Role of the histone methyltransferases Ezh2 and Suv4-20h1/Suv4-20h2 in neurogenesis

Mechanisms regulating neurogenesis involve broad and complex processes that represent intriguing therapeutic targets in the field of regenerative medicine.One influential factor guiding neural stem cell proliferation and cellular differentiation during neurogenesis are epigenetic mechanisms.We present an overview of epigenetic mechanisms including chromatin structure and histone modifications;and discuss novel roles of two histone modifiers,Ezh2 and Suv4-20h1/Suv4-20h2(collectively referred to as Suv4-20h),in neurodevelopment and neurogenesis.This review will focus on broadly reviewing epigenetic regulatory components,the roles of epigenetic components during neurogenesis,and potential applications in regenerative medicine.

RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia

Fibrous dysplasia(FD)is a rare,disabling skeletal disease for which there are no established treatments.Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand(RANKL)as a potential treatment strategy.In this study,we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre-and post-treatment in a phase 2 clinical trial of denosumab(NCT03571191)and in murine in vivo and ex vivo preclinical models.Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation,reduced cellularity,and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition.RNA sequencing of human and mouse tissue supported these findings.The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model,which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts.The results from this study demonstrated that,in addition to its expected antiosteoclastic effect,denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation,leading to increased bone formation within lesions.These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.

Disruption of Dhcr7 and Insig1/2 in cholesterol metabolism causes defects in bone formation and homeostasis through primary cilium formation

Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles of intracellular cholesterol metabolism in the development of craniofacial bones, the majority of which are formed through intramembranous ossification. Here, we show that an altered cholesterol metabolic status results in abnormal osteogenesis through dysregulation of primary cilium formation during bone formation. We found that cholesterol metabolic aberrations, induced through disruption of either Dhcr7(which encodes an enzyme involved in cholesterol synthesis) or Insig1 and Insig2(which provide a negative feedback mechanism for cholesterol biosynthesis), result in osteoblast differentiation abnormalities. Notably, the primary cilia responsible for sensing extracellular cues were altered in number and length through dysregulated ciliary vesicle fusion in Dhcr7 and Insig1/2 mutant osteoblasts. As a consequence, WNT/β-catenin and hedgehog signaling activities were altered through dysregulated primary cilium formation.Strikingly, the normalization of defective cholesterol metabolism by simvastatin, a drug used in the treatment of cholesterol metabolic aberrations, rescued the abnormalities in both ciliogenesis and osteogenesis in vitro and in vivo. Thus, our results indicate that proper intracellular cholesterol status is crucial for primary cilium formation during skull formation and homeostasis.

Viscoelastic analysis of single-component and composite PEG and alginate hydrogels

Hydrogels, three-dimensional hydrophilic polymer networks, are appealing candidate materials for study- ing the cellular microenvironment as their substantial water content helps to better mimic soft tissue. However, hydrogels can lack mechanical stiffness, strength, and tough- ness. Composite hydrogel systems have been shown to improve upon mechanical properties compared to their single- component counterparts. Poly （ethylene glycol） dimethacrylate （PEGDMA） and alginate are polymers that have been used to form hydrogels for biological applications. Single- component and composite PEGDMA and alginate systems were fabricated with a range of total polymer concentrations. Bulk gels were mechanically characterized using spherical indentation testing and a viscoelastic analysis framework. An increase in shear modulus with increasing polymer con- centration was demonstrated for all systems. Alginate hydro- gels were shown to have a smaller viscoelastic ratio than the PEGDMA gels, indicating more extensive relaxation over time. Composite alginate and PEGDMA hydrogels exhib- ited a combination of the mechanical properties of the con- stituents, as well as a qualitative increase in toughness. Additionally, multiple hydrogel systems were produced that had similar shear moduli, but different viscoelastic behaviors. Accurate measurement of the mechanical properties of hydrogels is necessary in order to determine what parameters are key in modeling the cellular microenvironment.

