Fiedler value: The cumulated dynamical contribution value of all edges in a complex network.

Fiedler value, as the minimal real part of (or the minimal) nonzero Laplacian eigenvalue, garners significant attention as a metric for evaluating network topology and its dynamics. In this paper, we address the quantification relation between Fiedler value and each edge in a directed complex network, considering undirected networks as a special case. We propose an approach to measure the dynamical contribution value of each edge. Interestingly, these contribution values can be both positive and negative, which are determined by the left and right Fiedler vectors. Further, we show that the cumulated dynamical contribution value of all edges is exactly the Fiedler value. This provides a promising angle on the Fiedler value in terms of dynamics and network structure. Therefore, the percentage of contribution of each edge to the Fiedler value is quantified. Numerical results reveal that network dynamics is significantly influenced by a small fraction of edges, say, one single directed edge contributes to over 90% of the Fiedler value in the Cat Cerebral Cortex network.

Lead exposure induces neurodysfunction through caspase-1-mediated neuronal pyroptosis.

Chronic lead (Pb) exposure causes neurodysfunction and contributes to the development of neurodegenerative disease. However, the mechanism of Pb-induced neurological dysfunction have yet to be fully elucidated. This study determined the role pyroptosis plays in Pb-induced neurodysfunction in neurons. We used both in vitro and in vivo approaches to explore whether Pb exposure induces caspase-1-mediated pyroptosis in neurons and its relationship to Pb-induced neurological disorders. Our findings showed that caspase-1-mediated pyroptosis in Pb-exposed neurons activated glycogen synthase kinase 3 protease activity by disrupting Ca2+/calmodulin-dependent protein kinase II/cAMP-response element binding protein pathway, leading to neurological disorders. Moreover, the caspase-1 inhibition VX-765 or the non-steroidal anti-inflammatory drug sodium para-aminosalicylic acid (PAS-Na) attenuated the Pb-induced neurological disorders by alleviating caspase-1 mediated neuronal pyroptosis. Our novel studies suggest that caspase-1-mediated pyroptosis in neurons represents a potential mechanism for Pb-induced neurodysfunction, identifying a putative target for attenuating the neurodegenerative effects induced by this metal.

A ratiometric fluorescent probe for the detection of biological thiols based on a new supramolecular design.

A new ratiometric fluorescent probe is designed and prepared based on the concept of supramolecular encapsulation and dye competition. This supramolecular probe is based on two commercially-available dyes, one common guest and a simple-to-synthesize host. Fluorescence spectroscopy confirms that the supramolecular probe is capable of detecting thiols quantitatively with a broad linear region in phosphate buffered saline or fetal bovine serum. Mechanistic study shows a reaction between thiol specie and the guest to alter the distribution of encapsulated dyes. The supramolecular probes are demonstrated to quantitatively detect extracellular biological thiols by plate reader, which shows it keeps its effectiveness in complex buffered systems.

Searching for Key Cycles in a Complex Network.

Searching for key nodes and edges in a network is a long-standing problem. Recently cycle structure in a network has received more attention. Is it possible to propose a ranking algorithm for cycle importance? We address the problem of identifying the key cycles of a network. First, we provide a more concrete definition of importance-in terms of Fiedler value (the second smallest Laplacian eigenvalue). Key cycles are those that contribute most substantially to the dynamical behavior of the network. Second, by comparing the sensitivity of Fiedler value to different cycles, a neat index for ranking cycles is provided. Numerical examples are given to show the effectiveness of this method.

pH-sensing supramolecular fluorescent probes discovered by library screening.

A new design concept for pH-sensing supramolecular fluorescent probes is reported. Supramolecular fluorescent pH probes based on pro-guest are designed and prepared. Pro-guests are designed to degrade under acidic condition and convert to competitive guests to displace encapsulated dyes, which leads to a significant enhancement in fluorescence intensity. A library of potential fluorescent pH probes is generated and screened to discover workable probes. These probes are capable of detecting the acidic pH in solution phase. We confirm that these supramolecular probes could detect the acidic environment in endosomal compartments in live cells.

Pairwise learning problems with regularization networks and Nyström subsampling approach.

