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 ...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.展开更多
Group testing is a method that can be used to estimate the prevalence of rare infectious diseases,which can effectively save time and reduce costs compared to the method of random sampling.However,previous literature ...Group testing is a method that can be used to estimate the prevalence of rare infectious diseases,which can effectively save time and reduce costs compared to the method of random sampling.However,previous literature only demonstrated the optimality of group testing strategy while estimating prevalence under some strong assumptions.This article weakens the assumption of misclassification rate in the previous literature,considers the misclassification rate of the infected samples as a differentiable function of the pool size,and explores some optimal properties of group testing for estimating prevalence in the presence of differential misclassification conforming to this assumption.This article theoretically demonstrates that the group testing strategy performs better than the sample by sample procedure in estimating disease prevalence when the total number of sample pools is given or the size of the test population is determined.Numerical simulation experiments were conducted to evaluate the performance of group tests in estimating prevalence in the presence of dilution effect.展开更多
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(RAN...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.展开更多
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 o...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.展开更多
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, 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.展开更多
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)me...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。展开更多
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 supplement...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</span><span style="font-family:""> </span><span style="font-family:Verdana;">-</span><span style="font-family:""> </span><span style="font-family:""><span style="font-family:Verdana;">120 d later with cows reassigned to their original groups. No differences (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> > 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, PGE</span><sub><span style="font-family:Verdana;">2</span></sub><span style="font-family:Verdana;"> and leptin were lower (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> < 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.展开更多
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<sup>&...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<sup>®</sup> (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. <i></span><i><span style="font-family:Verdana;">In vitro</span></i><span style="font-family:Verdana;"></i> 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<sup>®</sup>-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 </span><span style="font-family:Verdana;">(</span><span style="font-family:Verdana;"><i></span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"></i></span><span style="font-family:Verdana;"> < 0.05)</span> <span style="font-family:Verdana;">compared to 56/200 and 0/400 cows and embryonic volume was greatest (</span><span style="font-family:Verdana;"><i></span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"></i></span><span style="font-family:Verdana;"> < 0.05) in Replicate 1. However, percent blastocysts hatching from 0/200 cows</span><span style="font-family:Verdana;"> was similar (<i></span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"></i> > 0.10) to 56/400 cows and embryos recovered from 56/400 cows in Replicate 1 produced more (<i></span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"></i> < 0.05) PA compared to all other groups. For cows superovulated with the standard 400-mg FSH dose, feeding OG supported </span><i><span style="font-family:Verdana;">in vitro</span></i><span style="font-family:Verdana;"> embryo development similar to that observed for 0/200 cows.展开更多
Background: Many adults with intellectual disabilities (ID) have low physical activity (PA). Lack of PA is a risk factor for metabolic and cardiovascular diseases, and some types of cancer. The objective of this study...Background: Many adults with intellectual disabilities (ID) have low physical activity (PA). Lack of PA is a risk factor for metabolic and cardiovascular diseases, and some types of cancer. The objective of this study was to investigate the rate of PA in healthy older adults with ID. Methods: A cross-sectional analysis of baseline data. Participants were caregivers of persons with ID who were over 50 years old and living in a residential care center. A PA questionnaire and a daily rapport form were used to gather information about the type and rate of daily PA of persons with ID for 12 consecutive days. The Katz Index of Independence in Activities of Daily Living (ADL) was used to assess functional dependency. Results: Healthy older adults with ID do not engage in adequate regular PA as recommended by the US Department of Health and Human Services. Conclusion: The low participation in PA for persons with ID may be related to lack of appreciation of the benefits of PA, lack of support from their caregivers and difficulty finding experienced personnel to train them.展开更多
