Failure Of Contraction Research Articles

Disrupted T-tubular network accounts for asynchronous calcium release in MTM1-deficient skeletal muscle.

In mammalian skeletal muscle, the propagation of surface membrane depolarization into the interior of the muscle fibre along the transverse (T) tubular network is essential for the synchronized release of calcium from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs) in response to the conformational change in the voltage-sensor dihydropyridine receptors. Deficiency in 3-phosphoinositide phosphatase myotubularin (MTM1) has been reported to disrupt T-tubules, resulting in impaired SR calcium release. Here confocal calcium transients recorded in muscle fibres of MTM1-deficient mice were compared with the results from a model where propagation of the depolarization along the T-tubules was modelled mathematically with disruptions in the network assumed to modify the access and transmembrane resistance as well as the capacitance. If, in simulations, T-tubules were assumed to be partially or completely inaccessible to the depolarization and RyRs at these points to be prime for calcium-induced calcium release, all the features of measured SR calcium release could be reproduced. We conclude that the inappropriate propagation of the depolarization into the fibre interior is the initial critical cause of severely impaired SR calcium release in MTM1 deficiency, while the Ca2+ -triggered opening of RyRs provides an alleviating support to the diseased process. KEY POINTS: Myotubular myopathy is a fatal disease due to genetic deficiency in the phosphoinositide phosphatase MTM1. Although the causes are known and corresponding gene therapy strategies are being developed, there is no mechanistic understanding of the disease-associated muscle function failure. Resolving this issue is of primary interest not only for a fundamental understanding of how MTM1 is critical for healthy muscle function, but also for establishing the related cellular mechanisms most primarily or stringently affected by the disease, which are thus of potential interest as therapy targets. The mathematical modelling approach used in the present work proves that the disease-associated alteration of the plasma membrane invagination network is sufficient to explain the dysfunctions of excitation-contraction coupling, providing the first integrated quantitative framework that explains the associated contraction failure.

THE GLOBAL MARKET FOR EXCHANGE-TRADED DERIVATIVES: 21ST CENTURY TRENDS, INNOVATION AND FAILURE

Utilizing a comprehensive database spanning 110 exchanges in five geographic regions, we examine trends in trade activity and contract innovation of exchange-traded futures and options over the period 2002–2021. We find that global volume has experienced a ten-fold increase driven by significant increases at Asian and North American exchanges, and primarily in the equity, interest rate and currency asset classes. New contract innovation has been greatest in North America and in the energy and equity asset classes. Further, volume and open interest attributable to new contract innovation have now surpassed those of legacy contracts. Turnover showed a significant increase driven largely by trade activity in Asian markets. Finally, new contract failure rates have been highest at North American exchanges as well as in the interest rate and energy asset classes.

Why did contractors leave?: A case of child welfare service

ABSTRACT In 2009, the Nebraska state government began contracting for child welfare services. Five of the six contractors eventually terminated their contracts. Contract failure can have a significant and negative effect on recipients of these services. This study uses interviews and document analysis to describe the contracting process between 2005 and 2019 and examines the purposes of contracting and the reasons why the lead agencies left the contracts. The results show that the state government failed to manage the process adequately in terms of financial and human resources, contract design, communication, participation of stakeholders, monitoring and evaluation. Also, interviews point out the importance of the role of public officials in contract success.

Integrated contract in Law 14.133/2021: new law, same problems? A study of comparative law

The purpose of this article is to analyze whether expansion allowed cases for design-build biddings might improve positive impacts on the efficiency of public procedures. Hence, both Brazilian and international experiences will be studied with attention to design-build and turnkey contracts. In integrated contracting procurements, basic and executive projects must be done by the same company that shall execute the project and its further execution. Consequently, public Administration must only provide a draft. Resolutely, the hypothesis is that these amplification allowances increase the risks of other contract failures. The methodology used was a dialectical-inductive method comparing both Brazilian and international cases of integrated contracts. Firstly, it is demonstrated when Design-Build procurements were first allowed in Brazil and how and why their uses have been amplified. Additionally, the international scenario shall be examined to determine if restrictions imposed by most countries have accompanied the use of integrated contracts for public Administration in Brazil. Subsequently, a comparative examination of several hiring public models will be examined to answer whether integrated contracts biddings might benefit public sectors. The conclusion is that significant expansion of possibilities of using the integrated contracting, forecasted in Law 14.133/2021, poses risks of reducing the efficiency of public administration unless several measures are to be adopted in the planning phase with particular attention to those related to the draft selecting requirements, just like most developed countries have already done.

