Biomedical subjects

Xiao-Jing Wang

Publications and source records attributed to Xiao-Jing Wang.

At least 19 recordsLinked to original sources

PubMed2007

Mean-driven and fluctuation-driven persistent activity in recurrent networks.

Spike trains from cortical neurons show a high degree of irregularity, with coefficients of variation (CV) of their interspike interval (ISI) distribution close to or higher than one. It has been suggested that this irregularity might be a reflection of a particular dynamical state of the local cortical circuit in which excitation and inhibition balance each other. In this "balanced" state, the mean current to the neurons is below threshold, and firing is driven by current fluctuations, resulting in irregular Poisson-like spike trains. Recent data show that the degree of irregularity in neuronal spike trains recorded during the delay period of working memory experiments is the same for both low-activity states of a few Hz and for elevated, persistent activity states of a few tens of Hz. Since the difference between these persistent activity states cannot be due to external factors coming from sensory inputs, this suggests that the underlying network dynamics might support coexisting balanced states at different firing rates. We use mean field techniques to study the possible existence of multiple balanced steady states in recurrent networks of current-based leaky integrate-and-fire (LIF) neurons. To assess the degree of balance of a steady state, we extend existing mean-field theories so that not only the firing rate, but also the coefficient of variation of the interspike interval distribution of the neurons, are determined self-consistently. Depending on the connectivity parameters of the network, we find bistable solutions of different types. If the local recurrent connectivity is mainly excitatory, the two stable steady states differ mainly in the mean current to the neurons. In this case, the mean drive in the elevated persistent activity state is suprathreshold and typically characterized by low spiking irregularity. If the local recurrent excitatory and inhibitory drives are both large and nearly balanced, or even dominated by inhibition, two stable states coexist, both with subthreshold current drive. In this case, the spiking variability in both the resting state and the mnemonic persistent state is large, but the balance condition implies parameter fine-tuning. Since the degree of required fine-tuning increases with network size and, on the other hand, the size of the fluctuations in the afferent current to the cells increases for small networks, overall we find that fluctuation-driven persistent activity in the very simplified type of models we analyze is not a robust phenomenon. Possible implications of considering more realistic models are discussed.

Action Potentials↗

PubMed2006

Cortico-basal ganglia circuit mechanism for a decision threshold in reaction time tasks.

Growing evidence from primate neurophysiology and modeling indicates that in reaction time tasks, a perceptual choice is made when the firing rate of a selective cortical neural population reaches a threshold. This raises two questions: what is the neural substrate of the threshold and how can it be adaptively tuned according to behavioral demands? Using a biophysically based network model of spiking neurons, we show that local dynamics in the superior colliculus gives rise to an all-or-none burst response that signals threshold crossing in upstream cortical neurons. Furthermore, the threshold level depends only weakly on the efficacy of the cortico-collicular pathway. In contrast, the threshold and the rate of reward harvest are sensitive to, and hence can be optimally tuned by, the strength of cortico-striatal synapses, which are known to be modifiable by dopamine-dependent plasticity. Our model provides a framework to describe the main computational steps in a reaction time task and suggests that separate brain pathways are critical to the detection and adjustment of a decision threshold.

Action Potentials↗

PubMed2006

Influx of extracellular Ca2+ involved in jasmonic-acid-induced elevation of [Ca2+]cyt and JR1 expression in Arabidopsis thaliana.

