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This work presents a convex optimization framework for the planning and tracking of quadcopter trajectories with continuous-time safety guarantees. Using B-spline basis functions and the differential flatness property of quadcopters, a second-order cone program is formulated to generate optimal trajectories that respect safe state and input constraints in the continuous-time sense. A quadratic program (QP) based on control barrier functions is proposed to guarantee bounded trajectory tracking in continuous time by filtering a nominal controller, where the QP is shown to be always feasible. Furthermore, conditions that ensure the safe tracking controller respects thrust, roll angle, and pitch angle constraints are also proposed. The effectiveness of the proposed framework is demonstrated by real-world experiments using a Crazyflie2.1 nano quadcopter., Comment: 16 pages, 13 figures

The novel coronavirus disease 2019 continues to spread widely, not only causing physical disorders in patients but also impairing mental health, bringing a heavy burden on global public health. This study aimed to evaluate the anxiety and depression status of patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant in Shanghai.This study aimed to retrospectively analyze 2000 patients infected with the SARS-CoV-2 Omicron variant. Data from patients assessed with demographic information, anxiety and depressive symptoms were collected using a questionnaire. Clinical and laboratory data were collected using electronic medical system. Anxiety and depression were assessed using the Self-Rating Anxiety Scale, the Generalized Anxiety Disorder Scale, and the Patient Health Questionnaire. Clinical information and laboratory indicators included age, sex, blood pressure, blood glucose, basic disease, time of diagnosis onset, duration of hospitalization, vaccination status of novel coronavirus disease 2019, and virus-negative conversion time.This study will provide evidence-based suggestions for early psychological intervention in patients infected with the SARS-CoV-2 Omicron Variant.

This article studies the constrained switching (linear) system which is a discrete-time switched linear system whose switching sequences are constrained by a deterministic finite automaton. The stability of a constrained switching system is characterized by its constrained joint spectral radius that is known to be difficult to compute or approximate. Using the semitensor product of matrices, the matrix-form expression of a constrained switching system is shown to be equivalent to that of a lifted arbitrary switching system. Then, the constrained joint/generalized spectral radius of a constrained switching system is proven to be equal to the joint/generalized spectral radius of its lifted arbitrary switching system which can be approximated by off-the-shelf algorithms.

Periodic event-triggered control (PETC) evaluates the triggering rule periodically and is well-suited for implementation on digital platforms. This paper investigates PETC design for nonlinear systems affected by external disturbances under the impulsive system formulation. Sufficient conditions are provided to ensure the input-to-state stability of the resulting closed-loop system for the state feedback and the observer-based output feedback configurations separately. For each configuration, the sampling period and the triggering functions are provided explicitly. Sufficient conditions in the form of linear matrix inequalities are provided for the PETC design of incrementally quadratic nonlinear systems. Two examples are given to illustrate the effectiveness of the proposed method.

A wave of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant rapidly resulted in a steep increase in the infected population and an overloaded healthcare system. Effective medications for Omicron are currently limited. The previous observational study supports the efficacy and safety of Reyanning (RYN) mixture in the treatment of coronavirus disease 2019 (COVID-19).To evaluate the efficacy of RYN in asymptomatic and mildly infected patients with SARS-CoV-2 infection.This study was a prospective, open-label, randomized controlled trial. We consecutively recruited 2830 patients from Shanghai New International Expo Center mobile cabin hospital and randomized them in a 1:1 ratio to receive RYN plus standard care or receive standard care alone. The primary outcomes were the negative conversion of nucleic acid. Secondary outcomes included the hospital duration, new-onset symptoms, proportion of disease progression, and the viral load measured by the cycle threshold (Ct) value.A total of 1393 patients in the intervention group and 1407 patients in the control group completed the study. The negative conversion time of nucleic acid was significantly shortened in the intervention group (median: 6 d vs. 7 d, Hazard ratio: 0.768, 95CI %: 0.713-0.828, p0.0001). The negative conversion rate of nucleic acid was significantly higher in the intervention group (Day 3: 32.4% vs. 18.3%; Day7: 65.3% vs. 55.2%, p0.001). The hospitalization duration was significantly shortened in the intervention group (median: 8 d vs. 9 d, Hazard ratio: 0.759, 95% CI: 0.704-0.818, p0.0001). The proportion of new-onset fever (2.4% vs. 4.1%, p = 0.012), coughing (12.2% vs. 14.8%, p = 0.046), and expectoration (6.0% vs. 8.0%, p = 0.032) in the intervention group was significantly lower. RYN treatment increased Ct values and reduced the viral load. No disease progression and serious adverse events were reported during the study.RYN is a safe and effective treatment that can accelerate virus clearance and promote disease recovery in asymptomatic and mild Omicron infections.

