Alternative polyadenylation quantitative trait methylation mapping in human cancers provides clues into the molecular mechanisms of APA.

Genetic variants are involved in the orchestration of alternative polyadenylation (APA) events, while the role of DNA methylation in regulating APA remains unclear. We generated a comprehensive atlas of APA quantitative trait methylation sites (apaQTMs) across 21 different types of cancer (1,612 to 60,219 acting in cis and 4,448 to 142,349 in trans). Potential causal apaQTMs in non-cancer samples were also identified. Mechanistically, we observed a strong enrichment of cis-apaQTMs near polyadenylation sites (PASs) and both cis- and trans-apaQTMs in proximity to transcription factor (TF) binding regions. Through the integration of ChIP-signals and RNA-seq data from cell lines, we have identified several regulators of APA events, acting either directly or indirectly, implicating novel functions of some important genes, such as TCF7L2, which is known for its involvement in type 2 diabetes and cancers. Furthermore, we have identified a vast number of QTMs that share the same putative causal CpG sites with five different cancer types, underscoring the roles of QTMs, including apaQTMs, in the process of tumorigenesis. DNA methylation is extensively involved in the regulation of APA events in human cancers. In an attempt to elucidate the potential underlying molecular mechanisms of APA by DNA methylation, our study paves the way for subsequent experimental validations into the intricate biological functions of DNA methylation in APA regulation and the pathogenesis of human cancers. To present a comprehensive catalog of apaQTM patterns, we introduce the Pancan-apaQTM database, available at https://pancan-apaqtm-zju.shinyapps.io/pancanaQTM/.

SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition.

The cell-cycle checkpoint kinase WEE1 is emerging as a therapeutic target for cancer treatment. However, how its catalytic activity is regulated remains poorly understood, and reliable biomarkers for predicting response to WEE1 inhibitor remain to be identified. Here we identify an evolutionarily conserved segment surrounding its Lys177 residue that inhibits WEE1 activity through an intermolecular interaction with the catalytic kinase domain. Upon DNA damage, CHK1-dependent phosphorylation of WEE1 at Ser642 primes GCN5-mediated acetylation at Lys177, resulting in dissociation of the inhibitory segment from the kinase domain and subsequent activation of WEE1 and cell-cycle checkpoints. Conversely, SIRT1 associates with and deacetylates WEE1, which maintains it in an inactive state. Consequently, SIRT1 deficiency induces WEE1 hyperacetylation and activation, rendering cancer cells resistant to WEE1 inhibition. These results suggest that SIRT1 expression level and abundance of WEE1 Lys177 acetylation in tumor cells can serve as useful biomarkers for predicting WEE1 inhibitor sensitivity or resistance.

Corneal endothelial regeneration in human eyes using endothelium-free grafts.

BACKGROUND: To report on corneal endothelial regeneration, graft clarity, and vision recovery when using endothelium-free grafts. METHODS: We evaluated the donor's cell viability using trypan blue staining and dual staining with calcein acetoxy methyl ester and ethidium homodimer-1. To preserve eyeball integrity, we performed therapeutic penetrating keratoplasty using cryopreserved donor tissue without endothelium on 195 consecutive patients who suffered from corneal perforation due to progressive primary corneal disease such as herpes simplex keratitis, fungal keratitis, ocular thermal burns, keratoconus, and phlyctenular keratoconjunctivitis. Of these, 18 eyes recovered corneal graft clarity and underwent periodic slit-lamp microscopy, A-scan pachymetry, and in vivo confocal microscopy to observe the clinical manifestations, variations in corneal thickness, and repopulation of the corneal endothelial cells on the donor grafts. RESULTS: No viable cells were detected in the cryopreserved corneas. After the therapeutic penetrating keratoplasty, notable corneal graft edema was observed in all 18 eyes for 1-4 months, and no corneal endothelial cells were detected on the grafts during this period. Thereafter, we observed gradual and progressive regression and final resolution of the stromal edema, with complete recovery of corneal graft clarity. Through periodic confocal microscopy, we observed the corneal endothelium's regenerating process, along with single cells bearing multiple nuclei and cell division-like morphology. The regenerated endothelium on the grafts reached a mean cell density of 991 cells/mm2. Remarkable vision rehabilitation was achieved in all 18 patients. CONCLUSIONS: We obtained conclusive evidence that host-derived endothelial cells can regenerate a new endothelium over the endothelium-free graft, which possesses normal functions for corneal clarity and vision recovery.

