Intracavitary electrocardiography is an accurate guidance technique for peripherally inserted central catheters (PICC) tip location that is spreading widely among providers using non x-ray-based facilities. The principle behind this technology relies on the transmission of the electrocardiographic signal at the tip of the catheter and its use as an internal mobile electrode, allowing the system to identify the cavo-atrial junction (CAJ) through internal P-wave amplitude modulations. The gain in popularity of intracavitary electrography and its large diffusion have led manufacturers to offer various devices with heterogeneous properties, among which clinician who place PICCs have to choose. It is therefore important to understand differences between available techniques and devices. The potential impact might not only affect availability and costs but also the clinical impact through advantages and limitations regarding electric signal transmission PICC selection. Current perspectives on intracavitary electrocardiography will also be discussed, to give the reader a global view of the management of electrocardiographically guided PICCs, especially in an environment without x-ray support. The peripherally inserted central catheter (PICC) is a very commonly used medical device. As PICCs are peripherally inserted, the catheter needs to be guided from its insertion point to the central venous system. Currently, this is done using fluoroscopy-guided insertion (FGT), blind technique (BT), or electrocardiogram (ECG) based techniques.Fluoroscopy-guided insertion uses x-ray fluoroscopy and is considered the gold standard –3. By deMore recently, ECG-based techniques that rely on the modification of an intracavitary ECG signal to position the catheter tip optimally in the central vein have been developed . The useThis manuscript aims to review the rationale for optimal positioning of the catheter tip in the superior vena cava (SVC) and describes the current technologies of ECG-based techniques and their respective advantages and limitations.In order not to miss a major information, this narrative review integers at least the articles retrieved from Pubmed with the simplified research equation.Search:  AND “Electrocardiography”[Mesh] Filters: English, from 2008–2022.Peripherally inserted central catheters has always inspired numerous discussions of complications such as occlusion, infection, and thrombosis .Among these issues, it is known that positioning an internal catheter tip distant from the cavo-atrial junction (CAJ) makes the catheter more likely to undergo internal repositioning and venous thrombosis. As the distance from the catheter tip to the CAJ is the single and strong predictor of central thrombosis and tip repositioning , an optiAn intracardiac tip position too far from the CAJ may also be a source of unwanted events such as cardiac arrhythmias (tachycardia or bradycardia) due to direct irritation of the right atrium or ventricle –14, whicAccording to the distance from the tip to the CAJ, the PICC positions can be classified into three types  4)..4).1.T1: Tip is within 1 cm of the CAJ .2.T2: Tip is between 1 and 3 cm from the CAJ .3.T3: Tip is >3 cm below the CAJ or is not in the SVC .The electrocardiogram localization technology relies on the use of Lead II’s complex of Einthoven’s Triangle in order to obtain the maximal P-wave signal [limb electrodes at the right arm (RA) and left leg (LL)] .This surface tracing serves as reference and is compared to the same tracing seen in intracavitary through the PICC tip, which is used as an electrode.The P-wave varies between the two tracing reaching its highest value at the CAJ.The operator will therefore be able to find the position of the catheter related to the maximum height of the P-wave.Peripherally inserted central catheters are not a uniform product, there are a lot of subtle and less subtle variations on PICC design that deserve to be addressed.The actual catheters can be differentiated based on their material which is mostly polyurethane (PUR) but also silicone.They may also be differentiated by the location of the cut to adjust their length. Some catheters are trimmed on their “free end side” which is the proximal part of the catheter, closer to the hearth. While other are trimmed on their outer part, near to the hub, which is the distal part of the catheter.The distal catheter part may also vary regarding its design. It may be straight, i.e., with the same French size on the whole catheter or it may be “reverse tapered” which consists in a gradual augmentation of the French catheter size in the last centimeters of the catheter .Some catheters are non-valved while others are valved this permits aspiration with negative pressure, infusion with positive pressure and a closed system with neutral pressure.Among these, the strongest point of attention is the trim point which further determines the technique of insertion.There are two procedural techniques varying depending on the trim point .The patient is prepared using the standard maximal sterile barrier approach with external ECG electrodes placed the chest.The catheter is inserted into one of the upper arm veins using an ultrasound-guided out-of-plane control and modified Seldinger technique , with the arm abducted to approximately 75–90°.Before insertion, the catheter is trimmed to the approximate anticipated required length. This approximation is based on the following calculation, using anthropometric measurements: insertion site to axillary crease distance + axillary crease to sternal notch distance + sternal notch to the third intercostal space . The freThe PICC is advanced into the central circulation. On the display interface, both surface  and intracavitary  ECG traces are visible in real time, allowing the operator to see if the PICC is taking the correct path toward the heart. This is done by following P-wave modulations (see intracavitary ECG paragraph). The conductivity is ensured through either a solid or liquid medium (see conductivity paragraph).The tip is implanted at the CAJ and the puncture site is dressed using a catheter stabilization device .This technique allows the manufacturer to design the device with features such as a reverse-tapered hub-side catheter with a fixed, integrated valve , 20 Fig.The patient preparation, venous access, ECG following and PICC advancing into the central circulation, and site dressing are identical to those in technique A.The PICC is not trimmed before to advance it into the central circulation but the approximate anticipated required length is used to identify the position where a P-wave modification should happen.After the PICC implantation at the CAJ following P-wave modulations, the distal part of the PICC is then cut without the need to retire it and the removable part of the catheter is then connected.This technique allows the manufacturer to use tapered, open-ended distal tips or valved, closed distal tips  Figures.Thera are two distinct phase in tip positioning , the navTip navigation (using a reference electrode) consists in verifying the correct direction of the catheter. This can be achieved through the interpretations of the components of QRS waves allowing differentiation of non-central veins . Thus it is rather complicated .®) and instead of using the QRS complex, it uses the catheter tip and the Y shield as a low field magnetic complex. The position of the tip relative to the shield is electronically displayed on a screen, allowing the operator to follow the tip moves in real time toward SVC and identifying the wrong locations such as neck or contralateral side As long as the catheter is distant from the central position, the P-wave remains unchanged and is equivalent to the superficial ECG trace.The tip is not in the SVC, corresponding to a T3 position .(b)As the tip nears the CAJ, the intracavitary P-wave slowly increases in amplitude.The tip is within 3 cm of the CAJ, corresponding to a T2 position .(c)At the moment the catheter is at the CAJ level, the P-wave will show its maximal amplitude without initial negative deflection .The tip is within 1 cm of the CAJ, corresponding to a T1 position .(d)When the tip proceeds further than the CAJ, the P-wave will shrink again and present an initial negative deflection  25). Th. Th25). When the amplitude of the P-wave is more than 50% of the R part from QRS complex, the accuracy rate of PICC placement is superior to 99% .In order to integrates the catheter moves between abduction and adduction Zhu et al.  suggest The signal transmission between the catheter tip and lead may be achieved by using either a solid  or liquiThe solid medium is a metallic guide wire, while the liquid medium is generally saline water . Sodium The coupling of the ECG monitor to the PICC may be achieved through commercially available wire-based  or salinSeveral studies have compared ECG technologies with regard to their intracavitary electrode type (liquid vs. wire) and their capacity to identify the CAJ. The results from multiple implantable devices have been synthesized in a meta-analysis  that shoThe way conductivity is achieved may also have some importance in the PICC placement. When comparing wire vs. saline, some  have advDue to its importance, the central positioning of the tip should be the primary goal of each intervention.4) particle loss, which creates weak points and makes silicone more prone to mechanical failures  results in the loss of some of the manufactured smooth and round catheter tip . This inIntuitively, it makes sense that a rough catheter tip may not be ideal. Another option exists, combining technique B and a distally (inner) valved closed tip. This catheter configuration seems similar to an outer valve in regard to occlusion rates . The onlThe complication rates of silicone and PUR devices are apparently similar, though it is difficult to thoroughly address this point due to a lacunar specification of post-care informations in studies .It exists no points of comparison between ECG devices, in that way ECG technologies will be discussed relative to other techniques.Interventional radiology services are usually overwhelmed by PICC demands, delaying patient care and lowering discharge rates for outpatient therapies. This is usually linked to the fact that a PICC is regarded as a “last-in-line procedure” with no degree of priority vs. life-saving or complex interventional procedures , 46.The ECG system is very powerful in its capacity to improve productivity. The radiology outsourcing may lower organizational costs such as waiting delay for insertion from 6 times  and ECG When facing structural costs, the use of ECG technology is a straightforward means of budget containment , 49, witIn regard to medical skill substitution, ECG technology may be a good alternative when professionals have limited access to fluoroscopic devices, it may also provide a way to accommodate restrictions on the use of fluoroscopy by non-licensed practitioners such as PICC nurses . Skill s3), . When it is needed to enhance the ECG signal capacity, an hypertonic solution may be effective, Capasso et al.  such as port, jugular CVC, or tunneled CVC. More powerful trials oriented to PICCs should be run.Stenosis and obstructions are rather uncommon (3%) in populations without catheter history but may rise to 7.5% in populations with central catheterization history . In thesThese elements may clearly be considered a limiting factor of ECG technologies. Fluoroscopy permits a direct tract visualization which is greatly useful in identifying the right venous pathway which may be challenging to identify through indirect ECG visualization . ArteriaAt the same time, the scope of use of ECG guidance is constantly increasing in connection with clinical research and former limits of the system may be alleviated. Even if active magnetic device such as ventricular assist device are still problematic for ECG guidance , concomiConsidering secondary malposition diagnosis . Saline ECCG technology allows the following of the inserted tip in a way as effective as diagnostic CRX  and bedsWhat precision can be reached under ECG is a frequent subject of controversy between users who are more for the use of FX technology or more for the use of ECG technology , 3, 28. On one hand, ECG is especially interesting for premature infants as accumulated radiation dose may manifest years after exposure . On the The first kind of concession (technique A) is related to the length of catheter needed to ensure the capacity to observe the P-wave modifications  and by this means to position the catheter at the CAJ. Operators may need up to 2 cm of extra catheter length  while ElThe second type of concession is related to the disturbances caused by the device at the insertion point. These disturbances are either intravascular or extravascular.Should the device be reverse tapered to ensure better hemostasis (technique A), its increase in diameter (toward the hub) may be as high as 2F, with potential associated bloodstream perturbations .The different advantages and limits of PICC devices classified by technique and transmission medium are summarized in In practical use, a PICC and ECG can be combined in multiple ways, depending on the device’s trim point, material, valve position, and transmission medium, according to the operator’s choices. From a strategic point of view, the ECG-guided PICC is an effective alternative oriented toward undelayed patient management and optimized workflow, although it lacks some strengths that are needed in complex situations.SQ: conceptualization, critical review, editing of the draft, and decision to submit for publication. GG: preparation, visualization, data presentation, writing the initial draft, editing of the draft, and creation of the published work. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Learning to write in a foreign language is a complex cognitive process. The process-genre approach is a common instructional practice adopted by language teachers to develop learners’ writing abilities. However, the interacting elements of procedural knowledge, linguistic knowledge, and generic knowledge in this approach may exceed the capacity of an individual learner’s working memory, thus actually hindering the acquisition of writing skills. According to the collective working memory effect, it was hypothesized that teaching writing skills of English as a foreign language by adopting a process-genre approach in collaborative conditions could lead to better writing performance, lower cognitive load, and higher instructional efficiency. The reported experiment compared learning writing skills of English as a foreign language in individual and collaborative instructional conditions from a cognitive load perspective, a rarely adopted approach in this field. The results indicated that the collaborative instructional condition was more effective and efficient than the individual instructional condition in improving the quality of written products as well as in optimizing the cognitive (working memory) load experienced by the learners. Measures of cognitive load were used to support the cognitive load theory’s interpretation of the results, which is the unique contribution of this research study to the field. Learning to write in a foreign language is a complex problem-solving process, requiring not only a range of skills from writing English letters to composing complete essays but also the ability to make claims and provide appropriate supporting details . StudentThe collective working memory effect in cognitive load theory refers to the working memory space created by communicating and coordinating knowledge by each collaborator . An indiHowever, to our best knowledge, differences between the effectiveness of individual and collaborative instructional approaches in learning writing skills of English as a foreign language from a cognitive load perspective have never been investigated , 2018. MWriting involves a range of cognitive activities. The genre approach and process approach to teaching writing skills have been used extensively to promote learners’ abilities to write in English . The proTaking a social stance, a process-genre approach to teaching writing skills encourages interactions and collaborations, which involves some kinds of collaborative activities such as “modeling, eliciting, supporting, probing, and suggesting alternatives or extension” to a learner’s initial attempts , p. 72. Cognitive load theory aims at designing effective instructional materials and procedures to optimize learner cognitive resources in the process of acquiring complex knowledge structures . CognitiThe level of cognitive load experienced by the learners is determined by the level of element interactivity which refers to the degree to which information elements or components of a learning task should be processed simultaneously for meaningful learning . For exaThe levels of cognitive load that learners experience can be measured by subjective rating scales of effort, a simple and reliable instrument first adopted by E = (P-R)/√2, in which E stands for efficiency, P for performance z-score, and R for cognitive load rating z-score. In this study, the average of intrinsic cognitive load and extraneous cognitive load ratings were used to calculate the cognitive load z-score. According to this formula, higher values of instructional efficiency are achieved in situations where learning performance is high and cognitive load is low; lower values of instructional efficiency occur under conditions where learning performance is low and cognitive load is high.Cognitive load ratings are frequently combined with learning performance measures to calculate the relative instructional efficiency for different learning environments. Instructional efficiency in this study was calculated using Cognitive load theory considers a social interaction situation as a collective working memory system and extends the instructional focus from individual learning to collaborative learning. A collective working memory system can be developed from individual cognitive systems through collaboration, coordination, and communication. The collective working memory effect happens when learners acquire knowledge more effectively and efficiently through collaborating with others than through learning individually . The colCollective working memory refers to the working memory space created by communicating and coordinating knowledge by each collaborator . An indiUnder the individual learning condition, all the interacting elements of the learning task are processed in the individual learner’s working memory. By contrast, learners who collaborate with others in their learning distribute all the interactive elements among the working memories of group members. Consequently, a collaborator would experience lower levels of the cognitive load than an individual learner. This assumption was supported by Task complexity or element interactivity can influence the effectiveness of collaborative learning. For simple learning tasks, individual learning is expected to be more effective and efficient, as the transaction costs associated with sharing knowledge and coordinating communication will nullify the benefits offered by collaborative learning. By contrast, for complex tasks, the benefits offered by the collective working memory could be higher than the transaction costs, thus fostering efficient learning. Learning writing skills of English as a foreign language has long been regarded as a complex process that usually generates a heavy cognitive load . Based o(1)Participants taught through the process-genre approach in the collaborative learning condition would demonstrate better individual writing performances than participants in the individual learning condition.(2)Participants taught through the process-genre approach in the collaborative learning condition would experience lower levels of the cognitive load than participants in the individual learning condition.The reported experiment focused on the effect of collaboration in creating a collective working memory among the members of a group. Previous research studies seldom included controlled randomized experiments and assessed learners’ writing products as a means to evaluate the effectiveness of collaborative learning. Therefore, according to the collective working memory effect, the reported experiment was designed to test the hypotheses that learners of English as a foreign language in the collaborative process-genre instructional condition would achieve better individual learning outcomes in terms of writing skills, experience lower levels of cognitive load, and have higher instructional efficiency than learners in the individual process-genre instructional condition.n = 32) and the collaborative learning condition (CL) (n = 32). The participants in the collaborative learning condition were further randomly allocated into eight groups with four members in each. This arrangement was based on the rationale that groups consisting of no more than six members could maximize participation by all group members  voluntarily participated in this experiment after reading the recruitment notice. They studied at a technological university in Shandong Province, China. They were also briefed about the aims, the procedures, their rights through the study, and their rights to access the research results. They were requested to return the signed consent form if they determined to participate. These college students were on average 21.5 years old and had spent 11 years learning English as a foreign language at the time of the experiment, so they could be regarded as having an intermediate level of English proficiency. They were randomly allocated into the individual learning condition (IL) : General Training. Two independent raters examined their writings by complying with the IELTS writing band descriptors. These raters were proficient IELTS tutors with experience in applying the band descriptors in evaluating IELTS essays. An independent samples t-test indicated that the pre-test scores of the IL group  were not significantly different from the CL group , t(58) = 0.61, p > 0.05.The participants were required to write an essay as a pretest. The design of the pretest was based on Task 2 of the writing section in The Official Cambridge Guide to IELTS authored by The instructional material was about how to write complaint letters. The development of the teaching material was based on the book The instruction was delivered in seven phases see . The parHow do structural features reflect communicative purposes? and Are there alternative structures for this genre? The second part (10 min) elaborated on the common language features of complaint letters, such as phrases and sentence structures for specifying the problem, outlining the consequences, making and justifying a specific claim, and so on, with the questions for thinking and discussion being: Are there alternative ways to give reasons and solutions? By using graphic organizers, the third part (10 min) showed the essential steps in planning writing. The question for introspection and discussion in this phase was: If there exist alternative structures, how can these steps in essay planning be adapted to suit those structures? The fourth part (15 min) introduced a model letter, in which the participants were required to identify the structural features, explain the functions of each feature, and the language features that were used for achieving the purposes. The associated questions in this phase were: What tenses have been used mainly in each paragraph? and Why tenses were used in these ways? The fifth instructional phase (10 min) required the participants to plan a letter on a given topic and scenario. In these five phases, the participants in the collaborative instructional conditions were encouraged to learn the materials through collaboration, share their understandings, ask questions, and provide responses, while the individual learners were encouraged to talk to themselves or engage in an internal conversation. In the sixth phase (15 min), the participants were required to individually write a letter on the topic they discussed in the fifth