Measurement of Metabolic and Inflammatory Serum Markers and Immune Marker Gene Expression during Superovulation in Beef Cattle

Health status of donor cows during superovulation is important to ensure optimal embryo quality at time of collection. Because nutritional and metabolic status impact embryo quality some form of nutritional supplementation is often provided before and during superovulation. OmniGen-AF® (OG) feeding has been shown to assist in the maintenance of animal health through regulation of metabolic status and balance and supporting aspects of immune function. We observed feeding donor cows OG decreased percent degenerate embryos recovered following superovulation increased serum progesterone concentration and improved in vitro embryo development. Evaluation of OG feeding on markers of metabolic function and inflammatory and immune function in beef cattle embryo donors are reported here. Similarly, cow metabolic and inflammatory response with repeated superovulation protocols is not known. Biomarkers to monitor and evaluate cow health during superovulation may provide management options to improve embryo recovery and quality. Twenty-four Angus cross-bred cattle were randomly assigned to four treatment groups, fed 0 or 56 g/hd/day for 49 days and superovulated with 200 or 400 mg Folltropin V (FSH). Blood was collected weekly for analyses. The protocol was repeated on all cows 90 - 120 d later with cows reassigned to their original groups. No differences (P > 0.10) were observed due to OG feeding or FSH dose on metabolic and inflammatory markers. Replicate exerted a significant effect where serum concentration of albumin, IL1β, IL6, PGE2 and leptin were lower (P < 0.05) in Replicate 1 compared to 2. There was also a similar pattern of change in several of the metabolic and inflammatory markers during the superovulation protocol where concentrations were higher at the time of estrus and ovulation. Taken together, physiologic changes during the estrous cycle and the number of superovulation protocols can modulate metabolic markers and inflammatory response.

Effects of Feeding OmniGen-AF^®during Superovulation on <i>in Vitro</i>Development of Embryos Recovered from Donor Beef Cows

Embryo quality is crucial when selecting embryos for transfer. Variation in quality may be attributed to poor oocytes, semen, stress, inflammation, and potential immune system dysregulation. OmniGen-AF® (OG) feeding supports immune system function and animal health. Our laboratory recently reported lower percent degenerate embryos recovered and increased plasma progesterone in beef cattle donors fed OG during superovulation. In vitro development of embryos recovered from donor cows fed OG prior to collection is presented here. Embryos were recovered from 24 beef cows assigned to four treatment groups: 0 g OG/hd/d and 200 mg Folltropin®-V (FSH) (0/200);0 g OG/hd/d and 400 mg FSH (0/400), 56 g OG/hd/d, 200 mg FSH (56/200) and 56 g OG/hd/d and 400 mg FSH (56/400). Good to excellent quality early blastocysts were cultured for 8 d. and development through hatching, embryonic volume and plasminogen activator (PA) production were quantified. The complete protocol was repeated 90 - 120 d later as Replicate 2. Optimal development was observed by embryos recovered from 0/200 cows where percent blastocysts hatching was greater (P < 0.05) compared to 56/200 and 0/400 cows and embryonic volume was greatest (P < 0.05) in Replicate 1. However, percent blastocysts hatching from 0/200 cows was similar (P > 0.10) to 56/400 cows and embryos recovered from 56/400 cows in Replicate 1 produced more (P < 0.05) PA compared to all other groups. For cows superovulated with the standard 400-mg FSH dose, feeding OG supported in vitro embryo development similar to that observed for 0/200 cows.

Low-field, high-gradient NMR shows diffusion contrast consistent with localization or motional averaging of water near surfaces