Sampling-based box-covering algorithm for renormalization of networks.

Covering a network with minimum number of boxes is critical for using the renormalization technique to explore the network configuration space in a multiscale fashion. Here, we propose a versatile methodology composed of flexible representation and sampling of boxes, which have so far received scant attention, and the strategy of selecting boxes to cover the network. It is exemplified via random box sampling strategies and greedy methods to select boxes. We show that the key to substantially reduce the number of boxes is to give the selection priority to those boxes containing nodes that are not included in boxes bigger than themselves. Our algorithm achieves the improvement of diminishing the number of boxes amounting to nearly 25% compared with these well known algorithms.

Series-nonuniform rational B-spline signal feedback: From chaos to any embedded periodic orbit or target point.

The self-controlling feedback control method requires an external periodic oscillator with special design, which is technically challenging. This paper proposes a chaos control method based on time series non-uniform rational B-splines (SNURBS for short) signal feedback. It first builds the chaos phase diagram or chaotic attractor with the sampled chaotic time series and any target orbit can then be explicitly chosen according to the actual demand. Second, we use the discrete timing sequence selected from the specific target orbit to build the corresponding external SNURBS chaos periodic signal, whose difference from the system current output is used as the feedback control signal. Finally, by properly adjusting the feedback weight, we can quickly lead the system to an expected status. We demonstrate both the effectiveness and efficiency of our method by applying it to two classic chaotic systems, i.e., the Van der Pol oscillator and the Lorenz chaotic system. Further, our experimental results show that compared with delayed feedback control, our method takes less time to obtain the target point or periodic orbit (from the starting point) and that its parameters can be fine-tuned more easily.

Epidemic spreading on hierarchical geographical networks with mobile agents.

Hierarchical geographical traffic networks are critical for our understanding of scaling laws in human trajectories. Here, we investigate the susceptible-infected epidemic process evolving on hierarchical networks in which agents randomly walk along the edges and establish contacts in network nodes. We employ a metapopulation modeling framework that allows us to explore the contagion spread patterns in relation to multi-scale mobility behaviors. A series of computer simulations revealed that a shifted power-law-like negative relationship between the peak timing of epidemics τ 0 and population density, and a logarithmic positive relationship between τ 0 and the network size, can both be explained by the gradual enlargement of fluctuations in the spreading process. We employ a semi-analytical method to better understand the nature of these relationships and the role of pertinent demographic factors. Additionally, we provide a quantitative discussion of the efficiency of a border screening procedure in delaying epidemic outbreaks on hierarchical networks, yielding a rather limited feasibility of this mitigation strategy but also its non-trivial dependence on population density, infector detectability, and the diversity of the susceptible region. Our results suggest that the interplay between the human spatial dynamics, network topology, and demographic factors can have important consequences for the global spreading and control of infectious diseases. These findings provide novel insights into the combined effects of human mobility and the organization of geographical networks on spreading processes, with important implications for both epidemiological research and health policy.

Series-NonUniform Rational B-Spline (S-NURBS) model: a geometrical interpolation framework for chaotic data.

Time series is widely exploited to study the innate character of the complex chaotic system. Existing chaotic models are weak in modeling accuracy because of adopting either error minimization strategy or an acceptable error to end the modeling process. Instead, interpolation can be very useful for solving differential equations with a small modeling error, but it is also very difficult to deal with arbitrary-dimensional series. In this paper, geometric theory is considered to reduce the modeling error, and a high-precision framework called Series-NonUniform Rational B-Spline (S-NURBS) model is developed to deal with arbitrary-dimensional series. The capability of the interpolation framework is proved in the validation part. Besides, we verify its reliability by interpolating Musa dataset. The main improvement of the proposed framework is that we are able to reduce the interpolation error by properly adjusting weights series step by step if more information is given. Meanwhile, these experiments also demonstrate that studying the physical system from a geometric perspective is feasible.

Idiopathic hypereosinophilic syndrome with hepatic sinusoidal obstruction syndrome: A case report and literature review.

