Advances in microfluidic technology for sperm screening and in vitro fertilization.

About 18% of reproductive-age adults worldwide are affected by infertility. In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are widely used assisted reproductive technologies (ARTs) aimed at improving clinical outcomes. Efficient and noninvasive selection and isolation of highly motile sperm with intact DNA are essential for the success of IVF and ICSI and can potentially impact the therapeutic efficacy and the health of the offspring. Compared to traditional methods, microfluidic technology offers significant advantages such as low sample consumption, high efficiency, minimal damage, high integration, similar microenvironment, and high automation, providing a new platform for ARTs. Here, we review the current situation of microfluidic technology in the field of sperm motility screening and evaluation and IVF research. First, we focus on the working principle, structural design, and screening results of sperm selection microfluidic platforms. We then highlight how the multiple steps of the IVF process can be facilitated and integrated into a microfluidic chip, including oocyte capture, sperm collection and isolation, sperm sorting, fertilization, and embryo culture. Ultimately, we summarize how microfluidics can complement and optimize current sperm sorting and IVF protocols, and challenges and possible solutions are discussed.

Structure, bonding and electronic characteristics of amorphous Se.

Ovonic threshold switching (OTS) selectors can effectively improve the storage density and suppress the leakage current of advanced phase-change memory devices. As a prototypical OTS material, amorphous GeSe is widely investigated. But the attention paid to amorphous Se (i.e., the functional constituent in amorphous GeSe) has been very limited up to now. Here we have explored the structure, bonding and electronic characteristics of amorphous Se using ab initio molecular dynamics simulations. The results reveal that the Se atoms in amorphous Se tend to form 2-coordinated configurations, and they connect with each other to form long chains. The fraction of the vibrational density of state located in the high frequency range is relatively large, and the formation energy of the Se-Se bond is as large as 4.44 eV, hinting that the Se-Se bonds in chains possess high stability. In addition, the mid-gap state related to the OTS behavior is also found in amorphous Se despite the small proportion. Our findings enrich the knowledge of amorphous Se, which aids the applications of Se-based OTS selectors.

Dose-response associations of maternal prenatal noise exposure duration with antepartum depression status.

BACKGROUND: Antepartum depression has been reported to be associated with the intensity of maternal prenatal noise exposure; however, the association between noise exposure duration and the development of antepartum depression has not been established. This study aimed to determine the total and trimester-specific association of prenatal noise exposure duration with the development of antepartum depression. METHODS: From May 2018 to June 2021, we recruited 2,166 pregnant women from Shengjing Hospital, northeast China. We used a standardized questionnaire to assess women's prenatal noise exposure and used the Edinburgh Postnatal Depression Scale to assess pregnant women's antepartum depression during the 1st -, 2nd -, and 3rd - trimesters. We calculated a cumulative noise exposure score ranging from 0 to 3, with a higher score reflecting higher frequency and longer duration of noise exposure during pregnancy. RESULTS: Women who were exposed to noise for ≥ 15 min per day had an increased risk of antepartum depression compared with women who were not exposed to noise during pregnancy [odds ratio (OR) = 1.83, 95%CI:1.18, 2.83]. Noise exposure in a specific trimester was associated with higher risk of depression in the same trimester and subsequent trimesters. We observed increases in antepartum depression risk with increasing cumulative noise exposure scores (P for trend < 0.05 for all). Pregnant women with the highest scores had the highest risk of antepartum depression during the first (OR = 1.30, 95%CI:1.02, 1.65), second (OR = 1.75, 95%CI:1.23, 2.50) trimesters. Women with a cumulative noise exposure score of 2 had the highest risk of antepartum depression during the third trimester (OR = 1.79, 95%CI:1.14, 2.80), as well as during the whole pregnancy (OR = 1.94, 95%CI:1.14, 3.30). CONCLUSIONS: Maternal prenatal noise exposure duration was positively associated with antepartum depression risk in a dose-response manner. It is necessary to develop strategies by which pregnant women can avoid excessive exposure to noise to prevent antepartum depression.

WTAP dysregulation-mediated HMGN3-m6A modification inhibited trophoblast invasion in early-onset preeclampsia.

