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Per- and polyfluoroalkyl substances (PFAS) are a class of man-made chemicals of global concern for many health and regulatory agencies due to their widespread use and persistence in the environment (in soil, air, and water), bioaccumulation, and toxicity. This concern has catalyzed a need to aggregate data to support research efforts that can, in turn, inform regulatory and statutory actions. An ongoing challenge regarding PFAS has been the shifting definition of what qualifies a substance to be a member of the PFAS class. There is no single definition for a PFAS, but various attempts have been made to utilize substructural definitions that either encompass broad working scopes or satisfy narrower regulatory guidelines. Depending on the size and specificity of PFAS substructural filters applied to the U.S. Environmental Protection Agency (EPA) DSSTox database, currently exceeding 900,000 unique substances, PFAS substructure-defined space can span hundreds to tens of thousands of compounds. This manuscript reports on the curation of PFAS chemicals and assembly of lists that have been made publicly available to the community via the EPA’s CompTox Chemicals Dashboard. Creation of these PFAS lists required the harvesting of data from EPA and online databases, peer-reviewed publications, and regulatory documents. These data have been extracted and manually curated, annotated with structures, and made available to the community in the form of lists defined by structure filters, as well as lists comprising non-structurable PFAS, such as polymers and complex mixtures. These lists, along with their associated linkages to predicted and measured data, are fueling PFAS research efforts within the EPA and are serving as a valuable resource to the international scientific community.

Digital technologies are changing how businesses strategize and organize internationally. They not only enable cost reduction in businesses crossing national boundaries but also enable novel types of products and business models. Yet, barriers to cross-border businesses persist or even re-emerge, such that the study of international business remains important in the digital age, but may have to shift focus. We argue that businesses operating internationally develop digital business strategies that are interdependent with their internationalization strategies. In doing so, they have to account for differences across national contexts including informal institutions, formal institutions, and resource endowments. We offer a conceptual framework linking external and internal antecedents to digital business and internationalization strategies. We focus in particular on three digital strategies: owning digital platforms, participating in digital platforms, and transforming traditional businesses for the digital world. On this basis, we discuss the contributions of the papers in this special issue and conclude by outlining an agenda for future research.

Genome-wide chromosome conformation capture analysis in C. elegans reveals that the dosage compensation complex, a condensin complex, remodels the X chromosomes of hermaphrodites into a sex-specific topology distinct from autosomes while regulating gene expression chromosome-wide. X-chromosome takes shapes Dosage compensation in the roundworm Caenorhabditis elegans is a good model for understanding the role of three-dimensional chromosome organization in regulating gene expression. Here, Barbara Meyer and colleagues use genome-wide chromosome conformation capture techniques in wild-type XX hermaphrodite embryos and those lacking the dosage compensation complex (DCC), to obtain three-dimensional maps of the C. elegans genome. The DCC remodels hermaphrodite X chromosomes into a spatial conformation of topologically associating domains that is distinct from that on autosomes. The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure 1 , 2 . Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X ( rex sites) to reduce chromosome-wide gene expression by half 3 , 4 , 5 , 6 , 7 . Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes 5 , 6 . By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (∼1 Mb) resembling mammalian topologically associating domains (TADs) 8 , 9 . TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.

Continuous monitoring of intraocular pressure, particularly during sleep, remains a grand challenge in glaucoma care. Here we introduce a class of smart soft contact lenses, enabling the continuous 24-hour monitoring of intraocular pressure, even during sleep. Uniquely, the smart soft contact lenses are built upon various commercial brands of soft contact lenses without altering their intrinsic properties such as lens power, biocompatibility, softness, transparency, wettability, oxygen transmissibility, and overnight wearability. We show that the smart soft contact lenses can seamlessly fit across different corneal curvatures and thicknesses in human eyes and therefore accurately measure absolute intraocular pressure under ambulatory conditions. We perform a comprehensive set of in vivo evaluations in rabbit, dog, and human eyes from normal to hypertension to confirm the superior measurement accuracy, within-subject repeatability, and user comfort of the smart soft contact lenses beyond current wearable ocular tonometers. We envision that the smart soft contact lenses will be effective in glaucoma care. Continuous monitoring of intraocular pressure remains a grand challenge in glaucoma care. Here the authors develop smart soft contact lenses for continuous 24-hour monitoring of intraocular pressure in human eyes, even during sleep.