The fact that dietary restriction (DR) and long-term rapamycin treatment (RALL) can ameliorate the aging process has been reported by many researchers. As the interface between external and genetic factors, epigenetic modification such as DNA methylation may have latent effects on the aging rate at the molecular level. To understand the mechanism behind the impacts of dietary restriction and rapamycin on aging, DNA methylation and gene expression changes were measured in the hippocampi of different-aged mice. Examining the single-base resolution of DNA methylation, we discovered that both dietary restriction and rapamycin treatment can maintain DNA methylation in a younger state compared to normal-aged mice. Through functional enrichment analysis of genes in which DNA methylation or gene expression can be affected by DR/RALL, we found that DR/RALL may retard aging through a relationship in which DNA methylation and gene expression work together not only in the same gene but also in the same biological process. This study is instructive for understanding the maintenance of DNA methylation by DR/RALL in the aging process, as well as the role of DR and RALL in the amelioration of aging.

Fusarium crown rot (FCR), caused by Fusarium species, is a serious soilborne fungal disease in many wheat growing regions in the world. A reliable FCR assessment method is essential for germplasm screening and host resistance studies. Here, we report a new assay in which we inoculated wheat seedlings grown in a glasshouse for FCR by injecting spore suspensions into the seedling stems. The effects of inoculum concentration and injection time points on disease severity were investigated. Of different treatments, the injection of 107macroconidia/ml suspension at one leaf and one heart stage gave best results. A collection of 92 emmer-derived hexaploid bread wheats, 43 barley germplasms, and four wheat genotypes with known resistance levels to FCR was used to validate this new method. Repeatability of the two trials in the validation experiments was high (r = 0.97, P < 0.01). Two emmer-derived hexaploid bread wheat and three Chinese barley germplasms showed consistent resistance to FCR in multiple rounds of selection. The short timeframe of this assay for phenotypic screening makes it a valuable tool to eliminate germplasms with undesirable susceptibility to FCR at seedling stage before costly field assays.

The optimal control problem for the kinematic bicycle model is considered where the trajectories are required to satisfy the safety constraints in the continuous-time sense. Based on the differential flatness property of the model, necessary and sufficient conditions in the flat space are provided to guarantee safety in the state space. The optimal control problem is relaxed to the problem of solving three second-order cone programs (SOCPs) sequentially, which find the safe path, the trajectory duration, and the speed profile, respectively. Solutions of the three SOCPs together provide a sub-optimal solution to the original optimal control problem. Simulation examples and comparisons with state-of-the-art optimal control solvers are presented to demonstrate the effectiveness of the proposed approach., Comment: 8 pages, 5 figures