Dendritic cells （DC）, although a minor population in hematopoietic cells, produce type I interferons （IFN） and other cytokines and are essential for innate immunity. They are also potent antigen presenters and reg...Dendritic cells （DC）, although a minor population in hematopoietic cells, produce type I interferons （IFN） and other cytokines and are essential for innate immunity. They are also potent antigen presenters and regulate adaptive immunity. Among DC subtypes plasmacytoid DC （pDC） produce the highest amounts of type I IFN. In addition, pro- and anti-inflammatory cytokines such as IL-12 and IL-10 are induced in DC in response to Toll like receptor （TLR） signaling and upon viral infection. Proteins in the IRF family control many aspects of DC activity. IRF-8 and IRF-4 are essential for DC development. They differentially control the development of four DC subsets. IRF-8^-/- mice are largely devoid of pDC and CD8α^＋ DC, while IRF-4^-/- mice lack CD4^＋ DC. IRF-8^-/-, IRF4^-/-, double knock-out mice have only few CD8α CD4^-DC that lack MHC Ⅱ. IRF proteins also control type Ⅰ IFN induction in DC. IRF-7, activated upon TLR signaling is required for IFN induction not only in pDC, but also in conventional DC （cDC） and non-DC cell types. IRF-3, although contributes to IFN induction in fibroblasts, is dispensable in IFN induction in DC. Our recent evidence reveals that type Ⅰ IFN induction in DC is critically dependent on IRF-8, which acts in the feedback phase of IFN gene induction in DC. Type Ⅰ IFN induction in pDC is mediated by MyD88 dependent signaling pathway, and differs from pathways employed in other cells, which mostly rely on TLR3 and RIG-Ⅰ family proteins. Other pro-inflammatory cytokines are produced in an IRF-5 dependent manner. However, IRF-5 is not required for IFN induction, suggesting the presence of separate mechanisms for induction of type Ⅰ IFN and other pro-inflammatory cytokines. IFN and other cytokines produced by activated DC in turn advance DC maturation and change the phenotype and function of DC. These processes are also likely to be governed by IRF family proteins.展开更多
The matrix metalloproteinase (MMP) stromelysin-3 (ST3) has long been implicated to play an important role in extracellular matrix (ECM) remodeling and cell fate determination during normal and pathological processes. ...The matrix metalloproteinase (MMP) stromelysin-3 (ST3) has long been implicated to play an important role in extracellular matrix (ECM) remodeling and cell fate determination during normal and pathological processes. However like other MMPs, the molecular basis of ST3 function in vivo remains unclear due to the lack of information on its physiological substrates. Furthermore, ST3 has only weak activities toward all tested ECM proteins. Using thyroid hormone-dependent Xenopus laevis metamorphosis as a model, we demonstrated previously that ST3 is important for apoptosis and tissue morphogenesis during intestinal remodeling. Here, we used yeast two-hybrid screen with mRNAs from metamorphosing tadpoles to identify potential substrate of ST3 during development. We thus isolated the 37 kd laminin receptor precursor (LR). We showed that LR binds to ST3 in vitro and can be cleaved by ST3 at two sites distinct from where other MMPs cleave. Through peptide sequencing, we determined that the two cleavage sites are in the extracellular domain between the transmembrane domain and laminin binding sequence. Furthermore, we demon strated that these cleavage sites are conserved in human LR. These results together with high levels of human LR and ST3 expression in carcinomas suggest that LR is a likely in vivo substrate of ST3 and that its cleavage by ST3 may alter cell-extracellular matrix interaction, thus, playing a role in mediating the effects of ST3 on cell fate and behavior ob- served during development and pathogenesis.展开更多
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 i...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.展开更多
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 ...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.展开更多
The biological effects of thyroid hormone (T3) are mediated by the thyroid hormone receptor (TR). Amphibian metamorphosis is one of the most dramatic processes that are dependent on T3. T3 regulates a series of orches...The biological effects of thyroid hormone (T3) are mediated by the thyroid hormone receptor (TR). Amphibian metamorphosis is one of the most dramatic processes that are dependent on T3. T3 regulates a series of orchestrated developmental changes, which ultimately result in the conversion of an aquatic herbivorous tadpole to a terrestrial carnivorous frog. T3 is presumed to bind to TRs, which in turn recruit coactivators, leading to gene activation. The best-studied coactivators belong to the p160 or SRC family. Members of this family include SRC1/NCoA-1, SRC2/TIF2/GRIP1, and SRC3/pCIP/ACTR/AIB-1/RAC-3/TRAM-1. These SRCs interact directly with liganded TR and function as adapter molecules to recruit other coactivators such as p300/CBP. Here, we studied the expression patterns of these coactivators during various stages of development. Amongst the coactivators cloned in Xenopus laevis, SRC3 was found to be dramatically upregulated during natural and T3-induced metamorphosis, and SRC2 and p300 are expressed throughout postembryonic development with little change in their expression levels. These results support the view that these coactivators participate in gene regulation by TR during metamorphosis.展开更多