Electroretinogram examinations serve as routine clinical procedures in ophthalmology for the diagnosis and management of many ocular diseases. However, the rigid form factor of current corneal sensors produces a mismatch with the soft, curvilinear, and exceptionally sensitive human cornea, which typically requires the use of topical anesthesia and a speculum for pain management and safety. Here we report a design of an all-printed stretchable corneal sensor built on commercially-available disposable soft contact lenses that can intimately and non-invasively interface with the corneal surface of human eyes. The corneal sensor is integrated with soft contact lenses via an electrochemical anchoring mechanism in a seamless manner that ensures its mechanical and chemical reliability. Thus, the resulting device enables the high-fidelity recording of full-field electroretinogram signals in human eyes without the need of topical anesthesia or a speculum. The device, superior to clinical standards in terms of signal quality and comfortability, is expected to address unmet clinical needs in the field of ocular electrodiagnosis. Though smart contact lenses are an attractive technology for recording electroretinogram signals, existing approaches suffer from poor mechanical reliability, chemical stability and wettability. Here, the authors report an all-printed stretchable corneal sensor built on commercial soft contact lenses.

Background It is recommended that school-aged children accrue 30 minutes of daily moderate-to-vigorous physical activity (MVPA) in school. Current literature is inconclusive about the long-term associations between school-based physical activity and academic achievement. In this study, we use a large sample and longitudinal design to rigorously evaluate whether school-day MVPA is associated with academic achievement. Methods In a diverse suburban public school district, 4936 Grade 4 students were recruited in 40 elementary schools. Students wore accelerometers to measure school-day MVPA for 15 days across three semesters. Academic performance data was collected across Grade 3 fall to Grade 5 spring, including teacher-assigned grades and standardized test scores. Multilevel modeling was conducted controlling for student demographics and school characteristics. Results Cross-sectional analyses found small negative associations in Grade 4. Grade 4 full-year mean daily school-day MVPA had β = −-0.066, β = −-0.063, β = −-0.066, and β = −-0.058 associations ( p  <  0.001) with Grade 4 math, reading, spelling, and writing grades respectively, and Grade 4 full-year mean daily school-day MVPA had β = −-0.206 and β = −-0.283 ( p  <  0.001) associations with Grade 4 math and English Language Arts (ELA) standardized test scores respectively out of approximately 500 points. Longitudinal analyses found no significant associations between Grade 4 full-year mean daily school-day MVPA and Grade 5 Fall course grades. Results also indicated small negative associations for students attaining 30+ minutes of daily school-day MVPA compared to those attaining less than 15 minutes, but only in Grade 4 Fall cross-sectional analyses where teacher-assigned reading, spelling, and writing grades were − 1.666, − 1.638, and − 1.993 points lower respectively ( p  <  0.001). Conclusion The cross-sectional findings, while statistically significant in a negative direction, have a negligible association when translated practically. For example, even if students attained twice the recommended amount of school-day MVPA – which would constitute an approximately 300% increase from current levels – results suggest that grades would only decrease by 2 points on a 100-point scale. Furthermore, longitudinal analyses suggest school-day MVPA does not have a predictive association with course grades or standardized test scores. Findings suggest school-based MVPA implemented in accordance with recommendations does not meaningfully detract from academic progress. Trial registration ClinicalTrials.gov , NCT03765047. Registered 05 December 2018 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03765047

Engineered nucleases target specific DNA sequences for gene disruption in nonmodel organisms. Evolutionary studies necessary to dissect diverse biological processes have been limited by the lack of reverse genetic approaches in most organisms with sequenced genomes. We established a broadly applicable strategy using zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) for targeted disruption of endogenous genes and cis-acting regulatory elements in diverged nematode species.

Objectives. To characterize the immunogenicity of a quadrivalent human papillomavirus vaccine (QHPV) in human immunodeficiency virus (HIV)-infected children, we studied their immune responses to 3 or 4 doses. Methods. HIV-infected children aged 7-12 years with a CD4 cell percentage of > 15% of lymphocytes, received 3 doses of QHPV with or without a fourth dose after 72 weeks. Type-specific and cross-reactive antibodies and cell-mediated immunity were measured. Results. Type-specific antibodies to HPV6, 11, and 16 were detected in 100% and > 94% of children at 4 and 72 weeks, respectively, after the third QHPV dose. Corresponding numbers for HPV18 were 97% and 76%, respectively. A fourth QHPV dose increased seropositivity to > 96% for all vaccine genotypes. Four weeks after the third QHPV dose, 67% of vaccinées seroconverted to HPV31, an HPV16-related genotype not in the vaccine; 69% and 39% of vaccinees developed mucosal HPV16 and 18 immunoglobulin G antibodies, respectively; and 60% and 52% of vaccinées developed cytotoxic T lymphocytes (CTLs) for HPV16 and 31, respectively. Conclusions. Three QHPV doses generated robust and persistent antibodies to HPV6, 11, and 16 but comparatively weaker responses to HPV18. A fourth dose increased antibodies against all vaccine genotypes in an anamnestic fashion. CTLs and mucosal antibodies against vaccine genotypes, as well as cross-reactive antibodies and CTL against nonvaccine genotypes, were detected.