Covalent Modification of Synthetic Hydrogels with Bioactive Proteins via Sortase-Mediated Ligation

Synthetic extracellular matrices are widely used in regenerative medicine and as tools in building in vitro physiological culture models. Synthetic hydrogels display advantageous physical properties, but are challenging to modify with large peptides or proteins. Here, a facile, mild enzymatic postgrafting approach is presented. Sortase-mediated ligation was used to conjugate human epidermal growth factor fused to a GGG ligation motif (GGG-EGF) to poly(ethylene glycol) (PEG) hydrogels containing the sortase LPRTG substrate. The reversibility of the sortase reaction was then exploited to cleave tethered EGF from the hydrogels for analysis. Analyses of the reaction supernatant and the postligation hydrogels showed that the amount of tethered EGF increases with increasing LPRTG in the hydrogel or GGG-EGF in the supernatant. Sortase-tethered EGF was biologically active, as demonstrated by stimulation of DNA synthesis in primary human hepatocytes and endometrial epithelial cells. The simplicity, specificity, and reversibility of sortase-mediated ligation and cleavage reactions make it an attractive approach for modification of hydrogels.National Institutes of Health (U.S.) (5R01EB010246)National Institutes of Health (U.S.) (5UH2TR000496)Institute for Collaborative Biotechnologies (W911NF-09-0001)National Institutes of Health (U.S.) (1T32GM008334)United States. Defense Advanced Research Projects Agency. Microphysiological Systems Program (W911NF-12-2-0039)Begg New Horizon Fund for Undergraduate Research at MITNational Institutes of Health (U.S.) (Biotechnology Training Program NIH/NIGMS 5T32GM008334))Biophysical Instrumentation FacilityVirginia and Daniel K. Ludwig Graduate FellowshipSwiss National Science Foundation (Postdoctoral Fellowship

TRPV4 mediates cell damage induced by hyperphysiological compression and regulates COX2/PGE2 in intervertebral discs

Background Aberrant mechanical loading of the spine causes intervertebral disc (IVD) degeneration and low back pain. Current therapies do not target the mediators of the underlying mechanosensing and mechanotransduction pathways, as these are poorly understood. This study investigated the role of the mechanosensitive transient receptor potential vanilloid 4 (TRPV4) ion channel in dynamic compression of bovine nucleus pulposus (NP) cells in vitro and mouse IVDs in vivo. Methods Degenerative changes and the expression of the inflammatory mediator cyclooxygenase 2 (COX2) were examined histologically in the IVDs of mouse tails that were dynamically compressed at a short repetitive hyperphysiological regime (vs sham). Bovine NP cells embedded in an agarose-collagen hydrogel were dynamically compressed at a hyperphysiological regime in the presence or absence of the selective TRPV4 antagonist GSK2193874. Lactate dehydrogenase (LDH) and prostaglandin E2 (PGE2) release, as well as phosphorylation of mitogen-activated protein kinases (MAPKs), were analyzed. Degenerative changes and COX2 expression were further evaluated in the IVDs of trpv4-deficient mice (vs wild-type; WT). Results Dynamic compression caused IVD degeneration in vivo as previously shown but did not affect COX2 expression. Dynamic compression significantly augmented LDH and PGE2 releases in vitro, which were significantly reduced by TRPV4 inhibition. Moreover, TRPV4 inhibition during dynamic compression increased the activation of the extracellular signal-regulated kinases 1/2 (ERK) MAPK pathway by 3.13-fold compared to non-compressed samples. Trpv4-deficient mice displayed mild IVD degeneration and decreased COX2 expression compared to WT mice. Conclusions TRPV4 therefore regulates COX2/PGE2 and mediates cell damage induced by hyperphysiological dynamic compression, possibly via ERK. Targeted TRPV4 inhibition or knockdown might thus constitute promising therapeutic approaches to treat patients suffering from IVD pathologies caused by aberrant mechanical stress

Effects of Early Life Stress on Bone Homeostasis in Mice and Humans

Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (μCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies

