Feedback regulation of cholesterol synthesis： sterol-accelerated ubiquitination and degradation of HMG CoA reductase

3-Hydroxy-3-methylglutaryl coenzyme A （HMG CoA） reductase produces mevalonate, an important intermediate in the synthesis of cholesterol and essential nonsterol isoprenoids. The reductase is subject to an exorbitant amount of feedback control through multiple mechanisms that are mediated by sterol and nonsterol end-products of mevalonate metabolism. Here, I will discuss recent advances that shed light on one mechanism for control of reductase, which involves rapid degradation of the enzyme. Accumulation of certain sterols triggers binding of reductase to endoplasmic reticulum （ER） membrane proteins called Insig-1 and Insig-2. Reductase-Insig binding results in recruitment of a membrane-associated ubiquitin ligase called gp78, which initiates ubiquitination of reductase. This ubiquitination is an obligatory reaction for recognition and degradation of reductase from ER membranes by cytosolic 26S proteasomes. Thus, sterol-accelerated degradation of reductase represents an example of how a general cellular process （ER-associated degradation） is used to control an important metabolic pathway （cholesterol synthesis）.

Negative feedback regulation of cellular antiviral signaling by RBCKl-mediated degradation of IRF3

Viral infection causes host cells to produce type I interferons （IFNs）, which are critically involved in viral clearance. Previous studies have demonstrated that activation of the transcription factor interferon regulatory factor （IRF）3 is essential for virus-triggered induction of type I IFNs. Here we show that the E3 ubiquitin ligase RBCC protein interacting with PKC1 （RBCK1） catalyzes the ubiquitination and degradation of IRF3. Overexpression of RBCK1 negatively regulates Sendai virus-triggered induction of type I IFNs, while knockdown of RBCK1 has the opposite effect. Plaque assays consistently demonstrate that RBCKI negatively regulates the cellular antiviral response. Furthermore, viral infection leads to induction of RBCK1 and subsequent degradation of IRF3. These findings suggest that the cellular antiviral response is controlled by a negative feedback regulatory mechanism involving RBCKl-mediated ubiquitination and degradation of IRF3.

POSITIVE PERIODIC SOLUTION FOR A NONAUTONOMOUS LOGISTIC MODEL WITH LINEAR FEEDBACK REGULATION

A nonautonomous delayed logistic model with linear feedback regulation is proposed in this paper. Sufficient conditions are derived for the existence, uniqueness and global asymptotic stability of positive periodic solution of the model

Existence of Two Periodic Solutions of a Delayed Single Species Model with Feedback Regulation and Harvest Term

By means of the continuation theorem of the coincidence degree theory,the existence of two periodic solutions of a delayed single species model with feedback regulation and harvest term is obtained.

Output Feedback Regulation for 1-D Anti-Stable Wave Equation with External System Disturbance

This paper has studied the output feedback regulation problem for 1-D anti-stable wave equation with distributed disturbance and a given reference signal generated by a finite-dimensional exosystem. We first design an observer for both exosystem and auxiliary PDE system to recover the state. Then we show the well-posedness of the regulator equations and propose an observer-based feedback control law to regulate the tracking error to zero exponentially and keep all the states bounded.

Feedback regulation system for spraying parameters based on online droplet mass deposit measurements

In order to effectively optimize and regulate spraying parameters based on actual spraying performance and improve pesticide utilization rate,in this research,a feedback regulation system for the regulation of spraying parameters was designed based on droplet mass deposit online measurement.The system consisted of an online droplet mass deposit measurement module,wireless transmission module,decision module,and spraying parameters regulation module.First,the droplet mass deposits on the sampling points were measured.Based on the deviation between the measured and expected droplet mass,the expected spraying parameters were determined by the decision module.The spraying parameter was regulated to the expected value by regulating the pulse duty cycle on the pump motor using a micro control unit and a relay.Evaluation tests were conducted indoors using an indoor spraying platform and outdoors using an unmanned aerial vehicle.The results showed that the relative errors between the expected and measured droplet mass deposit after regulation were 6.84%and 11.48%for the indoor and outdoor tests,respectively.Therefore,an optimal spraying performance was observed after regulation.This research provided an experimental platform to quickly optimize spraying parameters and also provided technical references for precision spraying.