phase by using the skills learned in the first four phases. The last phase of the experiment (5 min) was a subjective cognitive load rating questionnaire  introduced the purposes and structural features of complaint letters, as well as the functions of each structural component. The structural features of complaint letters covered in this study include the following: the introductory paragraph elicits the purpose of complaint letters; the body paragraphs elaborate on the problems that letters are about and the suggested solutions; and the conclusion paragraph generally states the expectations and closes the letter. The associated questions for thinking  and discussion (for collaborative learners) were: ionnaire .Traditionally, subjective ratings of working memory load have proven to be able to collect reliable and valid estimations of mental load in a non-intrusive way . The cogIELTS General Training Writing Task 1: Writing band descriptors published by the British Council. The band descriptors cover four categories: task achievement, coherence and cohesion, lexical resource, and grammatical range and accuracy. Each category has the 9-point scale, ranging from one to nine. Each letter was given one score for each category, and the sum of the scores in the four categories was the rater’s score for the letter. The highest mark for a letter was 36. Two independent raters assessed students’ letters. The average value of two raters’ markings was used as the final score of the letter. The inter-rater reliability was calculated using a Person intra-class correlation (ICC). The ICC measure of 0.92 indicated a high degree of inter-rater reliability.The quality of the letters was assessed according to the p > 0.05) and the assumptions were satisfied. After controlling for the effect of pretest, it was found that the participants in the CL instructional condition demonstrated significantly better letter writing performance  and significantly higher instructional efficiency  than those in the IL instructional condition. In terms of category scores, the learners in the CL teaching condition significantly outperformed those learners in the IL teaching condition in all the four subscales: task achievement , coherence and cohesion , lexical resource , as well as grammatical range and accuracy . The participants in the IL instructional condition experienced significantly higher levels of intrinsic cognitive load , significantly higher levels of extraneous cognitive load , and significantly higher levels of overall cognitive load  than the participants in the CL condition.An analysis of covariance (ANCOVA) was conducted to compare the two instructional groups’ letter scores, scores of each subcategory, the ratings of intrinsic cognitive load, extraneous cognitive load, and overall cognitive load, as well as the indicators of instructional efficiency. Levene’s test was conducted  = 143.44, p = 0.001, r = 0.84] as well as the four subscales: task achievement , coherence and cohesion , lexical resource , and grammatical range and accuracy . In addition, cognitive load ratings and instructional efficiency were related to the covariate, pretest. The correlation to the covariate, pretests, was also observed in intrinsic cognitive load, overall cognitive load, and instructional efficiency. Students in the CL instructional condition had lower cognitive load ratings and higher instructional efficiency than the participants in the IL condition: intrinsic cognitive load , overall cognitive load , and instructional efficiency . However, it should be noted that the covariate, pretest, was not significantly related to extraneous cognitive load , which indicates that the differences in participants’ perception of extraneous cognitive load could be largely attributed to the dependent variable, instructional conditions.The covariate, which is pretest in the study, was significantly related to the letter writing performance, which means that the participants in the CL condition had significantly better performance than the students in the IL condition in terms of the overall scores [The reported experiment was conducted to test the hypotheses generated by cognitive load theory that learners of English as a foreign language in a collaborative instructional condition would show better writing performance, lower levels of cognitive load, and higher instructional efficiency than learners in an individual learning condition. Even though relations to the covariate, pretest, were observed, the results of the study generally supported the hypotheses. As for the first hypothesis, this randomized experimental study found that the students in the collaborative learning condition demonstrated higher overall post-test letter writing scores and higher subcategory scores  than the participants in the individual learning condition. The second research hypothesis was also supported as the participants in the collaborative learning condition indicated lower overall cognitive load ratings than the participants in the individual learning condition. It was also found that the collaborative learning condition generated higher instructional efficiency in terms of developing writing skills than the individual learning condition. Moderate and significant negative correlations were found between the ratings of intrinsic cognitive load and the letter-writing performance scores for both instructional conditions. The results demonstrated the collective working memory effect  in the dFirst, the study contributed to the research area of writing in a foreign language by conceptualizing the research and interpreting the findings from the perspective of cognitive load theory. In an attempt to account for the role of specific cognitive mechanisms in improving writing performance, it is possible to assume that the collaborative instructional approach had created an effective pool of knowledge about language and a pool of cognitive resources that beneficially influenced the quality of written products . The intSecond, the findings are consistent with the collective working memory effect, in that learning English as a foreign language writing skills in the collaborative instructional condition is more effective and efficient than in the individual learning condition . As learIn addition, this study also indicates that adopting a process-genre approach in a collaborative condition could lead to significantly better writing performance than in an individual learning condition, which is particularly consistent with research studies on developing self-regulation of writing processes and generic knowledge through collaborations e.g., . AccordiFurthermore, the results of the reported study are also consistent with previous research in the field of collaborative learning of writing skills e.g., , in thatThe reported study still has some limitations that require further research. First, this study did not consider the foreign language proficiency of the participants as a variable in collaborative teaching of English as a foreign language writing skill. According to the expertise reversal effect in cognitive load theory, the effectiveness of specific instructional techniques and procedures depends on the levels of the learner’s prior knowledge in the domain . This efIn conclusion, the results of the reported experimental study supported the hypothesis generated by cognitive load theory. Learning English as a foreign language writing skills through a process-genre approach in the collaborative instructional condition was more effective and efficient than in the individual instructional condition. Subjective ratings of the cognitive load supported the interpretation of results within a cognitive load framework. The findings have implications for the innovations of teaching approaches, the developments of course materials, and curriculum designs in the field of teaching foreign language writing skills.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.DJ: conceptualization, methodology, resources, data curation, writing – original draft, and review and editing. SK: supervision and writing – review and editing. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The talus-like rock mass is a special kind of geomaterial widely distributed in southwestern China, which has induced serious engineering disasters for tunneling engineering. However, the mechanical behavior of the talus-like rock mass remains unclear as the previous studies mainly focused on similar geomaterials such as the soil–rock mixtures. In this paper, we have carried out both experimental and discrete element method (DEM)-based numerical analyses to investigate the shearing characteristics of the talus-like rock mass collected from a real project site. Large-scale direct shear tests reveal that the strength parameters increase with the block content, which is different from the traditional soil–rock mixture. A dependence has been discovered in that the specimen dilation becomes more obvious under lower normal stress and larger block content. It is also observed that higher normal stress is beneficial for crushing blocks. The force chains obtained in the DEM simulations show that distinct internal structures are generated in the rock samples with different block contents. The distribution of coordination number establishes the dependence of fabric stability on block content during shearing. Bond-break evolution reveals the tendencies of crushed particles were consistent with those of experimental tests. The findings provide a more in-depth understanding about the mechanical behavior of the talus-like rock mass, which helps to uncover the cause of the collapse of the real tunnel project. For most regions in southwestern China, the geological conditions are more complex and the rock mass is extremely fragmentized because of the high altitudes, diverse topography and landforms, intricate geological tectonic belts and abundant groundwater resources. These special geological conditions gave birth to some special kinds of rock masses or geologic structures, such as the layered phyllite strata , soil–roGenerally, in order to explore the mechanical properties and obtain the mechanical parameters of geomaterials, the in-situ survey and laboratory tests were always utilized ,5. RecenThe experimental method enables us to investigate the overall mechanical behavior of geomaterials. However, it is unable to capture the microscopic characteristics inside the geomaterials. Therefore, the DEM (discrete element method) has been developed to be another useful tool to study the particle-formed geomaterials such as soil–rock mixture ,25,26. TIn this paper, we adopted the laboratory large-scale direct shear test and DEM-based numerical simulation to investigate the shearing characteristics of the talus-like rock mass. Firstly, three types of samples from the talus-like rock mass with different block contents, namely the mixture, fine grain and rocky block samples, were tested by large-scale shear tests. The shearing characteristics and mechanical parameters were analyzed and compared. Afterwards, the DEM models were established corresponding to the shear tests and the mechanical behaviors of the talus-like rock mass were analyzed. The results of the laboratory tests and DEM models were also compared and discussed, which gave deeper understanding about the talus-like rock mass.L = 600 mm, width W = 400 mm and height H = 200 mm), vertical and horizontal loading units, a steel frame, an oil pressure controller, and a control/data acquisition system. The vertical rectangular loading plate above the shear box provides the vertical pressure by moving down through a high-precision oil cylinder with a capacity of 100 kN. During the shearing process, a horizontal traction load is applied to the left side of the lower shear box while keeping the upper shear box fixed. All the load and displacement data are monitored through the load cell installed at the end of the loading system. A standard vibrating screen machine with standard square-hole test sieve  or rock blocks (block content = 100%) are rarely studied . The comThe main