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Summary Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. Introduction To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. Methods A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n  = 45) and risedronate (35 mg/week, n  = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. Results PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. Conclusions Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

Baricitinib (BARI) is a JAK1-2 inhibitor approved for the treatment of adults with moderately to severely active rheumatoid arthritis (RA). RA-BE-REAL is a 3-year, prospective, observational study of adult RA patients (pts) evaluating adherence to treatment in clinical practice. To describe pt and disease characteristics of pts enrolling into RA-BE-REAL in 5 European countries. The primary endpoint of RA-BE-REAL is time until discontinuation of initial treatment for all causes (excluding sustained clinical response) over a 24-month (M) period. Secondary endpoints include clinical and pt reported outcomes, healthcare resource utilization and treatment patterns over a 36M period. Two pt cohorts are assessed: cohort A, started treatment with BARI (2-mg or 4-mg), and cohort B, any other targeted synthetic (ts)DMARDs or biologic (b)DMARD (Fig. 1). Treatment initiation and changes are at the discretion of the pt and physician. Data is collected at baseline and at routine visits (~3M, 6M, 12M, 18M, 24M and 36M). Summaries are presented with t-test and chi-square test of independence. Between October 2018 and March 2020, 1074 adult RA pts were enrolled from France, Germany, Italy, Spain, and UK. In cohort A, 88.2% of pts are treated with BARI 4-mg. At time of enrolment pts in cohort A are more likely to commence treatment as a monotherapy as compared to pts in cohort B who are more likely to commence treatment in combination with csDMARDs (p<0.001). Cohort A are more likely to be older (59.2 vs 57.0, mean years p=0.009) and have higher Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (1.4 vs 1.3, p=0.03). A greater percentage of cohort A pts have received prior treatment with either 1 b/tsDMARD (15.3 vs 11.0%), 2 b/tsDMARD (20.2 vs 14.7%) or >2 b/tsDMARD (15.9 vs 12.9%), while cohort B are more likely to be treatment naïve (61.4 vs 48.5%). There are no significant differences in other baseline characteristics shown in Table 1. There are few but potentially clinically important differences between cohorts. Pts in cohort A are more likely to be older, have a longer disease duration, have received prior b/tsDMARD treatment, and are more likely to receive treatment as a monotherapy as compared to pts in cohort B. The authors would like to acknowledge Luke Healy for medical writing support. Rieke Alten Speakers bureau: Janssen Pharmaceuticals, Eli Lilly and Company, Pfizer Inc., and Galapagos, and Gilead Sciences, Consultant of: Eli Lilly and Company, Pfizer Inc., Galapagos NV, and Gilead Sciences, Grant/research support from: Bristol-Myers Squibb, Eli Lilly and Company, Pfizer Inc., Galapagos NV, and Gilead Sciences, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Gilead Sciences, Eli Lilly and Company, and Pfizer Inc., Consultant of: AbbVie, Gilead Sciences, Eli Lilly and Company, and Pfizer Inc., Marco Matucci-Cerinic Speakers bureau: Actelion, Janssen Pharmaceuticals, MSD, Eli Lilly and Company, Biogen Inc., Grant/research support from: MSD, Actelion., Jean-Hugues Salmon: None declared, Pedro López-Romero Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, WALID FAKHOURI Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Inmaculada De La Torre Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Anja Gentzel-Jorczyk Employee of: Eli Lilly and Company, Thorsten Holzkaemper Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Bruno Fautrel Consultant of: AbbVie, Biogen, Bristol-Myers Squibb, Celgene, Janssen Pharmaceuticals, Eli Lilly and Company, Medac, MSD, NORDIC Pharma, Novartis, Pfizer Inc., Roche, Sanofi-Aventis, SOBI, UCB, Grant/research support from: AbbVie, MSD, Pfizer Inc. [Display omitted] Table 1Patient disposition and baseline characteristics.Cohort ABaricitinib(n=509)Cohort BOverall(n=1074)TNFi(n=338)non-TNFi(n=161)tsDMARD(n=66)Combination Therapywith any csDMARD238 (46.8)231 (40.9)110 (19.5)38 (6.7)617 (57.4)monotherapy271 (53.2)107 (18.9)51 (9.0)28 (5.0)457 (42.6)Values represent n (%)Cohort ACohort Bp-valueOverall (n=1074)(n=509)(n=565)Age in years59.2 (13.2)57.0 (13.9)0.00958.0 (13.6)Disease duration in years10.3 (9.2)9.1 (9.8)0.059.7 (9.5)CDAI24.1 (11.7)23.9 (12.4)0.7524.0 (12.1)Swollen joint count5.2 (4.8)4.7 (4.9)0.184.9 (4.8)Tender joint count7.3 (6.1)7.8 (6.5)0.197.6 (6.3)PhGA5.6 (2.0)5.5 (2.1)0.395.6 (2.0)PGA5.9 (2.3)5.8 (2.4)0.495.9 (2.4)Pain VAS59.0 (23.1)56.4 (24.3)0.0857.6 (23.8)HAQ-DI1.4 (0.7)1.3 (0.7)0.031.4 (0.7)b/tsDMARDs treatment any time before enrolment; n (%)<0.001*Naïve247 (48.5)347 (61.4)594 (55.3)1 b/tsDMARD78 (15.3)62 (11.0)140 (13.0)2 b/tsDMARDs103 (20.2)83 (14.7)186 (17.3)>2 b/tsDMARDs81 (15.9)73 (12.9)154 (14.3)Values represent mean (SD), unless otherwise stated.b/tsDMARD, biologic/targeted synthetic disease-modifying antirheumatic drug; CDAI, Clinical Disease Activity Index; HAQ-DI, Healthy Assessment Questionnaire-Disability Index; P(h)GA, Patient's (Physician's) global assessment of disease activity; VAS, Visual analogue scale. *chi-square test of independence for comparison of b/tsDMARD treatment received before enrolment.