Nuclear magnetic resonance(NMR)measurements of water diffusion have been extensively used to probe microstructure in porous materials,such as biological tissue,however primarily using pulsed gradient spin echo(PGSE)methods.Low-field single-sided NMR systems have built-in static gradients(SG)much stronger than typical PGSE maximum gradient strengths,which allows for the signal attenuation at extremely high b-values to be explored.Here,we perform SG spin echo(SGSE)and SG stimulated echo(SGSTE)diffusion measurements on biological cells,tissues,and gels.Measurements on fixed and live neonatal mouse spinal cord,lobster ventral nerve cord,and starved yeast cells all show multiexponential signal attenuation on a scale of b with significant signal fractions observed at b×Do>1 with b as high as 400 ms/um2.These persistent signal fractions trend with surface-to-volume ratios for these systems,as expected from porous media theory.An exception found for the case of fixed vs.live spinal cords was attributed to faster exchange or permeability in live spinal cords than in fixed spinal cords on the millisecond timescale.Data suggests the existence of multiple exchange processes in neural tissue,which may be relevant to the modeling of time-dependent diffusion in gray matter.The observed multi-exponential attenuation is from protons on water and not macromolecules because it remains proportional to the normalized signal when a specimen is washed with D20.The signal that persists to b×Do>1 is also drastically reduced after delipidation,indicating that it originates from lipid membranes that restrict water diffusion.The multiexponential or stretched exponential character of the signal attenuation at b×Do>1 appears mono-exponential when viewed on a scale of(b×Do)/3,suggesting it may originate from localization or motional averaging of water near membranes on sub-micron length scales.To try to disambiguate these two contributions,signal attenuation curves were compared at varying temperatures.While the curves align when normalizing them using the localization length scale,they separate on a motional averaging length scale.This supports localization as the source of non-Gaussian displacements,but this interpretation is still provisional due to the possible confounds of heterogeneity,exchange,and relaxation.Measurements on two types of gel phantoms designed to mimic extracellular matrix.one with charged functional groups synthesized from polyacrylic acid(PAC)and another with uncharged functional groups synthesized from polyacrylamide(PAM),both exhibit signal at b×Do>1,potentially due to water interacting with macromolecules.These preliminary finding motivate future research into contrast and attenuation mechanisms in tissue with low-field,high-gradient NMR。

Folate and vitamin B12 in idiopathic male infertility

Although methylenetetrahydrofolate reductase, a folate enzyme gene, has been associated with idiopathic male infertility, few studies have examined other folate-related metabolites and genes. We investigated whether idiopathic male infertility is associated with variants in folate, vitamin B12 （B12） and total homocysteine （tHcy）-related genes and measured these metabolites in blood. We conducted a case-control study that included 153 men with idiopathic infertility and 184 fertile male controls recruited at the Fertility Center and Antenatal Care Center, University Hospital, Malmo and Lund, Sweden. Serum folate, red cell folate （RCF）, serum B12, plasma tHcy and semen quality were measured. Subjects were genotyped for 20 common variants in 12 genes related to folate/B12/ homocysteine metabolism. Metabolite concentrations and genotype distributions were compared between cases and controls using linear and logistic regression with adjustment for covariates. The phosphatidylethanolamine N-methyltransferase （PEMT） M 175V and TCblR rs173665 polymorphisms were significantly associated with infertility （P=0.01 and P=0.009, respectively）, but not with semen quality. Among non-users of supplements, infertile men had lower serum folate concentrations than fertile men （12.89 vs. 14.73 nmoll^- 1 P=0.02）, but there were no significant differences in RCF, B 12 or tHcy. Folate, B 12 and tHcy concentrations were not correlated with any semen parameters. This study provides little support for low folate or B12 status in the pathogenesis of idiopathic male infertility. Although additional data are needed to confirm these initial findings, our results suggest that PEMTand TCbIR, genes involved in choline and B12 metabolism, merit further investigation in idiopathic male infertility.

An everlasting role of genetics and genomics in public health: a meeting report of ACGA-HKSMG International Conference on Genetic and Genomic Medicine 2008

The Association of Chinese Geneticists in America （ACGA） and the Hong Kong Society of Medical Genetics （HKSMG） held their first joint Conference on Genetic and Genomic Medicine in Hong Kong from June 9-11 in 2008 at the Cheung Kung Hai Conference Center, William MW Mong Block, Li Ka Shing Faculty of Medicine, the University of Hong Kong. Other co-organizers included the University of Hong Kong and Chinese Society of Medical Genetics. A satellite conference ＂ACGA-WZMC International Symposium of Genetics and Translational Medicine＂, co-organized with Wenzhou Medical College and Chinese Society of Medical Genetics, was held from June 12-14, 2008 at Wenzhou, Zhejiang Province of China.

