Browsing by Subject "REPAIR"

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  • Nieminen, H. J.; Gahunia, H. K.; Pritzker, K. P. H.; Ylitalo, T.; Rieppo, L.; Karhula, S. S.; Lehenkari, P.; Haeggstörm, E.; Saarakkala, S. (2017)
    Objective: Histopathological grading of osteochondral (OC) tissue is widely used in osteoarthritis (OA) research, and it is relatively common in post-surgery in vitro diagnostics. However, relying on thin tissue section, this approach includes a number of limitations, such as: (1) destructiveness, (2) sample processing artefacts, (3 ) 2D section does not represent spatial 3D structure and composition of the tissue, and (4) the final outcome is subjective. To overcome these limitations, we recently developed a contrast-enhanced mu CT (CE mu CT) imaging technique to visualize the collagenous extracellular matrix (ECM) of articular cartilage (AC). In the present study, we demonstrate that histopathological scoring of OC tissue from CE mu CT is feasible. Moreover, we establish a new, semi-quantitative OA mu CT grading system for OC tissue. Results: Pathological features were clearly visualized in AC and subchondral bone (SB) with mu CT and verified with histology, as demonstrated with image atlases. Comparison of histopathological grades (OARSI or severity (0-3)) across the characterization approaches, CE mu CT and histology, excellent (0.92, 95% CI = [0.84, 0.96], n = 30) or fair (0.50, 95% CI = [0.16, 0.74], n = 27) intra-class correlations (ICC), respectively. A new mu CT grading system was successfully established which achieved an excellent cross-method (mu CT vs histology) reader-to-reader intra-class correlation (0.78, 95% CI = [0.58, 0.89], n = 27). Conclusions: We demonstrated that histopathological information relevant to OA can reliably be obtained from CE mu CT images. This new grading system could be used as a reference for 3D imaging and analysis techniques intended for volumetric evaluation of OA pathology in research and clinical applications. (C) 2017 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International.
  • Jokela, Aleksi; Stenroos, Antti; Kosola, Jussi; Valle, Xavier; Lempainen, Lasse (2022)
    Hamstring injuries are among the most common muscle injuries. They have been reported in many different sports, such as running, soccer, track and field, rugby, and waterskiing. However, they are also present among the general population. Most hamstring injuries are mild strains, but also moderate and severe injuries occur. Hamstring injuries usually occur in rapid movements involving eccentric demands of the posterior thigh. Sprinting has been found to mainly affect the isolated proximal biceps femoris, whereas stretching-type injuries most often involve an isolated proximal injury of the semimembranosus muscle. The main cause of severe 2- or 3-tendon avulsion is a rapid forceful hip flexion with the ipsilateral knee extended. Most hamstring injuries are treated non-surgically with good results. However, there are also clear indications for surgical treatment, such as severe 2- or 3-tendon avulsions. In athletes, more aggressive recommendations concerning surgical treatment can be found. For a professional athlete, a proximal isolated tendon avulsion with clear retraction should be treated operatively regardless of the injured tendon. Surgical treatment has been found to have good results in severe injuries, especially if the avulsion injury is repaired in acute phase. In chronic hamstring injuries and recurring ruptures, the anatomical apposition of the retracted muscles is more difficult to be achieved. This review article analyses the outcomes of surgical treatment of hamstring ruptures. The present study confirms the previous knowledge that surgical treatment of hamstring tendon injuries causes good results with high satisfaction rates, both in complete and partial avulsions. Early surgical repair leads to better functional results with lower complication rates, especially in complete avulsions. KEY MESSAGEs Surgical treatment of hamstring tendon ruptures leads to high satisfaction and return to sport rates. Both complete and partial hamstring tendon ruptures have better results after acute surgical repair, when compared to cases treated surgically later. Athletes with hamstring tendon ruptures should be treated more aggressively with operative methods.