Presently, over-the-counter drugs that can treat upper respiratory tract infections (URTI) are rarely effective and safe. Chaiqin Qingning Capsule (CQQNC), a Chinese patent medicine, which has been verified by long-term clinical practice is recommended by Chinese experts for the treatment of URTI with fever. This study conducted a prospective, double-blinded, randomized, multicenter controlled trial to evaluate the effectiveness and safety of CQQNC in the treatment of URTI.The study was conducted at 4 clinical centers in China. Eligible subjects were recruited and randomized 1:1 to the CQQNC group and Qingkailing Capsule (QKLC) group. Both groups were administered orally three times a day for three consecutive days. Primary outcomes were the antipyretic onset time and the temperature recovery time. Secondary outcomes included the symptom disappearance rate, symptom score, and drug safety assessment.A total of 269 subjects were analyzed (134 subjects in the CQQNC group, 135 subjects in the QKLC group). The antipyretic onset time and the temperature recovery time were significantly shortened in the CQQNC group (median: 5 h vs. 10 h, p 0.0001, median: 19 h vs. 27 h, p 0.0001). CQQNC was more effective than the QKLC in improving the symptoms of pharyngodynia and rhinobyon (85.07% vs. 71.11%, p = 0.008; 76.99% vs. 64.41%, p = 0.043), and in improving the overall symptom scores (-15.10 ± 3.23 vs. -13.35 ± 3.58, p 0.0001). During the trial, no serious adverse events were reported in the two groups.CQQNC is effective and safe in the treatment of URTI with fever, and worthy of clinical application. (http://www.chictr.org.cn, ChiCTR-IPR-16009049).

As the first multidimensional NMR approach, 2D J-resolved (2DJ) spectroscopy is distinguished by signal resolution and detection sensitivity with remarkable advantages for the exhaustive evaluation of complex mixtures and environmental samples due to its carbonless feature without the requirement of 13C connectivity. Generally, the 2DJ signal assignment of metabolic mixtures is problematic in spite of references to experimental NMR databases, owing to the existence of metabolic "dark matter." In this study, a new method to predict 2DJ spectra was developed with a combination of quantum mechanical (QM) computation and machine learning (ML). The predictive accuracy of J-coupling constants was evaluated using validated data. The root-mean-square deviation (RMSD) for QM computation was 3.52 Hz, while the RMSD for QM + ML was 1.21 Hz, indicating a substantial increase in predictive accuracy. The proposed model was applied to predict the 2DJ spectra of 60 standard substances and 55 components of seawater. Furthermore, two practical environmental samples were used to evaluate the robustness of the constructed predictive model. A J-coupling tree and J-split spectra produced from QM + ML of aliphatic moieties had good consistency with the experimental data, as compared with the theoretical data produced by QM computation. The predicted J-coupling tree for the J-coupling multiplet analysis of freely rotating bonds in the complex mixture, which is traditionally difficult, was interpretable. In addition, in silico identification of the J-split 1H NMR signals, which was independent of experimental databases, aided in the discovery of new components in a mixture.

Grain size and shape have significant effects on grain weight and is also an important breeding target due to market and industry requirements. In this study, the genetic loci associated with six grain morphology traits including thousand grain weight, grain length (GL), grain width, grain length to width ratio (GLWR), grain area (GA) and grain perimeter (GP) in a population of 300 Chinese wheat germplasm were investigated through genome wide association mapping. A total of 189 SNPs were significantly related to the six grain traits based on the BLUP data from three environments. Of these SNPs, 24 SNPs for GA, GL, GLWR, and GP were continuously detected under all three experiments. These SNPs were distributed on chromosome 2A, 2B, 2D, 4D, 5A, and 6D, respectively. Some SNPs such as Affx-88368872 on 2A, Affx-109472887 on 6D, and Affx-108968182, Affx-111286671, Affx-110418048, Affx-109838962, Affx-88484232 on 5A were associated with multiple traits. In addition, a chromosome region tagged by 11 SNPs (585,117,524–595,658,182 bp) on chromosome 2D had significant effects on GLWR. Several genes inside the regions on chromosome 5A and 2D may play crucial roles in determining seed size and weight. We will characterize the function of these genes in grain development in our future experiments. This study provides novel insights into the genetic basis of grain morphology traits in wheat.