Tissue engineering aims to regenerate new biological tissue for replacing diseased or injured tissues. We propose a new approach to accelerate the deposition of cell-secreted matrix proteins into extracellular matrix fibrils. We examined whether dynamic substrates with nanoscale ligand features allowing for α5β1 integrin recruiting, cellular tension generation, and α5β1 integrin mobility would enhance fibronectin matrix assembly in a ligand model system that is routinely not sufficient for its induction. To this end, we developed biodynamic substrates consisting of cell adhesive fragment from the 9th and 10th type repeats of fibronectin (FNf ) functionalized to 100 nm prefabricated albumin nanoparticles (ANPs). FNf–ANPs modulated cellular spreading processes, promoting the development of stellate or dendritic morphologies. Concomitant with the spreading, FNf–ANPs rapidly recruited β1 integrins to focal contacts and promoted the migration of β1 integrins centripetally from the cell periphery toward the center. FNf–ANPs stimulated the deposition of secreted fibronectin into matrix fibrils; FNf, the key ligand alone, was not sufficient for fibronectin fibrillogenesis. When FNf–ANPs were displayed from “immobilized” substrates, abolishing any mobility of ligated β1 integrins, fibronectin matrix assembly was abrogated, implicating the role of dynamic matrix display on matrix assembly. Receptor ligation of FNf–ANPs via noncontractile adhesions was not sufficient to stimulate fibrillogenesis, and Rho-kinase inhibitors abolished fibronectin matrix deposition. Our approach highlights the possibility of engineering integrin-based extracellular matrix assembly using nanotechnology, which may have implications for improved biomaterials for wound repair and basic understanding of matrix remodeling within pathogenesis and biomedicine.

This paper presents a novel philosophical analysis of the problem of law enforcement’s use of biased face recognition technology (FRT) in liberal democracies. FRT programs used by law enforcement in identifying crime suspects are substantially more error-prone on facial images depicting darker skin tones and females as compared to facial images depicting Caucasian males. This bias can lead to citizens being wrongfully investigated by police along racial and gender lines. The author develops and defends “A Liberal Argument Against Biased FRT,” which concludes that law enforcement use of biased FRT is inconsistent with the classical liberal requirement that government treat all citizens equally before the law. Two objections to this argument are considered and shown to be unsound. The author concludes by suggesting that equality before the law should be preserved while the problem of machine bias ought to be resolved before FRT and other types of artificial intelligence (AI) are deployed by governments in liberal democracies.

