Unifying Mechanisms Research Articles

RNA splicing controls organ-wide maturation of postnatal heart in mice.

Postnatal cardiac development requires the orchestrated maturation of diverse cellular components for which unifying control mechanisms are still lacking. Using full-length sequencing, we examined the transcriptomic landscape of the maturating mouse heart (E18.5-P28) at single-cell and transcript isoform resolution. We identified dynamically changing intercellular networks as a molecular basis of the maturing heart and alternative splicing (AS) as a common mechanism that distinguished developmental age. Manipulation of RNA-binding proteins (RBPs) remodeled the AS landscape, cardiac cell maturation, and intercellular communication through direct binding of splice targets, which were enriched for functions related to general, as well as cell-type-specific, maturation. Overexpression of an RBP nuclear cap-binding protein subunit 2 (NCBP2) in neonatal hearts repressed cardiac maturation. Together, our data suggest AS regulation by RBPs as an organ-level control mechanism in mammalian postnatal cardiac development and provide insight into the possibility of manipulating RBPs for therapeutic purposes.

Particle separation mechanisms in suspension-feeding fishes: key questions and future directions

Key unresolved questions about particle separation mechanisms in suspension-feeding fishes are identified and discussed, focusing on areas with the potential for substantial future discovery. The published hypotheses that are explored have broad applicability to biological filtration and bioinspired improvements in commercial and industrial crossflow microfiltration processes and microfluidics. As the first synthesis of the primary literature on the particle separation mechanisms of marine, estuarine, and freshwater suspension-feeding fishes, the goals are to enable comparisons with invertebrate suspension-feeding processes, stimulate future theoretical and empirical studies, and further the development of biomimetic physical and computational fluid dynamics models. Of the eight particle separation mechanisms in suspension-feeding fishes, six have been proposed within the past twenty years (inertial lift and shear-induced migration, reduction of effective gap size by vortices, cross-step filtration, vortical flow along outer faces of gill raker plates, ricochet filtration, and lateral displacement). The pace of discovery is anticipated to continue accelerating. Multidisciplinary collaboration and integration among biologists and engineers (including chemical, mechanical, biomedical, and filtration engineering) will result in new perspectives to identify patterns and potential unifying mechanisms across the breadth of suspension-feeding fish taxa, morphology, and function.

Dystonia genes and their biological pathways.

High-throughput sequencing has been instrumental in uncovering the spectrum of pathogenic genetic alterations that contribute to the etiology of dystonia. Despite the immense heterogeneity in monogenic causes, studies performed during the past few years have highlighted that many rare deleterious variants associated with dystonic presentations affect genes that have roles in certain conserved pathways in neural physiology. These various gene mutations that appear to converge towards the disruption of interconnected cellular networks were shown to produce a wide range of different dystonic disease phenotypes, including isolated and combined dystonias as well as numerous clinically complex, often neurodevelopmental disorder-related conditions that can manifest with dystonic features in the context of multisystem disturbances. In this chapter, we summarize the manifold dystonia-gene relationships based on their association with a discrete number of unifying pathophysiological mechanisms and molecular cascade abnormalities. The themes on which we focus comprise dopamine signaling, heavy metal accumulation and calcifications in the brain, nuclear envelope function and stress response, gene transcription control, energy homeostasis, lysosomal trafficking, calcium and ion channel-mediated signaling, synaptic transmission beyond dopamine pathways, extra- and intracellular structural organization, and protein synthesis and degradation. Enhancing knowledge about the concept of shared etiological pathways in the pathogenesis of dystonia will motivate clinicians and researchers to find more efficacious treatments that allow to reverse pathologies in patient-specific core molecular networks and connected multipathway loops.

Unifying Mechanisms of Metabolic Signalling

Unifying Mechanisms of Metabolic Signalling

Strengthening vaccination delivery system resilience in the context of protracted humanitarian crisis: a realist-informed systematic review