  • FINNISH Finnish Instability Should; Kukkonen, Juha; Elamo, Sami; Flinkkilä, Tapio; Paloneva, Juha; Mäntysaari, Miia; Joukainen, Antti; Lehtinen, Janne; Lepola, Vesa; Holstila, Milja; Kauko, Tommi; Aarimaa, Ville (2022)
    Objectives To compare the success rates of arthroscopic Bankart and open Latarjet procedure in the treatment of traumatic shoulder instability in young males. Design Multicentre randomised controlled trial. Setting Orthopaedic departments in eight public hospitals in Finland. Participants 122 young males, mean age 21 years (range 16-25 years) with traumatic shoulder anteroinferior instability were randomised. Interventions Arthroscopic Bankart (group B) or open Latarjet (group L) procedure. Main outcome measures The primary outcome measure was the reported recurrence of instability, that is, dislocation at 2-year follow-up. The secondary outcome measures included clinical apprehension, sports activity level, the Western Ontario Shoulder Instability Index, the pain Visual Analogue Scale, the Oxford Shoulder Instability Score, the Constant Score and the Subjective Shoulder Value scores and the progression of osteoarthritic changes in plain films and MRI. Results 91 patients were available for analyses at 2-year follow-up (drop-out rate 25%). There were 10 (21%) patients with redislocations in group B and 1 (2%) in group L, p=0.006. One (9%) patient in group B and five (56%) patients in group L returned to their previous top level of competitive sports (p=0.004) at follow-up. There was no statistically significant between group differences in any of the other secondary outcome measures. Conclusions Arthroscopic Bankart operation carries a significant risk for short-term postoperative redislocations compared with open Latarjet operation, in the treatment of traumatic anteroinferior instability in young males. Patients should be counselled accordingly before deciding the surgical treatment.
  • Sihvonen, Raine; Paavola, Mika; Malmivaara, Antti; Itälä, Ari; Joukainen, Antti; Nurmi, Heikki; Kalske, Juha; Ikonen, Anna; Järvelä, Timo; Järvinen, Tero A. H.; Kanto, Kari; Karhunen, Janne; Knifsund, Jani; Kröger, Heikki; Kääriäinen, Tommi; Lehtinen, Janne; Nyrhinen, Jukka; Paloneva, Juha; Päiväniemi, Outi; Raivio, Marko; Sahlman, Janne; Sarvilinna, Roope; Tukiainen, Sikri; Välimäki, Ville-Valtteri; Äärimaa, Ville; Toivonen, Pirjo; Järvinen, Teppo L. N.; FIDELITY Finnish Degenerative (2018)
    Objective To assess if arthroscopic partial meniscectomy (APM) is superior to placebo surgery in the treatment of patients with degenerative tear of the medial meniscus. Methods In this multicentre, randomised, participant-blinded and outcome assessor-blinded, placebo-surgery controlled trial, 146 adults, aged 35-65 years, with knee symptoms consistent with degenerative medial meniscus tear and no knee osteoarthritis were randomised to APM or placebo surgery. The primary outcome was the between-group difference in the change from baseline in the Western Ontario Meniscal Evaluation Tool (WOMET) and Lysholm knee scores and knee pain after exercise at 24 months after surgery. Secondary outcomes included the frequency of unblinding of the treatment-group allocation, participants' satisfaction, impression of change, return to normal activities, the incidence of serious adverse events and the presence of meniscal symptoms in clinical examination. Two subgroup analyses, assessing the outcome on those with mechanical symptoms and those with unstable meniscus tears, were also carried out. Results In the intention-to-treat analysis, there were no significant between-group differences in the mean changes from baseline to 24 months in WOMET score: 27.3 in the APM group as compared with 31.6 in the placebo-surgery group (between-group difference, -4.3; 95% CI, -11.3 to 2.6); Lysholm knee score: 23.1 and 26.3, respectively (-3.2; -8.9 to 2.4) or knee pain after exercise, 3.5 and 3.9, respectively (-0.4; -1.3 to 0.5). There were no statistically significant differences between the two groups in any of the secondary outcomes or within the analysed subgroups. Conclusions In this 2-year follow-up of patients without knee osteoarthritis but with symptoms of a degenerative medial meniscus tear, the outcomes after APM were no better than those after placebo surgery. No evidence could be found to support the prevailing ideas that patients with presence of mechanical symptoms or certain meniscus tear characteristics or those who have failed initial conservative treatment are more likely to benefit from APM.