Risk of gestational diabetes recurrence and the development of type 2 diabetes among women with a history of gestational diabetes and risk factors: a study among 18 clinical centers in China

Background:Gestational diabetes mellitus(GDM)brings health issues for both mothers and offspring,and GDM prevention is as important as GDM management.It was shown that a history of GDM was significantly associated with a higher maternal risk for GDM recurrence.The incidence of GDM recurrence was unclear because of the incidence of second-child was low before 2016 in China.We aim to investigate the prevalence of GDM recurrence and its associated high-risk factors which may be useful for the prediction of GDM recurrence in China.Methods:A retrospective study was conducted which enrolled participants who underwent regular prenatal examination and delivered twice in the same hospital of 18 research centers.All participants were enrolled from January 2018 to October 2018,where they delivered the second baby during this period.A total of 6204 women were enrolled in this study,and 1002 women with a history of GDM were analyzed further.All participants enrolled in the study had an oral glucose tolerance test(OGTT)result at 24 to 28 weeks and were diagnosed as GDM in the first pregnancy according to the OGTT value(when any one of the following values is met or exceeded to the 75-g OGTT:0 h[fasting],≥5.10 mmol/L;1 h,≥10.00 mmol/L;and 2 h,≥8.50 mmol/L).The prevalence of GDM recurrence and development of type 2 diabetes mellitus were calculated,and its related risk factors were analyzed.Results:In 6204 participants,there are 1002 women(1002/6204,16.15%)with a history of GDM and 5202 women(5202/6204,83.85%)without a history of GDM.There are significant differences in age(32.43±4.03 years vs.33.00±3.34 years vs.32.19±3.37 years,P<0.001),pregnancy interval(4.06±1.44 years vs.3.52±1.43 years vs.3.38±1.35 years,P=0.004),prepregnancy body mass index(BMI)(27.40±4.62 kg/m^(2)vs.23.50±3.52 kg/m^(2)vs.22.55±3.47 kg/m^(2),P<0.001),history of delivered macrosomia(22.7%vs.11.0%vs.6.2%,P<0.001)among the development of diabetes mellitus(DM),recurrence of GDM,and normal women.Moreover,it seems so important in the degree of abnormal glucose metabolism in the first pregnancy to the recurrence of GDM and the development of DM.There are significant differences in OGTT levels of the first pregnancy such as area under the curve of OGTT value(18.31±1.90 mmol/L vs.16.27±1.93 mmol/L vs.15.55±1.92 mmol/L,P<0.001),OGTT fasting value(5.43±0.48 mmol/L vs.5.16±0.49 mmol/L vs.5.02±0.47 mmol/L,P<0.001),OGTT 1-hour value(10.93±1.34 mmol/L vs.9.69±1.53 mmol/L vs.9.15±1.58 mmol/L,P<0.001),OGTT 2-hour value(9.30±1.66 mmol/L vs.8.01±1.32 mmol/L vs.7.79±1.38 mmol/L,P<0.001),incidence of impaired fasting glucose(IFG)(fasting plasma glucose≥5.6 mmol/L)(31.3%vs.14.6%vs.8.8%,P<0.001),and incidence of two or more abnormal OGTT values(68.8%vs.39.7%vs.23.9%,P<0.001)among the three groups.Using multivariate analysis,the factors,such as age(1.07[1.02-1.12],P=0.006),prepregnancy BMI(1.07[1.02,1.12],P=0.003),and area under the curve of OGTT in the first pregnancy(1.14[1.02,1.26],P=0.02),have an effect on maternal GDM recurrence;the factors,such as age(1.28[1.01-1.61],P=0.04),pre-pregnancy BMI(1.26[1.04,1.53],P=0.02),and area under the curve of OGTT in the first pregnancy(1.65[1.04,2.62],P=0.03),have an effect on maternal DM developed further.Conclusions:The history of GDM was significantly associated with a higher maternal risk for GDM recurrence during follow-up after the first pregnancy.The associated risk factors for GDM recurrence or development of DM include age,high pre-pregnancy BMI,history of delivered macrosomia,the OGTT level in the first pregnancy,such as the high area under the curve of OGTT,IFG,and two or more abnormal OGTT values.To prevent GDM recurrence,women with a history of GDM should do the preconception counseling before preparing next pregnancy.