Dnmt3a2, a de novo DNA methyltransferase, is induced by neuronal activity and participates in long-term memory formation with the increased expression of synaptic plasticity genes. We wanted to determine if Dnmt3a2 with its partner Dnmt3L may influence motor behavior via the dopaminergic system. To this end, we generated a mouse line, Dnmt3a2/3LDat/wt, with dopamine transporter (DAT) promotor driven Dnmt3a2/3L overexpression. The mice were studied with behavioral paradigms (e.g., cylinder test, open field, and treadmill), brain slice patch clamp recordings, ex vivo metabolite analysis, and in vivo positron emission tomography (PET) using the dopaminergic tracer 6-[18F]FMT. The results showed that spontaneous activity and exercise performance were enhanced in Dnmt3a2/3LDat/wt mice compared to Dnmt3a2/3Lwt/wt controls. Dopaminergic substantia nigra pars compacta neurons of Dnmt3a2/3LDat/wt animals displayed a higher fire frequency and excitability. However, dopamine concentration was not increased in the striatum, and dopamine metabolite concentration was even significantly decreased. Striatal 6-[18F]FMT uptake, reflecting aromatic L-amino acid decarboxylase activity, was the same in Dnmt3a2/3LDat/wt mice and controls. [18F]FDG PET showed that hypothalamic metabolic activity was tightly linked to motor behavior in Dnmt3a2/3LDat/wt mice. Furthermore, dopamine biosynthesis and motor-related metabolic activity were correlated in the hypothalamus. Our findings suggest that Dnmt3a2/3L, when overexpressed in dopaminergic neurons, modulates motor performance via activation of the nigrostriatal pathway. This does not involve increased dopamine synthesis.

The genetics of aging is typically concerned with lifespan determination that is associated with alterations in expression levels or mutations of particular genes. Previous reports in C. elegans have shown that the bmk-1 gene has important functions in chromosome segregation, and this has been confirmed with its mammalian homolog, KIF11. However, this gene has never been implicated in aging or lifespan regulation. Here we show that the bmk-1 gene is an important lifespan regulator in worms. We show that reducing bmk-1 expression using RNAi shortens worm lifespan by 32%, while over-expression of bmk-1 extends worm lifespan by 25%, and enhances heat-shock stress resistance. Moreover, bmk-1 over-expression increases the level of hsp-16 and decreases ced-3 in C. elegans. Genetic epistasis analysis reveals that hsp-16 is essential for the lifespan extension by bmk-1. These findings suggest that bmk-1 may act through enhanced hsp-16 function to protect cells from stress and inhibit the apoptosis pathway, thereby conferring worm longevity. Though it remains unclear whether this is a distinct function from chromosomal segregation, bmk-1 is a potential new target for extension of lifespan and enhancement of healthspan.

With ever-increasing elder population, the high incidence of age-related diseases such as neurodegenerative disorders has turned out to be a huge public concern. Especially the elders and their families dreadfully suffer from the learning, behavioral and cognitive impairments. The lack of effective therapies for such a horrible symptom makes a great demanding for biological mechanism study for cognitive aging. Epigenetics is an emerging field that broadens the dimensions of mammalian genome blueprint. It is, unlike genetics, not only inheritable but also reversible. Recent studies suggest that DNA methylation, one of major epigenetic mechanisms, plays a pivotal role in the pathogenesis of age-related neurodegenerations and cognitive defects. In this review, the evolving knowledge of age-related cognitive functions and the potential DNA methylation mechanism of cognitive aging are discussed. That indicates the impairment of DNA methylation may be a crucial but reversible mechanism of behavioral and cognitive related neurodegeneration. The methods to examine the dynamics of DNA methylation patterns at tissue and single cell level and at the representative scale as well as the whole genome single base resolution are also briefly discussed. Importantly, the challenges of DNA methylation mechanism of cognitive aging research are brought up, and the possible solutions to tackle these difficulties are put forward.