BackgroundChildhood vaccination is among the most effective public health interventions available for the prevention of communicable disease, but coverage in many humanitarian settings is sub-optimal. This systematic review critically evaluated peer-review and grey literature evidence on the effectiveness of system-level interventions for improving vaccination coverage in protracted crises, focusing on how they work, and for whom, to better inform preparedness and response for future crises.MethodsRealist-informed systematic review of peer-reviewed and grey literature. Keyword-structured searches were performed in MEDLINE, EMBASE and Global Health, CINAHL, the Cochrane Collaboration and WHOLIS, and grey literature searches performed through the websites of UNICEF, the Global Polio Eradication Initiative (GPEI) and Technical Network for Strengthening Immunization Services. Results were independently double-screened for inclusion on title and abstract, and full text. Data were extracted using a pre-developed template, capturing information on the operating contexts in which interventions were implemented, intervention mechanisms, and vaccination-related outcomes. Study quality was assessed using the MMAT tool. Findings were narratively synthesised.Results50 studies were included, most describing interventions applied in conflict or near-post conflict settings in sub-Saharan Africa, and complex humanitarian emergencies. Vaccination campaigns were the most commonly addressed adaptive mechanism (n = 17). Almost all campaigns operated using multi-modal approaches combining service delivery through multiple pathways (fixed and roving), health worker recruitment and training and community engagement to address both vaccination supply and demand. Creation of collaterals through service integration showed generally positive evidence of impact on routine vaccination uptake by bringing services closer to target populations and leveraging trust that had already been built with communities. Robust community engagement emerged as a key unifying mechanism for outcome improvement across almost all of the intervention classes, in building awareness and trust among crisis-affected populations. Some potentially transformative mechanisms for strengthening resilience in vaccination delivery were identified, but evidence for these remains limited.ConclusionA number of interventions to support adaptations to routine immunisation delivery in the face of protracted crisis are identifiable, as are key unifying mechanisms (multi-level community engagement) apparently irrespective of context, but evidence remains piecemeal. Adapting these approaches for local system resilience-building remains a key challenge.

The Impact of the Unification of the Policies of the EAEU Countries and Their Allies on Long-Term Socio-Economic Processes within the Eurasian Union

In the context of the development of a new round of the global economic crisis, the growth of regional and global instability, the factor of importance of improving the tools for the integration development of the Eurasian Economic Union is extremely acute. Strategic planning is one of the most important mechanisms for improving integration processes. It is the long-term development documents that are able to foresee and successfully coordinate the problems of wealth inequality, the quality of living standards, the access of various social strata of society to financial services, etc. However, such program documents are doomed to failure without the presence of reasonable priorities, focused mainly on the implementation of structural changes in the economies of the EAEU and its potential new members, as well as today’s observers of the Eurasian Economic Union.Aim. The purpose of the study is to analyze the current state of long-term socio-economic planning and forecasting within the boundaries of the EAEU. A mechanism of “transinstitutional cooperation” is proposed, focused on strengthening integration ties through institutional transformations. The macro-regional approach is considered as an effective model of cooperation between states within the framework of various socio-economic tools.Task. Thus, the objectives of the study were: to demonstrate the tools for the development of “transinstitutional interaction” within the boundaries of the Eurasian Economic Union, to give examples of such cooperation based on the possible cooperation of the EAEU countries with potential members of the union (Uzbekistan), as well as to analyze the legislative framework and the accumulated experience of “strategizing” in borders of the Eurasian economic integration.Methods. The research methods are comparative analysis when comparing the standard and interregional approaches of “transinstitutional interaction” for the development of the EAEU states, the method of expert assessments — when developing recommendations for improving the mechanisms of strategic planning in the Russian Federation, methods of structural and logical analysis — when determining the priority tools in the development of the Russian Federation and the Republic of Uzbekistan.Results. As a result, the main challenges of the EAEU in terms of improving the strategic planning tool were identified. A mechanism of “transinstitutional cooperation” is proposed, focused on strengthening integration ties through institutional transformations. The macro-regional approach is considered as an effective model of cooperation between states within the framework of various socio-economic tools. The prospects for integration ties between the EAEU countries and the Republic of Uzbekistan are analyzed in order to analyze the possibilities of unifying strategic planning mechanisms within the framework of “transinstitutional cooperation”. Recommendations are given for improving the strategic planning of the Russian Federation as a locomotive state in the development of strategic planning in the EAEU.Conclusion. As the data presented in the paper show, the member states of the EAEU+ (Eurasian integration countries + observer countries + potential members of the union — Uzbekistan) face similar problems with regard to the strategic development of their territories. The “transinstitutional approach” presented by the authors will allow the members of the Eurasian Economic Union to unite in solving socio-economic challenges, to systematize efforts towards improving the mechanisms of socioeconomic development, significantly saving on the “scale effect” in the search for new socio-economic tools, testing its effectiveness and process control of achieved indicators.