testing procedures are shown in The testing apparatus recorded the shear stress of the specimen as a function of the shear displacement of the lower box in the cases of different normal stresses. The strength parameters, i.e., cohesion and friction angle, can be derived from the shear–displacement curves and normal stresses. The dilatancy of the specimen during the shearing process was analyzed by monitoring the normal displacement of the vertical loading plate. In addition, the particle crushing characteristics was analyzed by comparing the grading curves before and after shearing. These testing results were analyzed and presented in the following subsections.The shear–displacement relationships for the three samples of talus-like rock mass under different normal stresses are shown in The obtained shear–displacement relationships for the mixture of talus-like rock mass showed some similar characteristics presented by previous studies on the soil–rock mixture of similar geomaterials. However, there are still differences between the present talus-like rock mass and the traditional soil–rock mixture . Previouτ = c + σ·tanφ, where τ, σ, c and φ are the shear stress, normal stress, cohesion, and friction angle, respectively. The calculated shear strength parameters (cohesion and friction angle) are listed in According to the shear–displacement relationships shown in The shear strength parameters in The different types of geomaterials may exhibit different deformation characteristics during shearing tests, either dilatancy or compression. The dilatancy feature has a significant effect on the physical and mechanical properties. In the case of pure fine grains, the specimens behaved similarly under different normal stresses b: the veAs shown in Comparing the dilatancy of the three samples of talus-like rock mass with different block contents, it can be found that the compression mainly happened to the mixture and fine grains because the smaller amount of rock blocks may induce decreased volume expansion. The rocky blocks showed more obvious dilatancy due to the dense contact and adjustment of rock blocks during the shearing test.The particle crushing appeared in the specimen formed by the mixture of the talus-like rock mass during the shearing test because of the interaction of rock blocks, which can be demonstrated by the difference between the particle size distribution curves before and after the shearing test, as shown in Furthermore, the percentages for different individual grain sizes before and after the shearing test are shown in Bg [Bp as the area between the line of D = 0.074 mm and the part of the particle size distribution curve before testing with D > 0.074 mm. The total breakage Bt is defined as the area between the particle size distribution curves before and after testing. Thus, Hardin’s index is derived as Br = Bt/Bp  is usually used to study the heterogeneous and discontinuous geomaterial, such as the soil–rock mixture ,31,32,33Based on the random extension algorithm for polygonal block generation by Xu et al. , this paDue to the lack of the relationship between the macro parameters of the talus-like rock mass and the micro parameters of the particles and contacts, we used the trial-and-error method to calibrate the micro parameters for DEM simulations. The calibration procedures mainly consisted of four steps: (1) specify an initial value for each parameter according to previous studies given the particle size and execute the calibration model c–e to obAfter the calibration of parameters for both fine grains and rocky blocks, the obtained parameters were used for modeling the mixture of talus-like rock mass. The lithology of the fine grains may be consistent with that of the blocks for that the fine grains mainly came from the rock debris or the powders by the breakage of rock blocks. Therefore, the contact parameters of the fine grain–rock block inherited that from the rock–rock contacts for the sake of simplicity, as listed in The DEM simulation could reveal internal microscopic phenomena, such as the force chains and bond-break evolution, which could not be captured during the laboratory test. In addition, we compared the dilatancy via DEM model and made a comparison with the laboratory tests.The internal force chain of the specimen was generated by assembling the contact forces between disks, which reflected the true stressed region during shearing tests. The internal force chain distributions of fine grains under different normal stresses are shown in The force chain distributions of the mixture of talus-like rock mass are shown in Z = 2Nc/Np, where Nc and Np are the numbers of contacts and particles, respectively [The coordination number is the average number of contacts per particle and a measure of the packing density of a granular assembly, which is defined as ectively ,43. Figuectively . The cooectively . As for ectively , which wThe parallel bonding model was employed in this paper to model the rock blocks by bonding the particles belonging to the rock blocks together. During the shear process, the bonds between particles would be broken if the stress exceeded the bonding strength . As a reThe bond-break development inside the rocky block sample under different normal stresses are summarized in bB [Nbond-break was the total number of broken bonding contacts and Nbond was the total number of bonding contacts before shearing test. The bB values for both rocky block and mixture samples of talus-like rock mass are shown in bB than the mixture model under the same normal stress, same as that the increase in VBP promoted the breakage of blocks [In order to evaluate the particle crushing characteristics quantitatively, the meso-ratio of block breakage Bb  was usedf blocks .(1)In the laboratory tests, it was observed that the strain hardening phenomenon mainly occurred at the later of the shearing tests for the mixture and rocky block samples. For the fine grains, the small normal stress  induced plastic flow and strain hardening whereas larger normal stresses promoted weak strain softening. Both the cohesion and friction angle increased from fine grains to rocky blocks, showing a dependency on the increasing block content. It was also found that the higher normal stress induced less dilatancy and the increased block content promoted the dilatancy.(2)The laboratory tests showed that the particle crushing phenomenon became more obvious as the normal stress increased, resulting in the decrease in coarse particle proportion and the increase in fine grain proportion. Meanwhile, the particles in the middle range remained almost unchanged for both the mixture and rocky block samples.(3)In the DEM-based numerical simulations, the dependency of the force chains on the block content was obtained. The fine grain specimen mainly generated uniform thin force chains while coarser force chains were formed in the samples with higher block content, i.e., the rocky block and mixture samples. In addition, the obvious rock skeleton was observed in the models of rocky blocks and the mixture, implying that the coarse grains were the main bearing component as block content increased.(4)The evolution of the coordination number was also found to be dependent on the block content, showing that the rocky blocks inside the specimen could help stabilize the fabric during shearing, consistent with the gradual decrease in coordination number during shearing. It is also observed that the larger normal stress promoted larger coordination number and more compacted and stable fabric during the shear process.(5)The bond-break evolution obtained by the DEM simulation revealed its dependency on the normal stress, i.e., higher normal stress increased the bond-break number and promoted the increase rate. Consequently, the meso-ratio of block breakage had a positive relationship with the normal stress. It was also found that more bond breaks occurred inside the rocky block specimen than in the mixture of the talus-like rock mass.This paper investigated the shearing characteristics of three samples of talus-like rock mass, i.e., the mixture, fine grain and rocky block samples, based on the laboratory shear tests and DEM numerical simulations. The main conclusions are summarized as follows:The phenomena captured by the laboratory shear tests and the microscopic observations in the DEM simulations threw light on the shearing characteristics of the talus-like rock mass. The findings will help us to better understand the interaction between the surrounding rock mass and the tunnel support system, and thus be beneficial to optimizing the design of the tunnel supporting and mitigating the engineering disasters during tunnel construction.


Recent developments on the grading of cardiac pathologies suggest flow-related metrics for a deeper evaluation of cardiac function. Blood flow evaluation employs space-time resolved cardiovascular imaging tools, possibly integrated with direct numerical simulation (DNS) of intraventricular fluid dynamics in individual patients. If a patient-specific analysis is a promising method to reproduce flow details or to assist virtual therapeutic solutions, it becomes impracticable in nearly-real-time during a routine clinical activity. At the same time, the need to determine the existence of relationships between advanced flow-related quantities of interest (QoIs) and the diagnostic metrics used in the standard clinical practice requires the adoption of techniques able to generalize evidences emerging from a finite number of single cases. In this study, we focus on the left ventricular function and use a class of reduced-order models, relying on the Polynomial Chaos Expansion (PCE) technique to learn the dynamics of selected QoIs based on a set of synthetic cases analyzed with a high-fidelity model (DNS). The selected QoIs describe the left ventricle blood transit and the kinetic energy and vorticity at the peak of diastolic filling. The PCE-based surrogate models provide straightforward approximations of these QoIs in the space of widely used diagnostic metrics embedding relevant information on left ventricle geometry and function. These surrogates are directly employable in the clinical analysis as we demonstrate by assessing their robustness against independent patient-specific cases ranging from healthy to diseased conditions. The surrogate models are used to perform global sensitivity analysis at a negligible computational cost and provide insights on the impact of each diagnostic metric on the QoIs. Results also suggest how common flow transit parameters are principally dictated by ejection fraction. Several studies in the literature have highlighted how flow-mediated metrics participate to the progression or regression of cardiac pathologies4, making intracardiac fluid dynamics an increasingly integral part of clinical evaluations. Cardiovascular imaging allows, to some extent, to measure cardiac fluid dynamics in vivo with results that are accumulating5. To date, various diagnostic techniques are used for the identification of flow-related LV functional properties through the use of tools such as 2D-transthoracic echocardiography, 4D-transesophageal echocardiography, and cardiac magnetic resonance (CMR), even though they present several limitations and are not routinely employed in clinical applications. At the same time, the direct numerical simulation (DNS) of the equation governing blood flow, carefully integrated with the boundary information obtained from routine diagnostic imaging, represents an alternate approach that is becoming popular in clinical research involving intraventricular fluid dynamics8; this approach is demonstrating usefulness for analyzing patient-specific cardiac flow conditions9. DNS also represents a viable tool to integrate existing imaging technology and extend it with the capability of reproducing flow details in virtual conditions corresponding to hypothetical therapeutic solutions10.The study of fluid dynamics inside the left ventricle (LV) of the human heart is of considerable interest for the identification of long and short-term