Lineage tracing reveals the phylodynamics, plasticity, and paths of tumor evolution.

Tumor evolution is driven by the progressive acquisition of genetic and epigenetic alterations that enable uncontrolled growth and expansion to neighboring and distal tissues. The study of phylogenetic relationships between cancer cells provides key insights into these processes. Here, we introduced an evolving lineage-tracing system with a single-cell RNA-seq readout into a mouse model of Kras;Trp53(KP)-driven lung adenocarcinoma and tracked tumor evolution from single-transformed cells to metastatic tumors at unprecedented resolution. We found that the loss of the initial, stable alveolar-type2-like state was accompanied by a transient increase in plasticity. This was followed by the adoption of distinct transcriptional programs that enable rapid expansion and, ultimately, clonal sweep of stable subclones capable of metastasizing. Finally, tumors develop through stereotypical evolutionary trajectories, and perturbing additional tumor suppressors accelerates progression by creating novel trajectories. Our study elucidates the hierarchical nature of tumor evolution and, more broadly, enables in-depth studies of tumor progression.

The competitive nature of signal transducer and activator of transcription complex formation drives phenotype switching of T cells.

Signal transducers and activators of transcription (STATs) are key molecular determinants of T-cell fate and effector function. Several inflammatory diseases are characterized by an altered balance of T-cell phenotypes and cytokine secretion. STATs, therefore, represent viable therapeutic targets in numerous pathologies. However, the underlying mechanisms by which the same STAT proteins regulate both the development of different T-cell phenotypes and their plasticity during changes in extracellular conditions remain unclear. In this study, we investigated the STAT-mediated regulation of T-cell phenotype formation and plasticity using mathematical modelling and experimental data for intracellular STAT signalling proteins. The close fit of our model predictions to the experimental data allows us to propose a potential mechanism for T-cell switching. According to this mechanism, T-cell phenotype switching is the result of the relative redistribution of STAT dimer complexes caused by the extracellular cytokine-dependent STAT competition effects. The developed model predicts that the balance between the intracellular STAT species defines the amount of the produced cytokines and thereby T-cell phenotypes. The model predictions are consistent with the experimentally observed interferon-γ to interleukin-10 switching that regulates human T helper type 1/type 1 regulatory T-cell responses. The proposed model is applicable to a number of STAT signalling circuits.

Solving the Dynamic Correlation Problem of the Susceptible-Infected-Susceptible Model on Networks.

The susceptible-infected-susceptible (SIS) model is a canonical model for emerging disease outbreaks. Such outbreaks are naturally modeled as taking place on networks. A theoretical challenge in network epidemiology is the dynamic correlations coming from that if one node is infected, then its neighbors are likely to be infected. By combining two theoretical approaches-the heterogeneous mean-field theory and the effective degree method-we are able to include these correlations in an analytical solution of the SIS model. We derive accurate expressions for the average prevalence (fraction of infected) and epidemic threshold. We also discuss how to generalize the approach to a larger class of stochastic population models.

Effect of circumcision of HIV-negative men on transmission of human papillomavirus to HIV-negative women: a randomised trial in Rakai, Uganda.