Irony Detection in Twitter: The Role of Affective Content

© ACM 2016. This is the author's version of the work. It is posted here for your personal use. Not for redistribution. The definitive Version of Record was published in ACM Transactions on Internet Technology, Vol. 16. http://dx.doi.org/10.1145/2930663.[EN] Irony has been proven to be pervasive in social media, posing a challenge to sentiment analysis systems. It is a creative linguistic phenomenon where affect-related aspects play a key role. In this work, we address the problem of detecting irony in tweets, casting it as a classification problem. We propose a novel model that explores the use of affective features based on a wide range of lexical resources available for English, reflecting different facets of affect. Classification experiments over different corpora show that affective information helps in distinguishing among ironic and nonironic tweets. Our model outperforms the state of the art in almost all cases.The National Council for Science and Technology (CONACyT Mexico) has funded the research work of Delia Irazu Hernandez Farias (Grant No. 218109/313683 CVU-369616). The work of Viviana Patti was partially carried out at the Universitat Politecnica de Valencia within the framework of a fellowship of the University of Turin cofunded by Fondazione CRT (World Wide Style Program 2). The work of Paolo Rosso has been partially funded by the SomEMBED TIN2015-71147-C2-1-P MINECO research project and by the Generalitat Valenciana under the grant ALMAMATER (PrometeoII/2014/030).Hernandez-Farias, DI.; Patti, V.; Rosso, P. (2016). Irony Detection in Twitter: The Role of Affective Content. ACM Transactions on Internet Technology. 16(3):19:1-19:24. https://doi.org/10.1145/2930663S19:119:24163Rob Abbott, Marilyn Walker, Pranav Anand, Jean E. Fox Tree, Robeson Bowmani, and Joseph King. 2011. 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Clinical Features, Cardiovascular Risk Profile, and Therapeutic Trajectories of Patients with Type 2 Diabetes Candidate for Oral Semaglutide Therapy in the Italian Specialist Care

Introduction: This study aimed to address therapeutic inertia in the management of type 2 diabetes (T2D) by investigating the potential of early treatment with oral semaglutide. Methods: A cross-sectional survey was conducted between October 2021 and April 2022 among specialists treating individuals with T2D. A scientific committee designed a data collection form covering demographics, cardiovascular risk, glucose control metrics, ongoing therapies, and physician judgments on treatment appropriateness. Participants completed anonymous patient questionnaires reflecting routine clinical encounters. The preferred therapeutic regimen for each patient was also identified. Results: The analysis was conducted on 4449 patients initiating oral semaglutide. The population had a relatively short disease duration (42%  60% of patients, and more often than sitagliptin or empagliflozin. Conclusion: The study supports the potential of early implementation of oral semaglutide as a strategy to overcome therapeutic inertia and enhance T2D management

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Old and new oral anticoagulants : food, herbal medicines and drug interactions

The most commonly prescribed oral anticoagulants worldwide are the vitamin K antagonists (VKAs) such as warfarin. Factors affecting the pharmacokinetics of VKAs are important because deviations from their narrow therapeutic window can result in bleedings due to over-anticoagulation or thrombosis because of under-anticoagulation. In addition to pharmacodynamic interactions (e.g., augmented bleeding risk for concomitant use of NSAIDs), interactions with drugs, foods, herbs, and over-the-counter medications may affect the risk/benefit ratio of VKAs. Direct oral anticoagulants (DOACs) including Factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) and thrombin inhibitor (dabigatran) are poised to replace warfarin. Phase-3 studies and real-world evaluations have established that the safety profile of DOACs is superior to those of VKAs. However, some pharmacokinetic and pharmacodynamic interactions are expected. Herein we present a critical review of VKAs and DOACs with focus on their potential for interactions with drugs, foods, herbs and over-the-counter medications

Identification of the TRPV4 ion channel as a mechanotransducer and therapeutic target in low back pain

