A varying‐coefficient generalized odds rate model with time‐varying exposure: An application to fitness and cardiovascular disease mortality

Varying‐coefficient models have become a common tool to determine whether and how the association between an exposure and an outcome changes over a continuous measure. These models are complicated when the exposure itself is time‐varying and subjected to measurement error. For example, it is well known that longitudinal physical fitness has an impact on cardiovascular disease (CVD) mortality. It is not known, however, how the effect of longitudinal physical fitness on CVD mortality varies with age. In this paper, we propose a varying‐coefficient generalized odds rate model that allows flexible estimation of age‐modified effects of longitudinal physical fitness on CVD mortality. In our model, the longitudinal physical fitness is measured with error and modeled using a mixed‐effects model, and its associated age‐varying coefficient function is represented by cubic B‐splines. An expectation‐maximization algorithm is developed to estimate the parameters in the joint models of longitudinal physical fitness and CVD mortality. A modified pseudoadaptive Gaussian‐Hermite quadrature method is adopted to compute the integrals with respect to random effects involved in the E‐step. The performance of the proposed method is evaluated through extensive simulation studies and is further illustrated with an application to cohort data from the Aerobic Center Longitudinal Study.     

De novo phenol bioproduction from glucose using biosensor-assisted microbial coculture engineering

Microbial biosynthesis has been extensively adapted for the production of commodity chemicals using renewable feedstocks. This study integrated metabolite biosensors into rationally designed microbial cocultures to achieve high-efficiency bioproduction of phenol from simple carbon substrate glucose. Specifically, two sets of E. coli–E. coli cocultures were first constructed for accommodation of two independent phenol biosynthesis pathways via 4-hydroxybenzoate (4HB) and tyrosine (TYR), respectively. Biosensor-assisted microbial cell selection mechanisms were subsequently incorporated into the coculture systems to address the insufficient pathway intermediate provision that limited the overall bioproduction. For the 4HB- and TYR-dependent pathways, this approach improved the phenol production by 2.3- and 3.9-fold, respectively, compared to the monoculture controls. Notably, the use of biosensor-assisted cell selection strategy in monocultures resulted in reduced phenol production, highlighting the advantage of coculture engineering for coupling with biosensing. After stepwise optimization, the phenol bioproduction yield of the engineered coculture's reached 0.057 g/g glucose. Furthermore, the coculture biosynthesis was successfully scaled up at both shake flask and bioreactor levels. Overall, the findings of this study demonstrate the outstanding potential of coupling biosensing and modular coculture engineering for advancing microbial biosynthesis of valuable molecules from renewable carbon substrates.     

Phloem Unloading Strategies and Mechanisms in Crop Fruits

Journal of Plant Growth Regulation - Carbohydrate produced by photosynthesis is loaded into phloem via collection phloem, translocated via the transport phloem, and unloaded by release phloem into...     

肺炎链球菌感染早期IFN-β通过调节巨噬细胞炎症反应保护宿主

该文旨在探讨干扰素-β(interferon-β,IFN-β)在肺炎链球菌(Streptococcus pneumoniae,S.pn)感染早期对宿主炎症免疫的影响.使用外源重组IFN-β蛋白(recombinant IFN-β,rIFN-β)预处理WT小鼠及其腹腔渗出巨噬细胞(peritoneal exudate m...     

膝关节内干细胞/祖细胞在软骨再生中作用研究进展

关节软骨(AC)由于缺乏血管、神经和淋巴,一旦损伤无法自我修复.虽然以外源性细胞为基础的治疗策略在一定程度上能够再生关节软骨,但仍然存在手术间隔长、供体有限、细胞体外培养易去分化和病原体传播等风险.成人膝关节存在许多类型干细胞/祖细胞(SCPCs),当软骨损伤时,就会被动员,迁移到损伤部位,参与再生修复.因此,基于趋化...     

