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Abstract Background Triple negative breast cancer (TNBC) represents a particularly aggressive and clinically challenging subtype of breast cancer, characterized by its invasive nature and generally poor prognosis. Treatment options for unresectable TNBC are limited. In recent years, the advent of PD-1/PD-L1 immune checkpoint inhibitors has offered a promising new treatment option for unresectable TNBC. The role of PD-1/PD-L1 immune checkpoint inhibitors (ICIs) in unresectable TNBC management remains a subject of debate. This article aims to synthesize evidence from randomized controlled trials (RCTs) through a meta-analysis (MA) to provide a comprehensive evaluation of the efficacy and safety profile of ICIs in the treatment of unresectable TNBC. Method We searched PubMed, Embase, Cochrane library, Web of Science, and ClinicalTrials.gov for the eligible RCTs which compared the efficacy and safety of PD-1/PD-L1 ICIs and chemotherapy alone. The outcomes analyzed included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse effects (AEs). Results This meta-analysis included 11 trials. Therapy with PD-L1 inhibitors was superior to chemotherapy in terms of OS in both the intention-to-treat (ITT) population and the PD-L1-positive population. (ITT: HR: = 0.90 [0.81, 0.99], P = 0.04, I2 = 48%; PD-L1 + : HR = 0.82 [0.70, 0.95], P = 0.01, I2 = 64%); In terms of PFS, treatment with PD-L1 inhibitors prolonged PFS in both the ITT and PD-L1-positive populations compared with chemotherapy (ITT: HR: = 0.85 [0.77, 0.93], P = 0.0006, I2 = 46%; PD-L1 + : HR = 0.72 [0.62, 0.83], P

This paper presents a once-differentiable control strategy for a class of uncertain nonaffine nonlinear systems based on self-structuring neural networks (SSNNs) approximation, such that the system output tracks the desired trajectory. The optimal weight for each neuron in current SSNN is time-varying signals factually, and current stability analysis is only fit for a dwell time. Current SSNN control laws are not smooth and even not continuous, due to addition or pruning of neurons in the approximation procedure. In this paper, a new SSNN estimator and a new weight update law are proposed to ensure the optimal SSNN weights being constant values and the control law being once-differentiable. The effectiveness of the proposed control law is illustrated by the stability analysis in the whole tracking procedure and shown by the simulation results.

Variable Stiffness Actuators (VSAs) have been introduced to develop new-generation compliant robots. However, the control of VSAs is still challenging because of model perturbations such as parametric uncertainties and external disturbances. This paper proposed a non-linear disturbance observer (NDOB)-based composite control approach to control both stiffness and position of VSAs under model perturbations. Compared with existing non-linear control approaches for VSAs, the distinctive features of the proposed approach include: (1) A novel modeling method is applied to analysis the VSA dynamics under complex perturbations produced by parameter uncertainties, external disturbances, and flexible deflection; (2) A novel composite controller integrated feedback linearization with NDOB is developed to increase tracking accuracy and robustness against uncertainties. Both simulations and experiments have verified the effectiveness of the proposed method on VSAs.

Designing robust control for hypersonic vehicles in reentry is difficult, due to the features of the vehicles including strong coupling, non-linearity, and multiple constraints. This paper proposed a characteristic model-based robust model predictive control (MPC) for hypersonic vehicles with reentry constraints. First, the hypersonic vehicle is modeled by a characteristic model composed of a linear time-varying system and a lumped disturbance. Then, the identification data are regenerated by the accumulative sum idea in the gray theory, which weakens effects of the random noises and strengthens regularity of the identification data. Based on the regenerated data, the time-varying parameters and the disturbance are online estimated according to the gray identification. At last, the mixed H2/H∞ robust predictive control law is proposed based on linear matrix inequalities (LMIs) and receding horizon optimization techniques. Using active tackling system constraints of MPC, the input and state constraints are satisfied in the closed-loop control system. The validity of the proposed control is verified theoretically according to Lyapunov theory and illustrated by simulation results.

This paper focuses on modeling and control of a class of serial variable stiffness actuators (SVSAs) based on level mechanisms for robotic applications. A multi-input multi-output complex nonlinear dynamic model is derived to fully describe SVSAs and the relative degree of the model is determined accordingly. Due to nonlinearity, high coupling, and parametric uncertainty of SVSAs, a neural network-based adaptive control strategy based on feedback linearization is proposed to handle system uncertainties. The feasibility of the proposed approach for position and stiffness tracking of SVSAs is verified by simulation results.