Pairwise learning usually refers to the learning problem that works with pairs of training samples, such as ranking, similarity and metric learning, and AUC maximization. To overcome the challenge of pairwise learning in the large scale computation, this paper introduces Nyström sampling approach to the coefficient-based regularized pairwise algorithm in the context of kernel networks. Our theorems establish that the obtained Nyström estimator achieves the minimax error over all estimators using the whole data provided that the subsampling level is not too small. We derive the function relation between the subsampling level and regularization parameter that guarantees computation cost reduction and asymptotic behaviors' optimality simultaneously. The Nyström coefficient-based pairwise learning method does not require the kernel to be symmetric or positive semi-definite, which provides more flexibility and adaptivity in the learning process. We apply the method to the bipartite ranking problem, which improves the state-of-the-art theoretical results in previous works. By developing probability inequalities for U-statistics on Hilbert-Schmidt operators, we provide new mathematical tools for handling pairs of examples involved in pairwise learning.

Sodium Para-aminosalicylic Acid Inhibits Lead-Induced Neuroinflammation in Brain Cortex of Rats by Modulating SIRT1/HMGB1/NF-κB Pathway.

Lead (Pb) is considered to be a major environmental pollutant and occupational health hazard worldwide which may lead to neuroinflammation. However, an effective treatment for Pb-induced neuroinflammation remains elusive. The aim of this study was to investigate the mechanisms of Pb-induced neuroinflammation, and the therapeutic effect of sodium para-aminosalicylic acid (PAS-Na, a non-steroidal anti-inflammatory drug) in rat cerebral cortex. The results indicated that Pb exposure induced pathological damage in cerebral cortex, accompanied by increased levels of inflammatory factors tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß). Moreover, Pb decreased the expression of silencing information regulator 2 related enzyme 1 (SIRT1) and brain-derived neurotrophic factor (BDNF), and increased the levels of high mobile group box 1 (HMGB1) expression and p65 nuclear factor-κB (NF-κB) phosphorylation. PAS-Na treatment ameliorated Pb-induced histopathological changes in rat cerebral cortex. Moreover, PAS-Na reduced the Pb-induced increase of TNF-α and IL-1ß levels concomitant with a significant increase in SIRT1 and BDNF levels, and a decrease in HMGB1 and the phosphorylation of p65 NF-κB expression. Thus, PAS-Na may exert anti-inflammatory effects by mediating the SIRT1/HMGB1/NF-κB pathway and BDNF expression. In conclusion, in this novel study PAS-Na was shown to possess an anti-inflammatory effect on cortical neuroinflammation, establishing its efficacy as a potential treatment for Pb exposures.

Sodium para-aminosalicylic acid ameliorates lead-induced hippocampal neuronal apoptosis by suppressing the activation of the IP3R-Ca2+-ASK1-p38 signaling pathway.

Lead (Pb) is a naturally occurring heavy metal, which can damage the brain and affect learning and memory. Sodium para-aminosalicylic acid (PAS-Na), a non-steroidal anti-inflammatory drug, can readily cross the blood-brain barrier. Our previous studies have found that PAS-Na alleviated Pb-induced hippocampal ultrastructural damage and neurodegeneration, but the mechanism has yet to be defined. Here, we investigated the molecular mechanisms that mediate Pb-induced apoptosis in hippocampal neurons, and the efficacy of PAS-Na in alleviating its effects. This work showed that juvenile developmental Pb exposure impaired rats cognitive ability by inducing apoptotic cell death in hippocampal neurons. Pb-induced neuronal apoptosis was accompanied by increased inositol 1,4,5-trisphosphate receptor (IP3R) expression and enhanced intracellular calcium [Ca2+]i levels, which resulted in increased phosphorylation of neuronal apoptosis signal-regulating kinase 1 (ASK1) and p38. Activation of ASK1 and p38 was blocked by IP3R inhibitor and a Ca2+ chelator. Importantly, PAS-Na treatment improved the Pb-induced effects on cognitive deficits in rats, concomitant with rescued neuronal apoptosis. In addition, PAS-Na reduced the expression of IP3R and the ensuing increase in intracellular Ca2+ and decreased the phosphorylation of ASK1 and p38 in Pb-exposed neurons. Taken together, this study demonstrates that the IP3R-Ca2+-ASK1-p38 signaling pathway mediates Pb-induced apoptosis in hippocampal neurons, and that PAS-Na, at a specific dose-range, ameliorates these changes. Collectively, this study sheds novel light on the cellular mechanisms that mediate PAS-Na efficacy, laying the groundwork for future research to examine the treatment potential of PAS-Na upon Pb poisoning.