pathologies11. Another clinical metric commonly employed to describe diastolic function is the ratio E/A12; it is defined as the ratio between the early (E-wave) and atrial (A-wave) peaks of the mitral inflow velocity, that is measured from pulsed-wave Doppler. This metric is used—in conjunction with others- for the classification of diastolic dysfunction as it reveals to which degree the LV fills passively during the early phase of diastole and how much LV filling must rely on the active support of atrial contraction to be completed14. As for LV geometry, the ventricular length and diameter measured at the end of diastole  are also important determinants of the ventricular function15. All such metrics affect intracardiac blood flow although they do not represent direct measurements of fluid dynamics phenomena. More sophisticated tools and methods, such as 4D flow magnetic resonance imaging (MRI) and DNS, allow identifying flow-specific quantities that provide a more profound description of intraventricular fluid dynamics. For example, the kinetic energy (KE) is a quantitative measure of LV blood flow vitality particularly during diastolic filling17. The vorticity field, and its average value 20; indeed, vortices represent the underlying structure of intraventricular flow and they are crucial for stability and for the dynamic balance between rotating blood and myocardial tissue21. The description of blood transit through the LV is also fundamental in cardiovascular physiology22 to identify properties of blood transport and mixing inside the LV in order to assess the residence time and the rapidity of blood wash-out; phenomena that can be related to the risk of thrombus formation23.The standard clinical assessment of cardiac pathology is based on a series of quantitative metrics that are directly or indirectly related to LV flow. First, the ejection fraction (EF), i.e. the reduction of LV volume normalized with the initial value, represents the main measure of myocardial contraction and it is critical to describe the cardiac systolic LV functionThe objective of this study is to explore the existence of relationships and dependencies between advanced flow-related quantities and the metrics used in the standard clinical assessment of cardiac function. This can lead on the one side to recognize the role (if any) of clinical metrics for describing blood flow properties, and on the other to identify the incremental value (if any) provided by more advanced flow analysis.25. These surrogates are a class of reduced-order models (ROMs) that allow decreasing the complexity of a given high-fidelity model (HFM) by learning the dynamics of a quantity of interest (QoI) directly from the HFM’s response. As a consequence, the surrogate is able to capture the key features of the underlying dynamics for the specific QoI; at the same time, the high computational cost of physics-based simulations performed with the HFM is drastically reduced to a limited number of runs necessary to calibrate the surrogate model. This allows to perform in-depth analyses (otherwise unfeasible on the HFM) such as global sensitivity analysis (GSA) and Monte Carlo simulations (MCS) at a negligible computational cost . The use of PCE-based surrogates in cardiovascular research is becoming popular for uncertainty quantification purposes to provide relevant information to assist the clinical practice. As an example, in the context of cardiovascular numerical simulations, the stochastic collocation method is used to propagate uncertainty from clinical data to the predictions of hemodynamic quantities and surgical outcomes in29; while in30, uncertainty quantification based on the PCE is applied to 3D patient-specific cardiovascular models.To answer these questions we apply surrogate models based on the Polynomial Chaos Expansion (PCE) technique32 where flow equations are solved in a regular Cartesian grid with a distribution of fictitious forces concentrated at the immersed solid boundaries (whose intensity is matched to ensure fulfillment of the boundary conditions); this computational approach is often employed to analyze LV fluid dynamics33. In the same framework, the dynamics of the mitral valve (MV) are reproduced by a kinematic model that was introduced and validated in previous studies8.This study combines numerical simulations of blood flow in the LV with PCE surrogates to provide new insights on the fundamental understanding of the LV function. In the proposed framework of analysis, the HFM is given by a DNS method of intraventricular fluid dynamics that allows to simulate and analyze cardiac flow in individual patients. Numerical simulations are based on the immersed boundary method (IBM)22. Surrogates are also computed for the following two dynamic QoIs: (iii) the ventricular kinetic energy, and (iv) the vorticity, both measured at the peak of early diastolic filling, hereinafter 34. The core of the vortex ring develops from the beginning of the early filling and reaches its full development when this phase approaches its peak21. Recent studies have shown that at the E-wave peak the vortex is well-formed and differentiates healthy from pathological conditions20.Surrogate models are used to approximate two QoIs describing LV blood transit as (i) the direct volume, hereinafter EF = E/A; the LV shape ratio EDD and the ratio 35 and the transformation between LV size and blood velocity under different ventricular conditions20.The response surfaces of the QoIs are approximated in the space of four parameters that we select among the diagnostic clinical metrics describing the overall LV health. These parameters embed relevant information on LV geometry and function and help discriminating healthy and diseased patients in numerous clinical conditions. The selected parameters are the ejection fraction, Calibration and validation of surrogate models is preformed on different datasets generated by running the HFM multiple times for a parameterized geometry that can be altered to arbitrary values of the governing clinical parameters. GSA is then performed for each QoI to assess the relative impact of the variability of the governing parameters. In addition, we assess the robustness of the predictions provided by the surrogates in comparison with results obtained by DNS (with the HFM) for several patient-specific cases under both healthy and diseased conditions. Finally, the application of surrogate models in the present study allows us to uncover how common global flow transit quantities are related to standard clinical parameters.8. Based on preliminary analysis against patient-specific cases, we identify four governing parameters, namely EF, E/A, 41 . Comparative results are shown in Fig. 27.Once the PCE approximations of the QoIs are available, GSA on the surrogate models is performed at a negligible computational cost44 are computed as analytical post-processing of the PCE coefficients42, for the inputs EF, E/A, 44. The parameter which explains more the variability of all the selected QoIs is EF; specifically, the variance of EF. As for EF reflects about the E/A plays a secondary role .Figure 45.The description of the cardiac mechanical function is commonly performed by measuring a series of geometrical and physical parameters  that represent physical phenomena describing the cardiac activity. Recent years have witnessed rapid advancements in imaging technology and methods of image analysis that provide deeper informative content regarding cardiac function. By first principles, heart function is about creating and sustaining blood motion; therefore, placing the focus on measures associated with blood flow promises further progress along this lineImaging technology dedicated to blood flow (e.g. 4D Flow MRI) presents significant costs and complexity making it not appropriate to evaluations performed during the clinical routine. On the other hand, clinical assessments of blood flow can only be based on a few global, integral parameters and do not require explicit knowledge of the time- and space-resolved three-dimensional velocity vector field. This study presents, for the first time, the application of surrogate models to LV blood flow, calibrated on a series of statistically selected flow fields, to reproduce global parameters that are suggested to be of clinical interest.The proposed surrogate model is characterized by simplicity and reproducibility, making it appropriate for straightforward application in clinical routine; it demonstrates a significant accuracy when tested on 20 patient-specific  cases, by providing predictions very close to the results obtained with the DNS. This accuracy is excellent when the surrogate model is employed to evaluate the flow transit across the ventricle in terms of direct and residual flows.EF typically present a worsening of flow transit characterized by reduction of the direct flow accompanied by an increase of the residual volume. The excellent reliability of the surrogate model . The difference should be partly imputable to the simplifying assumptions that are present in the numerical model; it can also be attributed -in some cases- to the limited accuracy of the calculation during imaging post-processing that are non-trivial  and that sometimes gives rise to non-physical differences between LV inflow and outflow measurements. A more consistent comparison of literature data with our findings can be performed by correcting the literature data taking into account the balance of mass between inflow and outflow. This balance, even in presence of regurgitation, corresponds to an exact relationship between the direct and residual volumesEF on the global flow transit parameters in a wide range of LV conditions.It is possible to observe that the surrogate models suggest a sensibly linear relationship for both entclass1pt{minimaentclass1pt{minimaentclass1pt{minimaentclass1pt{minimaEF is the main determinant for overall quality of blood transit across the LV is in agreement with the common clinical knowledge, in absence of atrial fibrillation, for the decision of anticoagulant therapy55. It must be remarked, however, that this does not invalidate the need for a blood flow analysis in the cardiac chambers. It rather stresses that simple global properties, like 57. In such cases, physics-based analysis of space-time-extended transit properties of intraventricular blood flow may be required to assess risk factors at the individual level and improve screening and prevention.The finding that This study suggests how some common properties associated with blood flow can be estimated with surrogate models based on standard clinical parameters. Such surrogate models require a preparatory effort for the initial calibration (DNS or 4D Flow MRI), then they present a notable simplicity and can be employed in real-time during the clinical analysis.EF, E/A, 15, especially in presence of diastolic dysfunction where the flow can play a role; in addition, they can be considered, in the first instance, as independent. Our findings are the basis for more in-depth assessments involving further parameters to account for the regional function, synchrony, and deformation properties. Many of such parameters, however, are closely correlated to the value of EF58 that is preferred here as a starting point. As such, in future work, we aim to extend the analysis to other clinical parameters, possibly even in substitution of EF, by separating the properties concurring with the definition of its value. In a broader perspective, this work aims to suggest a method for a combined analysis of multiple clinical evaluations in a possible direct and non-invasive way.Merging surrogate models and DNS represents a promising winning approach to describe the most important metrics in the cardiology field. In this exploratory study, we analyze the most common cardiological parameters such as t is time59. The position vector marks the points of the LV material, and their velocity is obtained from temporal differentiation. Instead, MVs geometries are extracted from the images with the use of dedicated software , limitedly to the completely open (at the