This paper studies the performance of a continuous controller when implemented on digital devices via sampling and quantization, by leveraging passivity analysis. Degradation of passivity indices from a continuous-time control system to its sampled, input and output quantized model is studied using a notion of quasi-passivity. Based on that, the passivity property of a feedback-connected system where the continuous controller is replaced by its sampled and quantized model is studied, and conditions that ensure the state boundedness of the interconnected system are provided. Additionally, the approximate bisimulation-based control implementation where the controller is replaced by its approximate bisimilar symbolic model whose states are also quantized is analyzed. Several examples are provided to illustrate the theoretical results.

Robust global stabilization of nonlinear systems by observer-based feedback controllers is a challenging task. This article investigates the problem of designing observer-based stabilizing controllers for incrementally quadratic nonlinear systems with external disturbances. The nonlinearities considered in the system model satisfy the incremental quadratic constraints, which are characterized by incremental multiplier matrices and encompass many common nonlinearities. The simultaneous search for the observer and the controller gain matrices is formulated as a feasibility problem of linear matrix inequalities, for two parameterizations (i.e., the block diagonal parameterization and the block anti-triangular parameterization) of the incremental multiplier matrices, respectively. The closed-loop system implementing the observer-based feedback controller is proven to be input-to-state stable with respect to external disturbances. Using the proposed continuous-time observer-based controllers, event-triggered controllers with time regularization are constructed for globally Lipschitz systems, such that the closed-loop system is Zeno-free and input-to-state practically stable., Comment: to be published in IEEE TAC

Barrier functions (also called certificates) have been an important tool for the verification of hybrid systems, and have also played important roles in optimization and multi-objective control. The extension of a barrier function to a controlled system results in a control barrier function. This can be thought of as being analogous to how Sontag extended Lyapunov functions to control Lyapunov functions in order to enable controller synthesis for stabilization tasks. A control barrier function enables controller synthesis for safety requirements specified by forward invariance of a set using a Lyapunov-like condition. This paper develops several important extensions to the notion of a control barrier function. The first involves robustness under perturbations to the vector field defining the system. Input-to-State stability conditions are given that provide for forward invariance, when disturbances are present, of a "relaxation" of set rendered invariant without disturbances. A control barrier function can be combined with a control Lyapunov function in a quadratic program to achieve a control objective subject to safety guarantees. The second result of the paper gives conditions for the control law obtained by solving the quadratic program to be Lipschitz continuous and therefore to gives rise to well-defined solutions of the resulting closed-loop system.

Polarization aberration (PA) is a serious issue that affects imaging quality for optical systems with high numerical aperture. Numerous studies have focused on the distribution rule of PA on the pupil, but the field remains poorly studied. We previously developed an orthonormal set of polynomials to reveal the pupil and field dependences of PA in rotationally symmetric optical systems. However, factors, such as intrinsic birefringence of cubic crystalline material in deep ultraviolet optics and tolerance, break the rotational symmetry of PA. In this paper, we extend the polynomials from rotationally symmetric to M-fold to describe the PA of M-fold optical systems. Two examples are presented to verify the polynomials.

In this note, we propose a matrix-based approach for asynchronous sequential machines. Using semi-tensor product of matrices, we convert an asynchronous machine into a discrete-time bilinear system, and study its dynamics by investigating its structure matrices. We give simple algorithms for cycle detection and reachability analysis, and moreover, provide a control design method for the model matching of two input/state machines.