Plants defend themselves from most microbial attacks via mechanisms including cell wall fortification, production of antimicrobial compounds, and generation of reactive oxygen species. Successful pathogens overcome these host defenses, as well as obtain nutrients from the host. Perturbations of plant metabolism play a central role in determining the outcome of attempted infections. Metabolomic analyses, for example between healthy, newly infected and diseased or resistant plants, have the potential to reveal perturbations to signaling or output pathways with key roles in determining the outcome of a plant–microbe interaction. However, application of this -omic and its tools in plant pathology studies is lagging relative to genomic and transcriptomic methods. Thus, it is imperative to bring the power of metabolomics to bear on the study of plant resistance/susceptibility. This review discusses metabolomics studies that link changes in primary or specialized metabolism to the defense responses of plants against bacterial, fungal, nematode, and viral pathogens. Also examined are cases where metabolomics unveils virulence mechanisms used by pathogens. Finally, how integrating metabolomics with other -omics can advance plant pathology research is discussed.

This paper considers possible future legislation that requires the exclusive use of autonomous cars. The author develops and defends a ‘Liberal Argument Against Mandated Autonomous Cars’, which argues that such a law would be incompatible with classical liberalism, provided that the following condition holds: In the event where the car must ‘choose’ between running over a young person or an old person, or both, autonomous cars are programmed to respond by running over old people in order to save young people. Such a law requiring the use of these cars, provided that these assumptions hold, would violate the important value in classical liberalism that all individuals ought to be treated equally before the law. The paper concludes by arguing that alternative ways of dealing with this problem come with their own set of unpalatable problems.

Connexins are the primary components of gap junctions, providing direct links between cells under many physiological processes. Here, we demonstrate that in addition to this canonical role, Connexins act as transcriptional regulators. We show that Connexin 43 (Cx43) controls neural crest cell migration in vivo by directly regulating N-cadherin transcription. This activity requires interaction between Cx43 carboxy tail and the basic transcription factor-3, which drives the translocation of Cx43 tail to the nucleus. Once in the nucleus they form a complex with PolII which directly binds to the N-cadherin promoter. We found that this mechanism is conserved between amphibian and mammalian cells. Given the strong evolutionary conservation of connexins across vertebrates, this may reflect a common mechanism of gene regulation by a protein whose function was previously ascribed only to gap junctional communication. Connexins are components of gap junctions that link cells and allow intercellular communication. Here, the authors show that the Connexin 43 carboxy tail interacts with basic transcription factor-3, leading to nuclear translocation and direct regulation of N-cadherin expression and neural crest migration.

The plant leaf apoplast is a dynamic environment subject to a variety of both internal and external stimuli. In addition to being a conduit for water vapor and gas exchange involved in transpiration and photosynthesis, the apoplast also accumulates many nutrients transported from the soil as well as those produced through photosynthesis. The internal leaf also provides a protective environment for endophytic and pathogenic microbes alike. Given the diverse array of physiological processes occurring in the apoplast, it is expedient to develop methods to study its contents. Many established methods rely on vacuum infiltration of an apoplast wash solution followed by centrifugation. In this study, we describe a refined method optimized for maize (Zea mays) seedling leaves, which not only provides a simple procedure for obtaining apoplast fluid, but also allows direct calculation of apoplast hydration at the time of harvest for every sample. In addition, we describe an abbreviated method for estimating apoplast hydration if the full apoplast extraction is not necessary. Finally, we show the applicability of this optimized apoplast extraction procedure for plants infected with the maize pathogen Pantoea stewartii ssp stewartii, including the efficient isolation of bacteria previously residing in the apoplast. The approaches to establishing this method should make it generally applicable to other types of plants.