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Currently, therapeutic and diagnostic applications of antibodies are primarily limited to cell surface-exposed and extracellular proteins. However, research has been conducted on cell-penetrating peptides (CPP), as well as cytosol-penetrating antibodies, to overcome these limitations. In this context, a heparin sulfate proteoglycan (HSPG)-binding antibody was serendipitously discovered, which eventually localizes to the cytosol of target cells. Functional characterization revealed that the tested antibody has beneficial cytosol-penetrating capabilities and can deliver cargo proteins (up to 70 kDa) to the cytosol. To achieve tumor-specific cell targeting and cargo delivery through conditional activation of the cell-penetrating antibody in the tumor microenvironment, a single-chain Fc fragment (scFv) and a VL domain were isolated as masking units. Several in vitro assays demonstrated that fusing the masking protein with a cleavable linker to the cell penetration antibody results in the inactivation of antibody cell binding and internalization. Removal of the mask via MMP-9 protease cleavage, a protease that is frequently overexpressed in the tumor microenvironment (TME), led to complete regeneration of binding and cytosol-penetrating capabilities. Masked and conditionally activated cytosol-penetrating antibodies have the potential to serve as a modular platform for delivering protein cargoes addressing intracellular targets in tumor cells. [ABSTRACT FROM AUTHOR]

Abstract Background Congenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder. CHD may segregate in families due to significant contribution of genetic factors in the disease etiology. The aim of the study was to identify pathophysiological mechanisms in families segregating CHD. Methods We used whole exome sequencing to identify rare genetic variants in ninety consenting participants from 32 Danish families with recurrent CHD. We applied a systems biology approach to identify developmental mechanisms influenced by accumulation of rare variants. We used an independent cohort of 714 CHD cases and 4922 controls for replication and performed functional investigations using zebrafish as in vivo model. Results We identified 1785 genes, in which rare alleles were shared between affected individuals within a family. These genes were enriched for known cardiac developmental genes, and 218 of these genes were mutated in more than one family. Our analysis revealed a functional cluster, enriched for proteins with a known participation in calcium signaling. Replication in an independent cohort confirmed increased mutation burden of calcium-signaling genes in CHD patients. Functional investigation of zebrafish orthologues of ITPR1, PLCB2, and ADCY2 verified a role in cardiac development and suggests a combinatorial effect of inactivation of these genes. Conclusions The study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.

The Water-Energy-Food Nexus has emerged over the past decade as a useful concept to reduce trade-offs and increase synergies in promoting goals of water, energy and food securities. While WEF scholarship substantiates the biophysical interlinkages and calls for increased and effective coordination across sectors and levels, knowledge on conditions for effective coordination is still lacking. Analysing WEF nexus governance from a polycentricity perspective may contribute to better understanding coordination. In this paper, we propose a conceptual framework for analysing WEF nexus governance based on the Institutional Analysis and Development (IAD) framework and the concept of Networks of Adjacent Action Situations (NAAS). The interdependence among transactions for pursuing WEF securities by actors in different action situations generates the need for coordination for changing or sustaining institutions, policy goals and policy instruments that guide actions leading to sustainable outcomes. Coordination is attained through arrangements based on cooperation, coercion or competition. Coordination in complex social-ecological systems is unlikely to be achieved by a single governance mode but rather by synergistic combinations of governance modes. Particular coordination arrangements that emerge in a context depend on the distribution of authority, information and resources within and across interlinked decision-making centres. Further, integrating the political ecology based conceptualisations of power into the analytical framework extends the governance analysis to include the influence of power relations on coordination. Methodological innovation in delineating action situations and identifying the unit of analysis as well as integrating different sources and types of data is required to operationalise the conceptual framework.

[This corrects the article DOI: 10.1371/journal.pgen.1009679.].