Combining Multiple Classifiers using Ensemble Method for Anomaly Detection in Blockchain Networks: A Comprehensive Review

Blockchain is one of the most anticipated technology revolutions, with immense promise in various applications. It is a distributed and encrypted database that can address a range of challenges connected to online security and trust. While many people identify Blockchain with cryptocurrencies such as Bitcoin, it has a wide range of applications in supply chain management, health, Internet of Things (IoT), education, identity theft prevention, logistics, and the execution of digital smart contracts. Although Blockchain Technology (BT) has numerous advantages for Decentralized Applications (DApps), it is nevertheless vulnerable to abuse, smart contract failures, security, theft, trespassing, and other concerns. As a result, using Machine Learning (ML) models to detect anomalies is an excellent way to detect and safeguard blockchain networks from criminal activity. Adapting ensemble learning methods in ML to create better prediction outcomes is a viable approach for anomaly identification. Ensemble learning, as the name implies, refers to creating a stronger and more accurate classification by combining the prediction results of numerous weak models. As a result, an in-depth evaluation of ensemble learning methodologies for anomaly detection in the blockchain network ecosystem is applied in this paper. It comprises numerous ensemble methods (e.g., averaging, voting, stacking, boosting, bagging). The review collects data from three established databases, which are Scopus, Web of Science (WoS), and Google Scholar. Specific keywords are employed, such as Blockchain, Ethereum, Bitcoin, Anomaly Detection, and Ensemble Learning, employing advanced searching algorithms. The results of the search found 60 primary articles from 2017 to 2022 (30 from Scopus, 20 from the WoS, and 10 from Google Scholar). Based on these findings, we decided to divide our debate into three primary themes: (1) the fundamentals of Blockchain Technology (BT), (2) the overview of ensemble learning, and (3) the integration and analysis of ensemble learning in blockchain networks for anomaly detection. In terms of awareness and knowledge, the results are also discussed in terms of what they mean and where future research should go.

A Foot Soldier in Cardiac Metabolism: A Conversation With Heinrich Taegtmeyer, MD, DPhil.

A Foot Soldier in Cardiac Metabolism: A Conversation With Heinrich Taegtmeyer, MD, DPhil.

A Functional Human-on-a-Chip Autoimmune Disease Model of Myasthenia Gravis for Development of Therapeutics.

Myasthenia gravis (MG) is a chronic and progressive neuromuscular disease where autoantibodies target essential proteins such as the nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction (NMJ) causing muscle fatigue and weakness. Autoantibodies directed against nAChRs are proposed to work by three main pathological mechanisms of receptor disruption: blocking, receptor internalization, and downregulation. Current in vivo models using experimental autoimmune animal models fail to recapitulate the disease pathology and are limited in clinical translatability due to disproportionate disease severity and high animal death rates. The development of a highly sensitive antibody assay that mimics human disease pathology is desirable for clinical advancement and therapeutic development. To address this lack of relevant models, an NMJ platform derived from human iPSC differentiated motoneurons and primary skeletal muscle was used to investigate the ability of an anti-nAChR antibody to induce clinically relevant MG pathology in the serum-free, spatially organized, functionally mature NMJ platform. Treatment of the NMJ model with the anti-nAChR antibody revealed decreasing NMJ stability as measured by the number of NMJs before and after the synchrony stimulation protocol. This decrease in NMJ stability was dose-dependent over a concentration range of 0.01–20 μg/mL. Immunocytochemical (ICC) analysis was used to distinguish between pathological mechanisms of antibody-mediated receptor disruption including blocking, receptor internalization and downregulation. Antibody treatment also activated the complement cascade as indicated by complement protein 3 deposition near the nAChRs. Additionally, complement cascade activation significantly altered other readouts of NMJ function including the NMJ fidelity parameter as measured by the number of muscle contractions missed in response to increasing motoneuron stimulation frequencies. This synchrony readout mimics the clinical phenotype of neurological blocking that results in failure of muscle contractions despite motoneuron stimulations. Taken together, these data indicate the establishment of a relevant disease model of MG that mimics reduction of functional nAChRs at the NMJ, decreased NMJ stability, complement activation and blocking of neuromuscular transmission. This system is the first functional human in vitro model of MG to be used to simulate three potential disease mechanisms as well as to establish a preclinical platform for evaluation of disease modifying treatments (etiology).