Early-onset preeclampsia (ePE) originates from abnormal implantation and placentation that involves trophoblast invasion, but its pathophysiology is not entirely understood. N6-methyladenosine (m6A) regulators mediate the progression of various cancers. The invasiveness of trophoblast cells is similar to that of tumor cells. However, little is known regarding the potential role of m6A modification in ePE and the underlying mechanism. This study aimed to explore the m6A level in placental tissue samples collected from ePE patients and to investigate whether m6A modification was an essential part of PE pathogenesis. The m6A level in placental tissue samples of 80 PE participants was examined. MeRIP-microarray, RNA-Seq, luciferase reporter assay, and RNA immunoprecipitation chip (RIP) assay were performed. The m6A level in the ePE group was significantly reduced compared with the control group. Wilms' tumor 1-associating protein (WTAP) regulated trophoblast cell migration and invasion. Mechanistically, the high mobility group nucleosomal binding domain 3 (HMGN3) gene was a target gene of WTAP in trophoblast (p < .05). WTAP enhanced the stability of HMGN3 mRNA through binding with its 3'-UTR m6A site(+485A, +522A). HMGN3 was recognized by m6A recognition protein insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), which was inhibited when knocking down WTAP. Both m6A and WTAP levels were downregulated in ePE. The m6A modification mediated by WTAP/IGF2BP1/HMGN3 axis might contribute to abnormal trophoblast invasion. Our work provided a foundation for further exploration of RNA epigenetic regulatory patterns in ePE, and indicated a new treatment strategy for ePE.

Structural, mechanical, electronic and optical properties of biphenylene hydrogenation: a first-principles study.

Biphenylene networks typically exhibit a metallic electronic nature, while hydrogenation can open the band gap changing it to a semiconductor. This property makes hydrogenated biphenylene a promising candidate for use in semiconductor optoelectronic materials and devices. In this work, three representative configurations of hydrogenated biphenylene, denoted by α, ß and γ, were investigated. The structural, mechanical, electronic, and optical properties of these hydrogenated biphenylene configurations were calculated by first-principles calculations. Band gaps with HSE correction were 4.69, 4.42 and 4.39 eV for α, ß, and γ configurations, respectively. Among these three configurations, ß presents the best electronic performance and special elastic properties (negative Poisson's ratio), while γ exhibits the best elastic properties. In addition, we comprehensively analyze the mechanical properties of these configurations and provide evidence that hydrogenated biphenylene possibly exhibits a negative-Poisson's-ratio along the zigzag and armchair directions when hydrogen atoms are added to biphenylene in certain ways. Furthermore, although the electronic properties of γ are weaker than those of ß, they are also excellent. In addition, the binding energies of ß and γ are relatively lower, which indicates that ß and γ are more stable. Our findings demonstrate that the hydrogenated biphenylene is a promising material with significant application potential in optoelectronic devices.

Trimester-specific association of perceived indoor air quality with antenatal depression: China Medical University Birth Cohort Study.

Antenatal depression is associated with adverse birth and long-term outcomes for mothers and children. Pregnant women spend 90% of time indoors; however, the association between indoor air quality and risk of antenatal depression has not been established. In this study, we aim to determine the total and trimester-specific association of perceived indoor air quality (PIAQ) with antenatal depression. A total of 2166 pregnant women were enrolled during the first trimester and evaluated during the second and third trimesters in the China Medical University Birth Cohort Study, a prospective pre-birth cohort study in northeastern China. PIAQ scores were obtained during each of three trimesters, which a higher score indicated a worse indoor air quality. Antenatal depression was screened using an Edinburgh Postnatal Depression Scale (EPDS) and defined as an EPDS score ≥ 9. Prevalence of antenatal depression was 26.7%, 20.6%, and 20.9% during the first, second, and third trimesters, respectively. A higher PIAQ score was positively associated with a depression score throughout pregnancy (ß = 0.27, 95% CI = 0.15-0.39). Trimester-specific adverse PIAQ exposure was associated with a higher depression score in the same trimester, but not with a higher score in a subsequent trimester. A dose-response pattern and incremental increases in risk of depression were observed with calculated adverse PIAQ exposures across all three trimesters, with the highest risk (OR = 3.24; 95% CI = 2.28-4.78) among women with adverse PIAQ across all three trimesters. The hazardous association between adverse PIAQ exposure and risk of depression were less pronounced among women with higher physical activity levels (P for interaction < 0.001). The results of present study provided important evidence that pregnant women's mental health was linked to indoor air quality during pregnancy. These findings could be helpful in the development of guidelines to prevent antenatal depression by improving indoor air quality.

Association of maternal caffeine intake during pregnancy with low birth weight, childhood overweight, and obesity: a meta-analysis of cohort studies.

