Linkage Architecture Research Articles

Discovering Explainable Biomarkers for Breast Cancer Anti-PD1 Response via Network Shapley Value Analysis

Background and objectiveImmunotherapy holds promise in enhancing pathological complete response rates in breast cancer, albeit confined to a select cohort of patients. Consequently, pinpointing factors predictive of treatment responsiveness is of paramount importance. Gene expression and regulation, inherently operating within intricate networks, constitute fundamental molecular machinery for cellular processes and often serve as robust biomarkers. Nevertheless, contemporary feature selection approaches grapple with two key challenges: opacity in modeling and scarcity in accounting for gene-gene interactions MethodsTo address these limitations, we devise a novel feature selection methodology grounded in cooperative game theory, harmoniously integrating with sophisticated machine learning models. This approach identifies interconnected gene regulatory network biomarker modules with priori genetic linkage architecture. Specifically, we leverage Shapley values on network to quantify feature importance, while strategically constraining their integration based on network expansion principles and nodal adjacency, thereby fostering enhanced interpretability in feature selection. We apply our methods to a publicly available single-cell RNA sequencing dataset of breast cancer immunotherapy responses, using the identified feature gene set as biomarkers. Functional enrichment analysis with independent validations further illustrates their effective predictive performance ResultsWe demonstrate the sophistication and excellence of the proposed method in data with network structure. It unveiled a cohesive biomarker module encompassing 27 genes for immunotherapy response. Notably, this module proves adept at precisely predicting anti-PD1 therapeutic outcomes in breast cancer patients with classification accuracy of 0.905 and AUC value of 0.971, underscoring its unique capacity to illuminate gene functionalities ConclusionThe proposed method is effective for identifying network module biomarkers, and the detected anti-PD1 response biomarkers can enrich our understanding of the underlying physiological mechanisms of immunotherapy, which have a promising application for realizing precision medicine.

Novel cell wall polysaccharide genotypes and structures of lactococcal strains isolated from milk and fermented foods

The biosynthetic machinery for cell wall polysaccharide (CWPS) formation in Lactococcus lactis and Lactococcus cremoris is encoded by the cwps locus. The CWPS of lactococci typically consists of a neutral rhamnan component, which is embedded in the peptidoglycan, and to which a surface-exposed side chain oligosaccharide or polysaccharide pellicle (PSP) component is attached. The rhamnan component has been shown for several lactococcal strains to consist of a repeating rhamnose trisaccharide subunit, while the side chain is diverse in glycan content, polymeric status and glycosidic linkage architecture. The observed structural diversity of the CWPS side chain among lactococcal strains is reflected in the genetic diversity within the variable 3′ region of the corresponding cwps loci. To date, four distinct cwps genotypes (A, B, C, D) have been identified, while eight subtypes (C1 through to C8) have been recognized among C-genotype strains. In the present study, we report the identification of three novel subtypes of the lactococcal cwps C genotypes, named C9, C10 and C11. The CWPS of four isolates representing C7, C9, C10 and C11 genotypes were analysed using 2D NMR to reveal their unique CWPS structures. Through this analysis, the structure of one novel rhamnan, three distinct PSPs and three exopolysaccharides were elucidated. Results obtained in this study provide further insights into the complex nature and fascinating diversity of lactococcal CWPSs. This highlights the need for a holistic view of cell wall-associated glycan structures which may contribute to robustness of certain strains against infecting bacteriophages. This has clear implications for the fermented food industry that relies on the consistent application of lactococcal strains in mesophilic production systems.

In search of the Goldilocks zone for hybrid speciation II: hard times for hybrid speciation?