The April 2022 issue

This April 2022 issue contains five technical papers and two editorial notes. The first technical paper, Data-Plane Security Applications in Adversarial Settings , by Liang Wang and colleagues, investigates security issues that may arise when creating and running data-plane applications for programmable switches. This work moves security analysis and design forward in this particular area. This paper also calls for a more thorough rethinking of security for data-plane applications for programmable switches. The second technical paper, One Bad Apple Can Spoil Your IPv6 Privacy , by Said Jawad Saidi and colleagues, leverages IPv6 passive measurements to pinpoint that a non-negligible portion of devices encodes their MAC address in their IPv6 address. This threatens users' privacy, allowing content providers and CDNs to consistently track users and their devices across multiple sessions and locations. Overall, the paper is an excellent contribution toward privacy-by-design solutions and a nicely executed measurements study that clarifies the problem and provides solid suggestions to mitigate the problem. The third technical paper, Hyper-Specific Prefixes: Gotta Enjoy the Little Things in Interdomain Routing , by Khwaja Zubair Sediqi and colleagues, investigates the presence of high-specific prefixes (HSP) on the BGP Internet routing during the last decade. These prefixes are more-specific than /24 (/48) for IPv4 (IPv6) and are commonly filtered by Autonomous Systems operators. Overall this paper offers a nice contribution to the understanding of the BGP universe, with a clear message and a nice quantification of the phenomenon. The authors clearly present and motivate the work, offering also to not experts a nice view of the routing complexity of the nowadays internet. The fourth technical paper, Programming Socket-Independent Network Functions with Nethuns , by Nicola Bonelli and colleagues, proposes a new solution to transparently develop packet-processing programs on top of different network I/O frameworks. The authors design and develop an open-source library, nethuns, serving as a unified programming abstraction for network functions that natively supports multi-core programming. Not only is this work very relevant to our community, but also the code is released open-source through a BSD license, which can be used to foster more research in the area, towards unifying programming mechanisms of end-host networking. The fifth technical paper, Measuring DNS over TCP in the Era of Increasing DNS Response Sizes: A View from the Edge , by Mike Kosek and colleagues, studies one of the foundations of today's Internet: the Domain Name Service (DNS). The original RFC document of DNS instructs to send queries either over UDP (DoUDP) or TCP (DoTCP). This paper presents a measurement study on DoTCP focusing on two perspectives: failure rates and response times. Finally, we have two editorial notes. A Case for an Open Customizable Cloud Network , by Dean H. Lorenz and his colleagues, argues for the desirability of the new ecosystem of managed network solutions to connect to the Cloud, outlines the main requirements and sketches possible solutions. Recommendations for Designing Hybrid Conferences , by Vaibhav Bajpai and colleagues, presents guidelines and considerations-spanning technology, organization and social factors-for organizing successful hybrid conferences. I hope that you will enjoy reading this new issue and welcome comments and suggestions on CCR Online (https://ccronline.sigcomm.org) or by email at ccr-editor at sigcomm.org.

Electronic Cigarette Use and the Risk of Cardiovascular Diseases.

Electronic cigarettes or e-cigarettes are the most frequently used tobacco product among adolescents. Despite the widespread use of e-cigarettes and the known detrimental cardiac consequences of nicotine, the effects of e-cigarettes on the cardiovascular system are not well-known. Several in vitro and in vivo studies delineating the mechanisms of the impact of e-cigarettes on the cardiovascular system have been published. These include mechanisms associated with nicotine or other components of the aerosol or thermal degradation products of e-cigarettes. The increased hyperlipidemia, sympathetic dominance, endothelial dysfunction, DNA damage, and macrophage activation are prominent effects of e-cigarettes. Additionally, oxidative stress and inflammation are unifying mechanisms at many levels of the cardiovascular impairment induced by e-cigarette exposure. This review outlines the contribution of e-cigarettes in the development of cardiovascular diseases and their molecular underpinnings.

Microbial feedbacks on soil organic matter dynamics underlying the legacy effect of diversified cropping systems