What is the mechanism through which transcription factors (TFs) assemble specifically along the enhancer DNA? The IFN-β enhanceosome provides a good model system: it is small; its components' crystal structures are available; and there are biochemical and cellular data. In the IFN-β enhanceosome, there are few protein-protein interactions even though consecutive DNA response elements (REs) overlap. Our molecular dynamics (MD) simulations on different motif combinations from the enhanceosome illustrate that cooperativity is achieved via unique organization of the REs: specific binding of one TF can enhance the binding of another TF to a neighboring RE and restrict others, through overlap of REs; the order of the REs can determine which complexes will form; and the alternation of consensus and non-consensus REs can regulate binding specificity by optimizing the interactions among partners. Our observations offer an explanation of how specificity and cooperativity can be attained despite the limited interactions between neighboring TFs on the enhancer DNA. To date, when addressing selective TF binding, attention has largely focused on RE sequences. Yet, the order of the REs on the DNA and the length of the spacers between them can be a key factor in specific combinatorial assembly of the TFs on the enhancer and thus in function. Our results emphasize cooperativity via RE binding sites organization.

p53 can serve as a paradigm in studies aiming to figure out how allosteric perturbations in transcription factors (TFs) triggered by small changes in DNA response element (RE) sequences, can spell selectivity in co-factor recruitment. p53-REs are 20-base pair (bp) DNA segments specifying diverse functions. They may be located near the transcription start sites or thousands of bps away in the genome. Their number has been estimated to be in the thousands, and they all share a common motif. A key question is then how does the p53 protein recognize a particular p53-RE sequence among all the similar ones? Here, representative p53-REs regulating diverse functions including cell cycle arrest, DNA repair, and apoptosis were simulated in explicit solvent. Among the major interactions between p53 and its REs involving Lys120, Arg280 and Arg248, the bps interacting with Lys120 vary while the interacting partners of other residues are less so. We observe that each p53-RE quarter site sequence has a unique pattern of interactions with p53 Lys120. The allosteric, DNA sequence-induced conformational and dynamic changes of the altered Lys120 interactions are amplified by the perturbation of other p53-DNA interactions. The combined subtle RE sequence-specific allosteric effects propagate in the p53 and in the DNA. The resulting amplified allosteric effects far away are reflected in changes in the overall p53 organization and in the p53 surface topology and residue fluctuations which play key roles in selective co-factor recruitment. As such, these observations suggest how similar p53-RE sequences can spell the preferred co-factor binding, which is the key to the selective gene transactivation and consequently different functional effects.

p53-response elements (p53-REs) are organized as two repeats of a palindromic DNA segment spaced by 0 to 20 base pairs (bp). Several experiments indicate that in the vast majority of the human p53-REs there are no spacers between the two repeats; those with spacers, particularly with sizes beyond two nucleotides, are rare. This raises the question of what it indicates about the factors determining the p53-RE genomic organization. Clearly, given the double helical DNA conformation, the orientation of two p53 core domain dimers with respect to each other will vary depending on the spacer size: a small spacer of 0 to 2 bps will lead to the closest p53 dimer-dimer orientation; a 10-bp spacer will locate the p53 dimers on the same DNA face but necessitate DNA looping; while a 5-bp spacer will position the p53 dimers on opposite DNA faces. Here, via conformational analysis we show that when there are 0-2 bp spacers, p53-DNA binding is cooperative; however, cooperativity is greatly diminished when there are spacers with sizes beyond 2 bp. Cooperative binding is broadly recognized to be crucial for biological processes, including transcriptional regulation. Our results clearly indicate that cooperativity of the p53-DNA association dominates the genomic organization of the p53-REs, raising questions of the structural organization and functional roles of p53-REs with larger spacers. We further propose that a dynamic landscape scenario of p53 and p53-REs can better explain the selectivity of the degenerate p53-REs. Our conclusions bear on the evolutionary preference of the p53-RE organization and as such, are expected to have broad implications to other multimeric transcription factor response element organization.