BACKGROUND: Epidemiological studies reported inconsistent results on the associations between maternal caffeine intake during pregnancy and risk of low birth weight (LBW) and childhood overweight and obesity in their offspring. METHODS: We conducted a meta-analysis of cohort studies to quantitatively assess these associations. Pertinent studies were identified by searching PubMed and Embase through June 2019. Study-specifics risk estimates were combined using fixed effects models, or random-effects models when significant heterogeneity was detected. Dose-response analysis was modeled by using restricted cubic splines. RESULTS: A total of 15 cohort studies, with 102,347 pregnancy women, was included in the meta-analysis. The pooled relative risk (RR) for LBW was 1.33 (95% CI: 1.12, 1.57) for mothers with the highest compared with the lowest level of caffeine intake during pregnancy, with significant heterogeneity across studies (I2 = 49.3%, P = 0.032). The pooled RR was 1.07 (95% CI: 1.02, 1.11) for each 100 mg/day increase of caffeine intake. The pooled RR for childhood overweight and obesity was 1.39 (95% CI: 1.15, 1.69) for mothers with the highest compared with the lowest level of caffeine intake during pregnancy. No significant heterogeneity across studies was detected (I2 = 38.9%, P = 0.179). The pooled RR was 1.31 (95% CI: 1.11, 1.55) for each 100 mg/day increase of caffeine intake. No evidence of publication bias was indicated. CONCLUSIONS: Maternal caffeine intake during pregnancy is associated with higher risk of LBW and childhood overweight and obesity. Further studies may focus on investigating the potential mechanisms before the recommendation of complete avoidance of caffeine intake during pregnancy.

Integration of transcriptome and proteome profiles in placenta accreta reveals trophoblast over-migration as the underlying pathogenesis.

BACKGROUND: Placenta accreta (PA) is a major cause of maternal morbidity and mortality in modern obstetrics, few studies have explored the underlying molecular mechanisms. METHODS: In our study, transcriptome and proteome profiling were performed in placental tissues from ten participants including five cases each in the PA and control groups to clarify the pathogenesis of PA. RESULTS: We identified differential expression of 37,743 transcripts and 160 proteins between the PA and control groups with an overlap rate of 0.09%. The 33 most-significant transcripts and proteins were found and further screened and analyzed. Adhesion-related signature, chemotaxis related signatures and immune related signature were found in the PA group and played a certain role. Sum up two points, three significant indicators, methyl-CpG-binding domain protein 2 (MeCP2), podocin (PODN), and apolipoprotein D (ApoD), which participate in "negative regulation of cell migration", were downregulated at the mRNA and protein levels in PA group. Furthermore, transwell migration and invasion assay of HTR-8/SVneo cell indicated the all of them impaired the migration and invasion of trophoblast. CONCLUSION: A poor correlation was observed between the transcriptome and proteome data and MeCP2, PODN, and ApoD decreased in transcriptome and proteome profiling, resulting in increased migration of trophoblasts in the PA group, which clarify the mechanism of PA and might be the biomarkers or therapy targets in the future.

The imprinted H19 lncRNA antagonizes let-7 microRNAs.

Abundantly expressed in fetal tissues and adult muscle, the developmentally regulated H19 long noncoding RNA (lncRNA) has been implicated in human genetic disorders and cancer. However, how H19 acts to regulate gene function has remained enigmatic, despite the recent implication of its encoded miR-675 in limiting placental growth. We noted that vertebrate H19 harbors both canonical and noncanonical binding sites for the let-7 family of microRNAs, which plays important roles in development, cancer, and metabolism. Using H19 knockdown and overexpression, combined with in vivo crosslinking and genome-wide transcriptome analysis, we demonstrate that H19 modulates let-7 availability by acting as a molecular sponge. The physiological significance of this interaction is highlighted in cultures in which H19 depletion causes precocious muscle differentiation, a phenotype recapitulated by let-7 overexpression. Our results reveal an unexpected mode of action of H19 and identify this lncRNA as an important regulator of the major let-7 family of microRNAs.

Nitrogen Doped γ-Graphyne: A Novel Anode for High-Capacity Rechargeable Alkali-Ion Batteries.