Amino acid starvation‐induced LDLR trafficking accelerates lipoprotein endocytosis and LDL clearance

Mammalian cells utilize Akt‐dependent signaling to deploy intracellular Glut4 toward cell surface to facilitate glucose uptake. Low‐density lipoprotein receptor (LDLR) is the cargo receptor mediating endocytosis of apolipoprotein B‐containing lipoproteins. However, signaling‐controlled regulation of intracellular LDLR trafficking remains elusive. Here, we describe a unique amino acid stress response, which directs the deployment of intracellular LDLRs, causing enhanced LDL endocytosis, likely via Ca²⁺ and calcium/calmodulin‐dependent protein kinase II‐mediated signalings. This response is independent of induction of autophagy. Amino acid stress‐induced increase in LDL uptake in vitro is comparable to that by pravastatin. In vivo, acute AAS challenge for up to 72 h enhanced the rate of hepatic LDL uptake without changing the total expression level of LDLR. Reducing dietary amino acids by 50% for 2 to 4 weeks ameliorated high fat diet‐induced hypercholesterolemia in heterozygous LDLR‐deficient mice, with reductions in both LDL and VLDL fractions. We suggest that identification of signaling‐controlled regulation of intracellular LDLR trafficking has advanced our understanding of the LDLR biology, and may benefit future development of additional therapeutic strategies for treating hypercholesterolemia.     

STARD3NL inhibits the osteogenic differentiation by inactivating the Wnt/β‐catenin pathway via binding to Annexin A2 in osteoporosis

Osteoporosis is one of the leading forms of systemic diseases related to bone metabolism in the world. STARD3 N‐terminal like (STARD3NL) showed robust association with osteoporosis‐related traits. Yet, the molecular functional mechanisms of STARD3NL in osteoblasts is still obscure. In this study, we demonstrated a high level of STARD3NL expression in the bone tissues from the patients with low bone mass and ovariectomized (OVX)‐induced osteoporotic mice. We identified Stard3nl as a potent factor that negatively and positively regulates osteoblast differentiation and cell proliferation, respectively. Furthermore, inhibition of Stard3nl induced β‐catenin gene expression and the nuclear translocation of β‐catenin, as well as Wnt signalling activities, contributing to the activation of Wnt/β‐catenin signalling. Mechanistic studies revealed that Stard3nl bound with Annexin A2 (Anxa2) to suppress β‐catenin expression, resulting into the suppression of Wnt signalling and downstream osteogenic differentiation. Moreover, adeno‐associated virus 9 (AAV9)‐mediated silencing of Stard3nl reversed bone loss in OVX‐induced osteoporotic mice by the injection into the knee joints. Collectively, our study revealed that Stard3nl suppressed osteogenesis via binding with Anxa2, resulting into the inactivation of Wnt signalling. It also highlights the preventive and therapeutic potential of STARD3NL as a specific and novel target for osteoporotic patients.     

Numerical simulations of surface plasmon resonance system for monitoring DNA hybridization and detecting protein-lipid film interactions

This paper presents a simple method to extract information about thin organic films from surface plasmon resonance (SPR) spectra. From numerical simulations it was found that a shift (Δθ _SPR) of an absorption peak in the SPR spectrum was directly proportional to the product of the thin organic film thickness and the refractive index difference between the thin organic film and a buffer soaking the sample. It was also found that Δθ _SPR was not sensitive to the thin organic film support of a gold film and a glass cover slip. Relationships between Δθ _SPR and distributions of macromolecule structures, in the thin organic films were theoretically established. Formulae were derived for a homemade SPR system to calculate length, transverse area, density and surface concentration of macromolecules in the thin organic film. The validity of these treatments was checked by precisely measuring the size of a single distearoylphosphatidylcholine molecule on a gold-supported phospholipid film; by quantitatively monitoring hybridization of synthesized oligonucleotides strands based on a biotin/avidin system; and by quantitatively detecting the steric hindrance of rabbit C-reactive protein specifically bound to phospholipid monolayers composed of synthesized lipids. Received: 4 May 1998 / Revised version: 27 July 1998 / Accepted: 27 August 1998