BACKGROUND: Hypereosinophilic syndrome (HES) is classified as primary, secondary or idiopathic. Idiopathic HES (IHES) has a variable clinical presentation and may involve multiple organs causing severe damage. Hepatic sinusoidal obstruction syndrome (HSOS) is characterized by damage to the endothelial cells of the hepatic sinusoids of the hepatic venules, with occlusion of the hepatic venules, and hepatocyte necrosis. We report a case of IHES with HSOS of uncertain etiology. CASE SUMMARY: A 70-year-old male patient was admitted to our hospital with pruritus and a rash on the extremities for > 5 mo. He had previously undergone antiallergic treatment and herbal therapy in the local hospital, but the symptoms recurred. Relevant examinations were completed after admission. Bone marrow aspiration biopsy showed a significantly higher percentage of eosinophils (23%) with approximately normal morphology. Ultrasound-guided hepatic aspiration biopsy indicated HSOS. Contrast-enhanced computed tomography (CT) of the upper abdomen showed hepatic venule congestion with hydrothorax and ascites. The patient was initially diagnosed with IHES and hepatic venule occlusion. Prednisone, low molecular weight heparin and ursodeoxycholic acid were given for treatment, followed by discontinuation of low molecular weight heparin due to ecchymosis. Routine blood tests, biochemical tests, and imaging such as enhanced CT of the upper abdomen and pelvis were reviewed regularly. CONCLUSION: Hypereosinophilia may play a facilitating role in the occurrence and development of HSOS.

Risk estimation of infectious diseases determines the effectiveness of the control strategy.

Usually, whether to take vaccination or not is a voluntary decision, which is determined by many factors, from societal factors (such as religious belief and human rights) to individual preferences (including psychology and altruism). Facing the outbreaks of infectious diseases, different people often have different estimations on the risk of infectious diseases. So, some persons are willing to vaccinate, but other persons are willing to take risks. In this paper, we establish two different risk assessment systems using the technique of dynamic programming, and then compare the effects of the two different systems on the prevention of diseases on complex networks. One is that the perceived probability of being infected for each individual is the same (uniform case). The other is that the perceived probability of being infected is positively correlated to individual degrees (preferential case). We show that these two risk assessment systems can yield completely different results, such as, the effectiveness of controlling diseases, the time evolution of the number of infections, and so on.

Susceptible-infected-susceptible model on networks with eigenvector localization.

It is a longstanding debate on the absence of threshold for susceptible-infected-susceptible (SIS) model on networks with finite second order moment of degree distribution. The eigenvector localization of the adjacency matrix for a network gives rise to the inactive Griffiths phase featuring slow decay of the activity localized around highly connected nodes due to the dynamical fluctuation. We show how it dramatically changes our understanding of the SIS model, opening up new possibilities for the debate. We derive the critical condition for Griffiths to active phase transition: on average, an infected node can further infect another one in the characteristic lifespan of the star subgraph composed of the node and its nearest neighbors. The system approaches the critical point of avoiding the irreversible dynamical fluctuation and the trap of absorbing state. As a signature of the phase transition, the infection density of a node is not only proportional to its degree, but also proportional to the exponentially growing lifespan of the star. And the divergence of the average lifespan of the stars is responsible for the vanishing threshold in the thermodynamic limit. The eigenvector localization exponentially reinforces the infection of highly connected nodes, while it inversely suppresses the infection of small-degree nodes.

Consensus of self-driven agents with avoidance of collisions.

In recent years, many efforts have been addressed on collision avoidance of collectively moving agents. In this paper, we propose a modified version of the Vicsek model with adaptive speed, which can guarantee the absence of collisions. However, this strategy leads to an aggregated state with slowly moving agents. We therefore further add a certain repulsion, which results in both faster consensus and longer safe distance among agents, and thus provides a powerful mechanism for collective motions in biological and technological multiagent systems.

Optimal view angle in collective dynamics of self-propelled agents.

We study a system of self-propelled agents with the restricted vision. The field of vision of each agent is only a sector of disk bounded by two radii and the included arc. The inclination of these two radii is characterized by the view angle. The consideration of restricted vision is closer to the reality because natural swarms usually do not have a panoramic view. Interestingly, we find that there exists an optimal view angle, leading to the fastest direction consensus. The value of the optimal view angle depends on the density, the interaction radius, the absolute velocity of swarms, and the strength of noise. Our findings may invoke further efforts and attentions to explore the underlying mechanism of the collective motion.

Diversity-optimized cooperation on complex networks.