High energy density is the major demand for next-generation rechargeable batteries, while the intrinsic low alkali metal adsorption of traditional carbon-based electrode remains the main challenge. Here, the mechanochemical route is proposed to prepare nitrogen doped γ-graphyne (NGY) and its high capacity is demonstrated in lithium (LIBs)/sodium (SIBs) ion batteries. The sample delivers large reversible Li (1037 mAh g-1 ) and Na (570.4 mAh g-1 ) storage capacities at 100 mA g-1 and presents excellent rate capabilities (526 mAh g-1 for LIBs and 180.2 mAh g-1 for SIBs) at 5 A g-1 . The superior Li/Na storage mechanisms of NGY are revealed by its 2D morphology evolution, quantitative kinetics, and theoretical calculations. The effects on the diffusion barriers (Eb ) and adsorption energies (Ead ) of Li/Na atoms in NGY are also studied and imine-N is demonstrated to be the ideal doping format to enhance the Li/Na storage performance. Besides, the Li/Na adsorption routes in NGY are optimized according to the experimental and the first-principles calculation results. This work provides a facile way to fabricate high capacity electrodes in LIBs/SIBs, which is also instructive for the design of other heteroatomic doped electrodes.

ALG3-CDG: lethal phenotype and novel variants in Chinese siblings.

Congenital disorders of glycosylation (CDG) are a group of genetic, mostly multisystem disorders, which often involve the central nervous system. ALG3-CDG is one the some 130 known CDG. Here we report two siblings with a severe phenotype and intrauterine death. Whole-exome sequencing revealed two novel variants in ALG3: NM_005787.6:c.512G>T (p.Arg171Leu) inherited from the mother and NM_005787.6:c.511C>T (p.Arg171Trp) inherited from the father.

Origin of short- and medium-range order in supercooled liquid Ge3Sb2Te6 using ab initio molecular dynamics simulations.

Phase-change materials such as Ge-Sb-Te compounds have attracted much attention due to their potential value in electrical data storage. In contrast to the amorphous and crystalline phases, supercooled liquids are far from being deeply understood despite their inevitable role in both amorphization and crystallization processes. To this end, we have studied the dynamics properties and structural characteristics of liquid and supercooled liquid Ge3Sb2Te6 during the fast cooling process. As the temperature decreases, chemical bonds become more homogeneous, but coordination numbers of Ge, Sb and Te atoms change very little. Meanwhile, the structural order of short-range configuration is obviously enhanced. Further studies suggest that Ge-centered, Sb-centered and Te-centered configurations change to the more ordered defective octahedrons mainly by adjusting the bond-angle relationship and bond length, rather than just by changing the coordination environment. It is the more ordered octahedrons that promote the formation of medium-range order. Our findings provide a deep insight into the origin of local structural order in supercooled liquid Ge3Sb2Te6, which is of great importance for the comprehensive understanding of amorphization and crystallization processes.

Prediction of iatrogenic preterm birth in patients with scarred uterus: a retrospective cohort study in Northeast China.

BACKGROUND: To build a novel and simple model to predict iatrogenic preterm birth in pregnant women with scarred uteri. METHODS: In this retrospective, observational, single-centre cohort study, data from 2315 patients with scarred uteri were collected. Multiple logistic regression analysis and mathematical modelling were used to develop a risk evaluation tool for iatrogenic preterm birth. After modelling, the calibration and discrimination of the model along with decision curve analysis were checked and performed to ensure clinical applicability. RESULTS: Among the 2315 patients, 417 (18.0%) had iatrogenic preterm births. The following variables were included in the model: interpregnancy interval (0 to < 12 months, OR 5.33 (95% Cl 1.79-15.91), P = 0.003; 13 to < 24 months (reference), 25 to < 60 months, OR 1.80 (95% CI 0.96-3.40), P = 0.068; ≥ 60 months, OR 1.60 (95% Cl 0.86-2.97), P = 0.14), height (OR 0.95, (95% CI 0.92-0.98), P = 0.003), parity (parity ≤1 (reference), parity = 2, OR 2.92 (95% CI 1.71-4.96), P < 0.0001; parity ≥3, OR 8.26, (95% CI 2.29-29.76), P = 0.001), number of vaginal bleeding (OR 1.81, (95% Cl 1.36-2.41), P < 0.0001), hypertension in pregnancy (OR 9.52 (95% CI 6.46-14.03), P < 0.0001), and placenta previa (OR 4.21, (95% CI 2.85-6.22), P < 0.0001). Finally, a nomogram was developed. CONCLUSIONS: In this study, we built a model to predict iatrogenic preterm birth for pregnant women with scarred uteri. The nomogram we created can assist doctors in evaluating the risk of iatrogenic preterm birth and help in making referrals; thus, better medical care can be given to improve the prognosis of patients and foetuses.