Crop rotations have well-known aboveground and belowground benefits. At regional to continental scales, the unifying mechanisms of how diversified rotations alter soil organic matter (SOM) dynamics have not been demonstrated. We assessed how increasing crop rotational diversity across a soil-climate gradient affected the integrated response of SOM chemistry, microbial community composition, and its enzymatic potential to degrade SOM. Agroecosystems with the same crop rotational diversity (all sampled during the corn phase) shared similarities in molecular SOM patterns with a strong microbial signature, pointing to common transformation processes. Differences in SOM chemistry between rotations were mainly characterized by shifts in microbial necromass markers and in lipids produced or transformed by microbes rather than by intact plant lipids. Microbial resource allocation to enzymes, which catalyze the decomposition of organic matter, differed between systems. Lower resource investment into recalcitrant C-degrading enzymes with increasing crop diversity indicates higher resource availability for the microbial community. Our multivariate analyses suggest that this could be regulated via relative changes in microbial functional groups – emergence of relatively more non-oxidase producing microorganisms like arbuscular mycorrhizal fungi rather than an absolute decrease in oxidase producing microbes. These uniform responses to increased crop rotational diversity over a wide geographical area point to enhanced stabilization of microbial-derived SOM and functional shifts in the microbial community as a common mechanism underlying the positive plant-soil feedback in diversified cropping systems.

Improving the law enforcement functions of executive authorities to ensure information security as a direction of modern Russian legal policy

The article raises both theoretical issues of the functions of public authorities, their transformation depending on a specific historical period and legal policy, and practical tasks related to the expansion of law enforcement functions of executive authorities (on the example of Roskomnadzor). As part of the theoretical part of the work, a justification is made for the use of legal policy tools to determine the goals and priorities of legal regulation in the field of information security; the analysis of the concepts of “functions of the state” and “functions of public authorities” is carried out; Based on the analysis of doctrinal documents, it is stated that in the information sphere there are executive authorities that are not actually law enforcement, but at the moment they have the powers of law enforcement agencies. The practice-oriented part of the work explores specific functions directly related to information security, and outlines ways to improve them (unifying blocking mechanisms and increasing their transparency, using artificial intelligence to recognize negative or fake content, etc.).

Targeting cytochrome P450 46A1 and brain cholesterol 24-hydroxylation to treat neurodegenerative diseases.

The brain cholesterol content is determined by the balance between the pathways of in situ biosynthesis and cholesterol elimination via 24-hydroxylation catalyzed by CYP46A1 (cytochrome P450 46A1). Both pathways are tightly coupled and determine the rate of brain cholesterol turnover. Evidence is accumulating that modulation of CYP46A1 activity by gene therapy or pharmacologic means could be beneficial in case neurodegenerative and other brain diseases and affect brain processes other than cholesterol biosynthesis and elimination. This minireview summarizes these other processes, most common of which include abnormal protein accumulation, memory and cognition, motor behavior, gene transcription, protein phosphorylation as well as autophagy and lysosomal processing. The unifying mechanisms, by which these processes could be affected by CYP46A targeting are also discussed.

Transformational strategies for optimizing use of medications and related therapies through us pharmacists and pharmacies: Findings from a national study

SettingNonoptimized medication therapies (NOMTs) are associated with likely avoidable illnesses and mortality affecting millions of people and costing an estimated $528 billion per year in excess health spending in the United States. The coronavirus disease 2019 (COVID-19) pandemic brought into focus barriers limiting the ability of U.S. pharmacists and pharmacies to provide services that can reduce NOMTs and improve U.S. population health. ObjectivesThis National Science Foundation Center for Health Organization Transformation study explored potential strategies that U.S. pharmacists, pharmacies, and their partners could implement to reduce NOMTs while also delivering other forms of value to U.S. populations from 2021 to 2025 (during and after the COVID-19 pandemic). DesignA panel of senior leaders representing the U.S. pharmacist and pharmacy sector participated in a 4-round Delphi process to identify unmet needs, barriers, change drivers, and priority strategies for meeting those needs. Data were gathered and analyzed by public health researchers, most of whom are outside the pharmacist and pharmacy sector. ResultsA comprehensive set of evidence-based strategies with potential to reduce NOMTs, protect and improve population health and well-being, and strengthen the sector were identified. Four transformational strategies were recommended: comprehensive payment and practice transformation, strengthening pharmacy data interoperability infrastructure, development of unifying measurement and management mechanisms, and development of a more robust national research infrastructure. Strengthening health equity was a cross-cutting strategy affecting all areas. ConclusionThe results may be of interest to policy makers, pharmacists, pharmacies, physicians, nurses and other clinicians, pharmaceutical firms, plan sponsors, plans, health systems, clinics, aging care, digital technology companies, and others interested in optimizing outcomes from medications and related therapies for U.S. populations.

Insulin Signal Transduction Perturbations in Insulin Resistance.