BACKGROUND: Randomised trials show that male circumcision reduces the prevalence and incidence of high-risk human papillomavirus (HPV) infection in men. We assessed the efficacy of male circumcision to reduce prevalence and incidence of high-risk HPV in female partners of circumcised men. METHODS: In two parallel but independent randomised controlled trials of male circumcision, we enrolled HIV-negative men and their female partners between 2003 and 2006, in Rakai, Uganda. With a computer-generated random number sequence in blocks of 20, men were assigned to undergo circumcision immediately (intervention) or after 24 months (control). HIV-uninfected female partners (648 of men from the intervention group, and 597 of men in the control group) were simultaneously enrolled and provided interview information and self-collected vaginal swabs at baseline, 12 months, and 24 months. Vaginal swabs were tested for high-risk HPV by Roche HPV Linear Array. Female HPV infection was a secondary endpoint of the trials, assessed as the prevalence of high-risk HPV infection 24 months after intervention and the incidence of new infections during the trial. Analysis was by intention-to-treat. An as-treated analysis was also done to account for study-group crossovers. The trials were registered, numbers NCT00425984 and NCT00124878. FINDINGS: During the trial, 18 men in the control group underwent circumcision elsewhere, and 31 in the intervention group did not undergo circumcision. At 24-month follow-up, data were available for 544 women in the intervention group and 488 in the control group; 151 (27·8%) women in the intervention group and 189 (38·7%) in the control group had high-risk HPV infection (prevalence risk ratio=0·72, 95% CI 0·60-0·85, p=0·001). During the trial, incidence of high-risk HPV infection in women was lower in the intervention group than in the control group (20·7 infections vs 26·9 infections per 100 person-years; incidence rate ratio=0·77, 0·63-0·93, p=0·008). INTERPRETATION: Our findings indicate that male circumcision should now be accepted as an efficacious intervention for reducing the prevalence and incidence of HPV infections in female partners. However, protection is only partial; the promotion of safe sex practices is also important. FUNDING: The Bill & Melinda Gates Foundation, National Institutes of Health, and Fogarty International Center.

Male circumcision for the prevention of HSV-2 and HPV infections and syphilis.

BACKGROUND: Male circumcision significantly reduced the incidence of human immunodeficiency virus (HIV) infection among men in three clinical trials. We assessed the efficacy of male circumcision for the prevention of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) infections and syphilis in HIV-negative adolescent boys and men. METHODS: We enrolled 5534 HIV-negative, uncircumcised male subjects between the ages of 15 and 49 years in two trials of male circumcision for the prevention of HIV and other sexually transmitted infections. Of these subjects, 3393 (61.3%) were HSV-2-seronegative at enrollment. Of the seronegative subjects, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision after 24 months (control group). At baseline and at 6, 12, and 24 months, we tested subjects for HSV-2 and HIV infection and syphilis, along with performing physical examinations and conducting interviews. In addition, we evaluated a subgroup of subjects for HPV infection at baseline and at 24 months. RESULTS: At 24 months, the cumulative probability of HSV-2 seroconversion was 7.8% in the intervention group and 10.3% in the control group (adjusted hazard ratio in the intervention group, 0.72; 95% confidence interval [CI], 0.56 to 0.92; P=0.008). The prevalence of high-risk HPV genotypes was 18.0% in the intervention group and 27.9% in the control group (adjusted risk ratio, 0.65; 95% CI, 0.46 to 0.90; P=0.009). However, no significant difference between the two study groups was observed in the incidence of syphilis (adjusted hazard ratio, 1.10; 95% CI, 0.75 to 1.65; P=0.44). CONCLUSIONS: In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure. (ClinicalTrials.gov numbers, NCT00425984 and NCT00124878.)

Male circumcision and anatomic sites of penile high-risk human papillomavirus in Rakai, Uganda.

Male circumcision (MC) reduces penile high-risk human papillomavirus (HR-HPV) on the coronal sulcus and urethra. HR-HPV varies by anatomic site, and it is unknown whether MC decreases HR-HPV on the penile shaft. We assessed the efficacy of MC to reduce HR-HPV on the penile shaft and compared it to known efficacy of MC to reduce HR-HPV on the coronal sulcus. HIV-negative men randomized to receive immediate circumcision (intervention) or circumcision delayed for 24 months (control) were evaluated for HR-HPV at 12 months postenrollment using the Roche HPV Linear Array assay. Among swabs with detectable ß-globin or HPV, year 1 HR-HPV prevalence on the coronal sulcus was 21.5% in the intervention arm and 36.3% in the control arm men [adjusted prevalence risk ratios (PRRs) = 0.57, 95% CI 0.39-0.84, p = 0.005]. On the shaft, year 1 HR-HPV prevalence was 15.5% in the intervention and 23.8% in the control arm (adjusted PRR = 0.66, 95% CI 0.39-1.12, p = 0.12). Efficacy of MC to reduce HR-HPV on the shaft was similar to efficacy on the coronal sulcus (p = 0.52). In a sensitivity analysis in which swabs without detectable ß-globin or HPV were included as HPV negative, prevalence of HR-HPV on the shaft was lower in the intervention arm (7.8%) than control arm (13.6%; PRR 0.57, 95% CI 0.33-0.99, p < 0.05). HR-HPV was more frequently detected on the coronal sulcus than penile shaft among uncircumcised men (36.3% vs. 23.8%, respectively, p = 0.02) and circumcised men (21.5% vs. 15.5%, respectively, p = 0.24). MC reduced HR-HPV prevalence on both the coronal sulcus and shaft.