Hybridization opens a unique window for observing speciation mechanisms and is a potential engine of speciation. One controversially discussed outcome of hybridization is homoploid hybrid speciation by reciprocal sorting, where a hybrid population maintains a mixed combination of the parental genetic incompatibilities, preventing further gene exchange between the newly formed population and the two parental sources. Previous work showed that, for specific linkage architectures (i.e., the genomic location and order of hybrid incompatibilities), reciprocal sorting could reliably result in hybrid speciation. Yet, the sorting of incompatibilities creates a risk of population extinction. To understand how the demographic consequences of the purging of incompatibilities interact with the formation of a hybrid species, we model an isolated hybrid population resulting from a single admixture event. We study how population size, linkage architecture, and the strength of the incompatibility affect survival of the hybrid population, resolution/purging of the genetic incompatibilities and the probability of observing hybrid speciation. We demonstrate that the extinction risk is highest for intermediately strong hybrid incompatibilities. In addition, the linkage architecture displaying the highest hybrid speciation probabilities changes drastically with population size. Overall, this indicates that population dynamics can strongly affect the outcome of hybridization and the hybrid speciation probability.

Structural Design and Experiments of a Dynamically Balanced Inverted Four-Bar Linkage as Manipulator Arm for High Acceleration Applications

Industrial robotic manipulators in pick-and-place applications require short settling times to achieve high productivity. The fluctuating reaction forces and moments on the base of a dynamically unbalanced manipulator, however, cause base vibrations, leading to increased settling times. These base vibrations can be eliminated with dynamic balancing, which is achieved, in general, with the addition of counter-masses and counter-inertias. Adding these elements, however, comes at the cost of increased moving mass and inertia, resulting in lower natural frequencies and again higher settling times. For a minimal settling time it is therefore essential that a balanced mechanism has high natural frequencies with an optimal mass distribution. A dynamically balanced inverted four-bar linkage architecture is therefore favoured over architectures which depend on counter-masses and counter-rotating flywheels. The goal of this paper is to present and experimentally verify a structural design of a manipulator arm with high natural frequencies that is based on a dynamically balanced inverted four-bar linkage. The dynamical properties and the robustness to manufacturing tolerances are both verified with simulations and experiments. Experiments for 5.2 G tip accelerations show, when fully balanced, a reduction of 99.3% in reaction forces and 97.8% in reaction moments as compared to the unbalanced mechanism. The manipulator reached 21 G tip accelerations and a first natural frequency of 212 Hz was measured, which is significantly high and more than adequate for implementation in high acceleration applications.

Stiffness Compensation Through Matching Buckling Loads in a Compliant Four-Bar Mechanism

Abstract In this paper, a novel alternative method of stiffness compensation in buckled mechanisms is investigated. This method involves the use of critical load matching, i.e., matching the first two buckling loads of a mechanism. An analytical simply supported five-bar linkage model consisting of three rigid links, a prismatic slider joint, and four torsion springs in the revolute joints is proposed for the analysis of this method. It is found that the first two buckling loads are exactly equal when the two grounded springs are three times stiffer than the two ungrounded springs. The force–deflection characteristic of this linkage architecture showed statically balanced behavior in both symmetric and asymmetric actuation. Using modal analysis, it was shown that the sum of the decomposed strain energy per buckling mode is constant throughout the motion range for this architecture. An equivalent lumped-compliant mechanism is designed; finite element and experimental analysis showed near-zero actuation forces, verifying that critical load matching may be used to achieve significant stiffness compensation in buckled mechanisms.

The Grand 4R Four-Bar Based Inherently Balanced Linkage Architecture for synthesis of shaking force balanced and gravity force balanced mechanisms

Considering balancing as starting point in the design of mechanisms and manipulators is known as inherent balancing. Inherently balanced linkage architectures then form the basis from which balanced mechanism solutions are synthesized, needing no countermasses contrary to balancing of given mechanisms. In this paper a new and advanced inherently balanced linkage architecture with the 4R four-bar linkage as a basis is presented, the Grand 4R Four-Bar Based Inherently Balanced Linkage Architecture. With 24 links it is 26 times overconstrained yet movable with stationary center of mass. It is shown that all theories for tracing the center of mass of a four-bar linkage are found inside. It is shown also how from this architecture a variety of new normally constrained 2-DoF balanced linkages are derived by removing a selection of links. This is done for the situations that all links are mass symmetric, for which 32 solutions are presented, and that all links have a general mass distribution. As an example, the balance conditions for the TWIN-4B, a solution of two similar 4R four-bar linkages, one inside the other, are derived and it is shown how this solution can be transformed into a spatial inherently balanced double Bennett linkage.