This paper develops a control approach with correctness guarantees for the simultaneous operation of lane keeping and adaptive cruise control. The safety specifications for these driver assistance modules are expressed in terms of set invariance. Control barrier functions (CBFs) are used to design a family of control solutions that guarantee the forward invariance of a set, which implies satisfaction of the safety specifications. The CBFs are synthesized through a combination of sum-of-squares program and physics-based modeling and optimization. A real-time quadratic program is posed to combine the CBFs with the performance-based controllers, which can be either expressed as control Lyapunov function conditions or as black-box legacy controllers. In both cases, the resulting feedback control guarantees the safety of the composed driver assistance modules in a formally correct manner. Importantly, the quadratic program admits a closed-form solution that can be easily implemented. The effectiveness of the control approach is demonstrated by simulations in the industry-standard vehicle simulator Carsim. Note to Practitioners —Safety is of paramount importance for the control of automated vehicles. This paper is motivated by the problem of designing controllers that are provably correct for the simultaneous operation of two driver assistance modules, lane keeping and adaptive cruise control. This is a challenging problem partially, because the lateral and longitudinal dynamics of the vehicles are coupled, with few results known to exist that provide formal guarantees. In this paper, we employ an assume-guarantee formalism between these two subsystems, such that they can be considered individually; based on that, we use optimization to design safe sets that serves as “supervisors” for vehicle behavior, such that the trajectories of the closed-loop system are confined within the safe sets using predetermined bounds on wheel force and steering angle. The feedback controller is constructed by solving convex quadratic programs online, which can also be given in closed form, making the implementation much easier. One particular advantage of this control approach is that the safety set and the performance controller can be designed separately, which enables the integration of a legacy controller into a correct-by-construction solution.

Ageing, a leading cause of the decline/deficits in human learning, memory, and cognitive abilities, is a major risk factor for age-associated neurodegenerative disorders such as Alzheimer’s disease. Emerging evidence suggests that epigenetics, an inheritable but reversible biochemical process, plays a crucial role in the pathogenesis of age-related neurological disorders. DNA methylation, the best-known epigenetic mark, has attracted most attention in this regard. DNA methyltransferases (DNMTs) are key enzymes in mediating the DNA methylation process, by which a methyl group is transferred, faithfully or anew, to genomic DNA sequences. Biologically, DNMTs are important for gene imprinting. Accumulating evidence suggests that DNMTs not only play critical roles, including gene imprinting and transcription regulation, in early development stages of the central nervous system (CNS), but also are indispensable in adult learning, memory, and cognition. Therefore, the impact of DNMTs and DNA methylation on age-associated cognitive functions and neurodegenerative diseases has emerged as a pivotal topic in the field. In this review, the effects of each DNMT on CNS development and healthy and pathological ageing are discussed.

Safety critical systems involve the tight coupling between potentially conflicting control objectives and safety constraints. As a means of creating a formal framework for controlling systems of this form, and with a view toward automotive applications, this paper develops a methodology that allows safety conditions -- expressed as control barrier functions -- to be unified with performance objectives -- expressed as control Lyapunov functions -- in the context of real-time optimization-based controllers. Safety conditions are specified in terms of forward invariance of a set, and are verified via two novel generalizations of barrier functions; in each case, the existence of a barrier function satisfying Lyapunov-like conditions implies forward invariance of the set, and the relationship between these two classes of barrier functions is characterized. In addition, each of these formulations yields a notion of control barrier function (CBF), providing inequality constraints in the control input that, when satisfied, again imply forward invariance of the set. Through these constructions, CBFs can naturally be unified with control Lyapunov functions (CLFs) in the context of a quadratic program (QP); this allows for the achievement of control objectives (represented by CLFs) subject to conditions on the admissible states of the system (represented by CBFs). The mediation of safety and performance through a QP is demonstrated on adaptive cruise control and lane keeping, two automotive control problems that present both safety and performance considerations coupled with actuator bounds.

Glucagon-like peptide-1 (GLP-1), released from gut endocrine L cells in response to glucose, regulates appetite, insulin secretion, and gut motility. How glucose given orally, but not systemically, induces GLP-1 secretion is unknown. We show that human duodenal L cells express sweet taste receptors, the taste G protein gustducin, and several other taste transduction elements. Mouse intestinal L cells also express alpha-gustducin. Ingestion of glucose by alpha-gustducin null mice revealed deficiencies in secretion of GLP-1 and the regulation of plasma insulin and glucose. Isolated small bowel and intestinal villi from alpha-gustducin null mice showed markedly defective GLP-1 secretion in response to glucose. The human L cell line NCI-H716 expresses alpha-gustducin, taste receptors, and several other taste signaling elements. GLP-1 release from NCI-H716 cells was promoted by sugars and the noncaloric sweetener sucralose, and blocked by the sweet receptor antagonist lactisole or siRNA for alpha-gustducin. We conclude that L cells of the gut "taste" glucose through the same mechanisms used by taste cells of the tongue. Modulating GLP-1 secretion in gut "taste cells" may provide an important treatment for obesity, diabetes and abnormal gut motility.