The changes in cytosolic Ca2+ levels play important roles in the signal transduction pathways of many environmental and developmental stimuli in plants and animals. We demonstrated that the increase in cytosolic free Ca2+ concentration ([Ca2+]cyt) of Arabidopsis thaliana leaf cells was induced by exogenous application of jasmonic acid (JA). The elevation of [Ca2+]cyt was detected within 1 min after JA treatment by the fluorescence intensity using laser scanning confocal microscopy, and the elevated level of fluorescence was maintained during measuring time. With pretreatment of nifedipine (Nif), a nonpermeable L-type channel blocker, the fluorescence of [Ca2+]cyt induced by JA was inhibited in a dose-dependent manner. In contrast, verapamil, another L-type channel blocker, had no significant effect. Furthermore, Nif repressed JA-induced gene expression of JR1 but verapamil did not. JA-induced gene expression could be mimicked by higher concentration of extracellular Ca2+. W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide], an antagonist of calmodulin (CaM), blocked the JA induction of JR1 expression while W-5 [N-(6-aminohexyl)-1-naphthalenesulfonamide], its inactive antagonist, had no apparent effect. These data provide the evidence that the influx of extracellular Ca2+ through Nif sensitive plasma membrane Ca2+ channel may be responsible for JA-induced elevation of [Ca2+]cyt and downstream gene expression, CaM may be also involved in JA signaling pathway.

Arabidopsis↗

PubMed2006

Loss of transforming growth factor-beta type II receptor promotes metastatic head-and-neck squamous cell carcinoma.

The prognosis of head-and-neck squamous cell carcinoma (HNSCC) has not been improved in the past 20 years. Validation of HNSCC biomarkers for targeted therapy has been hindered by a lack of animal models mimicking human HNSCC at both the pathological and molecular levels. Here we report that overexpression of K-ras or H-ras and loss of transforming growth factor-beta type II receptor (TGFbetaRII) are common events in human HNSCC. Activation of either K-ras or H-ras in combination with TGFbetaRII deletion from mouse head-and-neck epithelia caused HNSCC with complete penetrance, some of which progressed to metastases. These tumors displayed pathology indistinguishable from human HNSCCs and exhibited multiple molecular alterations commonly found in human HNSCCs. Additionally, elevated endogenous TGFbeta1 in these lesions contributed to inflammation and angiogenesis. Our data suggest that targeting common oncogenic pathways in tumor epithelia together with blocking the effect of TGFbeta1 on tumor stroma may provide a novel therapeutic strategy for HNSCC.

Animals↗

PubMed2006

Reactivation of developmentally expressed p63 isoforms predisposes to tumor development and progression.

Genes that are active during normal development are frequently reactivated during neoplastic transformation. We now report that developmentally expressed TAp63 isoforms are frequently reactivated in human squamous cell carcinomas. To determine the consequences of TAp63 reactivation, we induced TAp63alpha expression during chemically-induced skin carcinogenesis. Deregulated TAp63alpha expression dramatically accelerated tumor development and progression, frequently resulting in epithelial-mesenchymal transitions to spindle cell carcinomas and lung metastases. Consistent with this observation, we detected high levels of Twist and N-cadherin in tumors overexpressing TAp63alpha. Thus, as observed for other developmental pathways, aberrant reactivation of TAp63 predisposes to tumor development and progression.

Animals↗

PubMed2006

A biophysically based neural model of matching law behavior: melioration by stochastic synapses.

In experiments designed to uncover the neural basis of adaptive decision making in a foraging environment, neuroscientists have reported single-cell activities in the lateral intraparietal cortex (LIP) that are correlated with choice options and their subjective values. To investigate the underlying synaptic mechanism, we considered a spiking neuron model of decision making endowed with synaptic plasticity that follows a reward-dependent stochastic Hebbian learning rule. This general model is tested in a matching task in which rewards on two targets are scheduled randomly with different rates. Our main results are threefold. First, we show that plastic synapses provide a natural way to integrate past rewards and estimate the local (in time) "return" of a choice. Second, our model reproduces the matching behavior (i.e., the proportional allocation of choices matches the relative reinforcement obtained on those choices, which is achieved through melioration in individual trials). Our model also explains the observed "undermatching" phenomenon and points to biophysical constraints (such as finite learning rate and stochastic neuronal firing) that set the limits to matching behavior. Third, although our decision model is an attractor network exhibiting winner-take-all competition, it captures graded neural spiking activities observed in LIP, when the latter were sorted according to the choices and the difference in the returns for the two targets. These results suggest that neurons in LIP are involved in selecting the oculomotor responses, whereas rewards are integrated and stored elsewhere, possibly by plastic synapses and in the form of the return rather than income of choice options.