Low back pain (LBP) is the leading cause of disability worldwide and a huge global socio-economic burden. The costs related to LBP are projected to further increase in the coming decades due to the growth and aging of the global population. Degenerative disc disease, which is characterized by intervertebral disc (IVD) degeneration, inflammation, and nerve ingrowth, principally contributes to LBP. One of the main contributors to IVD degeneration is excessive or aberrant mechanical loading. Current treatments of LBP, including physical, psychological, pharmacological, and surgical approaches, have unclear mechanisms of action, low effect sizes, and are not beneficial in the long term. Targeted therapeutic strategies in preclinical development, such as molecular and gene therapy, selectively address the biological changes that occur in IVD degeneration. Nevertheless, despite the mechanical nature of LBP, mechanotransduction pathways are currently not targeted. This is mainly due to the very limited information on mechanosensing and mechanotransduction mechanisms in the IVD. Transient receptor potential (TRP) ion channels are promising therapeutic targets to treat LBP, as they can sense and transduce a variety of signals, including mechanical stress. The TRP vanilloid 4 (TRPV4) channel is especially interesting, as it was shown to mediate mechanical, inflammatory and pain signals. Its clinical potential is further highlighted by ongoing preclinical and clinical trials. The overall goal of this thesis was to investigate the potential role of TRPV4 in mediating hyperphysiological mechanical signals in the IVD, and its relevance as a therapeutic target to treat LBP. As a first step towards the investigation of TRPV4, we developed a novel in vitro compression model for mechanotransduction studies. Agarose-collagen composite hydrogels were fabricated and characterized in terms of material and mechanical properties. Bovine nucleus pulposus (NP) cell phenotype and mechanotransduction ability after dynamic compression were further analyzed. Agarose-collagen composite hydrogels combined the mechanical strength of agarose with the biofunctionality of collagen, which enhanced cell adhesion and the activation of focal adhesion kinases. Moreover, agarose-collagen scaffolds recapitulated the extracellular matrix (ECM) of the IVD, with their non-fibrillar matrix and collagen fibers, and allowed the exploration of mechanotransduction mechanisms in a reproducible system. In a second study, NP cell-laden agarose-collagen hydrogels and a mouse model were used to investigate the role of TRPV4 in transducing hyperphysiological dynamic compression. Degenerative changes and the expression of the inflammatory mediator cyclooxygenase 2 (COX2) were examined in mouse IVDs that were dynamically compressed at a hyperphysiological regime (versus sham). Cell damage and inflammation (prostaglandin E2 (PGE2) release) were measured in bovine NP cells embedded in agarose-collagen hydrogels and dynamically compressed at a hyperphysiological regime with or without TRPV4 inhibition. The activation of the mitogen-activated protein kinase (MAPK) pathways was analyzed. Finally, degenerative changes and COX2 expression were further evaluated in the IVDs of trpv4 knockout (KO) mice (versus wild-type). TRPV4 was shown to regulate the COX2/PGE2 inflammatory factors and mediate cell damage induced by hyperphysiological dynamic compression, possibly via the extracellular signal-regulated kinases 1/2 (ERK) pathway. In a final step, we investigated the role of TRPV4 as a transducer of hyperphysiological cyclic stretching and a potential therapeutic target. Human primary annulus fibrosus (AF) cells were seeded on silicone chambers and cyclically stretched at a hyperphysiological magnitude in the presence or absence of a TRPV4 inhibitor. Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 TRPV4 KO AF cells were generated, hyperphysiologically stretched, and compared to control cells. Gene and protein expression of inflammatory and catabolic mediators, as well as activation of MAPK pathways, were analyzed. This study identified TRPV4 as a mediator of stretch-induced inflammation in human AF cells. Moreover, it revealed TRPV4 pharmacological inhibition and gene editing as potential future therapeutic approaches to rescue mechanoflammation. In this thesis, in vitro and in vivo models of hyperphysiological compression and stretching were established and used to identify TRPV4 as mechanotransducer and therapeutic target in the IVD. A novel in vitro compression model was developed to mimic the ECM of the IVD and other native tissues composed of non-fibrillar matrix and collagens, and to investigate their mechanotransduction mechanisms. This system was instrumental to investigate the function of TRPV4 in IVD cells. The novel findings obtained with this model, together with those obtained in the mouse compression model and the stretching system demonstrate that TRPV4 mediates a mechanism leading from mechanical hyperphysiological loading to IVD degeneration and inflammation, which eventually lead to chronic LBP. TRPV4 modulation might thus constitute a promising therapeutic strategy to treat patients suffering from IVD pathologies caused by aberrant mechanical stress. Future studies should clarify the exact mechanism of action of TRPV4 inhibition and gene editing and examine their potential to mitigate chronic inflammation and LBP in preclinical and clinical trials

Cardiac Regenerative Medicine: The Potential of a New Generation of Stem Cells

Cardiac stem cell therapy holds great potential to prompt myocardial regeneration in patients with ischemic heart disease. The selection of the most suitable cell type is pivotal for its successful application. Various cell types, including crude bone marrow mononuclear cells, skeletal myoblast, and hematopoietic and endothelial progenitors, have already advanced into the clinical arena based on promising results from different experimental and preclinical studies. However, most of these so-called first-generation cell types have failed to fully emulate the promising preclinical data in clinical trials, resulting in heterogeneous outcomes and a critical lack of translation. Therefore, different next-generation cell types are currently under investigation for the treatment of the diseased myocardium. This review article provides an overview of current stem cell therapy concepts, including the application of cardiac stem (CSCs) and progenitor cells (CPCs) and lineage commitment via guided cardiopoiesis from multipotent cells such as mesenchymal stem cells (MSCs) or pluripotent cells such as embryonic and induced pluripotent stem cells. Furthermore, it introduces new strategies combining complementary cell types, such as MSCs and CSCs/CPCs, which can yield synergistic effects to boost cardiac regeneration

Translational cardiac stem cell therapy: advancing from first-generation to next-generation cell types

Acute myocardial infarction and chronic heart failure rank among the major causes of morbidity and mortality worldwide. Except for heart transplantation, current therapy options only treat the symptoms but do not cure the disease. Stem cell-based therapies represent a possible paradigm shift for cardiac repair. However, most of the first-generation approaches displayed heterogeneous clinical outcomes regarding efficacy. Stemming from the desire to closely match the target organ, second-generation cell types were introduced and rapidly moved from bench to bedside. Unfortunately, debates remain around the benefit of stem cell therapy, optimal trial design parameters, and the ideal cell type. Aiming at highlighting controversies, this article provides a critical overview of the translation of first-generation and second-generation cell types. It further emphasizes the importance of understanding the mechanisms of cardiac repair and the lessons learned from first-generation trials, in order to improve cell-based therapies and to potentially finally implement cell-free therapies