Cloning and Expression of Gene Responsible for High-Tillering Dwarf Phenotype in Indica Rice Mutant gsor23

High-tillering dwarf mutant gsor23 was generated from an indica rice variety Indica9 radiatied by y-ray. Genetic analysis showed that this phenotype was controlled by one single recessive gene, which was mapped within a physical distance of 386 kb between two insertion-deletion （InDel） markers CI-WT2 and C1-WT4 on the long arm of chromosome 1. There is a known gene DIO within this region, the mutation of which causes high-tillering in rice. Sequence analysis of the DIO allele in gsor23 revealed that the base cytosine （C） at the 404th position in the coding region was deleted, which would cause frameshift mutation after the 134th amino acids. The mutation site and indica background of gsor23 were different from the previously reported japonica mutants d10-1 and d10-2. Therefore, gsor23 is a novel allelic mutant of D10 which encodes the carotenoid-cleaving dioxygenase 8 （CCD8）, a key enzyme involved in the biosynthesis of the new plant hormone strigolactones （SLs）. After treatment with GR24, a synthetic analogue of SLs, the high-tillering phenotype of gsor23 was restored to normal. Real-time RT-PCR analysis showed that D10 expression was high in roots, but low in leaves. Compared with the wild type Indica9, the expression of the SL biosynthesis gene DIO was upregulated, while genes likely involved in the SL signal transduction pathway such as D3 and D14 were down-regulated in the gsor23 mutant.

A Study on the Molecular Switch of Gene Expression of the Mouse Heart Nuclear DNA Fragments

It is observed by in situ stain that LDH (1 5) ...nNAD + can probably enter the nucleopore and can be bound bound specifically with the genes that encode them. During the in vitro expression, the dilution of heart nuclear DNA fragments could enhance the expression activity of LDH/DNA and the amount of expressed LDH (1 5) is in proportion to the amount of dissociable LDH (1 5) on the LDH/DNA. With the integration of 14C Leu to the proteins, it is also observed that the addition of LDH (1 5) ...nNAD + can suppress the in vitro expression activity of LDH/DNA. AFM observation shows that the regulation sequence at the both ends of active genes may be bound with such active factors as proteins encoded by the genes which probably is the main molecular switch of gene expression and regulation we have been always searching for. Our work shows the prospective application of the combination of AFM and isotope labeling in the research of biological reaction.

MEP pathway products allosterically promote monomerization of deoxy-D-xylulose-5-phosphate synthase to feedback-regulate their supply

Isoprenoids are a very large and diverse family of metabolites required by all living organisms.All isoprenoids derive fromthe double-bond isomers isopentenyl diphosphate(IPP)and dimethylallyl diphosphate(DMAPP),which are produced by the methylerythritol 4-phosphate(MEP)pathway in bacteria and plant plastids.It has been reported that IPP and DMAPP feedback-regulate the activity of deoxyxylulose 5-phosphate synthase(DXS),a dimeric enzyme that catalyzes the main flux-controlling step of the MEP pathway.Here we provide experimental insights intotheunderlyingmechanism.Isothermal titration calorimetry and dynamic light scattering approaches showed that IPP and DMAPP can allosterically bind to DXS in vitro,causing a size shift.In silico ligand binding site analysis and docking calculations identified a potential allosteric site in the contact region between the two monomers of the active DXS dimer.Modulation of IPP and DMAPP contents in vivo followed by immunoblot analyses confirmed that high IPP/DMAPP levels resulted in monomerization and eventual aggregation of the enzyme in bacterial and plant cells.Loss of the enzymatically active dimeric conformation allows a fast and reversible reduction of DXS activity in response to a sudden increase or decrease in IPP/DMAPP supply,whereas aggregation and subsequent removal of monomers that would otherwise be available for dimerization appears to be a more drastic response in the case of persistent IPP/DMAPP overabundance(e.g.,by a blockage in their conversion to downstream isoprenoids).Our results represent an important step toward understanding the regulation of the MEP pathway and rational design of biotechnological endeavors aimed at increasing isoprenoid contents in microbial and plant systems.