Effects of genital ulcer disease and herpes simplex virus type 2 on the efficacy of male circumcision for HIV prevention: Analyses from the Rakai trials.

BACKGROUND: Randomized trials show that male circumcision (MC) reduces the incidence of HIV and herpes simplex virus type 2 (HSV-2) infections, and symptomatic genital ulcer disease (GUD). We assessed the role of GUD and HSV-2 in the protection against HIV afforded by MC. METHODS AND FINDINGS: HIV-uninfected men were randomized to immediate (n = 2,756) or delayed MC (n = 2,775) in two randomized trials in Rakai, Uganda. GUD symptoms, HSV-2 status, and HIV acquisition were determined at enrollment and at 6, 12, and 24 mo of follow up. Ulcer etiology was assessed by PCR. We estimated the prevalence and prevalence risk ratios (PRRs) of GUD in circumcised versus uncircumcised men and assessed the effects of HSV-2 serostatus as a risk-modifying factor for GUD. We estimated the proportion of the effect of MC on HIV acquisition that was mediated by symptomatic GUD, and by HSV-2 infection. Circumcision significantly reduced symptomatic GUD in HSV-2-seronegative men (PRR = 0.51, 95% [confidence interval] CI 0.43-0.74), HSV-2-seropositive men (PRR = 0.66, 95% CI 0.51-0.69), and in HSV-2 seroconverters (PRR = 0.48, 95% CI 0.30-0.79). The proportion of acute ulcers due to HSV-2 detected by PCR was 48.0% in circumcised men and 39.3% in uncircumcised men (chi(2)p = 0.62). Circumcision reduced the risk of HIV acquisition in HSV-2 seronegative men (incidence rate ratio [IRR] = 0.34, 95% CI 0.15-0.81), and potentially in HSV-2 seroconverters (IRR = 0.56, 95% CI 0.19-1.57; not significant), but not in men with prevalent HSV-2 at enrollment (IRR = 0.89, 95% CI 0.49-1.60). The proportion of reduced HIV acquisition in circumcised men mediated by reductions in symptomatic GUD was 11.2% (95% CI 5.0-38.0), and the proportion mediated by reduced HSV-2 incidence was 8.6% (95% CI -1.2 to 77.1). CONCLUSIONS: Circumcision reduced GUD irrespective of HSV-2 status, but this reduction played only a modest role in the protective effect of circumcision on HIV acquisition.

The effects of male circumcision on female partners' genital tract symptoms and vaginal infections in a randomized trial in Rakai, Uganda.

OBJECTIVE: The objective of the study was to assess effects of male circumcision on female genital symptoms and vaginal infections. STUDY DESIGN: Human immunodeficiency virus (HIV)-negative men enrolled in a trial were randomized to immediate or delayed circumcision (control arm). Genital symptoms, bacterial vaginosis (BV), and trichomonas were assessed in HIV-negative wives of married participants. Adjusted prevalence risk ratios (adjPRR) and 95% confidence intervals (CIs) were assessed by multivariable log-binomial regression, intent-to-treat analyses. RESULTS: A total of 783 wives of control and 825 wives of intervention arm men were comparable at enrollment. BV at enrollment was higher in control (38.3%) than intervention arm spouses (30.5%, P = .001). At 1 year follow-up, intervention arm wives reported lower rates of genital ulceration (adjPRR, 0.78; 95% CI, 0.63-0.97), but there were no differences in vaginal discharge or dysuria. The risk of trichomonas was reduced in intervention arm wives (adjPRR, 0.52; 95% CI, 0.05-0.98), as were the risks of any BV (adjPRR, 0.60; 95% CI, 0.38-0.94) and severe BV (prevalence risk ratios, 0.39; 95% CI, 0.24-0.64). CONCLUSION: Male circumcision reduces the risk of ulceration, trichomonas, and BV in female partners.