Action Potentials↗

PubMed2006

A recurrent network mechanism of time integration in perceptual decisions.

Recent physiological studies using behaving monkeys revealed that, in a two-alternative forced-choice visual motion discrimination task, reaction time was correlated with ramping of spike activity of lateral intraparietal cortical neurons. The ramping activity appears to reflect temporal accumulation, on a timescale of hundreds of milliseconds, of sensory evidence before a decision is reached. To elucidate the cellular and circuit basis of such integration times, we developed and investigated a simplified two-variable version of a biophysically realistic cortical network model of decision making. In this model, slow time integration can be achieved robustly if excitatory reverberation is primarily mediated by NMDA receptors; our model with only fast AMPA receptors at recurrent synapses produces decision times that are not comparable with experimental observations. Moreover, we found two distinct modes of network behavior, in which decision computation by winner-take-all competition is instantiated with or without attractor states for working memory. Decision process is closely linked to the local dynamics, in the "decision space" of the system, in the vicinity of an unstable saddle steady state that separates the basins of attraction for the two alternative choices. This picture provides a rigorous and quantitative explanation for the dependence of performance and response time on the degree of task difficulty, and the reason for which reaction times are longer in error trials than in correct trials as observed in the monkey experiment. Our reduced two-variable neural model offers a simple yet biophysically plausible framework for studying perceptual decision making in general.

Animals↗

PubMed2006

Abscisic acid stimulates a calcium-dependent protein kinase in grape berry.

It has been demonstrated that calcium plays a central role in mediating abscisic acid (ABA) signaling, but many of the Ca2+-binding sensory proteins as the components of the ABA-signaling pathway remain to be elucidated. Here we identified, characterized, and purified a 58-kD ABA-stimulated calcium-dependent protein kinase from the mesocarp of grape berries (Vitis vinifera x Vitis labrusca), designated ACPK1 (for ABA-stimulated calcium-dependent protein kinase1). ABA stimulates ACPK1 in a dose-dependent manner, and the ACPK1 expression and enzyme activities alter accordantly with the endogenous ABA concentrations during fruit development. The ABA-induced ACPK1 stimulation appears to be transient with a rapid effect in 15 min but also with a slow and steady state of induction after 60 min. ABA acts on ACPK1 indirectly and dependently on in vivo state of the tissues. Two inactive ABA isomers, (-)-2-cis, 4-trans-ABA and 2-trans, 4-trans-(+/-)-ABA, are ineffective for inducing ACPK1 stimulation, revealing that the ABA-induced effect is stereo specific to physiological active (+)-2-cis, 4-trans-ABA. The other phytohormones such as auxin indoleacetic acid, gibberellic acid, synthetic cytokinin N-benzyl-6-aminopurine, and brassinolide are also ineffective in this ACPK1 stimulation. Based on sequencing of the two-dimensional electrophoresis-purified ACPK1, we cloned the ACPK1 gene. The ACPK1 is expressed specifically in grape berry covering a fleshy portion and seeds, and in a developmental stage-dependent manner. We further showed that ACPK1 is localized in both plasma membranes and chloroplasts/plastids and positively regulates plasma membrane H+-ATPase in vitro, suggesting that ACPK1 may be involved in the ABA-signaling pathway.

Abscisic Acid↗

PubMed2006

Mouse models for human head and neck squamous cell carcinomas.

Mouse models of human cancer play an important role in understanding the mechanisms of carcinogenesis and have accelerated the search for finding new molecular targets for cancer therapy. However, genetically engineered mouse models for head and neck squamous cell carcinoma (HNSCC) have only recently overcome major technical obstacles and begun to be explored. Here we review the current progress in the development of mouse models for human HNSCC, with emphasis on conditional transgenic and knockout mouse models. These new models faithfully recapitulate human HNSCC at both the pathologic and molecular levels. These animal models will not only be useful to define the roles of specific genes in HNSCC development and progression but will also provide a unique tool for developing and testing new therapeutic approaches.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2006

Role of TGFbeta in skin inflammation and carcinogenesis.