  • Talman, Virpi; Kivelä, Milla Riikka (2018)
    The heart is a complex organ consisting of various cell types, each of which plays an important role in both physiological and pathophysiological conditions. The cells communicate with each other through direct cell-cell interactions and paracrine signaling, and both homotypic and heterotypic cell interactions contribute to the organized structure and proper function of the heart. Cardiomyocytes (CMs) and endothelial cells (ECs) are two of the most abundant cardiac cell types and they also play central roles in both cardiac remodeling and regeneration. The postnatal cell cycle withdrawal of CMs, which takes place within days or weeks after birth, represents the major barrier for regeneration in adult mammalian hearts, as adult CMs exhibit a very low proliferative capacity. Recent evidence highlights the importance of ECs not only as the most abundant cell type in the heart but also as key players in post-infarction remodeling and regeneration. In this MiniReview, we focus on blood vascular ECs and CMs and their roles and interactions in cardiac physiology and pathologies, with a special emphasis on cardiac regeneration. We summarize the known mediators of the bidirectional CM-EC interactions and discuss the related recent advances in the development of therapies aiming to promote heart repair and regeneration targeting these two cell types.
  • Mantere, Tuomo; Tervasmäki, Anna; Nurmi, Anna; Rapakko, Katrin; Kauppila, Saila; Tang, Jiangbo; Schleutker, Johanna; Kallioniemi, Anne; Hartikainen, Jaana M.; Mannermaa, Arto; Nieminen, Pentti; Hanhisalo, Riitta; Lehto, Sini; Suvanto, Maija; Grip, Mervi; Jukkola-Vuorinen, Arja; Tengström, Maria; Auvinen, Päivi; Kvist, Anders; Borg, Åke; Blomqvist, Carl; Aittomäki, Kristiina; Greenberg, Roger A.; Winqvist, Robert; Nevanlinna, Heli; Pylkäs, Katri (2017)
    Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578-1565) and controls (n = 337-1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts.c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.
  • Jensen, Annette Schophuus; Jorgensen, Troels Hojsgaard; Christersson, Christina; Nagy, Edit; Sinisalo, Juha; Furenas, Eva; Gjesdal, Ola; Eriksson, Peter; Vejlstrup, Niels; Johansson, Bengt; Hlebowicz, Joanna; Greve, Gottfried; Dellborg, Mikael; Skulstad, Helge; Kvidal, Per; Jokinen, Eero; Sairanen, Heikki; Thilen, Ulf; Sondergaard, Lars (2022)
    Background Little is known about the cause of death (CoD) in patients with transposition of the great arteries palliated with a Mustard or Senning procedure. The aim was to describe the CoD for patients with the Mustard and Senning procedure during short- (20 years) follow-up after the operation. Methods and Results This is a retrospective, descriptive multicenter cohort study including all Nordic patients (Denmark, Finland, Norway, and Sweden) who underwent a Mustard or Senning procedure between 1967 and 2003. Patients who died within 30 days after the index operation were excluded. Among 968 patients with Mustard/Senning palliated transposition of the great arteries, 814 patients were eligible for the study, with a mean follow-up of 33.6 years. The estimated risk of all-cause mortality reached 36.0% after 43 years of follow-up, and the risk of death was highest among male patients as compared with female patients (P=0.004). The most common CoD was sudden cardiac death (SCD), followed by heart failure/heart transplantation accounting for 29% and 27%, respectively. During short-, mid-, and long-term follow-up, there was a change in CoD with SCD accounting for 23.7%, 46.6%, and 19.0% (P=0.002) and heart failure/heart transplantation 18.6%, 22.4%, and 46.6% (P=0.0005), respectively. Conclusions Among patients corrected with Mustard or Senning transposition of the great arteries, the most common CoD is SCD followed by heart failure/heart transplantation. The CoD changes as the patients age, with SCD as the most common cause in adolescence and heart failure as the dominant cause in adulthood. Furthermore, the risk of all-cause mortality, SCD, and death attributable to heart failure or heart transplantation was increased in men >10 years after the Mustard/Senning operation.