Type 2 diabetes mellitus is a widespread medical condition, characterized by high blood glucose and inadequate insulin action, which leads to insulin resistance. Insulin resistance in insulin-responsive tissues precedes the onset of pancreatic β-cell dysfunction. Multiple molecular and pathophysiological mechanisms are involved in insulin resistance. Insulin resistance is a consequence of a complex combination of metabolic disorders, lipotoxicity, glucotoxicity, and inflammation. There is ample evidence linking different mechanistic approaches as the cause of insulin resistance, but no central mechanism is yet described as an underlying reason behind this condition. This review combines and interlinks the defects in the insulin signal transduction pathway of the insulin resistance state with special emphasis on the AGE-RAGE-NF-κB axis. Here, we describe important factors that play a crucial role in the pathogenesis of insulin resistance to provide directionality for the events. The interplay of inflammation and oxidative stress that leads to β-cell decline through the IAPP-RAGE induced β-cell toxicity is also addressed. Overall, by generating a comprehensive overview of the plethora of mechanisms involved in insulin resistance, we focus on the establishment of unifying mechanisms to provide new insights for the future interventions of type 2 diabetes mellitus.

The Role of Leptin in Fetal Growth during Pre-Eclampsia.

Leptin is secreted by the placenta and has a multi-facetted role in the regulation of functions related to pregnancy. Metabolic disorders and insufficient homeostatic compensatory mechanisms involving leptin during pregnancy play a decisive role in the development of pre-eclampsia (PE) and give rise to compromised intrauterine growth conditions and aberrant birth weight of offspring. This review was compiled to elucidate the metabolic background of PE and its relationship with adverse intrauterine growth conditions through the examination of leptin as well as to describe possible mechanisms linking leptin to fetal growth restriction. This review illustrates that leptin in PE is dysregulated in maternal, fetal, and placental compartments. There is no single set of unifying mechanisms within the spectrum of PE, and regulatory mechanisms involving leptin are specific to each situation. We conclude that dysregulated leptin is involved in fetal growth at many levels through complex interactions with parallel pregnancy systems and probably throughout the entirety of pregnancy.

Optimizing Energy Savings for a Fleet of Commercial Autonomous Trucks

In the era of Connected and Autonomous Vehicles, platooning has the potential to increase roadway capacity and reduce energy consumption. However, as vehicles try to form platoons they may also expend extra energy. Also, depending on its position within a platoon, the energy savings of each vehicle can be different. Thus, optimizing and quantifying the savings that may be gained from platooning is challenging. In this paper, we develop a simulation-optimization framework to tackle this challenge of quantifying energy savings from platooning. Our optimization model determines vehicle-to-platoon assignments given the current location, speed, and destination of all the vehicles and platoons on the freeway. The simulation model takes these platooning decisions from the optimization model and implements them. Vissim is used to simulate the actions taken by all the vehicles and platoons and capture the energy expended by each vehicle over its entire trip duration. To quantify the energy savings, the system is simulated with and without platooning. That is, the optimization model is turned off when assessing the performance of the system without platooning. In addition to the simulation-optimization framework, an accurate energy consumption model is developed in this paper, which is inspired by the work of Tadakuma and colleagues. The energy consumption model utilizes a hybrid prediction formula for aerodynamic drag reduction in multi-vehicle formations unifying both physical mechanisms and existing empirical study data. Our results show that a system wide savings of about 3% can be realized over 160 kilometers when platoons are formed strategically.

The Refractory Period Matters: Unifying Mechanisms of Macroscopic Brain Waves

The relationship between complex brain oscillations and the dynamics of individual neurons is poorly understood. Here we utilize maximum caliber, a dynamical inference principle, to build a minimal yet general model of the collective (mean field) dynamics of large populations of neurons. In agreement with previous experimental observations, we describe a simple, testable mechanism, involving only a single type of neuron, by which many of these complex oscillatory patterns may emerge. Our model predicts that the refractory period of neurons, which has often been neglected, is essential for these behaviors.

Inhibition of longevity regulator PAPP-A modulates tissue homeostasis via restraint of mesenchymal stromal cells.