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 wit...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.展开更多
The Luteinizing hormone/chorionic gonadotropin receptor (LHR) plays a critical role in human male sexual development. Both gain-of-function and loss-of-function mutations of the LHR have been described. Gain-of-functi...The Luteinizing hormone/chorionic gonadotropin receptor (LHR) plays a critical role in human male sexual development. Both gain-of-function and loss-of-function mutations of the LHR have been described. Gain-of-function mutations are dominant and cause constitutive activation of the receptor resulting in familial male-limited precocious puberty (FMPP). All activating mutations are single point mutations and are located in the transmembrane domain (TM). TM helix Ⅵ harbors the largest number of activating mutations with the codon of Asp-578 being the hot-spot of mutation. Besides causing abnormal sexual development, constitutively activated LHR may predispose an individual to the development of testicular neoplasia. The anti-thesis of FMPP is Leydig cell hypoplasia (LCH). This is caused by mutations that inactivate the LHR resulting in subnormal male sexual development or male pseudohermaphroditism. Inactivating mutations are recessive. The genetic cause of LCH is variable and there is no mutation hot-spot. Genotype-phenotype correlation can be identified in LCH with the milder form caused by mutated LHR with residual activity and the severe form caused by absence of signal transduction activity of the mutated receptor. Molecular diagnosis of the disorders caused by mutation of the LHR can be achieved by direct sequencing of the LHR gene.展开更多
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-hypophysea...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.展开更多
文摘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.
基金supported by the National Natural Science Foundation of China(Grant No.72091212).
文摘Group testing is a method that can be used to estimate the prevalence of rare infectious diseases,which can effectively save time and reduce costs compared to the method of random sampling.However,previous literature only demonstrated the optimality of group testing strategy while estimating prevalence under some strong assumptions.This article weakens the assumption of misclassification rate in the previous literature,considers the misclassification rate of the infected samples as a differentiable function of the pool size,and explores some optimal properties of group testing for estimating prevalence in the presence of differential misclassification conforming to this assumption.This article theoretically demonstrates that the group testing strategy performs better than the sample by sample procedure in estimating disease prevalence when the total number of sample pools is given or the size of the test population is determined.Numerical simulation experiments were conducted to evaluate the performance of group tests in estimating prevalence in the presence of dilution effect.
基金supported by the Intramural Research Program of the NIDCR, NICHD,and Clinical Center, National Institutes of Healthsupported by Amgen, Inc.+2 种基金supported in part by the NIDCR Genomics and Computational Biology Core:ZIC DC000086Veterinary Resources Core:ZIC DE000740-05supported by the Research on Women’s Health(ORWH)through the Bench to Bedside Program award#884515.
文摘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.
基金supported by grants from the National Institute of Dental and Craniofacial Research, NIH (DE024759, DE026208, DE026509, and DE026767), to J.I.UTHealth School of Dentistry faculty funds to J.I.
文摘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.
基金the National Institutes of Health-University of Cambridge Scholars Programthe laboratory of Dr.Constantine Stratakis at the National Institute of Child Health and Human Development at NIH
文摘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.
基金supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.VJW acknowledges additional supported by NIGMS grant(K99 GM140338-01)for this work.
文摘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。
文摘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</span><span style="font-family:""> </span><span style="font-family:Verdana;">-</span><span style="font-family:""> </span><span style="font-family:""><span style="font-family:Verdana;">120 d later with cows reassigned to their original groups. No differences (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> > 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, PGE</span><sub><span style="font-family:Verdana;">2</span></sub><span style="font-family:Verdana;"> and leptin were lower (</span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"> < 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.