  • Cavalli, Emma; Levinson, Clara; Hertl, Matthias; Broguiere, Nicolas; Brück, Oscar; Mustjoki, Satu; Gerstenberg, Anja; Weber, Daniel; Salzmann, Gian; Steinwachs, Matthias; Barreto, Goncalo; Zenobi-Wong, Marcy (2019)
    Treating cartilage injuries and degenerations represents an open surgical challenge. The recent advances in cell therapies have raised the need for a potent off-the-shelf cell source. Intra-articular injections of TGF-beta transduced polydactyly chondrocytes have been proposed as a chronic osteoarthritis treatment but despite promising results, the use of gene therapy still raises safety concerns. In this study, we characterized infant, polydactyly chondrocytes during in vitro expansion and chondrogenic redifferentiation. Polydactyly chondrocytes have a steady proliferative rate and re-differentiate in 3D pellet culture after up to five passages. Additionally, we demonstrated that polydactyly chondrocytes produce cartilage-like matrix in a hyaluronan-based hydrogel, namely transglutaminase cross-linked hyaluronic acid (HA-TG). We utilized the versatility of TG cross-linking to augment the hydrogels with heparin moieties. The heparin chains allowed us to load the scaffolds with TGF-beta 1 which induced cartilage-like matrix deposition both in vitro and in vivo in a subcutaneous mouse model. This strategy introduces the possibility to use infant, polydactyly chondrocytes for the clinical treatment of joint diseases.
  • Tuomenoksa, Asta; Pajo, Kati; Klippi, Anu (2016)
    This study applies conversation analysis to compare everyday conversation samples between a person with aphasia (PWA) and a familiar communication partner (CP) before and after intensive language-action therapy (ILAT). Our analysis concentrated on collaborative repair sequences with the assumption that impairment-focused therapy would translate into a change in the nature of trouble sources, which engender collaborative repair action typical of aphasic conversation. The most frequent repair initiation technique used by the CP was candidate understandings. The function of candidate understandings changed from addressing specific trouble sources pre-ILAT to concluding longer stretches of the PWA's talk post-ILAT. Alongside with these findings, we documented a clinically significant increase in the Western Aphasia Battery's aphasia quotient post-ILAT. Our results suggest that instead of mere frequency count of conversational behaviours, examining the type and function of repair actions might provide insight into therapy-related changes in conversation following impairment-focused therapy.
  • Zyla, Joanna; Kabacik, Sylwia; O'Brien, Grainne; Wakil, Salma; Al-Harbi, Najla; Kaprio, Jaakko; Badie, Christophe; Polanska, Joanna; Alsbeih, Ghazi (2019)
    Individual variability in response to radiation exposure is recognised and has often been reported as important in treatment planning. Despite many efforts to identify biomarkers allowing the identification of radiation sensitive patients, it is not yet possible to distinguish them with certainty before the beginning of the radiotherapy treatment. A comprehensive analysis of genome-wide single-nucleotide polymorphisms (SNPs) and a transcriptional response to ionising radiation exposure in twins have the potential to identify such an individual. In the present work, we investigated SNP profile and CDKN1A gene expression in blood T lymphocytes from 130 healthy Caucasians with a complex level of individual kinship (unrelated, mono- or dizygotic twins). It was found that genetic variation accounts for 66% (95% CI 37-82%) of CDKN1A transcriptional response to radiation exposure. We developed a novel integrative multi-kinship strategy allowing investigating the role of genome-wide polymorphisms in transcriptomic radiation response, and it revealed that rs205543 (ETV6 gene), rs2287505 and rs1263612 (KLF7 gene) are significantly associated with CDKN1A expression level. The functional analysis revealed that rs6974232 (RPA3 gene), involved in mismatch repair (p value = 9.68e-04) as well as in RNA repair (p value = 1.4e-03) might have an important role in that process. Two missense polymorphisms with possible deleterious effect in humans were identified: rs1133833 (AKIP1 gene) and rs17362588 (CCDC141 gene). In summary, the data presented here support the validity of this novel integrative data analysis strategy to provide insights into the identification of SNPs potentially influencing radiation sensitivity. Further investigations in radiation response research at the genomic level should be therefore continued to confirm these findings.