The functions of transforming growth factor beta-1(TGFbeta1) are cell-context specific. We have found that TGFbeta1 expression in human skin squamous cell carcinoma (SCC) samples has two distinct distribution patterns: (1) either predominantly in suprabasal layers or (2) throughout tumor epithelia including basal proliferative cells. To understand whether the spatial TGFbeta1 expression patterns affect its functions, we have generated several keratinocyte-specific transgenic mouse models in which TGFbeta1 overexpression can be induced either predominantly in the suprabasal epidermis or in the basal layer of the epidermis and hair follicles. Suprabasal TGFbeta1 overexpression inhibits keratinocyte proliferation, suppresses skin carcinogenesis at early stages, but promotes tumor invasion at later stages. In contrast, TGFbeta1 overexpression in the basal layer of the epidermis and hair follicles causes a severe inflammatory skin disorder and epidermal hyperproliferation. Given the importance of inflammation in cancer development, our data suggest that TGFbeta1-induced skin inflammation may override its tumor suppressive effect at early stages during skin carcinogenesis. This hypothesis is further suggested by our recent study that Smad3 knockout mice are resistant to skin chemical carcinogenesis at least in part via abrogation of endogenous TGFbeta1-induced inflammation. This review intends to summarize current insights into the role of TGFbeta1 in skin inflammation and carcinogenesis.

Animals↗

PubMed2006

Smad7-induced beta-catenin degradation alters epidermal appendage development.

To assess whether Smad signaling affects skin development, we generated transgenic mice in which a Smad antagonist, Smad7, was induced in keratinocytes, including epidermal stem cells. Smad7 transgene induction perturbed hair follicle morphogenesis and differentiation, but accelerated sebaceous gland morphogenesis. Further analysis revealed that independent of its role in anti-Smad signaling, Smad7 bound beta-catenin and induced beta-catenin degradation by recruiting an E3 ligase, Smurf2, to the Smad7/beta-catenin complex. Consequently, Wnt/beta-catenin signaling was suppressed in Smad7 transgenic hair follicles. Coexpression of the Smurf2 and Smad7 transgenes exacerbated Smad7-induced abnormalities in hair follicles and sebaceous glands. Conversely, when endogenous Smad7 was knocked down, keratinocytes exhibited increased beta-catenin protein and enhanced Wnt signaling. Our data reveal a mechanism for Smad7 in antagonizing Wnt/beta-catenin signaling, thereby shifting the skin differentiation program from forming hair follicles to sebaceous glands.

Animals↗

PubMed2006

Neural mechanism for stochastic behaviour during a competitive game.

Previous studies have shown that non-human primates can generate highly stochastic choice behaviour, especially when this is required during a competitive interaction with another agent. To understand the neural mechanism of such dynamic choice behaviour, we propose a biologically plausible model of decision making endowed with synaptic plasticity that follows a reward-dependent stochastic Hebbian learning rule. This model constitutes a biophysical implementation of reinforcement learning, and it reproduces salient features of behavioural data from an experiment with monkeys playing a matching pennies game. Due to interaction with an opponent and learning dynamics, the model generates quasi-random behaviour robustly in spite of intrinsic biases. Furthermore, non-random choice behaviour can also emerge when the model plays against a non-interactive opponent, as observed in the monkey experiment. Finally, when combined with a meta-learning algorithm, our model accounts for the slow drift in the animal's strategy based on a process of reward maximization.

Algorithms↗

PubMed2006

Role of TGF beta-mediated inflammation in cutaneous wound healing.