Residue interaction networks and loop motions are important for catalysis in dihydrofolate reductase (DHFR). Here, we investigate the effects of ligand binding and chain connectivity on network communication in DHFR. We carry out systematic network analysis and molecular dynamics simulations of the native DHFR and 19 of its circularly permuted variants by breaking the chain connections in ten folding element regions and in nine nonfolding element regions as observed by experiment. Our studies suggest that chain cleavage in folding element areas may deactivate DHFR due to large perturbations in the network properties near the active site. The protein active site is near or coincides with residues through which the shortest paths in the residue interaction network tend to go. Further, our network analysis reveals that ligand binding has "network-bridging effects" on the DHFR structure. Our results suggest that ligand binding leads to a modification, with most of the interaction networks now passing through the cofactor, shortening the average shortest path. Ligand binding at the active site has profound effects on the network centrality, especially the closeness.

Molecular dynamics simulations was used to reveal the detailed conformational behaviors of peptides and proteins and by comparing fragment and full length protein simulations, the role of each peptide segment in the folding process was investigated. The segments with different helical propensities play an important role during protein folding.

The impact of microsolvation on the strength of a representative low-barrier hydrogen bond is examined by using the 6-31+G-(d,p) for Hartree-Fock, Moller-Plesset and DFT calculations. Results reveal that the hydrogen bond of an enol and enolate anion is calculated at 30 kcal/mol. This bond is strengthened if the enol and the enolate anion is microsolvated by a molecule each. However, the bond is weakened when the microsolvation is asymmetrical.

Molecular dynamics simulations were conducted on a series of [p.sub.53] core domain tetramer-DNA complexes to gain insight into the factors that regulate the DNA bending. The results from simulations on the [p.sub.53] core domain tetramer-DNA complexes showed that the DNA bending extent was correlated to the concurrent interactions between [p.sub.53] dimer-dimer and [p.sub.53]-DNA.

Molecular dynamics (MD) simulations are performed on a series of 5'-GU-3' and 5'-UG-3' duplexes in different sequence contexts in order to characterize the underlying atomic forces that determine the structural and thermodynamic properties of GU tandem mismatches. The results emphasize the role of GG and GU stacking interactions on the structure and thermodynamics of GU mismatches in RNA.

The stable functional p53, which is a protein with marginal stability, is designed. Linearity, moderate size, and balanced hydrophobic and hydrophilic properties of the side chain are crucial to the stabilizing effect of the residue substit utions.

Objective To systematically investigate and validate the survey methodology for the epidemiological study of childhood sleep-disordered breathing (SDB) in mainland China using the Mandarin version of the Pediatric Sleep Questionnaire-Sleep-Related Breathing Disorder (PSQSRBD). Design A cross-sectional study using randomised, stratified, multistage, cluster sampling method. Setting A total of 11 kindergartens, 7 primary schools and 8 middle schools from 7 districts of Beijing, China. Participants A total of 9198 children with valid questionnaires (4736 boys and 4462 girls; age range 3.0-14.4 years) were included. Primary and secondary outcome measures Data on sociodemographic characteristics and PSQ-SRBD were collected. The score on PSQ-SRBD and the included factors were calculated with the effective data after data cleaning. Logistic regression and factor analysis with the principal components method were used to evaluate the validity of the questionnaire; reliability was assessed by retesting 5% of the respondents after 2±4 weeks of the initial test, and the intraclass correlation coefficient was calculated. Results The effective response rate of80.54% matched the sociodemographic characteristics of the respondents with respect to age group ratio and sex ratio in Beijing. With regard to construct validity of the PSQ-SRBD, the item score, except that of 'delayed growth', was highly correlated to the SRBD score as assessed by the logistic regression model. The exploratory factor analysis displayed a credible construct validity, with majority of the items grouped as the original dimensions. The test-retest reliability coefficient of each dimension's score ranged from 0.758 to 0.901, with an SRBD score of 0.730 indicating significant retest reliability. Conclusions This study conducted and validated a successful survey methodology for investigation of childhood SDB in Beijing, China. The questionnaire demonstrated credible construct validity and retest reliability, thereby supporting the applicability and generalisability of the PSQ-SRBD in a large epidemiological survey of childhood SDB in China. [ABSTRACT FROM AUTHOR]