  • Pätilä , Tommi; Miyagawa, Shigeru; Imanishi, Yukiko; Fukushima, Satsuki; Siltanen, Antti; Mervaala, Eero; Kankuri, Esko; Harjula, Ari; Sawa, Yoshiki (2015)
    Although cell therapy of the failing heart by intramyocardial injections of myoblasts to results in regenerative benefit, it has also been associated with undesired and prospectively fatal arrhythmias. We hypothesized that intramyocardial injections of myoblasts could enhance inflammatory reactivity and facilitate electrical cardiac abnormalities that can be reduced by epicardial myoblast sheet delivery. In a rat model of ischemic heart failure, myoblast therapy either by intramyocardial injections or epicardial cell sheets was given 2 weeks after occlusion of the coronary artery. Ventricular premature contractions (VPCs) were assessed, using an implanted three-lead electrocardiograph at 1, 7, and 14 days after therapy, and 16-point epicardial electropotential mapping (EEPM) was used to evaluate ventricular arrhythmogenicity under isoproterenol stress. Cardiac functioning was assessed by echocardiography. Both transplantation groups showed therapeutic benefit over sham therapy. However, VPCs were more frequent in the Injection group on day 1 and day 14 after therapy than in animals receiving epicardial or sham therapy (p <0.05 and p <0.01, respectively). EEPM under isoproterenol stress showed macroreentry at the infarct border area, leading to ventricular tachycardias in the Injection group, but not in the myoblast sheet- or sham-treated groups (p = 0.045). Both transplantation types modified the myocardial cytokine expression profile. In animals receiving epicardial myoblast therapy, selective reductions in the expressions of interferon gamma, interleukin (IL)-1 beta and IL12 were observed, accompanied by reduced infiltration of inflammatory CD11b- and CD68-positive leukocytes, compared with animals receiving myoblasts as intramyocardial injections. Intramyocardial myoblast delivery was associated with enhanced inflammatory and immunomodulatory reactivity and increased frequency of VPCs. In comparison to intramyocardial injection, the epicardial route may serve as the preferred method of skeletal myoblast transplantation to treat heart failure.
  • Rintala, Risto J. (2016)
    Persistent cloaca remains a challenge for pediatric surgeons and urologists. Reconstructive surgery of cloacal malformations aims to repair the anorectum, urinary tract, and genital organs, and achieve fecal and urinary continence as well as functional genital tract capable for sexual activity and pregnancy. Unfortunately, even in most experienced hands these goals are not always accomplished. The endpoint of the functional development of bowel, urinary, and genital functions is the completion of patient's growth and sexual maturity. It is unlikely that there will be any significant functional improvement beyond these time points. About half of the patients with cloaca attain fecal and urinary continence after their growth period. The remaining half stay clean or dry by adjunctive measures such as bowel management by enemas or ACE channel, and continent urinary diversion or intermittent catheterization. Problems related to genital organs such as obstructed menstruations, amenorrhea, and introitus stenosis are common and often require secondary surgery. Encouragingly, most adolescent and adult patients are capable of sexual life despite often complex vaginal primary and secondary reconstructions. Also, cloacal malformation does not preclude pregnancies, although they still are quite rare. Pregnant patients with cloaca require special care and follow-up to guarantee uncomplicated pregnancy and preservation of anorectal and urinary functions. Cesarean section is recommended for cloaca patients. The self-reported quality of life of cloaca patients appears to be comparable to that of female patients with less complex anorectal malformations. (C) 2016 Elsevier Inc. All rights reserved.