We propose a strategy for achieving maximum cooperation in evolutionary games on complex networks. Each individual is assigned a weight that is proportional to the power of its degree, where the exponent alpha is an adjustable parameter that controls the level of diversity among individuals in the network. During the evolution, every individual chooses one of its neighbors as a reference with a probability proportional to the weight of the neighbor, and updates its strategy depending on their payoff difference. It is found that there exists an optimal value of alpha, for which the level of cooperation reaches maximum. This phenomenon indicates that, although high-degree individuals play a prominent role in maintaining the cooperation, too strong influences from the hubs may counterintuitively inhibit the diffusion of cooperation. Other pertinent quantities such as the payoff, the cooperator density as a function of the degree, and the payoff distribution are also investigated computationally and theoretically. Our results suggest that in order to achieve strong cooperation on a complex network, individuals should learn more frequently from neighbors with higher degrees, but only to a certain extent.

Information filtering based on transferring similarity.

In this Brief Report, we propose an index of user similarity, namely, the transferring similarity, which involves all high-order similarities between users. Accordingly, we design a modified collaborative filtering algorithm, which provides remarkably higher accurate predictions than the standard collaborative filtering. More interestingly, we find that the algorithmic performance will approach its optimal value when the parameter, contained in the definition of transferring similarity, gets close to its critical value, before which the series expansion of transferring similarity is convergent and after which it is divergent. Our study is complementary to the one reported in [E. A. Leicht, P. Holme, and M. E. J. Newman, Phys. Rev. E 73, 026120 (2006)], and is relevant to the missing link prediction problem.

Synaptic modifications driven by spike-timing-dependent plasticity in weakly coupled bursting neurons.

In the course of development, sleep, or mental disorders, certain neurons in the brain display spontaneous spike-burst activity. The synaptic plasticity evoked by such activity is here studied in the presence of spike-timing-dependent plasticity (STDP). In two chemically coupled bursting model neurons, the spike-burst activity can translate the STDP related to pre- and postsynaptic spike activity into burst-timing-dependent plasticity (BTDP), based on the timing of bursts of pre- and postsynaptic neurons. The resulting BTDP exhibits exponential decays with the same time scales as those of STDP. In weakly coupled bursting neuron networks, the synaptic modification driven by the spike-burst activity obeys a power-law distribution. The model can also produce a power-law distribution of synaptic weights. Here, the considered bursting behavior is made of stereotypical groups of spikes, and bursting is evenly spaced by long intervals.

Asymmetric negotiation in structured language games.

We propose an asymmetric negotiation strategy to investigate the influence of high-degree agents on the agreement dynamics in a structured language game, the naming game. We introduce a model parameter, which governs the frequency of high-degree agents acting as speakers in communication. It is found that there exists an optimal value of the parameter that induces the fastest convergence to a global consensus on naming an object for both scale-free and small-world naming games. This phenomenon indicates that, although a strong influence of high-degree agents favors consensus achievement, very strong influences inhibit the convergence process, making it even slower than in the absence of influence of high-degree agents. Investigation of the total memory used by agents implies that there is some trade-off between the convergence speed and the required total memory. Other quantities, including the evolution of the number of different names and the relationship between agents' memories and their degrees, are also studied. The results are helpful for better understanding of the dynamics of the naming game with asymmetric negotiation strategy.

Geographical effect on small-world network synchronization.

We investigate the geographical effect on the synchronization of small-world oscillator networks. We construct small-world geographical networks by randomly adding links to one- and two-dimensional regular lattices, and we find that the synchronizability is a nonmonotonic function of both the coupling strength and the geographical distance of randomly added shortcuts. Our findings demonstrate that the geographical effect plays an important role in network synchronization, which may shed some light on the study of collective dynamics of complex networks.

Optimal contact process on complex networks.

Contact processes on complex networks are a recent subject of study in nonequilibrium statistical physics and they are also important to applied fields such as epidemiology and computer and communication networks. A basic issue concerns finding an optimal strategy for spreading. We provide a universal strategy that, when a basic quantity in the contact process dynamics, the contact probability determined by a generic function of its degree W(k) , is chosen to be inversely proportional to the node degree, i.e., W(k) approximately k;{-1} , spreading can be maximized. Computation results on both model and real-world networks verify our theoretical prediction. Our result suggests the determining role played by small-degree nodes in optimizing spreading, in contrast to the intuition that hub nodes are important for spreading dynamics on complex networks.

[Primary iris-ciliary body cyst and its relevancy with the change of anterior chamber angle].