In search of the Goldilocks zone for hybrid speciation.

Hybridization has recently gained considerable interest both as a unique opportunity for observing speciation mechanisms and as a potential engine for speciation. The latter remains a controversial topic. It was recently hypothesized that the reciprocal sorting of genetic incompatibilities from parental species could result in hybrid speciation, when the hybrid population maintains a mixed combination of the parental incompatibilities that prevents further gene exchange with both parental populations. However, the specifics of the purging/sorting process of multiple incompatibilities have not been examined theoretically. We here investigate the allele-frequency dynamics of an isolated hybrid population that results from a single hybridization event. Using models of two or four loci, we investigate the fate of one or two genetic incompatibilities of the Dobzhansky-Muller type (DMIs). We study how various parameters affect both the sorting/purging of the DMIs and the probability of observing hybrid speciation by reciprocal sorting. We find that the probability of hybrid speciation is strongly dependent on the linkage architecture (i.e. the order and recombination rate between loci along chromosomes), the population size of the hybrid population, and the initial relative contributions of the parental populations to the hybrid population. We identify a Goldilocks zone for specific linkage architectures and intermediate recombination rates, in which hybrid speciation becomes highly probable. Whereas an equal contribution of parental populations to the hybrid population maximizes the hybrid speciation probability in the Goldilocks zone, other linkage architectures yield unintuitive asymmetric maxima. We provide an explanation for this pattern, and discuss our results both with respect to the best conditions for observing hybrid speciation in nature and their implications regarding patterns of introgression in hybrid zones.

A new typology of DC tiltmeter based on the Watt's linkage architecture

The Extended Folded Pendulum Model is a new model aimed at describing the dynamical behavior of a folded pendulum generically oriented in space. This model highlights an analytic relationship between the folded pendulum orientation, referred to the direction of the gravitational acceleration, and its natural resonance frequency. This new feature is the key element for the implementation of high sensitivity stand-alone DC tiltmeters, opening new typologies of application to folded pendulums. In this paper, we present and discuss this model as extension of classical folded pendulum models, using the Tait–Bryan angles formalism. Experimental results obtained with monolithic folded pendulums configured as DC tiltmeters are discussed in connection with the model predictions, also in view of new interesting applications.

표준연동 아키텍처(HLA/RTI)기반 다해상도 연동 시뮬레이션 설계 및 구현

본 논문에서는 표준연동 아키텍처(HLA/RTI)기반 다해상도 연동이 가능한 시뮬레이션을 구성하여 공학급(QUEST), 교전급(SADM), 임무급(EADSIM)의 모델을 연동하였다. 공학급 모델은 전투실험 공학분석 시범체계에서 개발된 전투실험 통합개발환경(QUEST)을 이용하여 모델을 개발하였다. 교전급 모델은 SADM을 이용하여 개발하고 임무급 모델은 EADSIM을 이용하여 모델을 개발하였다. 여러 계층의 모델을 연동하기 위해 표준 연동 아키텍처 기반(HLA/RTI)으로 설계하고 구현하였다. 각기 다른 분산된 환경에서 수행되고 있는 시뮬레이션 프로그램들이 상호 연동을 위해 표준 연동 인터페이스 명세에 만족하는 연동 시뮬레이션을 설계하고 각 시뮬레이션 프로그램 간의 중계 역할을 담당하는 통합연동 게이트웨이를 개발하였다. 다해상도 연동 시뮬레이션을 통해 여러 계층 간의 모델을 연동하여 해양 무기체계 효과도 분석을 위한 모델충실도를 향상하고 운용자 필요에 따라 요구되는 전장 환경을 신속하게 구성할 수 있다. 또한 표준연동 아키텍처(HLA/RTI)를 기반으로 설계하게 된 다른 시뮬레이션 프로그램과도 쉽고 효율적으로 연동할 수 있다. In this paper, the multi-resolution simulation of standard linkage architecture is consists of the engineering-level (QUEST), engagement-level (SADM), the mission-level (EADSIM). It was developed the engineering-level model using battle experiment integrated development environment in the battle experimental engineering system. The engagement level model was developed using the SADM and the mission-level model was developed using EADSIM. The standard linkage architecture is designed and implemented in order to interlocking model of multiple layers. Each different simulation programs in a distributed environment was designed by HLA interface specifications for satisfying interworking. Also the integrated interoperation gateway was developed for relaying the each different simulation programs. The effective naval weapon system for measure of effectiveness develops using to improve the fidelity of the model between the various layers through multi-resolution interoperation simulation. According to the operator requirement is quickly battlefield environment can be constructed. The other simulation program that being designed through standards linkage architecture can linkage easily and efficiently.