Predictive protocol of flocks with small-world connection pattern.

By introducing a predictive mechanism with small-world connections, we propose a new motion protocol for self-driven flocks. The small-world connections are implemented by randomly adding long-range interactions from the leader to a few distant agents, namely, pseudoleaders. The leader can directly affect the pseudoleaders, thereby influencing all the other agents through them efficiently. Moreover, these pseudoleaders are able to predict the leader's motion several steps ahead and use this information in decision making towards coherent flocking with more stable formation. It is shown that drastic improvement can be achieved in terms of both the consensus performance and the communication cost. From the engineering point of view, the current protocol allows for a significant improvement in the cohesion and rigidity of the formation at a fairly low cost of adding a few long-range links embedded with predictive capabilities. Significantly, this work uncovers an important feature of flocks that predictive capability and long-range links can compensate for the insufficiency of each other. These conclusions are valid for both the attractive and repulsive swarm model and the Vicsek model.

Quantized Consensus of Multi-Agent Networks With Sampled Data and Markovian Interaction Links.

This paper investigates the joint effect of quantization, sampled data, and general Markovian interaction links on consensus networks with a leader under directed graphs. The diversity of edges formed by all the followers and the leader is also considered. Each agent in the network possesses continuous-time general linear dynamics. Each agent's state is measured only at sampling time instants, which is encoded before transmission. Subsequently, the encoded state is transmitted through noiseless digital communication links with Markovian switching rates. For this problem, a sufficient condition is derived to guarantee the convergence of the encoded states, based on which a necessary and sufficient condition is obtained to achieve consensus tracking in the mean-square sense. In addition, two sufficient conditions on coupling gain, one of which is fully distributed, are provided by proposing an optimal linear quadratic regulator-based gain matrix to ensure consensus tracking and then, the analysis of consensus region is presented. Finally, a numerical example is presented for illustrating the effectiveness of the theoretical results.

A variable stiffness gripper based on differential drive particle jamming.

Compared with rigid grippers, soft grippers show fantastic adaptability and flexibility in grasping irregularly shaped and fragile objects. However, the low stiffness of the soft actuator limits the scope of applications. Particle jamming has emerged as an important method to adjust the stiffness of soft grippers. This paper proposes a novel particle jamming mechanism based on the differential pressure drive. With the differential drive particle jamming mechanism, a soft actuator is designed, which is characterized by a dual-deformable chamber structure in which one chamber is filled with particles. The simultaneous inflation of the two chambers will result in the bending behavior without significant stiffening. However, if the air chamber is pressurized with a larger pressure, the differential pressure will cause the particles inside the particle chamber to jam each other, which increases the stiffness of the actuator significantly. Thus, the differential drive particle jamming mechanism can achieve the independent control of the stiffness and the bending angle. Both theoretical and experimental studies in this area have shown that the gripper based on the differential drive particle jamming mechanism can stiffen itself effectively, and achieve the independent control of the stiffness and the bending angle, which can be adopted in applications where both high stiffness and dexterity are required.

Semi-Global Output Consensus for Discrete-Time Switching Networked Systems Subject to Input Saturation and External Disturbances.

The semi-global output consensus problem for multiagent systems depicted by discrete-time dynamics subject to external disturbances and input saturation over switching networks is investigated in this paper. Assume that only a small part of subsystems have directly received the output of the exosystem. The distributed consensus algorithms are proposed by adopting the low-gain state feedback and the modified algebraic Riccati equation. Then, the outputs of all subsystems can reach synchronization asymptotically with those of the exosystem by using the proposed consensus protocols on some preconditions. Both the connected switching networks and the jointly connected switching networks are considered for the semi-global output consensus problem, respectively. Some numerical simulation results are shown to validate the theoretical analysis.