Method and Parameter Reliability of In-situ Direct Shear Test on Vibroflotation Gravel Piles

Vibroflotation gravel piles can improve the antisliding stability of soft soil foundations. However, in-situ direct shear tests have rarely been conducted on vibroflotation gravel piles, and the understanding of the test methods and the reliability of the derived parameters varies. Three groups of in-situ direct shear tests on vibroflotation gravel piles for a reservoir bank treatment project are conducted. The design diameter of the piles is 100 cm, and the pile filler is artificial sandstone gravel with a maximum particle size of 15 cm. The specimens are formed by applying a steel square frame to encase the top section of the piles. For the specimens of groups S1 and S2, only the section above the shear plane is encased with the frame. The shear surface of S1 contains a small amount of soft soil while that of S2 contains no soft soil. For group S3, two pile sections above and below the shear plane are encased with the frame, and a steel support is set upon the lower frame in the opposite direction of the shear force. The shear failure of the piles is a type of plastic shear contraction failure mode with more than 4.5% shear strain and no peak shear stress. The internal friction angles and cohesion values are 20.8° and 20 kPa for S1, 30.5° and 21 kPa for S2, and 35.0° and 30 kPa for S3. Test results show that the restraint of the steel frame enhances the bite force between the gravel particles in the shear process. Moreover, the rigid shear displacement constraint set upon the lower frame makes the test pile cut along the control shear surface, thereby increasing the shear strength. Therefore, the test parameters are higher than those under working conditions. To ensure consistency between the test conditions and the working conditions of the piles, this work proposes the following suggestions for improving test measures: 1) the pile section should not be encased below the shear plane and should be kept buried in soil; 2) some soil should be retained around the pile in the steel frame above the shear plane.

Data-Driven Prediction of Contract Failure of Public-Private Partnership Projects

The public-private partnership (PPP) has been adopted by many governments in developing countries to provide better public services. However, PPP projects have a high risk of contract failure. To proactively predict PPP contract failure and obtain the most significant failure factors from a quantitative perspective, this research compared the performance of different combinations of machine learning models and data-balancing techniques. Forty-three project-specific and country-specific factors were examined, and the top 15 were chosen for the transportation, water and sewer, and energy sectors. The results show that the selected model can forecast contract failure with a recall of 75.9%, 73.3%, and 76.2%, respectively. This study showed the effectiveness and applicability of machine learning in predicting PPP contract failure. The results can facilitate decision making by forecasting the probability of PPP contract failure in the early planning stage.

Klausula Boiler Plate dalam Pembuatan Kontrak Dagang Internasional

In an international trade contract, the parties are bound by different legal provisions, different languages and also different customs and cultures. This condition creates a big risk in implementing the substance of the contract. To anticipate this risk, there are several steps that can be taken by the parties in terms of arranging and creating the contents of their contracts. This article will discuss the part of the contract that is often regulated in international trade contracts, called the boiler plate clause. This article is the result of normative research, both related to national legal norms, namely the Civil Code, Uniform law and examples of international trade contracts. A contract is a mechanism for expressing all the wishes of the parties agreed to by other parties. In current developments, contract clauses are no longer just the essentials of the agreement. There are other clauses which have the function of further clarifying how the contract must be interpreted and as an effort to cover all opportunities for contract failure, including what are called boilerplate clauses. In the practice of making international trade contracts, there are several substances that need to be regulated in boilerplate clauses, including choice of law provisions, choice of forum provisions, language provisions, severability provisions, integration provisions, notices provisions, force majeure provisions, duration of contract provisions, obligation after termination provision.

Influence of particle size scale on mechanical properties of tailings under high pressure

Particle size has an effect on the mechanical properties of tailings materials. The mechanics and crushing characteristics of tailings at high pressure are a research focus for high tailings dams. Tailings with different particle sizes were tested under laboratory high-pressure triaxial compression. The effect of particle size on the compression characteristics of tailings was studied, along with the strength and deformation of tailings with different particle sizes. Based on particle size distribution, the crushing characteristics of the tailings were quantitatively analysed. A mathematical model for crushing index and tailings strength was established. Under high pressure, shearing contraction failure occurred in the tailings samples. The stress–strain relation of the tailings showed strain softening at low confining pressure and continuous hardening at high confining pressure. The confining pressure at which the stress–strain relation changed from strain softening to strain hardening increased with increased particle size. Due to the higher degree of particle crushing for coarse tailings during the shearing under high pressure, the volume deformation of the coarse samples decreases continuously further. It shows increase in the amount of particle breakage as the confining pressure, but the increase rate decreased with the confining pressure increased. The Box Lucas loading accumulation model was used to describe the change in particle breakage with confining pressure. The peak strength of tailings increased exponentially with the improved relative crushing rate.