peak of diastole) and completely closed (at the peak of systole) positions, these open positions are described parametrically by the degree of opening of each of the two leaflets, s range runs along the circumference and extends from the ring at the trailing edge8.The present numerical method has been extensively validated in previous studies from the computational point of view20, and by general comparison with clinical information61. Moreover, the global quantities that are used in this work, have been previously methodologically validated and satisfactorily compared with results obtained in clinical cases with advanced imaging techniques62. For this study, we use both patient-specific geometries (recorded and extracted as described above) and a parameterized geometry to calibrate the surrogate models. The geometries used for calibration purposes are created from the combination of two patient-specific geometries in healthy and pathological conditions, respectively. These two geometries are extracted and processed as previously described to obtain two reliable physiological and pathological borderline cases, according to the parameters used in the study. The parameterization of the ventricle occurs through the interpolation of the two borderline cases and, according to an independent search system, values of the parameters are automatically detected (one at a time) until the desired final geometry is obtained. As such, each geometry defined through this parametrization method is generated by imposing values of EF, E/A, EF between 0.7 and 0.3). As an example of the geometries used in this study, Fig. EF and E/A in panel (b) where the volume curve and dV/dt are represented; in panel (c), an example of a synthetic healthy case build with the parameterized geometry is shown, while panel (d) shows the correspondent volume curve and dV/dt, and exemplifies the parametrization method for the construction of the synthetic cases that we adopted. Specifically, Fig. dV/dt for the two borderline cases associated with maximum values of EF=0.7 and E/A=2 , and minimum values of EF=0.3 and E/A=0.5 ; within these two curves, all the synthetic cases generated for given values of the governing parameters are included. Note that the EDD and EDL values are imposed by modifying the geometry in the x, y, and z axes, while the The time-varying geometry of LV is extracted from 3D echocardiography; the moving borders are obtained by a semi-automatic procedure within a dedicated software . Subsequently, LV geometry during all phases of the heartbeat is described by the position vector The images of the human subjects were recorded at the Cardiovascular Department of the Azienda Sanitaria Universitaria Giuliano Isontina, Trieste. The geometries were provided in anonymous form for the numerical study. All procedures involving human subjects have been performed in accordance with the Declaration of Helsinki, and under the approval of the Ethics Committee of the University of Trieste (protocol no. 0025052).8, where the valvular dynamics is compared with that obtained by a complete fluid-structure interaction7. In this section, we briefly recall the main points of the method used. The intraventricular fluid dynamics is evaluated by numerical solution of the Navier-Stokes and continuity equations63. Time advancement is achieved using a fractional step method as follows. Velocity is preliminarily advanced in time by the Navier-Stokes Eq.  and from around the aortic valve to the upper edge of the computational domain; these additional boundaries represent surrogates of atrium and aorta. They are included for numerical convenience to avoid interference between the outflow and the inflow outside the LV and to avoid nonphysical sharp corners at the edge of the LV basal plane. The overall numerical implementation is extensively validated in previous studies63. In this study, it is used a bi-periodic domain with a grid made 12820. Additionally, it is also verified that the spatial and temporal resolutions employed here ensure a perfect relationship between the flow rate measured across the LV valves and the volumetric variation dV/dt in a series of conditions2. Once the parametric description of the model 8. The leaflet dynamics are obtained by least-squares minimization of the difference, integrated over the valvular surface 8.The numerical method is extensively described and validated in a dedicated methodological study33. The computation of the average vorticity inside the ventricle isV(t) is the ventricular volume, 64 and is computed as followsKE  is the concentration of a passive marker of particles. Equation (48. 10.The study of the flow transit is an important step for the evaluation of blood transport and mixing inside the LV, this is useful for the identification of the blood residences and wash-out properties; conditions that are related to the risk of the thrombus formation. Following the established literature in cardiologyEquation  starting25:42; coefficients 25.Let mentclasspt{minimaq is the maximum degree of the expansion, i.e., q, the series reduces to a number of terms equal to P which depends on q and M as shown in (In practical applications, the PCE  is oppormentclasspt{minima42. The number of regression points is generally 43, with the idea of employing the combinations of the roots of the next higher-order polynomial, i.e. q, which in turn increases the number of terms P in (Calibration of the PCE is performed using a non-intrusive approach based on regression, upon minimization of the variance of the residual rms P in .42:Moments of the QoI are estimated as follows44, consists in analytical post-processing of the PCE coefficients26, thus drastically reducing the associated computational cost. The use of the surrogate (27.Similarly, computation of global sensitivity metrics, such as the Sobol’ indicesurrogate  sensibly


The spherical pair has an important role in the inner frame of the stabilization mechanism of the aviation optoelectronic pod. However, its two-degrees-of-freedom (2-DOF) angular displacement signal is difficult to detect, seriously restricting its application in aviation optoelectronic pods. Therefore, this study proposes a new method to measure a spherical pair’s 2-DOF angular displacement using a spherical capacitive sensor. The capacitive sensor presented by this method realizes the measurement of the 2-DOF angular displacement of the spherical pair by integrating the spherical electrode groups in the ball head and the ball socket of the spherical pair. First, based on the geometric structure of the spherical pair, the structure of the capacitive sensor is designed, and the mathematical model for the capacitive sensor is deduced. Then, the sensor’s output capacitance, in different directions, is simulated by Ansoft Maxwell software. Finally, an experiment device is built for the measurement experiments. The simulation analysis and experimental results show that the spherical capacitive sensor has an approximately linear output in different directions, and the measured output capacitance is as high as  The aviation optoelectronic pod adopts a two-axis, four-frame, universal rotation mechanism to achieve high-precision and stable target tracking. The primary function of the outer frame is to rotate in a large range and to isolate wind resistance interference. The inner frame can achieve precise inertial stabilization within a small angle range of e system . The traThe accurate detection of the two-degrees-of-freedom (2-DOF) angular displacement signal of the spherical pair is one of the technical difficulties limiting its application and development. Therefore, the precise measurement of the 2-DOF angular displacement of the spherical pair is significant for promoting its application in aviation optoelectronic pods.At present, the optical detection method can be used to detect the angular displacement signal of the spherical pair. The method detects the angular displacement signal of the spherical surface by detecting the change in the surface image characteristics caused by the rotation of the spherical pair by an optical sensor or a visual sensor. However, the optical detection method has a complex optical system, and the measurement resolution is restricted by the degree of refinement of the surface image features ,3,4.Based on the theory of magnetic effects, W. Wang and J. Wang proposed an angle measurement technology, which uses sensor arrays to measure the spatial magnetic field changes in permanent magnets in a spherical pair to achieve angular displacement measurements . This meTo further improve the angular displacement detection, Penghao Hu’s team proposed a method based on eddy current sensors. This method uses eddy current sensors to measure changes in the shape of spherical secondary metal surfaces to achieve angular displacement detection . CompareThe above-mentioned angular displacement detection technology has a complex structure and error superposition introduced by multiple sensor units. They cannot be integrated into the spherical pair to measure its angular displacement signal, limiting the spherical pair’s application in the inner frame structure of aviation optoelectronic pods. Therefore, designing an integrated sensor with a spherical pair structure is significant for promoting the ball pairs’ application in aviation optoelectronic pods.The capacitive sensor has the advantages of high accuracy, a low cost, and a simple structure, which means it can be used in precision measurement fields, such as spherical pairs, CNC machine tools, and non-contact force–distance measurement ,14,15,16In this chapter, we propose a capacitive sensor with a spherical pair structure, which is based on the principle of variable area capacitive measurement. The functional relationship between the 2-DOF angular displacement signal of the spherical capacitive sensor and the theoretical output capacitance of the spherical capacitive sensor is deduced. We propose the decoupling and calculation methods of the 2-DOF angular displacement signal by analyzing the mathematical model established.As shown in d is the gap between the two electrodes.As is shown in H is The expressions of the differential areas In this study, our measurement object is the small-range angular displacement of the inner frame of the aviation optoelectronic pod, and its 2-DOF angular displacement range is quations  and 4),,±4∘, so quations  and (4),According to Equations –6), we , we 6), To simplify the next calculation process, we can write Equations  and 8)  8) as a Then, the impedance expression of Equation  can be wEquation  shows thEquation , which cA is the amplitude of the two sinusoidal excitation signals, and The voltage excitation signal can be written as a matrix The current signal G is the gain in the transconductance amplifier circuit).The current signal The In order to verify the effectiveness of the capacitive sensor designed in To verify the differential output capacitance of the capacitive sensor shown in Equation , we, accConsider the following case, that the sensing electrode moves in the directions In this study, the differential output capacitances As shown in To verify the decoupling method in The As shown in The above simulation results show that the decoupling method shown in Equation  is accurAs shown in The two DDS modules generate two sinusoidal excitation signals Equation .During the simulation experiment, we set the sensing electrode to move in the directions of In this chapter, a 3D finite element model was established and a signal processing circuit was designed according to the mathematical model of the capacitive sensor in In this chapter, based on the finite element model of the capacitive sensor and signal processing circuit in The 2-DOF angular displacement of the spherical pair can be regarded as a combination of 2-DOF angular displacements. To verify and analyze its measurement results, we decomposed the spherical pair’s 2-DOF angular displacement into a single DOF angular displacement of the azimuth axis of the driving electrode and a single DOF angular displacement of the