A positive feedback regulatory loop,SAAtNAP-SAG202/SARD1-ICS1-SA,in SA biosynthesis involved in leaf senescence but not defense response

Salicylic acid(SA)is an important plant hormone that regulates defense responses and leaf senescence.It is imperative to understand upstream factors that regulate genes of SA biosynthesis.SAG202/SARD1 is a key regulator for isochorismate synthase 1(ICS1)induction and SA biosynthesis in defense responses.The regulatory mechanism of SA biosynthesis during leaf senescence is not well understood.Here we show that AtNAP,a senescence-specific NAC family transcription factor,directly regulates a senescence-associated gene named SAG202 as revealed in yeast one-hybrid and in planta assays.Inducible overexpreesion of AtNAP and SAG202 lead to high levels of SA and precocious senescence in leaves.Individual knockout mutants of sag202 and ics1 have markedly reduced SA levels and display a significantly delayed leaf senescence phenotype.Furthermore,SA positively feedback regulates AtNAP and SAG202.Our research has uncovered a unique positive feedback regulatory loop,SA-AtNAP-SAG202-ICS1-SA,that operates to control SA biosynthesis associated with leaf senescence but not defense response.

Exact distributions for stochastic models of gene expression with arbitrary regulation

Stochasticity in gene expression can result in fluctuations in gene product levels. Recent experiments indicated that feedback regulation plays an important role in controlling the noise in gene expression.A quantitative understanding of the feedback effect on gene expression requires analysis of the corresponding stochastic model. However, for stochastic models of gene expression with general regulation functions, exact analytical results for gene product distributions have not been given so far. Here, we propose a technique to solve a generalized ON-OFF model of stochastic gene expression with arbitrary(positive or negative, linear or nonlinear) feedbacks including posttranscriptional or posttranslational regulation. The obtained results, which generalize results obtained previously, provide new insights into the role of feedback in regulating gene expression. The proposed analytical framework can easily be extended to analysis of more complex models of stochastic gene expression.

The Isogene 1-Deoxy-D-Xylulose 5-Phosphate Synthase 2 Controls Isoprenoid Profiles, Precursor Pathway Allocation, and Density of Tomato Trichomes

Plant isoprenoids are formed from precursors synthesized by the mevalonate （MVA） pathway in the cytosol or by the methyl-D-erythritol 4-phosphate （MEP） pathway in plastids. Although some exchange of precursors occurs, cytosolic sesquiterpenes are assumed to derive mainly from MVA, while plastidial monoterpenes are produced preferentially from MEP precursors. Additional complexity arises in the first step of the MEP pathway, which is typically catalyzed by two divergent 1-deoxy-D-xylulose 5-phosphate synthase isoforms （DXS1, DXS2）. In tomato （Solanum lycopersicum）, the SIDXS1 gene is ubiquitously expressed with highest levels during fruit ripening, whereas SIDXS2 transcripts are abundant in only few tissues, including young leaves, petals, and isolated trichomes. Specific down-regulation of SIDXS2 expression was performed by RNA interference in transgenic plants to investigate feedback mechanisms. SIDXS2 down-regulation led to a decrease in the monoterpene β-phellandrene and an increase in two sesquiterpenes in trichomes. Moreover, incorporation of MVA-derived precursors into residual monoterpenes and into sesquiterpenes was elevated as determined by comparison of ^13C to ^12C natural isotope ratios. A compensatory up-regulation of SIDXS1 was not observed. Down-regulated lines also exhibited increased trichome density and showed less damage by leaf-feeding Spodoptera littoralis caterpillars. The results reveal novel, non-redundant roles of DXS2 in modulating isoprenoid metabolism and a pronounced plasticity in isoprenoid precursor allocation.