Supramolecular Fluorescent Probes for the Detection of Reactive Oxygen Species Discovered via High-Throughput Screening.

Supramolecular fluorescent probes for the detection of reactive oxygen species (ROSs) are designed based on a pro-guest strategy. Nine commercially available fluorescent dyes, six host molecules, and a pro-guest are used to rapidly generate a library of 54 potential supramolecular probes. These potential supramolecular probes are screened in a high-throughput fashion using a plate reader to discover seven "hits" or workable probes. The mechanism is confirmed to be ROS-induced conversion from a low-binding-affinity pro-guest to a high-binding-affinity guest and the competitive displacement of the encapsulated fluorescent dye. The response to H2O2 of four supramolecular probes is found to be concentration-dependent and may be used for quantitative analysis of H2O2. The supramolecular probe is selectively responsive toward other oxidative agents, such as NaClO and Na2SO3. The cell study shows that supramolecular probes are capable of detecting H2O2 in human cancer cells (MCF-7 or HeLa).

Step-Growth Cyclo-Oligomerization for the Preparation of Functionalized Pillar[6]arenes with Alternating Methylene Bridge Substitutions.

Methylene-bridge-substituted pillar[6]arenes (PA[6]) are synthesized by step-growth cyclo-oligomerization. Dimers, trimers, tetramers, and hexamers with substituted methylene bridges are synthesized. Hexamers are converted to PA[6] derivatives with alternating methylene bridge substitutions by ring-closing reactions. PA[6] derivatives are further modified with pyrene groups or carboxylate groups by Suzuki-Miyaura coupling reactions. The modifications render PA[6] fluorescent or water-soluble. A host-guest chemistry study confirms that the water-soluble PA[6] derivative is a high-affinity host toward suitable guests in water.

Plumbagin attenuates traumatic tracheal stenosis in rats and inhibits lung fibroblast proliferation and differentiation via TGF-ß1/Smad and Akt/mTOR pathways.

Traumatic tracheal stenosis (TS) is a serious respiratory disease characterized by hyperplasia of airway granulation. Plumbagin (PLB) is a natural naphthoquinone component with anti-fibrotic properties. This research aimed to explore the roles of PLB in alleviating TS and the underlying mechanisms. For in vitro studies, lung fibroblasts (IMR-90 cells), with/without PLB treatment or TGF-ß1 induction, were used. The viability and proliferation of IMR-90 cells were examined by CCK-8 and EdU incorporation assays. The differentiation of IMR-90 cells was assessed by detecting the mRNA and protein expression levels of collagen (COL)-1 and alpha-smooth muscle actin (α-SMA). Besides, immunofluorescence assay was conducted to evaluate the localization of α-SMA in TGF-ß1-induced IMR-90 cells. Moreover, the combination of PLB with/without TßRI (SB-431,542), PI3K/Akt (Ly294002) or mTOR (rapamycin) inhibitor was pretreated on IMR-90 cells after TGF-ß1 induction. For in vivo studies, a rat model of TS was established. The pathological features and severity of TS were determined by hematoxylin and eosin staining. The protein levels of TGF-ß1/Smad and Akt/mTOR pathways were detected for both in vitro and in vivo models. PLB effectively inhibited the proliferation and differentiation of TGF-ß1-induced IMR-90 cells, and suppressed TGF-ß1/Smad and Akt/mTOR signaling pathways both in vivo and in vitro. Furthermore, PLB reduced the degree of TS in rats. Taken together, our results indicate that PLB regulates lung fibroblast activity and attenuates TS in rats by inhibiting TGF-ß1/Smad and Akt/mTOR signaling pathways. In conclusion, this study implies that PLB may serve as a promising therapeutic compound for TS.

Pro-guest and acyclic cucurbit[n]uril conjugated polymers for the controlled release of anti-tumor drugs.

We report "pro-guest" and acyclic cucurbit[n]uril conjugated polymers as supramolecular drug delivery systems (DDSs). These supramolecular DDSs could encapsulate anti-tumor drugs. Under acidic conditions, an acid-labile "pro-guest" degraded to become a "competing guest", which displaced and released the encapsulated drug at a tunable rate.