Developmental staging of male murine embryonic gonad by SAGE analysis

Despite the identification of key genes such as Sry integral to embryonic gonadal development, the genomic classification and identification of chromosomal activation of this process is still poorly understood. To better understand the genetic regulation of gonadal development, we performed Serial Analysis of Gene Expression （SAGE） to profile the genes and novel transcripts, and an average of 152,000 tags from male embryonic gonads at E10.5 （embryonic day 10.5）, E11.5, E12.5, E13.5, E15.5 and E17.5 were analyzed. A total of 275,583 non-singleton tags that do not map to any annotated sequence were identified in the six gonad libraries, and 47,255 tags were mapped to 24,975 annotated sequences, among which 987 sequences were uncharacterized. Utilizing an unsupervised pattern identification technique, we established molecular staging of male gonadal development. Rather than providing a static descriptive analysis, we developed algorithms to cluster the SAGE data and assign SAGE tags to a corresponding chromosomal position; these data are displayed in chromosome graphic format. A prominent increase in global genomic activity from E10.5 to E17.5 was observed. Important chromosomal regions related to the developmental processes were identified and validated based on established mouse models with developmental disorders. These regions may represent markers for early diagnosis for disorders of male gonad development as well as potential treatment targets.

Recent development and gene therapy for glycogen storage disease type Ia

Glycogen storage disease type Ia(GSD-Ia)is an autosomal recessive metabolic disorder caused by a deficiency in glucose-6-phosphatase-α(G6Pase-αor G6PC)that is expressed primarily in the liver,kidney,and intestine.G6Pase-αcatalyzes the hydrolysis of glucose-6-phosphate(G6P)to glucose and phosphate in the terminal step of gluconeogenesis and glycogenolysis,and is a key enzyme for endogenous glucose production.The active site of G6Pase-αis inside the endoplasmic reticulum(ER)lumen.For catalysis,the substrate G6P must be translocated from the cytoplasm into the ER lumen by a G6P transporter(G6PT).The functional coupling of G6Pase-αand G6PT maintains interprandial glucose homeostasis.Dietary therapies for GSD-Ia are available,but cannot prevent the long-term complication of hepatocellular adenoma that may undergo malignant transformation to hepatocellular carcinoma.Animal models of GSD-Ia are now available and are being exploited to both delineate the disease more precisely and develop new treatment approaches,including gene therapy.

Human semen quality and the secondary sex ratio

The aim of this study was to evaluate the association between semen quality and the secondary sex ratio （SSR）, defined as the ratio of male to female live births. Our study cohort comprised 227 male partners who were enrolled prior to conception in Michigan and Texas between 2005 and 2009, and prospectively followed through delivery of a singleton birth. The male partners provided a baseline and a follow-up semen sample a month apart. Semen analysis was conducted to assess 27 parameters including five general characteristics, six sperm head measures, 14 morphology measures, and two sperm chromatin stability assay measures. Modified Poisson regression models with a robust error variance were used to estimate the relative risk （RR） and 95% confidence interval （95% CI） of a male birth for each semen parameter, after adjusting for potential confounders. Of the 27 semen parameters, only the percentage of bicephalic sperm was significantly associated with the SSR （2nd VS Ist quartile, RR, 0.65, 95% CI, 0.45-0.95, P= 0.03; 4TM vs 1St quartile, RR, 0.61, 95% CI, 0.38-1.00, P 〈 0.05 before rounding to two decimal places）, suggestive of a higher percentage of bicephalic sperm being associated with an excess of female births. Given the exploratory design of the present study, this preconception cohort study suggests no clear signal that human semen quality is associated with offspring sex determination.