  • Thesleff, Tuomo; Lehtimaki, Kai; Niskakangas, Tero; Huovinen, Sanna; Mannerström, Bettina; Miettinen, Susanna; Seppänen-Kaijansinkko, Riitta; Ohman, Juha (2017)
    Several alternative techniques exist to reconstruct skull defects. The complication rate of the cranioplasty procedure is high and the search for optimal materials and techniques continues. To report long-term results of patients who have received a cranioplasty using autologous adipose-derived stem cells (ASCs) seeded on beta-tricalcium phosphate (betaTCP) granules. Between 10/2008 and 3/2010, five cranioplasties were performed (four females, one male; average age 62.0 years) using ASCs, betaTCP granules and titanium or resorbable meshes. The average defect size was 8.1 x 6.7 cm(2). Patients were followed both clinically and radiologically. The initial results were promising, with no serious complications. Nevertheless, in the long-term follow-up, three of the five patients were re-operated due to graft related problems. Two patients showed marked resorption of the graft, which led to revision surgery. One patient developed a late infection (7.3 years post-operative) that required revision surgery and removal of the graft. One patient had a successfully ossified graft, but was re-operated due to recurrence of the meningioma 2.2 years post-operatively. One patient had an uneventful clinical follow-up, and the cosmetic result is satisfactory, even though skull x-rays show hypodensity in the borders of the graft. Albeit no serious adverse events occurred, the 6-year follow-up results of the five cases are unsatisfactory. The clinical results are not superior to results achieved by conventional cranial repair methods. The use of stem cells in combination with betaTCP granules and supporting meshes in cranial defect reconstruction need to be studied further before continuing with clinical trials.
  • Haapaniemi, Emma; Botla, Sandeep; Persson, Jenna; Schmierer, Bernhard; Taipale, Jussi (2018)
    Here, we report that genome editing by CRISPR-Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR-Cas9.
  • Salonius, Eve; Rieppo, Lassi; Nissi, Mikko J.; Pulkkinen, Hertta J.; Brommer, Harold; Bruenott, Anne; Silvast, Tuomo S.; Van Weeren, P. Rene; Muhonen, Virpi; Brama, Pieter A. J.; Kiviranta, Ilkka (2019)
    Aim: The horse joint, due to its similarity with the human joint, is the ultimate model for translational articular cartilage repair studies. This study was designed to determine the critical size of cartilage defects in the equine carpus and serve as a benchmark for the evaluation of new cartilage treatment options. Material and Methods: Circular full-thickness cartilage defects with a diameter of 2, 4, and 8 mm were created in the left middle carpal joint and similar osteochondral (3.5 mm in depth) defects in the right middle carpal joint of 5 horses. Spontaneously formed repair tissue was examined macroscopically, with MR and mu CT imaging, polarized light microscopy, standard histology, and immunohistochemistry at 12 months. Results: Filling of 2 mm chondral defects was good (77.8 +/- 8.5%), but proteoglycan depletion was evident in Safranin-O staining and gadolinium-enhanced MRI (T-1Gd). Larger chondral defects showed poor filling (50.6 +/- 2.7% in 4 mm and 31.9 +/- 7.3% in 8 mm defects). Lesion filling in 2, 4, and 8 mm osteochondral defects was 82.3 +/- 3.0%, 68.0 +/- 4.6% and 70.8 +/- 15.4%, respectively. Type II collagen staining was seen in 9/15 osteochondral defects but only in 1/15 chondral defects. Subchondral bone pathologies were evident in 14/15 osteochondral samples but only in 5/15 chondral samples. Although osteochondral lesions showed better neotissue quality than chondral lesions, the overall repair was deemed unsatisfactory because of the subchondral bone pathologies. Conclusion: We recommend classifying 4 mm as critical osteochondral lesion size and 2 mm as critical chondral lesion size for cartilage repair research in the equine carpal joint model.