Patterns in the occurrence and development of tumors

Although we have made great progress in understanding tumor pathogenesis through studies on gene mutation and cancer stem cells, the clinical outcome continues to be unfavorable for many cancers. The biological characteristics of cancers including autonomous proliferation, invasion, metastasis, and post-treatment recurrence result from interactions between cancers and their microenvironment, which involves complex molecular interactions.

Experimental Study on Acupuncture Activating the Gonadotropin-releasing Hormone Neurons in Hypothalamus

Objective:To probe into the most effective site,extra-ordinary point,acupoint and channel for regulating reproductive endocrine function by means of the study on acupuncture activating the gonadotropin-releasing hormone neurons(GnRH) in hypothalamus.Methods:Female SD rats of reproductive age were used,and the in vivo study on GnRH neurons in hypothalamus was made with mimic sexual stimulation and feedback regulation.The neuron-activating effects of the acupoints on the channels pertaining to the zang-and fu-organs related with reproductive endocrine and the extra-ordinary points in different regions were studied using the discharge of the neuron as index,and then the neurons were labeled with horseradish peroxidase(HRP) .Results:Acupuncture was given at two acupoints each on the three yin channels of foot,the three yang channels of foot,the Conception Vessel and the Governor Vessel.The order of the mean increasing percentage in the hypothalamic GnRH neuron electric activity was:the Gallbladder Channel>the Spleen Channel>the Stomach Channel/the Bladder Channel/the Conception Vessel>the Liver Channel>the Kidney Channel>the Governor Vessel;for different acupoints,it was:Guanyuan(CV 4) >Sanyinjiao(SP 6) >Zusanli(ST 36) >Daimai(GB 26) /Yanglingquan(GB 34) >Shenshu(BL 23) >Weizhong(BL 40) >Yaoyangguan(GV 3) /Liangmen(ST 21) /Fujie(SP 14) >Qimen(LR 14) /Yingu(KI 10) >Tangzhong(CV 17) /Zhiyang(GV 9) ;for different positions,it was:the lower abdominal part/the lower limb part>the thoracodorsal part;for the extra-ordinary points,it was:Zigong(EX-CA1) >Dannang(EX-LE6) /Yaoyan(EX-B7) >Baichongwo(EX-LE3) /Qianzheng>Jingbi/Bizhong/Taiyang(EX-HN5) >Erbai(EX-UE2) /Dingchun;and for the distribution sites of the extra-ordinary points:lower abdominal region>the lower limb region>the craniofacial region>the upper limb region/the thoracodorsal region.Conclusion:For regulating the reproductive endocrine function,the acupoints located at the same neural segment with the reproductive organ should be selected as the main points,and it is necessary to combine with syndrome differentiation of the viscera and channels.

Chemotactic signaling in mesenchymal cells compared to amoeboid cells

Cell chemotaxis plays a pivotal role in normal development,inflammatory response,injury repair and tissue regeneration in all organisms.It is also a critical contributor to cancer metastasis,altered angiogenesis and neurite growth in disease.The molecular mechanisms regulating chemotaxis are currently being identified and key components may be pertinent therapeutic targets.Although these components appear to be mostly common in various cells,there are important differences in chemotactic signaling networks and signal processing that result in the distinct chemotactic behavior of mesenchymal cells compared to much better studied amoeboid blood cells.These differences are not necessarily predetermined based on cell type,but are rather chosen and exploited by cells to modify their chemotactic behavior based on physical constraints and/or environmental conditions.This results in a specific type of chemotactic migration in mesenchymal cells that can be selectively targeted in disease.Here,we compare the chemotactic behavior,signaling and motility of mesenchymal and amoeboid cells.We suggest that the current model of chemotaxis is applicable for small amoeboid cells but needs to be reconsidered for large mesenchymal cells.We focus on new candidate regulatory molecules and feedback mechanisms that may account for mesenchymal cell type-specific chemotaxis.

STABILITY ANALYSIS TO A PREDATOR-PREY SYSTEM WITH DELAY

In this paper,we consider a delayed predator-prey system and obtain sufficient conditions for the global asymptotic stability of the positive equilibrium.