Nomogram to predict postpartum hemorrhage in cesarean delivery for women with scarred uterus: A retrospective cohort study in China.

AIM: To develop nomograms predicting the risk of postpartum hemorrhage (PPH) in cesarean delivery for singleton pregnant women with a scarred uterus in the north of China. METHODS: A retrospective cohort study was conducted. Totally 3722 singleton pregnant women with a scarred uterus who underwent a cesarean delivery in a large teaching hospital of north China between January 2013 and December 2017 were enrolled. Nomograms, a kind of user-friendly tool, were developed to predict PPH (blood loss ≥1000 mL or accompanied by signs or symptoms of hypovolemia within 24 h after the birth process) based on the model generated by logistic regression analysis. The discrimination and calibration of models were evaluated, and decision curve analysis was developed. RESULTS: Among 3722 enrolled women, 243 (6.53%) had PPH. There are six identified factors associated with PPH: maternal age, placental location, placenta previa, hypertensive disorders of pregnancy, fetal position and placenta accreta spectrum (PAS). The model achieved a good calibration (Hosmer-Lemeshow test P value 0.77) and discrimination (area under curve c-statistics 0.90, 95% confidence interval 0.86-0.93). Decision curve analysis showed the threshold probability by using our model is between 1.0% and 85.7%. A nomogram was developed accordingly. And another nomogram for women without placenta previa and PAS was also developed. CONCLUSION: Two nomograms were first generated to predict PPH, respectively, for women with a scarred uterus and for women with a scarred uterus who do not have placenta previa or PAS. Placental location and fetal position were found to be closely related to PPH.

Inverted Hydration Layers on Bio-Magnesium Surfaces in the Initial Degradation Stage and their Influence on Adsorption of Amino Acid Analogues: The Metadynamics Simulations.

Deeply exploring the interaction of biomolecules with magnesium in solution is essential to understand the formation of complex bio-magnesium interfaces accompanied with corrosion products. Using the accelerated metadynamics simulations, we have investigated the interactions of amino acid analogues on clean and hydroxylated Mg(0001) surfaces by identifying their free energy barriers and adsorption sites. We find that there are two hydration layers stacked on the clean Mg(0001) surfaces and the hydroxylated Mg(0001) surfaces, which mainly determine the free energy barriers and adsorbed configurations. Further studies reveal that the water molecules in double hydration layers present two opposite orientations, depending on the charge distribution of the substrate. Specifically, oxygen atoms of water concentrate in the center of double hydration layers for a clean Mg surface but transfer to the outside surface once the Mg substrate is degraded. The reversed hydration layers greatly reduce the binding affinities of positively charged and electroneutral analogues. Overall, our simulation findings provide new insights into the interaction mechanism of biomolecules on a bio-magnesium device in the implantation initial stage, which is noteworthy for revealing the magnesium degradation mechanism in vivo.

Electronic and magnetic properties of SnSe monolayers doped by Ga, In, As, and Sb: a first-principles study.

A SnSe monolayer with an orthorhombic Pnma GeS structure is an important two-dimensional (2D) indirect band gap material at room temperature. Based on first-principles density functional theory calculations, we present systematic studies on the electronic and magnetic properties of X (X = Ga, In, As, Sb) atom doped SnSe monolayers. The calculated electronic structures show that the Ga-doped system maintains its semiconducting properties while the In-doped SnSe monolayer is half-metal. The As- and Sb-doped SnSe systems present the characteristics of an n-type semiconductor. Moreover, all considered substitutional doping cases induce magnetic ground states with a magnetic moment of ∼ 1 µB. In addition, the calculated formation energies also show that four types of doped systems are thermodynamically stable. These results provide a new route for the potential applications of doped SnSe monolayers in 2D photoelectronic and magnetic semiconductor devices.

The fracture behaviors of monolayer phosphorene with grain boundaries under tension: a molecular dynamics study.

The fracture behaviors of monolayer phosphorene (MP) with and without a grain boundary (GB) have been explored by molecular dynamics (MD) simulations. Firstly, in the case of perfect MP, fracture mostly happens on the bond in the zigzag direction when suffering random loading. With the existence of a GB, the crack propagates perpendicular to the GB in different ways under parallel tension to the GB, whereas it propagates along the GB under perpendicular tension to the GB. Then, we found that both the fracture strength and strain decrease with increasing temperature making fracture more likely at relatively high temperatures. Finally, we also found that, similar to graphene, the effect of strain rate on both the fracture strength and strain is not significant, demonstrating that MP is a typical brittle 2D material. Overall, our findings present a useful insight into utilizing phosphorene for mechanical design in electronic devices.