This paper presents a methodology for the development of control barrier functions (CBFs) through a backstepping inspired approach. Given a set defined as the superlevel set of a function, h, the main result is a constructive means for generating control barrier functions that guarantee forward invariance of this set. In particular, if the function defining the set has relative degree n, an iterative methodology utilizing higher order derivatives of h provably results in a control barrier function that can be explicitly derived. To demonstrate these formal results, they are applied in the context of bipedal robotic walking. Physical constraints, e.g., joint limits, are represented by control barrier functions and unified with control objectives expressed through control Lyapunov functions (CLFs) via quadratic program (QP) based controllers. The end result is the generation of stable walking satisfying physical realizability constraints for a model of the bipedal robot AMBER2.

Telomeres are specialized structures at the ends of chromosomes that consist of tandem repeats of the DNA sequence TTAGGG and several proteins that protect the DNA and regulate the plasticity of the telomeres. The telomere-associated protein TRF2 (telomeric repeat binding factor 2) is critical for the control of telomere structure and function; TRF2 dysfunction results in the exposure of the telomere ends and activation of ATM (ataxia telangiectasin mutated)-mediated DNA damage response. Recent findings suggest that telomere attrition can cause senescence or apoptosis of mitotic cells, but the function of telomeres in differentiated neurons is unknown. Here, we examined the impact of telomere dysfunction via TRF2 inhibition in neurons (primary embryonic hippocampal neurons) and mitotic neural cells (astrocytes and neuroblastoma cells). We demonstrate that telomere dysfunction induced by adenovirus-mediated expression of dominant-negative TRF2 (DN-TRF2) triggers a DNA damage response involving the formation of nuclear foci containing phosphorylated histone H2AX and activated ATM in each cell type. In mitotic neural cells DN-TRF2 induced activation of both p53 and p21 and senescence (as indicated by an up-regulation of β-galactosidase). In contrast, in neurons DN-TRF2 increased p21, but neither p53 nor β-galactosidase was induced. In addition, TRF2 inhibition enhanced the morphological, molecular and biophysical differentiation of hippocampal neurons. These findings demonstrate divergent molecular and physiological responses to telomere dysfunction in mitotic neural cells and neurons, indicate a role for TRF2 in regulating neuronal differentiation, and suggest a potential therapeutic application of inhibition of TRF2 function in the treatment of neural tumors.

Components or downstream targets of many signaling pathways such as Insulin/IGF-1 and TOR, as well as genes involved in cellular metabolism and bioenergetics can extend worm lifespan 20% or more. The C. elegans gene pch-2 and its homologs, including TRIP13 in humans, have been studied for their functions in cell mitosis and meiosis, but have never been implicated in lifespan regulation. Here we show that over-expression of TRIP13 in human fibroblasts confers resistance to environmental stressors such as UV radiation and oxidative stress. Furthermore, pch-2 overexpression in C. elegans extends worm lifespan, and enhances worm survival in response to various stressors. Conversely, reducing pch-2 expression with RNAi shortens worm lifespan. Additional genetic epistasis analysis indicates that the molecular mechanism of pch-2 in worm longevity is tied to functions of the sirtuin family, implying that pch-2 is another chromatin regulator for worm longevity. These findings suggest a novel function of the pch-2 gene involved in lifespan determination.