文摘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<sup>®</sup> (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. <i></span><i><span style="font-family:Verdana;">In vitro</span></i><span style="font-family:Verdana;"></i> 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<sup>®</sup>-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 </span><span style="font-family:Verdana;">(</span><span style="font-family:Verdana;"><i></span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"></i></span><span style="font-family:Verdana;"> < 0.05)</span> <span style="font-family:Verdana;">compared to 56/200 and 0/400 cows and embryonic volume was greatest (</span><span style="font-family:Verdana;"><i></span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"></i></span><span style="font-family:Verdana;"> < 0.05) in Replicate 1. However, percent blastocysts hatching from 0/200 cows</span><span style="font-family:Verdana;"> was similar (<i></span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"></i> > 0.10) to 56/400 cows and embryos recovered from 56/400 cows in Replicate 1 produced more (<i></span><i><span style="font-family:Verdana;">P</span></i><span style="font-family:Verdana;"></i> < 0.05) PA compared to all other groups. For cows superovulated with the standard 400-mg FSH dose, feeding OG supported </span><i><span style="font-family:Verdana;">in vitro</span></i><span style="font-family:Verdana;"> embryo development similar to that observed for 0/200 cows.
文摘Background: Many adults with intellectual disabilities (ID) have low physical activity (PA). Lack of PA is a risk factor for metabolic and cardiovascular diseases, and some types of cancer. The objective of this study was to investigate the rate of PA in healthy older adults with ID. Methods: A cross-sectional analysis of baseline data. Participants were caregivers of persons with ID who were over 50 years old and living in a residential care center. A PA questionnaire and a daily rapport form were used to gather information about the type and rate of daily PA of persons with ID for 12 consecutive days. The Katz Index of Independence in Activities of Daily Living (ADL) was used to assess functional dependency. Results: Healthy older adults with ID do not engage in adequate regular PA as recommended by the US Department of Health and Human Services. Conclusion: The low participation in PA for persons with ID may be related to lack of appreciation of the benefits of PA, lack of support from their caregivers and difficulty finding experienced personnel to train them.
文摘Dendritic cells （DC）, although a minor population in hematopoietic cells, produce type I interferons （IFN） and other cytokines and are essential for innate immunity. They are also potent antigen presenters and regulate adaptive immunity. Among DC subtypes plasmacytoid DC （pDC） produce the highest amounts of type I IFN. In addition, pro- and anti-inflammatory cytokines such as IL-12 and IL-10 are induced in DC in response to Toll like receptor （TLR） signaling and upon viral infection. Proteins in the IRF family control many aspects of DC activity. IRF-8 and IRF-4 are essential for DC development. They differentially control the development of four DC subsets. IRF-8^-/- mice are largely devoid of pDC and CD8α^＋ DC, while IRF-4^-/- mice lack CD4^＋ DC. IRF-8^-/-, IRF4^-/-, double knock-out mice have only few CD8α CD4^-DC that lack MHC Ⅱ. IRF proteins also control type Ⅰ IFN induction in DC. IRF-7, activated upon TLR signaling is required for IFN induction not only in pDC, but also in conventional DC （cDC） and non-DC cell types. IRF-3, although contributes to IFN induction in fibroblasts, is dispensable in IFN induction in DC. Our recent evidence reveals that type Ⅰ IFN induction in DC is critically dependent on IRF-8, which acts in the feedback phase of IFN gene induction in DC. Type Ⅰ IFN induction in pDC is mediated by MyD88 dependent signaling pathway, and differs from pathways employed in other cells, which mostly rely on TLR3 and RIG-Ⅰ family proteins. Other pro-inflammatory cytokines are produced in an IRF-5 dependent manner. However, IRF-5 is not required for IFN induction, suggesting the presence of separate mechanisms for induction of type Ⅰ IFN and other pro-inflammatory cytokines. IFN and other cytokines produced by activated DC in turn advance DC maturation and change the phenotype and function of DC. These processes are also likely to be governed by IRF family proteins.