Thirst regulates motivated behavior through modulation of brainwide neural population dynamics.

Physiological needs produce motivational drives, such as thirst and hunger, that regulate behaviors essential to survival. Hypothalamic neurons sense these needs and must coordinate relevant brainwide neuronal activity to produce the appropriate behavior. We studied dynamics from ~24,000 neurons in 34 brain regions during thirst-motivated choice behavior in 21 mice as they consumed water and became sated. Water-predicting sensory cues elicited activity that rapidly spread throughout the brain of thirsty animals. These dynamics were gated by a brainwide mode of population activity that encoded motivational state. After satiation, focal optogenetic activation of hypothalamic thirst-sensing neurons returned global activity to the pre-satiation state. Thus, motivational states specify initial conditions that determine how a brainwide dynamical system transforms sensory input into behavioral output.

The safety of adult male circumcision in HIV-infected and uninfected men in Rakai, Uganda.

BACKGROUND: The objective of the study was to compare rates of adverse events (AEs) related to male circumcision (MC) in HIV-positive and HIV-negative men in order to provide guidance for MC programs that may provide services to HIV-infected and uninfected men. METHODS AND FINDINGS: A total of 2,326 HIV-negative and 420 HIV-positive men (World Health Organization [WHO] stage I or II and CD4 counts > 350 cells/mm3) were circumcised in two separate but procedurally identical trials of MC for HIV and/or sexually transmitted infection prevention in rural Rakai, Uganda. Participants were followed at 1-2 d and 5-9 d, and at 4-6 wk, to assess surgery-related AEs, wound healing, and resumption of intercourse. AE risks and wound healing were compared in HIV-positive and HIV-negative men. Adjusted odds ratios (AdjORs) were estimated by multiple logistic regression, adjusting for baseline characteristics and postoperative resumption of sex. At enrollment, HIV-positive men were older, more likely to be married, reported more sexual partners, less condom use, and higher rates of sexually transmitted disease symptoms than HIV-negative men. Risks of moderate or severe AEs were 3.1/100 and 3.5/100 in HIV-positive and HIV-negative participants, respectively (AdjOR 0.91, 95% confidence interval [CI] 0.47-1.74). Infections were the most common AEs (2.6/100 in HIV-positive versus 3.0/100 in HIV-negative men). Risks of other complications were similar in the two groups. The proportion with completed healing by 6 wk postsurgery was 92.7% in HIV-positive men and 95.8% in HIV-negative men (p = 0.007). AEs were more common in men who resumed intercourse before wound healing compared to those who waited (AdjOR 1.56, 95% CI 1.05-2.33). CONCLUSIONS: Overall, the safety of MC was comparable in asymptomatic HIV-positive and HIV-negative men, although healing was somewhat slower among the HIV infected. All men should be strongly counseled to refrain from intercourse until full wound healing is achieved. TRIAL REGISTRATION: http://www.ClinicalTrials.gov; for HIV-negative men #NCT00425984 and for HIV-positive men, #NCT000124878.

Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial.