In the course of the electrification of powertrains, rolling element bearings are increasingly subject to electrical damage. In contrast to mechanically generated pittings, voltage-induced surface damage is a continuous process. Though several approaches for the description of the damage state of a bearing are known, a generally accepted quantification for the bearing damage has not been established yet. This paper investigates surface properties, which can be used as a metric damage scale for the quantification of the electric bearing damage progression. For this purpose, the requirements for suitable surface properties are defined. Afterwards, thrust ball bearings are installed on a test rig, with constantly loaded mechanically and periodically damaged electrically in multiple phases. After each phase, the bearings are disassembled, the bearing surfaces are graded and measured for 45 different standardized surface properties. These properties are evaluated with the defined requirements. For the ones meeting the requirements, critical levels are presented, which allow for a quantified distinction between grey frosting and corrugation surfaces. These values are compared with measurements presented in the literature showing that the identified surface properties are suitable for the quantification of electrical bearing damages.

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.

Rolling bearings face different damaging effects: Besides mechanical effects, current-induced bearing damage occurs in electrical drive systems. Therefore, it is of increasing interest to understand the differences leading to known electrical damage patterns. It is of utmost importance not to consider the harmful current passage in the machine element as an isolated phenomenon but to take into account the whole drive system consisting of the machine elements, the electric motor and the connected power electronics. This publication works toward providing an overview of the state-of-the-art of research regarding electrical bearing currents.

An evolving literature on the Water-Energy-Food (WEF) nexus argues that there is a need to better understand the conditions under which nexus coordination may occur. A case in point are hydropower investments on shared rivers which might impact the provision of energy, water and food security across borders. In international basins, governing the WEF nexus impacts of hydropower relies on voluntary negotiations between the respective countries involved. It has been argued that such negotiations may be facilitated by regional organizations, such as international river basin organizations (IRBOs), but this claim has hardly been investigated systematically. Drawing on regime theory in international relations and the literature on benefit sharing, this paper asks what role regional organizations may play in governing hydropower-related WEF nexus impacts. It compares three cases of hydropower planning on shared rivers. The Rusumo Falls and the Ruzizi III hydropower projects (HPPs) are joint investments in Africa's Great Lakes region facilitated by an IRBO and a regional energy organization, respectively. On the Mekong, Laos is constructing the Xayaburi dam despite reservations by the Mekong River Commission and downstream riparians. The paper finds IRBOs and regional energy organizations may play a role in facilitating cross-border nexus governance by supporting benefit-sharing arrangements and by fostering the application of environmental and social safeguards and international law principles. However, it also shows that the influence of regional organizations varies, and how successfully they support nexus governance also depends on whether the HPP is planned unilaterally or jointly; the availability and consensus on data on nexus impacts; and the presence or absence of donors and private sector capital and investors.

Introduction: Hyperparathyroidism significantly decreases quality of life, yet elderly patients are underdiagnosed and undertreated even though parathyroidectomy offers definitive cure with minimal morbidity. The purpose of this study is to determine why older patients with hyperparathyroidism are not appropriately diagnosed and referred for parathyroidectomy. Methods: We reviewed charts for a random sample of 25 patients aged 75 and older who had hyperparathyroidism and were referred for surgical evaluation, and 25 who were not referred. Two reviewers independently evaluated medical records to identify reasons for delayed diagnosis of hyperparathyroidism and reasons for nonreferral for parathyroidectomy. Results: The median age of our cohort was 84 (80-96) years, 90% were women, 60% were white, and median follow-up was 5.5 (1-17) years. In 58% of all patients, an elevated serum calcium was not acknowledged. Even when calcium and parathyroid hormone levels were both elevated, the diagnosis was missed in 28% of patients, and 16% with clear symptoms of hyperparathyroidism remained undiagnosed. For 42% of patients, a nonsurgeon informed them that surgery offered no benefit. Surgery was also rejected as a treatment for 36% of patients despite the development of new symptoms or rising calcium. Conclusions: Substantial gaps exist in processes for diagnosis and referral of patients with hyperparathyroidism that lead to underdiagnosis and undertreatment. To improve rates of diagnosis and treatment, strategies are needed to educate nonsurgeons and patients about the benefits of surgery and to modify care processes to more efficiently diagnose and refer patients.