OBJECTIVE: To investigate the characteristics of the size and distribution of primary iris-ciliary body cysts and its associated with the change of anterior chamber angle. METHODS: It was a cross sectional study. Patients with shallow anterior chambers found in routine health examinations were evaluated with UBM scan. Any primary iris-ciliary body cysts detected were recorded in the parameters of quantity, size, location, and quadrant. The shape of the angle in the UBM was compared to the surrounding area of angle without the cyst, and also whether the angle was narrowed or closed was recorded. The factors related to the corresponding narrowed or closed angle were analyzed. RESULTS: The 502 cysts were detected in 134 (29.32%) of the 457 patients, which were all primary iris-ciliary body cysts. The cysts were located in the iridociliary sulcus (41.24%) and pars plicata (58.37%) and distributions were 44.22% situated at the inferotemporal quadrant, 26.88% at the inferonasal quadrant, 23.11% at the superotemporal quadrant and 5.38% at the superonasal quadrant. The largest base size of the cysts was 0.6289 +/- 0.2329 mm and most were mid-sized cysts (86.05%). The incidence of the cysts with corresponding chamber angle narrowing or closure in the iridociliary sulcus was 82.13% (170/207), and in the pars plicata was 22.87% (67/293). The difference between them was statistical significant (chi2 = 170.83, P < 0.01). The relationship between the cyst size and the proportion of the cysts which caused corresponding angles narrowing or closure was analyzed by way of rectilinear correlation, and it was found to be a positive correlation (r = 0.9939, P < 0.01). CONCLUSIONS: The incidence of primary iris-ciliary body cysts in the normal population is high and some may cause corresponding angle narrowing or closure; The location and size of the cysts are the factors to induce narrowing or closure of the angle in the corresponding area.

Effects of corneal thickness distribution and apex position on postoperative refractive status after full-bed deep anterior lamellar keratoplasty.

OBJECTIVE: To investigate the effects of corneal thickness distribution and apex position on postoperative refractive status after full-bed deep anterior lamellar keratoplasty (FBDALK). METHODS: This is a retrospective analysis of patients who were diagnosed with advanced keratoconus between 2011 and 2014 in our hospital. The base of the cone in all patients did not exceed the central cornea at a 6-mm range. The FBDALK was performed by a same surgeon. All patients had a complete corneal suture removal and the follow-up records were intact. Patients who had graft-bed misalignment or who were complicated with a cataract or glaucoma were excluded. Uncorrected visual acuity (UCVA), best spectacle corrected visual acuity (BSCVA), and Pentacam examination data were recorded at two years postoperatively. The recorded data included the superior-inferior (S-I) and nasal-temporal (N-T) corneal thickness differences in 2, 4, 6, and 8 mm diameter concentric circles with the corneal apex as the center (S-I2 mm, S-I4 mm, S-I6 mm, S-I8 mm, N-T2 mm, N-T4 mm, N-T6 mm, and N-T8 mm), the linear, X-axis, and Y-axis distance between the corneal pupillary center and the cornea apex, total corneal astigmatism at a zone of 3 mm diameter from the corneal apex (TA3 mm), the astigmatic vector values J0 and J45, and the corneal total higher-order aberration for 3 and 6 mm pupil diameters (HOA3 mm and HOA6 mm). Statistical analysis was performed by SPSS 15.0. RESULTS: A total of 47 eyes of 46 patients met the criteria and were included in this study. The mean follow-up time was (28±7) months. The mean UCVA was 0.45±0.23 (logMAR) (MAR: minimum angle of resolution) and the mean BSCVA was 0.19±0.15 (logMAR), which were all significantly positively correlated with postoperative TA3 mm and HOA3 mm. The mean S-I corneal thickness differences were (44.62±37.74) µm, and the mean N-T was (38.57±32.29) µm. S-I2 mm was significantly positively correlated with J0 (r=0.31), J45 (r=0.42), HOA3 mm (r=0.37), and HOA6 mm (r=0.48). S-I4 mm and S-I8 mm were significantly positively correlated with HOA3 mm (r=0.30, r=0.40) and HOA6 mm (r=0.46, r=0.35). The X-axis distance between corneal pupillary center and corneal apex was significantly positively correlated with J45 (r=0.29). CONCLUSIONS: In patients with advanced keratoconus after FBDALK, the unevenly distributed thickness at corneal pupillary area and the misalignment of corneal apex and pupillary center might cause significant regular and irregular astigmatism, which affected the postoperative visual quality.