BACKGROUND: Ecological and observational studies suggest that male circumcision reduces the risk of HIV acquisition in men. Our aim was to investigate the effect of male circumcision on HIV incidence in men. METHODS: 4996 uncircumcised, HIV-negative men aged 15-49 years who agreed to HIV testing and counselling were enrolled in this randomised trial in rural Rakai district, Uganda. Men were randomly assigned to receive immediate circumcision (n=2474) or circumcision delayed for 24 months (2522). HIV testing, physical examination, and interviews were repeated at 6, 12, and 24 month follow-up visits. The primary outcome was HIV incidence. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00425984. FINDINGS: Baseline characteristics of the men in the intervention and control groups were much the same at enrollment. Retention rates were much the same in the two groups, with 90-92% of participants retained at all time points. In the modified intention-to-treat analysis, HIV incidence over 24 months was 0.66 cases per 100 person-years in the intervention group and 1.33 cases per 100 person-years in the control group (estimated efficacy of intervention 51%, 95% CI 16-72; p=0.006). The as-treated efficacy was 55% (95% CI 22-75; p=0.002); efficacy from the Kaplan-Meier time-to-HIV-detection as-treated analysis was 60% (30-77; p=0.003). HIV incidence was lower in the intervention group than it was in the control group in all sociodemographic, behavioural, and sexually transmitted disease symptom subgroups. Moderate or severe adverse events occurred in 84 (3.6%) circumcisions; all resolved with treatment. Behaviours were much the same in both groups during follow-up. INTERPRETATION: Male circumcision reduced HIV incidence in men without behavioural disinhibition. Circumcision can be recommended for HIV prevention in men.

Nonfragile State Estimation of Quantized Complex Networks With Switching Topologies.

This paper considers the nonfragile $H_\infty $ estimation problem for a class of complex networks with switching topologies and quantization effects. The network architecture is assumed to be dynamic and evolves with time according to a random process subject to a sojourn probability. The coupled signal is to be quantized before transmission due to power and bandwidth constraints, and the quantization errors are transformed into sector-bounded uncertainties. The concept of nonfragility is introduced by inserting randomly occurred uncertainties into the estimator parameters to cope with the unavoidable small gain variations emerging from the implementations of estimators. Both the quantizers and the estimators have several operation modes depending on the switching signal of the underlying network structure. A sufficient condition is provided via a linear matrix inequality approach to ensure the estimation error dynamic to be stochastically stable in the absence of external disturbances, and the $H_\infty $ performance with a prescribed index is also satisfied. Finally, a numerical example is presented to clarify the validity of the proposed method.

Composite Backstepping Consensus Algorithms of Leader-Follower Higher-Order Nonlinear Multiagent Systems Subject to Mismatched Disturbances.

This paper is devoted to solving the output consensus problem of leader-follower higher-order nonlinear multiagent systems subject to mismatched disturbances. The disturbances are allowed to be in higher-order forms. First, by constructing a generalized proportional-integral observer for each follower, estimates of the disturbances and their derivatives are obtained. At the same time, a distributed observer is also developed for the followers to estimate the leader state information. Second, based on the estimates of the disturbances and the leader state, together with the backstepping technique, a feedforward-feedback composite consensus control scheme is proposed. The designed distributed protocols guarantee asymptotic output consensus for the agents. Simulation results validate the effectiveness of the proposed composite control scheme.

Observer-Based Robust Coordinated Control of Multiagent Systems With Input Saturation.

This paper addresses the robust semiglobal coordinated control of multiple-input multiple-output multiagent systems with input saturation together with dead zone and input additive disturbance. Observer-based coordinated control protocol is constructed, by combining the parameterized low-and-high-gain feedback technique and the high-gain observer design approach. It is shown that, under some mild assumptions on agents' intrinsic dynamics, the robust semiglobal consensus or robust semiglobal swarm can be approached for undirected connected multiagent systems. Then, specific guidelines on the selection of the low-gain parameter, the high-gain parameter, and the high-gain observer gain have been provided. At last, numerical simulations are presented to illustrate the theoretical results.

Reaching Non-Negative Edge Consensus of Networked Dynamical Systems.

In this paper, the problem of non-negative edge consensus of undirected networked linear time-invariant systems is addressed by associating each edge of the network with a state variable, for which a distributed algorithm is constructed. Sufficient conditions referring only to the number of edges are derived for non-negative edge consensus of the networked systems. Subsequently, the linear programming method and a low-gain feedback technique are introduced to simplify the design of the feedback gain matrix for achieving the non-negative edge consensus. It is found that the low-gain feedback technique has a good effect on the non-negative edge consensus of the networked systems subject to input saturation. Numerical simulations are presented to verify the effectiveness of the theoretical results.