Understanding the impact of stress on teleostean reproduction

Fishes exert stress response in a various ways depending on the type of the stressor.The stress responses are activated through a cascade mechanism stimulated by the stressor which involves the hypothalamus-hypophyseal-interrenal(HHI)axis,catecholamines(CA),and gonadotropins.Adaptive stress responses may positively impact the fish survival and reproduction,while continuous or prolonged stress causes adverse effects on the fish reproduction.Corticotropin-releasing factor and adrenocorticotropic hormone are the principal hormones responsible for producing corticosteroids through the HHI axis.Cortisol acts differentially on the stress response as it helps at the early developmental stage;conversely,it impairs the gonadal function.CA have a critical role in maintaining body homeostasis and intermediary metabolism,and they also have a predominant role in reproductive function.Besides hormones,few genetic and epigenetic factors have been identified to understand the molecular responses to stress however,genome-wide associated studies will be initiated to investigate a complete picture of the stress mechanism.Further,recent evidence suggests a growing concern in determining the correlation between the stress hormone level and its associated gene function.Hence,this review highlights the regulation of stress responses in different axes,genetic and epigenetic factors related to stress,and the integration of recent technologies and novel hypotheses to unravel the stress response mechanism in fish reproduction.

Sorting and Processing of the Alzheimer's Disease Amyloid Precursor Protein Mediated by the AP-4 Complex

Proteolytic processing of the transmembrane amyloid precursor protein (APP) to aggregation-prone amyloid-β (Aβ) peptide underlies the development of Alzheimer’s disease.

ATP-binding cassette transporters at the zebrafish blood-brain barrier and the potential utility of the zebrafish as an in vivo model

The brain is protected from toxins by a tightly regulated network of specialized cells,including endothelial cells,pericytes,astrocyes,and neurons,known collectively as the blood-brain barrier(BBB).This selectively permeable barrier permits only the most crucial molecules essential for brain function to enter and employs a number of different mechanisms to prevent the entry of potentially harmful toxins and pathogens.In addition to a physical barrier comprised of endothelial cells that form tight junctions to restrict paracellular transport,there is an active protective mechanism made up of energy-dependent transporters that efflux compounds back into the bloodstream.Two of these ATP-binding cassette(ABC)transporters are highly expressed at the BBB:P-glycoprotein(P-gp,encoded by the ABCB1 gene)and ABCG2(encoded by the ABCG2 gene).Although a number of in vitro and in vivo systems have been developed to examine the role that ABC transporters play in keeping compounds out of the brain,all have inherent advantages and disadvantages.Zebrafish(Danio rerio)have become a model of interest for studies of the BBB due to the similarities between the zebrafish and mammalian BBB systems.In this review,we discuss what is known about ABC transporters in zebrafish and what information is still needed before the zebrafish can be recommended as a model to elucidate the role of ABC transporters at the BBB.

Maternal and fetal T cells in term pregnancy and preterm labor

Pregnancy is a state of immunological balance during which the mother and the developing fetus must tolerate each other while maintaining sufficient immunocompetence to ward off potential threats.The site of closest contact between the mother and fetus is the decidua,which represents the maternal–fetal interface.Many of the immune cell subsets present at the maternal–fetal interface have been well described;however,the importance of the maternal T cells in this compartment during late gestation and its complications,such as preterm labor and birth,has only recently been established.Moreover,pioneer and recent studies have indicated that fetal T cells are activated in different subsets of preterm labor and may elicit distinct inflammatory responses in the amniotic cavity,leading to preterm birth.In this review,we describe the established and proposed roles for maternal T cells at the maternal–fetal interface in normal term parturition,as well as the demonstrated contributions of such cells to the pathological process of preterm labor and birth.We also summarize the current knowledge of and proposed roles for fetal T cells in the pathophysiology of the preterm labor syndrome.It is our hope that this review provides a solid conceptual framework highlighting the importance of maternal and fetal T cells in late gestation and catalyzes new research questions that can further scientific understanding of these cells and their role in preterm labor and birth,the leading cause of neonatal mortality and morbidity worldwide.