In this paper, we present some preliminary results for compositional analysis of heterogeneous systems containing both discrete state models and continuous systems using consistent notions of dissipativity and passivity. We study the following problem: given a physical plant model and a continuous feedback controller designed using traditional control techniques, how is the closed-loop passivity affected when the continuous controller is replaced by a discrete (i.e., symbolic) implementation within this framework? Specifically, we give quantitative results on performance degradation when the discrete control implementation is approximately bisimilar to the continuous controller, and based on them, we provide conditions that guarantee the boundedness property of the closed-loop system., Comment: This is an extended version of our IEEE CDC 2015 paper to appear in Japan

The leader-following consensus problem of multi-agent systems over finite fields ${\mathbb F}_p$ is considered in this paper. Dynamics of each agent is governed by a linear equation over ${\mathbb F}_p$, where a distributed control protocol is utilized by the followers.Sufficient and/or necessary conditions on system matrices and graph weights in ${\mathbb F}_p$ are provided for the followers to track the leader.

Understanding molecular mechanisms of skin ageing is critical for developing effective anti-ageing strategies. Recently, it has been suggested that epigenetics maybe be involved in tissue ageing and age-related diseases; however, the evidence regarding skin ageing has been very limited. We ran a pilot study in mouse skin to test whether DNA methyltransferases (Dnmts), DNA demethylases such as ten-eleven translocation enzymes (Tets) and DNA methylation of gene promoters change with age by quantitative RT-PCR and methylated DNA immunoprecipitation (MeDIP)-chip. We discovered that the expression of Dnmt3a, Dnmt3b and Tet2 declines significantly with skin ageing. The genome-wide DNA methylation analysis indicates that both hypermethylation and hypomethylation in promoters of genes are taken place. Functional category of those genes suggests that inhibition of cell proliferation and activation of immune response are important adaptations likely induced by skin ageing. These findings shed new light on epigenetic regulation of skin ageing.

The ten-eleven translocation family of proteins (Tet1/2/3, Tets) converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which can be further oxidized and repaired by thymine DNA glycosylase (TDG), to influence gene transcription in embryonic and adult tissues. However the mechanisms of how Tets and TDG levels are regulated are unknown. We show that miR-29 can directly regulate Tet1-3 and TDG mRNA levels through binding to their 3′UTRs. miR-29 mimic decreases global 5hmC levels, a hallmark of Tet activity. Moreover, the mRNA levels for Tet3 and TDG are inversely correlated with the levels of miR-29 in aged mouse aorta implying that aging may affect methylation patterns via miRNA. In summary, our data show that Tets and TDG are direct targets of miR-29 and unravel a novel regulatory role for this miRNA in epigenetic DNA demethylation pathways.

Because the olfactory system plays a major role in food consumption, and because “food addiction” and associated morbidities have reached epidemic proportions, we tested the hypothesis that dietary energy restriction can modify adverse effects of cocaine on behavior and olfactory cellular and molecular plasticity. Mice maintained on an alternate day fasting (ADF) diet exhibited increased baseline locomotion and increased cocaine-sensitized locomotion during cocaine conditioning, despite no change in cocaine conditioned place preference, compared to mice fed ad libitum. Levels of dopamine and its metabolites in the olfactory bulb (OB) were suppressed in mice on the ADF diet compared to mice on the control diet, independent of acute or chronic cocaine treatment. The expression of several enzymes involved in dopamine metabolism including tyrosine hydroxylase, monoamine oxidases A and B (MAOA), and catechol-O-methyltransferase were significantly reduced in OBs of mice on the ADF diet. Both acute and chronic administration of cocaine suppressed the production of new OB cells, and this effect of cocaine was attenuated in mice on the ADF diet. Cocaine administration to mice on the control diet resulted in up-regulation of OB genes involved in mitochondrial energy metabolism, synaptic plasticity, cellular stress responses, and calcium- and cyclic AMP-mediated signaling, whereas multiple olfactory receptor genes were down-regulated by cocaine treatment. ADF abolished many of the effects of cocaine on OB gene expression. Our findings reveal that dietary energy intake modifies the neural substrates underlying some of the behavioral and physiological responses to repeated cocaine treatment, and also suggest novel roles for the olfactory system in addiction. The data further suggest that modification of dietary energy intake could provide a novel potential approach to addiction treatments.