Design and operation of a tripod walking robot via dynamics simulation

SUMMARYA mechanical design and dynamics walking simulation of a novel tripod walking robot are presented in this paper. The tripod walking robot consists of three 1-degree-of-freedom (DOF) Chebyshev–Pantograph leg mechanisms with linkage architecture. A balancing mechanism is mounted on the body of the tripod walking robot to adjust its center of gravity (COG) during walking for balancing purpose. A statically stable tripod walking gait is performed by synchronizing the motions of the three leg mechanisms and the balancing mechanism. A three-dimensional model has been elaborated in SolidWorks® engineering software environment for a characterization of a feasible mechanical design. Dynamics simulation has been carried out in the MSC.ADAMS® environment with the aim to characterize and to evaluate the dynamic walking performances of the proposed design with low-cost easy-operation features. Simulation results show that the proposed tripod walking robot with proper input torques, gives limited reaction forces at the linkage joints, and a practical feasible walking ability on a flatten ground.

KINEMATIC ANALYSIS AND PERFORMANCE EVALUATION OF 6R INSTRUMENTED SPATIAL LINKAGES

Six-degree-of-freedom instrumented spatial linkages are often used to measure anatomical joint motion for clinical studies or research applications in biomechanics. Their appropriate design is a fundamental issue to allow for accurate measurements and ease of application, and this mainly relies on addressing the kinematic analysis of the linkage. The aim of this paper is to integrate and extend past literature in the field by giving a generalized set of guidelines and ready-to-use mathematical relationships to approach the whole kinematic analysis of a general instrumented spatial linkage in a systematic way. The direct kinematics is formulated using common robotics formulation and, with reference to a specific linkage architecture, a geometrical approach is proposed to solve for the inverse kinematics in closed-form. Kinematic error analysis is addressed in a generalized way by using differential transformation theory, and it is then applied to the specific case under study. By the proper definition of a virtual joint, the inverse kinematics is used to estimate the static performance of the linkage over its specific task space.

Nonlinearly Additive Forces in Multivalent Ligand Binding to a Single Protein Revealed with Force Spectroscopy

We present evidence of multivalent interactions between a single protein molecule and multiple carbohydrates at a pH where the protein can bind four ligands. The evidence is based not only on measurements of the force required to rupture the bonds formed between concanavalin A (ConA) and alpha-D-mannose but also on an analysis of the polymer-extension force curves to infer the polymer architecture that binds the protein to the cantilever and the ligands to the substrate. We find that although the rupture forces for multiple carbohydrate connections to a single protein are larger than the rupture force for a single connection, they do not scale additively with increasing number. Specifically, the most common rupture forces are approximately 46, 68, and 85 pN at a loading rate of 650 +/- 25 pN/s, which we argue corresponds to 1, 2, and 3 ligands being pulled simultaneously from a single protein as corroborated by an analysis of the linkage architecture. As in our previous work polymer tethers allow us to discriminate between specific and nonspecific binding. We analyze the binding configuration (i.e., serial vs parallel connections) through fitting the polymer stretching data with modified wormlike chain (WLC) models that predict how the effective stiffness of the tethers is affected by multiple connections. This analysis establishes that the forces we measure are due to single proteins interacting with multiple ligands, the first force spectroscopy study that establishes single-molecule multivalent binding unambiguously.