Among many molecules known to influence wound healing, transforming growth factor beta 1 (TGF beta 1) has the broadest spectrum of actions, affecting all cell types that are involved in all stages of wound healing. Both positive and negative effects of TGF beta 1 on wound healing have been reported. However, the underlying mechanisms are largely unknown. We observed that endogenous TGF beta 1 was elevated in a narrow window of time after injury, and transgenic mice constitutively overexpressing wild-type TGF beta 1 in keratinocytes (K5.TGF beta 1wt) exhibited a significant delay in full-thickness wound healing as compared to non-transgenic mice. Delayed wound healing was associated with profound inflammation throughout all stages of wound healing in K5.TGF beta 1wt mice. Our data suggest that excessive and prolonged TGF beta 1 at the wound site does not benefit wound healing, which is partially owing to its pro-inflammatory effect. Future studies need to be conducted to assess whether tightly regulated TGF beta 1 expression will benefit wound healing. To this end, we have developed a gene-switch TGF beta 1 transgenic system that allows TGF beta 1 induction in keratinocytes temporally with desired levels. These mice will provide a tool to study stage-specific effects of TGF beta 1 on cutaneous wound healing.

Animals↗

PubMed2006

Stability of discrete memory states to stochastic fluctuations in neuronal systems.

Noise can degrade memories by causing transitions from one memory state to another. For any biological memory system to be useful, the time scale of such noise-induced transitions must be much longer than the required duration for memory retention. Using biophysically-realistic modeling, we consider two types of memory in the brain: short-term memories maintained by reverberating neuronal activity for a few seconds, and long-term memories maintained by a molecular switch for years. Both systems require persistence of (neuronal or molecular) activity self-sustained by an autocatalytic process and, we argue, that both have limited memory lifetimes because of significant fluctuations. We will first discuss a strongly recurrent cortical network model endowed with feedback loops, for short-term memory. Fluctuations are due to highly irregular spike firing, a salient characteristic of cortical neurons. Then, we will analyze a model for long-term memory, based on an autophosphorylation mechanism of calcium/calmodulin-dependent protein kinase II (CaMKII) molecules. There, fluctuations arise from the fact that there are only a small number of CaMKII molecules at each postsynaptic density (putative synaptic memory unit). Our results are twofold. First, we demonstrate analytically and computationally the exponential dependence of stability on the number of neurons in a self-excitatory network, and on the number of CaMKII proteins in a molecular switch. Second, for each of the two systems, we implement graded memory consisting of a group of bistable switches. For the neuronal network we report interesting ramping temporal dynamics as a result of sequentially switching an increasing number of discrete, bistable, units. The general observation of an exponential increase in memory stability with the system size leads to a trade-off between the robustness of memories (which increases with the size of each bistable unit) and the total amount of information storage (which decreases with increasing unit size), which may be optimized in the brain through biological evolution.

Action Potentials↗

PubMed2006

[Study on the asexual sporulation of Aspergillus niger under blue light induction and analysis of its subtractive library].

The effect of blue light (BL) on the morphological development of Aspergillus niger was studied by the scanning electron microscopy (SEM) observation. Comparing with the darkness, BL was able to stimulate development of sporangiophore and conidiosphore, promote grownth of mycelium. Suppression subtractive hybridization (SSH) was conducted with tester cDNA which was from 39 to approximately 40h-old mycelium cultured under darkness and driver cDNA which was from mycelium illuminated for 3 to approximately 4h under BL after dark growth. Some cDNA bands were obtained by suppression PCR (polymerase chain reaction) with the subtractive cDNA. Positive bacterial clones were randomly picked and identified by colony PCR method. Through sequence alignments from GenBank, most of differential cDNA fragments were highly identical with some redox enzymes existing in mitochondria, and the quantitative measurement of these differential mRNA by real time RT-PCR indicated that relative expression of the identified gene fragments under BL induction was higher than that under darkness. Furthermore, the result suggested that some respiratory chain redox enzymes of mitochondria were involved in the photoresponse and consequently influence the metabolism. Among differential cDNA fragments two unkown sequences were found and their complete gene and gene function remained to be investigated.

Aspergillus niger↗

PubMed2006

[Hemangiopoiet in modulates adhesive properties of endothelial cells].