文摘The matrix metalloproteinase (MMP) stromelysin-3 (ST3) has long been implicated to play an important role in extracellular matrix (ECM) remodeling and cell fate determination during normal and pathological processes. However like other MMPs, the molecular basis of ST3 function in vivo remains unclear due to the lack of information on its physiological substrates. Furthermore, ST3 has only weak activities toward all tested ECM proteins. Using thyroid hormone-dependent Xenopus laevis metamorphosis as a model, we demonstrated previously that ST3 is important for apoptosis and tissue morphogenesis during intestinal remodeling. Here, we used yeast two-hybrid screen with mRNAs from metamorphosing tadpoles to identify potential substrate of ST3 during development. We thus isolated the 37 kd laminin receptor precursor (LR). We showed that LR binds to ST3 in vitro and can be cleaved by ST3 at two sites distinct from where other MMPs cleave. Through peptide sequencing, we determined that the two cleavage sites are in the extracellular domain between the transmembrane domain and laminin binding sequence. Furthermore, we demon strated that these cleavage sites are conserved in human LR. These results together with high levels of human LR and ST3 expression in carcinomas suggest that LR is a likely in vivo substrate of ST3 and that its cleavage by ST3 may alter cell-extracellular matrix interaction, thus, playing a role in mediating the effects of ST3 on cell fate and behavior ob- served during development and pathogenesis.
文摘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.
文摘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.
文摘The biological effects of thyroid hormone (T3) are mediated by the thyroid hormone receptor (TR). Amphibian metamorphosis is one of the most dramatic processes that are dependent on T3. T3 regulates a series of orchestrated developmental changes, which ultimately result in the conversion of an aquatic herbivorous tadpole to a terrestrial carnivorous frog. T3 is presumed to bind to TRs, which in turn recruit coactivators, leading to gene activation. The best-studied coactivators belong to the p160 or SRC family. Members of this family include SRC1/NCoA-1, SRC2/TIF2/GRIP1, and SRC3/pCIP/ACTR/AIB-1/RAC-3/TRAM-1. These SRCs interact directly with liganded TR and function as adapter molecules to recruit other coactivators such as p300/CBP. Here, we studied the expression patterns of these coactivators during various stages of development. Amongst the coactivators cloned in Xenopus laevis, SRC3 was found to be dramatically upregulated during natural and T3-induced metamorphosis, and SRC2 and p300 are expressed throughout postembryonic development with little change in their expression levels. These results support the view that these coactivators participate in gene regulation by TR during metamorphosis.
基金supported by grants from the National Key Research and Development Program of China(No.2021YFC2700700)the National Natural Science Foundation of China(No.81801467)the State Key Development Program for Basic Research of China(No.2015CB943304)。
文摘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.
文摘The Luteinizing hormone/chorionic gonadotropin receptor (LHR) plays a critical role in human male sexual development. Both gain-of-function and loss-of-function mutations of the LHR have been described. Gain-of-function mutations are dominant and cause constitutive activation of the receptor resulting in familial male-limited precocious puberty (FMPP). All activating mutations are single point mutations and are located in the transmembrane domain (TM). TM helix Ⅵ harbors the largest number of activating mutations with the codon of Asp-578 being the hot-spot of mutation. Besides causing abnormal sexual development, constitutively activated LHR may predispose an individual to the development of testicular neoplasia. The anti-thesis of FMPP is Leydig cell hypoplasia (LCH). This is caused by mutations that inactivate the LHR resulting in subnormal male sexual development or male pseudohermaphroditism. Inactivating mutations are recessive. The genetic cause of LCH is variable and there is no mutation hot-spot. Genotype-phenotype correlation can be identified in LCH with the milder form caused by mutated LHR with residual activity and the severe form caused by absence of signal transduction activity of the mutated receptor. Molecular diagnosis of the disorders caused by mutation of the LHR can be achieved by direct sequencing of the LHR gene.
文摘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.