Pregnancy‐associated plasma protein‐A (PAPP‐A) is a secreted metalloprotease that increases insulin‐like growth factor (IGF) availability by cleaving IGF‐binding proteins. Reduced IGF signaling extends longevity in multiple species, and consistent with this, PAPP‐A deletion extends lifespan and healthspan; however, the mechanism remains unclear. To clarify PAPP‐A’s role, we developed a PAPP‐A neutralizing antibody and treated adult mice with it. Transcriptomic profiling across tissues showed that anti‐PAPP‐A reduced IGF signaling and extracellular matrix (ECM) gene expression system wide. The greatest reduction in IGF signaling occurred in the bone marrow, where we found reduced bone, marrow adiposity, and myelopoiesis. These diverse effects led us to search for unifying mechanisms. We identified mesenchymal stromal cells (MSCs) as the source of PAPP‐A in bone marrow and primary responders to PAPP‐A inhibition. Mice treated with anti‐PAPP‐A had reduced IGF signaling in MSCs and dramatically decreased MSC number. As MSCs are (1) a major source of ECM and the progenitors of ECM‐producing fibroblasts, (2) the originating source of adult bone, (3) regulators of marrow adiposity, and (4) an essential component of the hematopoietic niche, our data suggest that PAPP‐A modulates bone marrow homeostasis by potentiating the number and activity of MSCs. We found that MSC‐like cells are the major source of PAPP‐A in other tissues also, suggesting that reduced MSC‐like cell activity drives the system‐wide reduction in ECM gene expression due to PAPP‐A inhibition. Dysregulated ECM production is associated with aging and drives age‐related diseases, and thus, this may be a mechanism by which PAPP‐A deficiency enhances longevity.

Physical mechanisms in hybrid additive manufacturing: A process design framework

This study defined hybrid additive manufacturing (AM) as “in-situ or series combination of an additive manufacturing process and secondary energy sources in which physical mechanisms are fundamentally altered/controlled to affect the resulting properties of material and/or part.” This definition includes in-situ secondary processes as well as process chains, and it is anchored in multi-physical mechanisms such that new hybrid-AM processes can be freely and systematically sought or invented through a systems approach epitomized by the “property – mechanism – energy source – hybrid-AM process (PMEH)” thought process. The sequence of driving forces in this framework are as such: desired material properties determine which mechanism is utilized and, in turn, the energy source to be applied, which ultimately defines the hybrid-AM process. The five unifying physical mechanisms that were identified in this study are: melt pool dynamics, microstructure development, stress state, surface evolution, and thermal gradients. Analysis of properties, mechanisms, energy sources, and processes was conducted on more than 100 papers, and the results ultimately show the effect of mechanisms on material properties. Mechanisms are further classified by energy source, which are in turn broken down by hybrid-AM process. Additionally, each mechanism was defined and reviewed in detail, highlighting the PMEH relationship for metal hybrid-AM materials. Further analysis compares reported mechanical property values for hybrid-AM processes to both AM only and wrought properties for 316 L, Alloy 718, and Titanium Gr 5. Finally, future directions of research as well as clear gaps in knowledge are identified, which includes lack of variety in utilized energy sources, lack of material diversity, process chain integration and improvement, and promising hybrid-AM processes. With the presented analysis and PMEH framework, it is determined that metal AM hybrid processes are well suited to address current problems and show promise in creating superior and versatile materials. Further growth in this field is expected to be exponential, and the developed PMEH framework will aid in framing these innovative processes.

Multiple epiphyseal dysplasia and related disorders: Molecular genetics, disease mechanisms, and therapeutic avenues

For the vast majority of the 6000 known rare disease the pathogenic mechanisms are poorly defined and there is little treatment, leading to poor quality of life and high healthcare costs. Genetic skeletal diseases (skeletal dysplasias) are archetypal examples of rare diseases that are chronically debilitating, often life-threatening and for which no treatments are currently available. There are more than 450 unique phenotypes that, although individually rare, have an overall prevalence of at least 1 per 4000 children. Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous disorder characterized by disproportionate short stature, joint pain, and early-onset osteoarthritis. MED is caused by mutations in the genes encoding important cartilage extracellular matrix proteins, enzymes, and transporter proteins. Recently, through the use of various cell and mouse models, disease mechanisms underlying this diverse phenotypic spectrum are starting to be elucidated. For example, ER stress induced as a consequence of retained misfolded mutant proteins has emerged as a unifying disease mechanisms for several forms of MED in particular and skeletal dysplasia in general. Moreover, targeting ER stress through drug repurposing has become an attractive therapeutic avenue.

Percutaneous Epicardial Ablation of Atrial Fibrillation

The observations afforded by epicardial mapping have not only increased the appreciation of distinct epicardial structures in the left atrium but also underscore the need to address the substrate transmurally. Although epicardial access and ablation have attendant risks, comparative studies with hybrid surgical approaches are lacking. In the search to find unifying mechanisms of atrial fibrillation, a conceptual shift that emphasizes the substrate in 3 dimensions, with the epicardium distinct from the endocardium, holds promise for future investigation and evolving therapeutic tools.