The expression of the imprinted gene pleckstrin homology-like domain family A member 2 in placental tissues of preeclampsia and its effects on the proliferation, migration and invasion of trophoblast cells JEG-3.

Preeclampsia (PE) is one of the most common hypertensive disorders and is a leading cause of morbidity and mortality for pregnant women and perinatal babies. Additionally, pleckstrin homology-like domain family A member 2 (PHLDA2) is associated with placental dysfunction. However, the effect of PHLDA2 on trophoblast cell proliferation, migration and invasion has not been investigated. In this study, 15 PE patients and 15 normal pregnant women were recruited and clinical characteristics were summarized. Pleckstrin homology-like domain family A member 2 levels in placental tissues were examined using real-time PCR and western blot. Overexpression plasmid and PHLDA2 siRNA was introduced into JEG-3 cells, respectively. Cell proliferation was measured using MTT assay and flow cytometry. Cell migration and invasion capacities were assessed by wound healing and Transwell assays. It was found that PE patients collectively presented proteinuria, elevated systolic blood pressure (SBP) and diastolic blood pressure (DBP), and lower gestational ages and birth weights. Pleckstrin homology-like domain family A member 2 levels in the preeclamptic placenta were significantly upregulated. Pleckstrin homology-like domain family A member 2 overexpression significantly arrested cells in the G0/G1 phase, inhibited cell proliferation and suppressed the migration and invasion of JEG-3 cells. Pleckstrin homology-like domain family A member 2 knockdown significantly blocked the cells in the S phase of the cell cycle. Knockdown of PHLDA2 alleviated the inhibition on the migration and invasion of trophoblast cells JEG-3. These findings illustrate that PHLDA2 may participate in PE pathogenesis and indicate its potential application in the early diagnosis of PE.

67-kDa Laminin receptor contributes to hypoxia-induced migration and invasion of trophoblast-like cells by mediating matrix metalloproteinase-9.

Insufficient trophoblast invasion often occurs in patients experiencing preeclampsia. The 67-kDa laminin receptor (LR1) is a multifunctional protein that binds to laminin and interacts with the extracellular matrix. We recently demonstrated that LR1 is implicated in trophoblast migration and invasion. However, whether LR1 is involved in hypoxia-mediated trophoblastic invasion remains unclear and requires further investigation. This study demonstrates that two trophoblast-like cell lines (JEG3 and BeWo cells) cultured at 3% oxygen exerted enhanced migratory and invasive capabilities as compared with their counterparts exposed to 20% oxygen. LR1 expression was increased in hypoxic JEG3 cells but decreased after transfection with hypoxia-inducible factor 1 alpha (HIF-1α) specific siRNA. Moreover, shRNA targeting LR1 mRNA significantly inhibited hypoxia-induced increase in matrix metalloproteinase (MMP)-9 activity in JEG3 cells. Forced overexpression of LR1 augmented JEG3 cell migration and invasion, and enhanced MMP-9 expression and activity. Additionally, the blockade of the MMP-9 effect with its neutralizing antibody reduced LR1 elevation-promoted trophoblastic invasion. In summary, this study demonstrates that LR1 contributes to hypoxia-induced migration and invasion of trophoblast cells at least partly by mediating MMP-9 in vitro.

Determinants of mRNA recognition and translation regulation by Lin28.

Lin28 is critical for stem cell maintenance and is also associated with advanced human malignancies. Our recent genome-wide studies mark Lin28 as a master post-transcriptional regulator of a subset of messenger RNAs important for cell growth and metabolism. However, the molecular basis underpinning the selective mRNA target regulation is unclear. Here, we provide evidence that Lin28 recognizes a unique motif in multiple target mRNAs, characterized by a small but critical 'A' bulge flanked by two G:C base pairs embedded in a complex secondary structure. This motif mediates Lin28-dependent stimulation of translation. As Lin28 is also known to inhibit the biogenesis of a cohort of miRNAs including let-7, we propose that Lin28 binding to different RNA types (precursor miRNAs versus mRNAs) may facilitate recruitment of different co-factors, leading to distinct regulatory outcomes. Our findings uncover a putative yet unexpected motif that may constitute a mechanistic base for the multitude of functions regulated by Lin28 in both stem cells and cancer cells.