Economic Theories of the Social Sector: From Nonprofits to Social Enterprise

Economic theories of organizations that depart from the standard models of profit-maximizing firms are reviewed. This document will discuss earlier theories of nonprofit organizations that focus on contract failure and will argue that this framework that underlies those theories cannot explain hybrid organizational forms such as social enterprise. These forms aim to balance social and financial objectives in order to avoid the rigidity of both for-profit and nonprofit forms. Conditions under which a social enterprise is likely to be preferable to either a nonprofit or for-profit alternative are characterized. Additionally, this paper highlights the importance of selecting managers and workers who are motivated by the mission of an organization.

Home Birth and the Maternity Outcomes Emergency: Attending to Race and Gender in Childbirth

Childbirth in the United States is in crisis. This is especially true for Black and brown mothers. This childbirth emergency constitutes a failure of the social contract: because society has failed to provide minimally decent care for all birthing mothers, but especially for Black and brown mothers, it is necessary to allow mothers to choose home birth. I amplify the voices of Black and brown scholars and midwives to defend home birth, and I argue that home birth is safe and empowering and that it is rational for those who desire it to choose it.

Statistical analysis of US government supply chain contract breaches

Approximately half of US government supply chain procurement contracts failed to meet all objectives. In 2018 the US government spent almost US$2bn on procurement contracts. Failed procurement projects represent a lot of public tax-payer dollars which are wasted each year. The US government does not necessarily intend for its government procurement contracts to fail, but when they are awarded on a fixed firm price basis, the entire project management is transferred to civilian contractors for a specific cost. When something goes wrong, contractors are forced to adjust the other parameters such as time, scope and/or quality. It appears many government supply chain procurement contracts are failing despite substantial analysis of project data by academic scholars and practitioners. In the literature, most researchers could not statistically identify the underlying causes of government procurement contract failures. In fact, the sample sizes surpassed 10,000 and in one case almost 60,000 cases were examined without generating a conclusive statistical result. It was clear a new study like ours was warranted. Thus, in this study, we collected a large sample of procurement project data from US government contractors. We tested several hypotheses in an attempt to identify which conditions affected government procurement contract breaches. We applied robust parametric statistical techniques, namely logistic regression, to test the hypotheses. We developed a statistically significant model which adequately explained US government supply chain procurement contract performance. This paper is in a scholarly format using statistical techniques which are primarily aimed at an academic audience rather than practitioners. We followed the well-known American Psychology Association conventions for writing style which resulted in this paper having a strong academic tone. Nonetheless, the results ought to be of interest to scholars and practitioners alike. Scholars will be able to replicate our research design with new sample sizes of at least 1,000 in other states or countries and cite our findings. Practitioners and government procurement programme managers should find it relevant that our statistical model correctly classified 67 per cent of US government procurement contract performance, with an 11 per cent effect size using only two predictors (project manager certification and ISO quality registered). We found that if a project manager was professionally certified, this increased the likelihood of contract success by 2.3 times. Decision makers could use this model for procurement policy revision or to inform selection criteria in government contract awards.

Accountability in Government Contracting Arrangements: Experimental Analysis of Blame Attribution Across Levels of Government

While governments increasingly turn to third-party providers to deliver public services and government responsibilities are increasingly shifted from the federal to the state and local levels, both contracting and the division of powers under federalism blur lines of accountability. Because recent experiments on blame shifting find mixed results and citizens have different expectations of federal, state, and local government, we ask the following: How does blame attribution in third-party governance compare across levels of government? To address this question, we employ a timely survey experiment to examine who is responsible for a prisoner’s death in the case of interstate prisoner transport, which is one of the few services that is provided across all levels of government and by government contractors. The results show that contracting reduces the level of blame attributed to the government and that blame for contract failures varies by the level of government. Across levels of government, we find the local government sees the largest reduction in blame by contracting out. Findings have implications for accountability in contracting arrangements in public safety contexts.