  • Deppermann, Arnulf; De Stefani, Elwys (2019)
    This article examines a recurrent format that speakers use for defining ordinary expressions or technical terms. Drawing on data from four different languages-Flemish, French, German, and Italian-it focuses on definitions in which a definiendum is first followed by a negative definitional component ('definiendum is not X'), and then by a positive definitional component ('definiendum is Y'). The analysis shows that by employing this format, speakers display sensitivity towards a potential meaning of the definiendum that recipients could have taken to be valid. By negating this meaning, speakers discard this possible, yet unintended understanding. The format serves three distinct interactional purposes: (a) it is used for argumentation, e.g. in discussions and political debates, (b) it works as a resource for imparting knowledge, e.g. in expert talk and instructions, and (c) it is employed, in ordinary conversation, for securing the addressee's correct understanding of a possibly problematic expression. The findings contribute to our understanding of how epistemic claims and displays relate to the turn-constructional and sequential organization of talk. They also show that the much quoted 'problem of meaning' is, first and foremost, a participant's problem. (C) 2018 Elsevier B.V. All rights reserved.
  • Krivanek, Jan; Soldatov, Ruslan A.; Kastriti, Maria Eleni; Chontorotzea, Tatiana; Herdina, Anna Nele; Petersen, Julian; Szarowska, Bara; Landova, Marie; Matejova, Veronika Kovar; Holla, Lydie Izakovicova; Kuchler, Ulrike; Zdrilic, Ivana Vidovic; Vijaykumar, Anushree; Balic, Anamaria; Marangoni, Pauline; Klein, Ophir D.; Yianni, Val; Neves, Vitor C. M.; Sharpe, Paul T.; Harkany, Tibor; Metscher, Brian D.; Bajenoff, Marc; Mina, Mina; Fried, Kaj; Kharchenko, Peter V.; Adameyko, Igor (2020)
    Understanding cell types and mechanisms of dental growth is essential for reconstruction and engineering of teeth. Therefore, we investigated cellular composition of growing and non-growing mouse and human teeth. As a result, we report an unappreciated cellular complexity of the continuously-growing mouse incisor, which suggests a coherent model of cell dynamics enabling unarrested growth. This model relies on spatially-restricted stem, progenitor and differentiated populations in the epithelial and mesenchymal compartments underlying the coordinated expansion of two major branches of pulpal cells and diverse epithelial subtypes. Further comparisons of human and mouse teeth yield both parallelisms and differences in tissue heterogeneity and highlight the specifics behind growing and non-growing modes. Despite being similar at a coarse level, mouse and human teeth reveal molecular differences and species-specific cell subtypes suggesting possible evolutionary divergence. Overall, here we provide an atlas of human and mouse teeth with a focus on growth and differentiation. Unlike human teeth, mouse incisors grow throughout life, based on stem and progenitor cell activity. Here the authors generate single cell RNA-seq comparative maps of continuously-growing mouse incisor, non-growing mouse molar and human teeth, combined with lineage tracing to reveal dental cell complexity.
  • Tauriainen, Asta; Hyvarinen, Anna; Raitio, Arimatias; Sankilampi, Ulla; Gärding, Mikko; Tauriainen, Tuomas; Helenius, Ilkka; Vanamo, Kari (2021)
  • Välimäki, Mika J.; Tölli, Maria A.; Kinnunen, Sini M.; Aro, Jani; Serpi, Raisa; Pohjolainen, Lotta; Talman, Virpi; Poso, Antti; Ruskoaho, Heikki J. (2017)
    Transcription factors are pivotal regulators of gene transcription, and many diseases are associated with the deregulation of transcriptional networks. In the heart, the transcription factors GATA4 and NKX2-5 are required for cardiogenesis. GATA4 and NKX2-5 interact physically, and the activation of GATA4, in cooperation with NKX2-5, is essential for stretch-induced cardiomyocyte hypertrophy. Here, we report the identification of four small molecule families that either inhibit or enhance the GATA4-NKX2-5 transcriptional synergy. A fragment-based screening, reporter gene assay, and pharmacophore search were utilized for the small molecule screening, identification, and optimization. The compounds modulated the hypertrophic agonist-induced cardiac gene expression. The most potent hit compound, N-[4-(diethylamino)phenyl]-5-methyl-3-phenylisoxazole-4-carboxamide (3, IC50 = 3 mu M), exhibited no activity on the protein kinases involved in the regulation of GATA4 phosphorylation. The identified and chemically and biologically characterized active compound, and its derivatives may provide a novel class of small molecules for modulating heart regeneration.