Sex Hormone-binding Globulin,Cardiometabolic Biomarkers,and Gestational Diabetes:A Longitudinal Study and Meta-analysis

Objective::This study investigated the prospective associations of circulating levels of sex hormone-binding globulin(SHBG)levels with cardiometabolic biomarkers and risk of gestational diabetes(GDM)during pregnancy.It also examines the longitudinal trajectory of SHBG in women with and without GDM.Methods::We conducted a nested case-control study of 107 incident GDM cases and 214 matched controls within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort.The cohort enrolled non-obese and obese women aged 18-40 years with a singleton pregnancy between 8 and 13 weeks of gestation from 2009 to 2013.GDM was ascertained via medical records review.Blood samples were drawn four times at gestational weeks 10-14,15-26,23-31,and 33-39.The prospective associations between SHBG levels and cardiometabolic biomarkers were examined using the Spearman partial correlation among the controls.The longitudinal trajectories of SHBG levels were examined among the cases and the controls.Meta-analysis of prospective studies were performed to examine the association between SHBG levels and GDM risk.Results::SHBG levels at gestational weeks 10-14 were significantly inversely associated with fasting insulin(r=-0.17,P=0.01)and insulin resistance as measured by HOMA-IR(r=-0.17,P=0.01)at gestational week 15-26.SHBG at gestational weeks 10-14 and 15-26 was lower in cases than controls(mean±standard deviation:(204.0±97.6)vs.(220.9±102.5)nmol/L,P=0.16 and(305.6±124.3)vs.(322.7±105.1)nmol/L,P=0.14,respectively),yet the differences were not significant.In the meta-analysis,SHBG was 41.5 nmol/L(95%confidence interval:23.9,59.1,P<0.01)significantly lower among women with GDM than without,and each 50 nmol/L increase in SHBG was significantly associated with an odds ratio of 0.85(95%confidence interval:0.76-0.95,P=0.01)for GDM.Conclusion::Lower SHBG levels in early pregnancy were prospectively associated with higher high insulin levels and insulin resistance in mid-pregnancy and subsequent risk of GDM,independent of adiposity.SHBG may serve as a marker for the identification of high-risk pregnancies during early pregnancy.

Surface Nanopatterning Using the Self-Assembly of Linear Polymers on Surfaces after Solvent Evaporation

The morphology of linear polybutadiene physisorbed on freshly cleaved mica from a dilute polymer solution is investigated through atomic force microscopy.A fine-structure study shows that the monolayer morphology in air(after rapid solvent evaporation)depends strongly on the molecular weight(Mw)of the linear polymer,the adsorbed amount,and the conformation adopted by the adsorbed polymer chains under good solvent conditions.The dependence of the observed polymer structure on Mw is most significant for samples with high surface density,where the intermolecular interactions among the adsorbed polymers are important.For high surface density,the adsorbed polymers tend to aggregate and minimize unfavorable contacts with air for all of the different Mw samples,leading to an isotropic structural pattern.These structural phenomena with increasing surface density are explained on the basis of the intermolecular interactions of the adsorbed polymers under good solvent conditions,and after the abrupt solvent evaporation corresponding to poor solvent conditions.The experimental observations are further discussed using the results obtained from molecular dynamics simulations of a simple coarse-grained model.

Carboxypeptidase E (NF-α1):a new trophic factor in neuroprotection

Carboxypeptidase E （CPE） is a prohormone-processing enzyme and sorting receptor that functions intracellularly. However, recent studies have demonstrated that CPE acts as atrophic factor extracellularly to up-regulate the expression of a pro-survival gene. This mini-review summarizes the roles of CPE in neuroprotection and the implications for neurodegenerative diseases.