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Mechanically induced signal transduction has an essential role in development. Cells actively transduce and respond to mechanical signals and their internal architecture must manage the associated forces while also being dynamically responsive. With unique assembly-disassembly dynamics and physical properties, cytoplasmic intermediate filaments play an important role in regulating cell shape and mechanical integrity. While this function has been recognized and appreciated for more than 30 years, continually emerging data also demonstrate important roles of intermediate filaments in cell signal transduction. In this review, with a particular focus on keratins and vimentin, the relationship between the physical state of intermediate filaments and their role in mechanotransduction signaling is illustrated through a survey of current literature. Association with adhesion receptors such as cadherins and integrins provides a critical interface through which intermediate filaments are exposed to forces from a cell's environment. As a consequence, these cytoskeletal networks are posttranslationally modified, remodeled and reorganized with direct impacts on local signal transduction events and cell migratory behaviors important to development. We propose that intermediate filaments provide an opportune platform for cells to both cope with mechanical forces and modulate signal transduction.

The connexin 43 (Cx43) hemichannel (HC) in the mechanosensory osteocytes is a major portal for the release of factors responsible for the anabolic effects of mechanical loading on bone formation and remodeling. However, little is known about how the Cx43 molecule responds to mechanical stimulation leading to the opening of the HC. Here, we demonstrate that integrin α5β1 interacts directly with Cx43 and that this interaction is required for mechanical stimulation-induced opening of the Cx43 HC. Direct mechanical perturbation via magnetic beads or conformational activation of integrin α5β1 leads to the opening of the Cx43 HC, and this role of the integrin is independent of its association with an extracellular fibronectin substrate. PI3K signaling is responsible for the shear stress-induced conformational activation of integrin α5β1 leading to the opening of the HC. These results identify an unconventional function of integrin that acts as a mechanical tether to induce opening of the HC and provide a mechanism connecting the effect of mechanical forces directly to anabolic function of the bone.

Intermediate filament cytoskeletal networks simultaneously support mechanical integrity and influence signal transduction pathways. Marked remodeling of the keratin intermediate filament network accompanies collective cellular morphogenetic movements that occur during early embryonic development in the frog Xenopus laevis. While this reorganization of keratin is initiated by force transduction on cell-cell contacts mediated by C-cadherin, the mechanism by which keratin filament reorganization occurs remains poorly understood. In this work we demonstrate that 14-3-3 proteins regulate keratin reorganization dynamics in embryonic mesendoderm cells from Xenopus gastrula. 14-3-3 co-localizes with keratin filaments near cell-cell junctions in migrating mesendoderm. Co-immunoprecipitation, mass spectrometry and bioinformatic analyses indicate Keratin 19 is a target of 14-3-3 in the whole embryo and, more specifically, mesendoderm tissue. Inhibition of 14-3-3 results in both the decreased exchange of keratin subunits into filaments and blocks keratin filament recruitment toward cell-cell contacts. Synthetically coupling 14-3-3 to Keratin 19 through a unique fusion construct conversely induces the localization of this keratin population to the region of cell-cell contacts. Taken together, these findings indicate that 14-3-3 acts on keratin intermediate filaments and is involved in their reorganization to sites of cell adhesion.

The connexin 43 (Cx43) hemichannel (HC) in the mechanosensory osteocytes is a major portal for the release of factors responsible for the anabolic effects of mechanical loading on bone formation and remodeling. However, little is known about how the Cx43 molecule responds to mechanical stimulation leading to the opening of the HC. Here, we demonstrate that integrin α5β1 interacts directly with Cx43 and that this interaction is required for mechanical stimulation-induced opening of the Cx43 HC. Direct mechanical perturbation via magnetic beads or conformational activation of integrin α5β1 leads to the opening of the Cx43 HC, and this role of the integrin is independent of its association with an extracellular fibronectin substrate. PI3K signaling is responsible for the shear stress-induced conformational activation of integrin α5β1 leading to the opening of the HC. These results identify an unconventional function of integrin that acts as a mechanical tether to induce opening of the HC and provide a mechanism connecting the effect of mechanical forces directly to anabolic function of the bone. [PUBLICATION ABSTRACT]

The significance of cytoplasmic intermediate filament proteins has previously been examined largely through various genetic approaches, including knockdown, knockout and transgenic overexpression. Few studies to date have attempted to examine the role of specifically the filamentous intermediate filament network in orchestrating various cell functions. To directly assess the role of the filamentous keratin intermediate filament network in regulation of cellular behavior, we created a PhotoActivatable disruptor of keratin Intermediate Filaments (PA-dIF). This genetically encoded construct consists of a peptide derived from the 2B2 region of Keratin 8 fused to the photosensitive LOV2 domain from Avena sativa phototropin-1. Upon 458 nm photoirradiation, PA-dIF disrupts keratin intermediate filaments in multiple species and cell types. Marked remodeling of the keratin intermediate filament network accompanies collective cellular morphogenetic movements that occur during gastrulation and neurulation in the Xenopus laevis frog embryo. Light-based activation of PA-dIF was able to disrupt keratin intermediate filaments in Xenopus cells and lead to tissue-specific disruption of morphogenetic processes. Altogether our data show a fundamental requirement for keratin intermediate filaments in orchestrating morphogenetic movements during early embryonic development that have yet to be revealed in other model systems. Moreover, our data validate the utility of a new genetically encoded photoactivatable tool for the disruption and examination of intermediate filaments.