In adaptive neural network (NN) control, fast adaptation through high-gain learning rates can cause high-frequency oscillations in control response resulting in system instability. This study presents a simple adaptive NN with proportional derivative (PD) control strategy to achieve fast and low-frequency adaptation for a class of uncertain non-linear systems. Variable-gain PD control without the knowledge of plant bounds is proposed to semi-globally stabilise the plant, so that NN approximation is applicable. A low-pass filter-based modification is applied to the adaptive law to filter out high-frequency content, so that tracking performance can be safely improved by the increase of learning rates. The novelties of this study with respect to adaptive NN control are as follows: (i) semi-global practical asymptotic tracking can be achieved by a simple adjustment of control parameters; and (ii) fast and low-frequency adaptation can be obtained via high-gain learning rates under guaranteed system stability. Simulation studies have demonstrated that the proposed approach can outperform its non-filtering counterpart in terms of tracking accuracy, energy cost and control smoothness. [ABSTRACT FROM AUTHOR]

This paper considers the leader-based consensus of heterogeneous multiple agents with nonlinear uncertain systems. Based on the information obtained from the following agents' neighbors, leader observers are designed by the following agents to estimate the leader's states and nonlinear dynamics. Then, to achieve leader-based consensus, adaptive distributed controllers are designed for the following agents to track the designed corresponding leader observers. The effectiveness of the leader observers and distributed consensus controllers are illustrated by formal proof and simulation results. [ABSTRACT FROM AUTHOR]

This paper presents a practical direct adaptive fuzzy H∞ tracking control (AFHC) approach for a class of uncertain nonlinear systems with unknown control gain functions and external disturbances. A modified output tracking error is defined to eliminate high gain at the control input and to improve transient performance. An ideal control law is developed to eliminate the restriction that the control gain function must be known a priori under the direct adaptive scheme. A nonlinearly parameterized fuzzy system without redundant parameters is proposed to online approximate the ideal control law. The direct AFHC is derived by virtue of the Lyapunov synthesis, where both the antecedent and the consequent parameters of fuzzy rules are updated by the proposed adaptive law. Simulation studies have demonstrated that the proposed approach can outperform previous approaches with similar or less control efforts. [ABSTRACT FROM AUTHOR]

p53 can serve as a paradigm in studies aiming to figure out how allosteric perturbations in transcription factors (TFs) triggered by small changes in DNA response element (RE) sequences, can spell selectivity in co-factor recruitment. p53-REs are 20-base pair (bp) DNA segments specifying diverse functions. They may be located near the transcription start sites or thousands of bps away in the genome. Their number has been estimated to be in the thousands, and they all share a common motif. A key question is then how does the p53 protein recognize a particular p53-RE sequence among all the similar ones? Here, representative p53-REs regulating diverse functions including cell cycle arrest, DNA repair, and apoptosis were simulated in explicit solvent. Among the major interactions between p53 and its REs involving Lys120, Arg280 and Arg248, the bps interacting with Lys120 vary while the interacting partners of other residues are less so. We observe that each p53-RE quarter site sequence has a unique pattern of interactions with p53 Lys120. The allosteric, DNA sequence-induced conformational and dynamic changes of the altered Lys120 interactions are amplified by the perturbation of other p53-DNA interactions. The combined subtle RE sequence-specific allosteric effects propagate in the p53 and in the DNA. The resulting amplified allosteric effects far away are reflected in changes in the overall p53 organization and in the p53 surface topology and residue fluctuations which play key roles in selective co-factor recruitment. As such, these observations suggest how similar p53-RE sequences can spell the preferred co-factor binding, which is the key to the selective gene transactivation and consequently different functional effects. [ABSTRACT FROM AUTHOR]