pitch axis of the sensing electrode.According to the Maxwell model simulation results, the driving electrodes and the sensing electrodes are constructed concerning the structure of simulation Model 1. The electrodes are shown in As is shown in During the experiment, we can tune the azimuth axis to control the angular displacement direction of the sensing electrode, and the pitch axis to control the angular displacement of the sensing electrode. The jointly controlled axes can enable the sensing electrode to rotate, relative to the driving electrode, in any direction.In this section, we perform measurement experiments based on the above sensor prototype and the signal processing circuit. We use the simulation results in First, we verify the signal processing circuit and plot the output curves of the driving circuit in By comparing the curves shown in We turn the five-axis platform to rotate the sensing electrodes in the directions of A comparison of the actual measured output capacitance and theoretical output capacitance of the sensor prototype, as the sensing electrode moves in the directions of It also can be seen from Equation , the solN, and let Therefore, compared with It can be seen from By taking the decoupled output capacitance of the sensor prototype as a dependent variable and variable, respectively, the curves, which can also be seen as the trajectory of the sensing electrode, are plotted in From This chapter developed a spherical pair capacitive sensor with a differential four-quadrant electrode setup and a signal processing circuit. Their feasibility and effectiveness were verified by actual measurements, which indicated that the measurement system, with the above components as the main body, can simultaneously measure 2-DOF angular displacement on a spherical pair.Simulation and experimental results show that the mathematical model established, based on the differential four-quadrant electrode structure, can accurately predict the variation relationship between the 2-DOF angular displacement signal of the sensing electrode and the differential output capacitance;The signal processing circuit can decouple the components Experimental results show that within the 2-DOF angular displacement range of The spherical capacitive sensor proposed in this study has an integrated structure. It can be integrated into the spherical pair, effectively avoiding the influence of accumulated installation errors on measurement accuracy. That is important for promoting the application of the spherical pair in aviation optoelectronic pods.This study presents a new method for measuring a spherical pair’s two-degrees-of-freedom (2-DOF) angular displacement using the proposed new spherical capacitive sensor with a four-quadrant differential electrode setup. The proposed spherical capacitive sensor has an integrated structure that occupies a smaller space and can be easily integrated into a spherical pair, compared to the existing angular displacement detection method. The mathematical models for detecting the 2-DOF angular displacement of the spherical pair are established. An experiment device constituted mainly by the sensor and signal processing circuit is tested. The details may be summarized as follows:


The cytoplasm of a living cell is a crowded place, containing hundreds of types of protein and other macromolecules. Cells reliably and continually perform thousands of biochemical reactions to maintain their health. Biomolecular condensates are fluid protein compartments that provide distinct local environments, within which they carry out cellular functions. How they prevent their contents mixing with the external environment without being encapsulated inside a lipid membrane is not fully understood. Many researchers approach this question by studying simpler systems in a test tube that contain only a few protein types although it is hard to relate their results to the complex cellular milieu. Computer simulations are used to explore the predictions of simple models of cellular behavior, but are also limited by the ability of human experimenters to recreate important aspects of the cytoplasm, in particular, its crowded nature. We have used a novel computer framework to perform dozens of simultaneous simulations that map out the influence of macromolecular crowding on the formation and structure of a biomolecular condensate. We find that the spatial structure of the model condensate is surprisingly insensitive to the composition and concentration of external macromolecules, even when its formation is assisted by steric repulsion from its environment.The crowded interior of a living cell makes performing experiments on simpler in vitro systems attractive. Although these reveal interesting phenomena, their biological relevance can be questionable. A topical example is the phase separation of intrinsically disordered proteins into biomolecular condensates, which is proposed to underlie the membrane-less compartmentalization of many cellular functions. How a cell reliably controls biochemical reactions in compartments open to the compositionally-varying cytoplasm is an important question for understanding cellular homeostasis. Computer simulations are often used to study the phase behavior of model biomolecular condensates, but the number of relevant parameters increases as the number of protein components increases. It is unfeasible to exhaustively simulate such models for all parameter combinations, although interesting phenomena are almost certainly hidden in their high-dimensional parameter space. Here, we have studied the phase behavior of a model biomolecular condensate in the presence of a polymeric crowding agent. We used a novel compute framework to execute dozens of simultaneous simulations spanning the protein/crowder concentration space. We then combined the results into a graphical representation for human interpretation, which provided an efficient way to search the model’s high-dimensional parameter space. We found that steric repulsion from the crowder drives a near-critical system across the phase boundary, but the molecular arrangement within the resulting biomolecular condensate is rather insensitive to the crowder concentration and molecular weight. We propose that a cell may use the local cytoplasmic concentration to assist the formation of biomolecular condensates, while relying on the dense phase to reliably provide a stable, structured, fluid milieu for cellular biochemistry despite being open to its changing environment. How the myriad biochemical reactions that support cellular life are spatially organized is a fundamental question in cell biology. It is equally crucial for a cell to regulate reactions despite the crowded nature of the cytoplasm. Estimates of the concentration of proteins in eukaryotic cytoplasm range from 100–450 mg/mL, which implies that specific macromolecular interactions compete with many random processes involving other molecules ,3. ConfiThe complexity of living cells has driven research on model condensates, which typically use unphysiologically high concentrations of one, or at most a few, species of IDP in a buffer, although their relevance to living cells has been strongly questioned ,40. An eFurther coarse-graining the stickers and spacers model reduces the force field complexity, but still requires assigning values to multiple parameters, including the IDP molecular weight, concentration, backbone stiffness, location of the multiple binding sites, and the interaction energies between all species . We have previously used Dissipative Particle Dynamics (DPD) simulations to explore the phase behavior and structure of a model biomolecular condensate formed of a single type of IDP modelled on the FUS low-complexity domain (FUS LC) ,54,55,56crowder) is added, which exerts a steric pressure on the IDP molecules (and itself), but is otherwise inert.Naively adding additional molecule types as crowding agents multiples the parameters geometrically, rendering it impossible to explore the parameter space of the model in a systematic way. We overcome this barrier by performing multiple, parallel simulations on a novel compute framework ,58. Our Even after these simplifications, the system has a six-dimensional parameter space—two molecular weights, two concentrations, the IDP self-attraction, and the crowder/IDP repulsion strength— which may affect the phase behavior in a non-trivial way. For simplicity, we set the IDP and crowder molecular weights to be equal and initially fix the crowder/IDP repulsion to a high value see . This leA final difficulty, which is intrinsic to all computational models with many parameters, is our inability to simultaneously visualize multiple states of the model as the parameters vary. We show that by using parallel hardware to accelerate dozens of simulations and displaying the results in a grid of visually rich simulation snapshots, we can rapidly locate the fruitful regions of the parameter space. Our results predict that the spatial arrangement, but not necessarily the dynamics, of the IDPs within the model condensate is surprisingly insensitive to the crowdedness of its environment, even when steric repulsion from the crowder is required for its formation. Biomolecular condensates, therefore, provide a stable, structured fluid environment for biochemical reactions because the molecular structure of IDPs decouples their internal state (to a certain degree) from their compositionally-varying surroundings.j to bead i, The Dissipative Particle Dynamics simulation technique (DPD) was invented to study complex fluids such as polymer mixtures, phospholipid membranes, diblock copolymers, etc. ,59,60,61Once the required bead types have been specified, they are connected into molecules by tying them together with Hookean springs, whose energy function is:sticky bead types E for the endcaps and F for the internal binding sites), which are separated by segments of inert backbone beads (B). The crowding agent is a self-avoiding, semi-flexible homopolymer composed of a single bead type (P). The solvent molecules are represented by a single bead (W). Both the sticky beads and the backbone beads of the IDP and crowder beads are hydrophilic, and we emphasize that there is no hydrophobic repulsion of the IDPs or crowder from the solvent. In the notation of [Three types of molecule are defined in the simulations. The IDPs are semi-flexible, linear polymers containing a set of binding sites 3, unless otherwise stated, and periodic boundary conditions are applied. The phase behavior of the model IDP/crowder system is studied by distributing a given number of IDPs and crowders randomly throughout the simulation box and filling the remaining space with solvent particles to an average density of m = 1, and the reduced system temperature is Simulations take place in a cubical box with dimensions 48 × 48 × 48  in two hours, while reducing the analysis time needed by the human to just five minutes for the visual inspection. This two hour process should be compared to the 7 days that are needed if the 20 simulations are executed sequentially.Both the simulator and visualization framework were inspired by a collaborative research project called POETS , which iThe main idea of POETS is to execute event-triggered applications using custom-built hardware, allowing applications to efficiently execute on thousands of lightweight threads. This idea has previously been applied successfully to DPD simulation, where it was used to tackle simulations of a large spatial size . HoweverThe fit between the event-triggered algorithms and contemporary multi-core CPUs also resulted in a very fast, multi-core, shared memory DPD simulator. The technical details are not the focus of this paper, but one of the main ideas is that it uses a very fine-grained spatial domain decomposition, so that each thread manages a unit volume cell. As beads move around in the simulation they are also moved between the cells in memory, rather than building and maintaining edge lists. The event-triggered nature of the algorithm makes it particularly amenable to SIMD vectorization, reduces