The formation and evolution of secondary organic aerosol (SOA) were investigated at Yorkville, GA, in late summer (mid-August to mid-October 2016). The organic aerosol (OA) composition was measured using two online mass spectrometry instruments, the high-resolution time-of-flight aerosol mass spectrometer (AMS) and the Filter Inlet for Gases and AEROsols coupled to a high-resolution time-of-flight iodide-adduct chemical ionization mass spectrometer (FIGAERO-CIMS). Through analysis of speciated organics data from FIGAERO-CIMS and factorization analysis of data obtained from both instruments, we observed notable SOA formation from isoprene and monoterpenes during both day and night. Specifically, in addition to isoprene epoxydiol (IEPOX) uptake, we identified isoprene SOA formation from non-IEPOX pathways and isoprene organic nitrate formation via photooxidation in the presence of NOx and nitrate radical oxidation. Monoterpenes were found to be the most important SOA precursors at night. We observed significant contributions from highly oxidized acid-like compounds to the aged OA factor from FIGAERO-CIMS. Taken together, our results showed that FIGAERO-CIMS measurements are highly complementary to the extensively used AMS factorization analysis, and together they provide more comprehensive insights into OA sources and composition.

International challenges have become the standard for validation of biomedical image analysis methods. Given their scientific impact, it is surprising that a critical analysis of common practices related to the organization of challenges has not yet been performed. In this paper, we present a comprehensive analysis of biomedical image analysis challenges conducted up to now. We demonstrate the importance of challenges and show that the lack of quality control has critical consequences. First, reproducibility and interpretation of the results is often hampered as only a fraction of relevant information is typically provided. Second, the rank of an algorithm is generally not robust to a number of variables such as the test data used for validation, the ranking scheme applied and the observers that make the reference annotations. To overcome these problems, we recommend best practice guidelines and define open research questions to be addressed in the future. Biomedical image analysis challenges have increased in the last ten years, but common practices have not been established yet. Here the authors analyze 150 recent challenges and demonstrate that outcome varies based on the metrics used and that limited information reporting hampers reproducibility.

Abstract Background Studies have demonstrated an association between anti-TNF/immunomodulator agents used in inflammatory bowel disease (IBD) and impaired hepatitis B virus (HBV) vaccine immunogenicity, but little data exist on whether specific medication types affect protective HBsAb titers. Our aim was to analyze this association. Methods This is a retrospective cohort study. Inclusion criteria: age ≥18, diagnosis of Crohn's disease (CD) or ulcerative colitis (UC), previous HBV vaccination series and/or ≥1 positive HBsAb, and record of IBD therapy in 6 months before titer level. Patients were stratified based upon medication exposures: anti-TNF, immunomodulator, combination anti-TNF and immunomodulatory, and a reference arm. Titer levels following vaccination and specific medication types given in the 6 months before titer were recorded. Seroprotection was defined as HBsAb ≥10 IU/l and ≥100 IU/l. Results The study cohort (N = 391) was 70.8% white, 51.4% female and 64.2% had CD and 35.8% had UC. The mean age was 45.8 years. A significantly lower percentage of patients exposed to anti-TNF, immunomodulator or dual therapy had titers ≥10 (P < 0.01). Regarding specific medications, only patients exposed to infliximab (P < 0.01) were less likely to have titer levels ≥10, after controlling for other medication exposures, age at titer level, and interval time between vaccination/titer level. This was not found for patients exposed to adalimumab, methotrexate, 6-mercaptopurine, or azathioprine. Conclusions Patients exposed to infliximab were significantly less likely to have protective HBsAb titer levels following vaccination, a trend not seen in patients on adalimumab. Efforts to vaccinate IBD patients against HBV before use of immunomodulators and anti-TNFs, infliximab specifically, and screen periodically thereafter must be reinforced. 10.1093/ibd/izx001_video1 izx001.video1 5721577734001

Pump–probe experiments with subfemtosecond resolution are the key to understanding electronic dynamics in quantum systems. Here we demonstrate the generation and control of subfemtosecond pulse pairs from a two-colour X-ray free-electron laser. By measuring the delay between the two pulses with an angular streaking diagnostic, we characterize the group velocity of the X-ray free-electron laser and show control of the pulse delay down to 270 as. We confirm the application of this technique to a pump–probe measurement in core-ionized para -aminophenol. These results reveal the ability to perform pump–probe experiments with subfemtosecond resolution and atomic site specificity. Researchers have demonstrated the generation and control of subfemtosecond pulse pairs from a two-colour X-ray free-electron laser and conducted pump–probe experiments in core-ionized molecules.