Specific p53 binding-induced DNA bending has important biological implications such as transcription activation. However, the detailed structures of the bent DNA and the p53-DNA complex are still unavailable, hampering our understanding of the mechanism for p53-induced DNA bending and its consequent biological significance. To gain insight into the p53 binding-induced DNA bending, we performed molecular dynamics simulations on DNA segments with the consensus sequence for p53-specific binding, half site DNA-p53 complexes, and full site DNA-p53 complexes. We show that each DNA-bound p53 core domain caused a local DNA conformational change within the quarter site; upon the binding of the p53 dimer, there was an apparent DNA bending at the center of the half site; when bound with two p53 dimers, the full site DNAs with two different sequences bent 20 and 35°, respectively. These results are in agreement with experimental observations. Our simulations demonstrate that the two p53 dimers favored a staggered conformation in which they make favorable interactions at the interface. This dimer-dimer interface organization necessitated conformational changes in the DNA, leading to the bending at the center of the full site, which in turn is dependent on the DNA sequence. Overall, our results provide the detailed atomic model for the DNA-p53 tetramer complex and delineate the roles of DNA-p53, p53 dimer-dimer interactions, and DNA sequence in specific p53 binding-induced DNA conformational changes. [ABSTRACT FROM AUTHOR]

Maintaining the native conformation is essential for the proper function of tumor suppressor protein p53. However, p53 is a low-stability protein that can easily lose its function upon structural perturbations such as those resulting from missense mutations, leading to the development of cancer. Therefore, it is important to develop strategies to design stable p53 which still maintains its normal function. Here, we compare the stabilities of the human and worm p53 core domains using molecular dynamics simulations. We find that the worm p53 is significantly more stable than the human form. Detailed analysis of the structural fluctuations shows that the stability difference lies in the peripheral structural motifs that contrast in their structural features and flexibility. The most dramatic difference in stability originates from loop L1, from the turn between helix H1 and β-strand S5, and from the turn that connects β-strands S7 and S8. Structural analysis shows significant differences for these motifs between the two proteins. Loop L1 lacks secondary structure, and the turns between helix Hi and strand S5 and between strands S7 and S8 are much longer in the human form p53. On the basis of these differences, we designed a mutant by shortening the turn between strands S7 and S8 to enhance the stability. Surprisingly, this mutant was very stable when probed by molecular dynamics simulations. In addition, the stabilization was not localized in the turn region. Loop L1 was also significantly stabilized. Our results show that stabilizing peripheral structural motifs can greatly enhance the stability of the p53 core domain and therefore is likely to be a viable alternative in the development of stable p53. In addition, loop- or turn-related mutants with different stabilities may also be used to probe the relationship between function, a particular structural motif, and its flexibility. [ABSTRACT FROM AUTHOR]

gp120 is key to the human immunodeficiency virus type 1 viral cell entry. Knowledge of the detailed conformational states of gpl20 is crucial to intervention, yet the unbound form is still resistant to structural characterization probably because of its flexibility. Toward this goal, we performed molecular dynamics simulations on the wild type gp120 core domain extracted from its ternary crystal structure and on a modeled mutant, S375W, that experimentally has a significantly different phenotype from the wild type. Although the mutant retained a bound-like conformation, the wild type drifted to a different conformational state. The wild type β strands 2 and 3 of the bridging sheet were very mobile and partially unfolded, and the organization among the inner and outer domains and β strands 20 and 21 of the bridging sheet, near the mutation site, was more open than in the bound form, although the overall structure was maintained. These differences were apparently a result of the strengthening of the hydrophobic core in the mutant. This stabilization further explains the experimentally significantly different thermodynamic properties between the wild type and the mutant. Taken together, our results suggest that the free form, although different from the bound state, shares many of the bound structural features. The observed loss of freedom near the binding site, rather than the previously hypothesized more dramatic conformational transition from the unbound to the bound state, appears to be the major contributor to the large entropy cost for the CD4 binding to the wild type. [ABSTRACT FROM AUTHOR]

Performs direct comparison of experimental and calculated folding free energies for hydrophobic deletion mutants of chymotrypsin inhibitor 2. Calculation of free energy perturbation using transition and denature-state structures; Conduction of molecular dynamic simulations for the thermal denaturation of enzyme inhibitor.

This paper addresses the leader-following formation problem of nonholonomic mobile robots. In the formation, only the pose (i.e., the position and direction angle) of the leader robot can be obtained by the follower. First, the leader-following formation is transformed into special trajectory tracking. And then, a neural network (NN) finite-time observer of the follower robot is designed to estimate the dynamics of the leader robot. Finally, finite-time formation control laws are developed for the follower robot to track the leader robot in the desired separation and bearing in finite time. The effectiveness of the proposed NN finite-time observer and the formation control laws are illustrated by both qualitative analysis and simulation results. [ABSTRACT FROM AUTHOR]