OBJECTIVE: To explore the effect of hemangiopoietin (HAPO) on the adhesive properties of human umbilical vein endothelial cells (HUVEC). METHODS: The adhesion of HUVEC and the expressions of CD54, CD102, CD106, CD31, CD62E, and CD62P were measured by adhesion assay, flow cytometry, and semi-quantitative RT-PCR. RESULTS: HAPO enhanced the total adherence of HUVEC in a concentration-dependent manner. Flow cytometry analysis revealed that the treatment of HAPO resulted in a significantly increased expression of CD106 and CD62E on HUVEC in a time-dependent manner. When HUVEC were incubated with HAPO for 6 h, the percentage of CD106 + HUVEC and CD62E HUVEC increased about 2.10 folds and 5.84 folds, respectively, compared with control. The time-course of adhesive molecules mRNA expression indicated that the expression of CD106 and CD62E reached at the maximum 1.86 folds and 6.16 folds, respectively, compared with control. CONCLUSION: HAPO may facilitate the homing of hematopoietic stem/progenitor cells.

Cell Adhesion Molecules↗

PubMed2006

[Glucoamylase enhancement regulated by blue light in Aspergillus niger].

Regulation of glucoamylase production in photoinduced A. niger under blue light were investigated. The results showed that continuous illumination of blue light was effective in promotion of conidiation, leading to more glucoamylase production due to the need of sporulation in A. niger. It was clear that 36h-old mycelium grown in dark was in the developmental stage of formation of conidiophore stalk and was most sensitive to BL A. niger cultures exhibited some competence stage to respond to blue light over a period of 36 h when early conidiophore stalk formed in darkness, and photoinduction at this critical period resulted in relatively higher yield of glucoamylase. The fluence-response data generated with blue light indicated that the optimum fluence required for the photomorphogenetic response in A. niger was no less than 450 (mol/m2 x s) to saturate the photoinduction system. The amount of glucoamylase gene (G1) transcripts accumulated during illumination with blue light was more than that in total darkness, whereas the threshold for G1 induction during illumination with increased gradient light was higher than that exposed directly to light of constant fluence, indicating the existence of a light adaptation mechanism for glucoamyalse production in response to blue light. Nevertheless, both high and low light were able to promote glucoamylase producing. Furthermore, suppression subtractive hybridization experiment revealed that some respiratory chain redox enzymes in mitochondria including alternative oxidase as well as sulfhydryl oxidase participated the photoresponse in A. niger and consequently influenced the metabolism. The results support a possibility of designing strategies to improve glucoamylase yield by application of blue light.

Aspergillus niger↗

PubMed2005

Inhibitory control by an integral feedback signal in prefrontal cortex: a model of discrimination between sequential stimuli.

The prefrontal cortex (PFC) is known to be critical for inhibitory control of behavior, but the underlying mechanisms are unclear. Here, we propose that inhibitory control can be instantiated by an integral signal derived from working memory, another key function of the PFC. Specifically, we assume that an integrator converts excitatory input into a graded mnemonic activity that provides an inhibitory signal (integral feedback control) to upstream afferent neurons. We demonstrate this scenario in a neuronal-network model for a temporal discrimination task. The task requires the working memory of the vibrational frequency (f1) of an initial stimulus (stimulus 1), followed by comparison of the frequency (f2) of a second stimulus (stimulus 2) with the stored f1 and a binary decision (f2 > f1 or f2 < f1). The integral feedback signal generated by stimulus 1 gates the later inputs based on the amplitude difference (f2 - f1). The feedback control signal enables a subset of neurons to reverse their tuning to f1 between stimulus 1 and stimulus 2, when they become tuned to the difference, f2 - f1. These neurons maintain a lower firing rate during the delay compared with their peak rate during stimulus 1. A second subset of neurons, tuned to f1 during the delay, reaches a rate during stimulus 2 that depends on the maximum of f1 and f2. Our work suggests a circuit mechanism for discrimination across time and predicts neuronal behavior that can be tested experimentally.

Discrimination, Psychological↗