the cache traffic, and allows for efficient shared memory multi-threading.https://www.southampton.ac.uk/isolutions/staff/iridis.page, accessed on 16 January 2023) our approach resulted in a 2× speed-up compared with the industry-standard code LAMMPS  in a single 64-core system. Two important aspects of this setup were:-It allowed the experiments to be completed in under two hours, which allowed them to be submitted to the “fast” low-latency queue in the Iridis job manager;-It means we do not need to use GPUs to achieve low latency, which is useful because GPUs are less common in many HPC clusters and they are heavily subscribed by chemists, physicists, and machine learning researchers. In our experience, it typically takes more than 2 hours for a GPU job to even start running, even though it may perform faster once it has started.We do not make claims about the relative efficiency of this approach for all computational problems, but for the experiments that were performed in this work using the Iridis data center . The rows have constant IDP concentration, which increases towards the bottom, and the columns have constant crowder concentration, which increases to the right. The crowder molecules are invisible in the figure for clarity, but The model IDP has six binding sites that are separated by ten backbone beads and is represented by the notation 6B10. Previous work showed that the critical affinity for such molecules lies in the range .68−0.74 . We set nity cp. .It might be expected that a sufficient concentration of the repulsive crowder could drive phase separation of IDPs whose affinity is low or even zero. This would represent a generic polymer phase separation driven by the steric repulsion between the molecules, as described by Flory–Huggins theory . In partWe calculated the crowder concentrations as follows. The densest case in the grid, which corresponds to the rightmost column in We next explored whether the internal organization of the IDPs in the dense phase is modified when the phase separation is assisted by the crowding agent compared to when it forms spontaneously . We previously found that the dense phase has a heterogeneous structure in which the binding sites of the IDPs meet at spatially-discrete junctions whose separation depends on the spacing of the binding sites but is less sensitive to their affinity . FurtheIn  top row a–c are pThe second column shows the mean junction separation within the condensed phase as a function of the crowder concentration for all of the IDP concentrations studied. The separation was clearly independent of the IDP concentration  and the crowder concentration is in the range where the dense phase is stable. Comparing the junction separation in The previous section showed that the structural organization of the IDPs in the equilibrium dense phase was independent of the IDP concentration (once the dense phase is stable), and was only weakly dependent on the crowder concentration. Next, we probed the dependence of this structure on the molecular weight of the crowder. Because we expected the reduced volume fraction of shorter crowders to impose a smaller osmotic pressure on the IDPs, we increased the IDP affinity from We then repeated these simulations with crowding polymers whose size was reduced from 48 to 24 monomers, and we kept their number fractions for each grid element the same as before . This efReplacing P48 crowders with P24 ones with the same number fraction halves the monomer volume fraction of the crowders. The IDPs phase separate at higher crowder concentrations, and more IDPs are in the dilute phase compared to We measured the quantitative structure of the dense phase in the presence of P24 crowders, and we show the results in 6 time steps for the same number fraction and same volume fraction. 6 time steps for the same number fraction and volume fraction.Next, we replaced the P24 crowders with P12 ones and qualitatively checked whether the dense phase remained stable. We selected the system in the third row and fourth column of vent cp. . We perf6 time steps, which ensured that the IDPs had time to disperse. The IDPs do not phase separate for this combination of concentration and affinity in the absence of the crowder (6 time steps).Next, we investigated the impact of reducing the enthalpic repulsion between the IDPs and crowder molecules on the phase separation. We again used the system in the third row and fourth column of  crowder a nor whe crowder b. The crepulsion c,d. ThisThe cellular cytoplasm is a complex, crowded fluid, and understanding the effects of this environment on the phase separation of disordered proteins into biomolecular condensates is a challenging task. Most in vitro assays and computational models focus on a single protein, and their relevance to living cells is an open question . A full Experiments on full-length FUS and its N-terminal low-complexity domain (FUS-LC) have shown that their dense phase is highly solvated ,43. The In the present work, we implemented a novel workflow to leverage multiple simultaneous simulations to explore the two-dimensional phase space of an IDP in the presence of a crowding agent. Interestingly, an analogous experimental microfluidic platform was recently used to rapidly scan multidimensional phase diagrams . MassiveWe used our workflow to explore the effects of adding a polymeric crowding agent on the phase separation of a model IDP using coarse-grained simulations. This provides a tractable model system to explore the range of possible responses of a BC to a crowded environment. The phase behavior of the model proteins is controlled by their molecular weight, and the number, distribution, and affinity of their sticky sites. In the absence of a crowding agent, they phase separate into coexisting dilute and dense phases when the affinity of their sticky sites is sufficiently strong, form a space-filling network without phase separation for lower affinities, and remain dispersed when their attractive interactions are weak or absent ,50,56. TWhen a polymeric crowding agent was added to IDPs in solution, we observed the following effects: 1) if the IDP affinity was just below the value at which spontaneous phase separation occurred, the crowder shifted the transition so that the IDPs phase separated into a dense phase; 2) the observed dense phase had a similar spatial structure to that of spontaneously formed droplets of the same IDPs with higher affinity. The formation of the model biomolecular condensate is therefore coupled to the crowdedness of its environment. This is in good agreement with recent experimental results of André et al. that showed that crowding lowered the dilute phase boundary and increased the dense phase concentration in the phase diagram of NPM1-RNA condensates . Alshare if the I the obseThe spatial arrangement of the IDPs in the crowding-assisted dense phase was similar to that observed previously for the same IDPs with higher affinity that spontaneously phase separate. The structure of the model BC was therefore not strongly dependent on the strength of the attractive interactions between the constituent IDPs. We also observed that the model condensate still formed when the repulsion between the IDPs and the crowder was substantially lowered and when we reduced the crowder molecular weight, keeping their volume fraction fixed. We hypothesize that the internal degrees of freedom of the IDPs, which are defined by their molecular sequence, are responsible for the robust structure of their dense phase. The punctate nature of their binding sites creates a spatial network of weak junctions connected by fluctuating spring-like lengths of the backbone that resist deformation when the osmotic pressure due to the surrounding fluid increases. Our results are in good agreement with the recent results of Alshareedah et al. who found that the viscoelastic properties of in vitro BCs were controlled by the combination of enthalpic (sequence-encoded interchain interactions) and entropic (fluctuations of the polymer chain-like IDPs) factors . This maComputational modelling provides a relatively inexpensive tool for exploring simplified representations of an experimental system, but it suffers from its own complexity issues, namely, that the number of parameters increases rapidly with increasing numbers of molecular species. Our exploration of the response of a model biomolecular condensate to the presence of a crowding agent illustrates the following powerful workflow for studying models with high-dimensional parameter spaces: (1) generate many examples of a system at different points in its parameter space simultaneously, and (2) rapidly compare the examples by viewing the data in a large grid of snapshots taken from different parameter space points, and identify the interesting regions. Further progress will likely involve using AI-enabled pattern recognition of the graphical arrays to identify the most interesting regions and direct costly computer resources towards the most efficient pathway for exploration.Biomolecular condensates are widely viewed as providing a localized environment for cells to spatiotemporally segregate their biochemistry, despite not being surrounded by a phospholipid membrane. The exchange of proteins between the dense and dilute phases and the crowding effect of other macromolecular species in the cytoplasm would appear to undermine their function. Our coarse-grained molecular simulations predict that a repulsive macromolecular crowding agent is able to drive a dilute solution of IDPs across their phase boundary into a dense phase, even when their attractive self-interactions are too weak to drive phase separation alone. However, crucially, the spatial arrangement of proteins within the resulting BC changes minimally from that of spontaneously phase separating IDPs. These results were also found when the molecular weight of the crowding polymer was reduced (by a factor of two), providing that their volume fraction was maintained, and when the crowder–IDP repulsion was reduced significantly. The dense phase structure was therefore predicted to be insensitive to the precise composition of its crowded environment. We propose that this arises because the pattern of attractive domains connected by entropic spring-like linkers along the IDPs creates a fluid, three-dimensional, network structure that resists deformation by the crowding polymers. Our results suggest that a cell may use the local cytoplasmic concentration of macromolecules to tune the formation of BCs, and that they may in turn sense, and respond to, changes in their environment. The effects of crowding on the model condensate are in good agreement with the experiments, and we expect that tailoring this workflow for multicomponent biomolecular condensates will help researchers to generate novel hypotheses that span the complexity gap between simplified computational models and biologically relevant systems.When the self-attraction of the IDPs is removed, a sufficiently high concentration of the crowder drives a Flory–Huggins-like demixing of the IDPs and crowder polymers, which visually resembles the model BC. However, the dense phase has no connected network structure, because the IDPs are unable to form transiently stable junctions. When the IDP self-attraction is turned back on, the model BC reforms with the same internal structure as before see . This suOur prediction of two visually similar dense phases, only one of which possesses a robust spatially organized structure, implies that the observation of a demixing transition in computational studies of IDP phase separation is insufficient to conclude that their dense phase is a good model of a biomolecular condensate. We believe that the crucial question is whether the spatial structure that we observed, which has not been reported in the literature by other groups, can be found in experiments of biological condensates. Experimental tests of this prediction by positionally mutating key residues in the IDP FUS and exploring the consequences for its phase behavior in the presence of a crowder are under way.