exposure to CDDP, and the effect on CDDP-induced apoptosis. The results shown that treatment of A2780s cells with CDDP (3 µg/ml) for 6-24h induced apoptosis, resulting in the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and accumulation of p53 and PUMA (p53 upregulated modulator of apoptosis) protein. Knockdown of P53 or PUMA by siRNA transfection blocked CDDP-induced apoptosis. Inhibition of ERK1/2 using PD98059, a selective MEK inhibitor, blocked the apoptotic cell death but prevented CDDP-induced accumulation of p53 and PUMA. Knockdown of P53 by siRNA transfection also blocked CDDP-induced accumulation of PUMA. We therefore concluded that CDDP activated ERK1/2 and induced-p53-dependent PUMA upregulation, resulting in triggering apoptosis in A2780s cells. Our study clearly demonstrates that the ERK1/2/p53/PUMA axis is related to CDDP-induced cell death in A2780s cells.

A one-dimensional lead(II) coordination polymer with terminal and bridging 5-carboxy-2-(pyridin-3-yl)-1H-imidazole-4-carboxylate ligands.

In the coordination polymer catena-poly[[[diaqua[5-carboxy-2-(pyridin-3-yl)-1H-imidazole-4-carboxylato-κ(2)N(3),O(4)]lead(II)]-µ-5-carboxy-2-(pyridin-3-yl)-1H-imidazole-4-carboxylato-κ(3)N(3),O(4):N(2)] dihydrate], {[Pb(C10H6N3O4)(H2O)2]·2H2O}n, the two 5-carboxy-2-(pyridin-3-yl)-1H-imidazole-4-carboxylate ligands have different coordination modes, one being terminal and the other bridging. The bridging ligand links Pb(II) cations into one-dimensional coordination polymer chains. The structure is also stabilized by intra- and interchain π-π stacking interactions between the pyridine rings, resulting in the formation of a two-dimensional network. Extensive hydrogen-bonding interactions lead to the formation of a three-dimensional supramolecular network.