Data-driven quantification of public–private partnership experience levels under uncertainty with Bayesian hierarchical model

Public–private partnership (PPP) is increasingly encouraged to deliver public services in developing countries. Many studies have been conducted to identify factors that affect PPP contract failure. Although a country’s PPP experience is of great importance in controlling the contract failure rate, most of the current studies are based on a qualitative perspective. This research develops a data-driven approach to quantify countries’ PPP experience levels through the Bayesian hierarchical model with uncertainties considered. First, detailed data exploration and selection have been carried out to clean the data source. Second, the number of change points in the dataset is identified based on the binary segmentation method. Third, the Bayesian hierarchical model is developed to locate the positions of the change points, and different experience levels are divided based on the location of change points. Findings show that: (i) PPP experience level is widely varying depending on PPP sectors. Four experience levels are suggested for the energy sector, while five levels are found for the transportation sector, and water & sewerage sector, (ii) PPP experience level is dispersed around the world, for example, Latin America and Caribbean (LAC) and East Asia and Pacific (EAP) regions have higher PPP experience levels than other regions, (iii) a country may have various experience levels in different sectors, such as India, and (iv) the learning rate will decreases as more PPP projects are initiated. This research can contribute to (a) a novel approach that could detect the change points in PPP project experience, and (b) support investors in the decision making process, such as selecting the most appropriate investment direction, contributing to the development of PPP projects in developing countries.

Diagnosis and management of pelvic floor dyssynergia

The term pelvic floor dyssynergia is commonly used interchangeably with the terms anismus, dyssynergic defecation or puborectalis syndrome. Patients with PFD commonly present with chronic constipation. The prevalence among the general population can range from 20-70% and among constipated patients it has been reported as high as 60%. This defecation disorder is basically caused by failure of relaxation or paradoxical contraction of the external anal sphincter and the puborectalis sling during defecation. Although there is no clear pathophysiological cause for this disorder, it has been linked to several factors such as abuse in childhood, poor toilet training, difficult childbirth, previous pelvic surgery or other psychological factors. The correct diagnosis is key to treating PFD and it starts with a thorough history and physical exam including a well performed digital rectal examination. Appropriate investigations following the initial visit can help to confirm the diagnosis and then treatment is prescribed accordingly. The patient should understand the nature of her constipation problem and participate fully in the management. The treatment is mainly conservative with diet, biofeedback and physiotherapy as the cornerstones of management. A multidisciplinary team approach will help for successful management of the patient. Surgery is normally not necessary for these patients and is only performed in extremely difficult refractory cases. By taking the time to make the correct diagnosis, patients with PFD can avoid frustration, unnecessary testing and surgery.

The first commodity futures index of 1933

We document the properties of the first diversified commodity futures index introduced by the Dow Jones & Company in 1933, and use its live track record to study the properties of the asset class in an experimental setting that does not suffer from backfill, selection, or survivorship biases. Despite the setbacks posed by contract failure and trading suspensions of several index constituents, the index appreciated by 3.7% per year between 1933 and 1998, while an investment in collateralized front-month futures returned 4.5% in excess of the risk-free rate. We quantify the impact of trading suspensions and contract failure on estimates of the risk premium.

Hansmann’s Contract Failure Theory: Correct but Irrelevant?

We assess whether nonprofit status serves as a valuable indicator of trust in the presence of information asymmetry, as Hansmann posited in his (1980) theory on the role of nonprofit enterprise. Using choice-based conjoint analysis, we find that in the absence of additional information (such as consumer ratings and third-party certifications), nonprofit status serves as an important value signal to consumers. However, in the presence of consumer ratings and third-party certifications, nonprofit status becomes less relevant. We also find some evidence of a nonprofit halo effect, in which consumers have a strong preference for nonprofit organizations when consumer ratings are low. Given that Hansmann was writing before the ubiquitous availability of online rating and certification information, we find that his theory was prescient, but that it provides little explanation for consumer behavior in the current environment. As information becomes more abundant and organizational forms continue to converge, it is likely that the contract failure thesis will become increasingly obsolete.

Wealth effects of dividend regulation: Evidence from China

By exploring a natural experiment where the Chinese regulatory body introduced a dividend regulatory change in 2012, this article investigates the wealth effects of dividend regulation which increases firms’ dividends. I find that firms’ share price reacted positively (negatively) to regulatory events increasing (decreasing) investors’ expectation of dividends. The effects are more pronounced for firms with low dividends or domiciled in weak legal environments, robust to different research designs. The findings are consistent with the notion that low dividends in China are a manifestation of implicit contract failure. Dividend regulation provides remedies to low investor protection arising from weak legal environments. JEL Classification: G14, G35, G38, K22