Sites Of Calcification Research Articles

Postfunctionalization of biological valve leaflets with a polyphenol network and anticoagulant recombinant humanized type III collagen for improved anticoagulation and endothelialization.

Almost all commercial bioprosthetic heart valves (BHVs) are crosslinked with glutaraldehyde (GLUT); however, issues such as immune responses, calcification, delayed endothelialization, and especially severe thrombosis threaten the service lifespan of BHVs. Surface modification is expected to impart GLUT-crosslinked BHVs with versatility to optimize service performance. Here, a postfunctionalization strategy was established for GLUT-crosslinked BHVs, which were firstly modified with metal-phenolic networks (MPNs) to shield the exposed calcification site, and then anticoagulant recombinant humanized type III collagen (rhCOLIII) was immobilized to endow them with long-term antithrombogenicity and enhanced endothelialization properties. The postfunctionalization coating exhibited promising mechanical properties and resistance to enzymatic degradation capability resembling that of GLUT-crosslinked porcine pericardium (GLUT-PP). With the introduction of meticulously tailored rhCOLIII, the anti-coagulation and re-endothelialization properties of TA/Fe-rhCOLIII were significantly improved. Furthermore, the mild inflammatory response and reduced calcification were evidenced in TA/Fe-rhCOLIII by subcutaneous implantation. In conclusion, the efficacy of the proposed strategy combining anti-inflammatory MPNs and multifunctional rhCOLIII to improve anticoagulation, reduce the inflammatory response, and ultimately achieve rapid reendothelialization was supported by both ex vivo and in vivo experiments. Altogether, the current findings may provide a simple strategy for enhancing the service function of BHVs after implantation and show great potential in clinical applications.

3-Dimensional Images of Mitral Annulus Perforation: An Alien’s Mouth

In this clinical vignette, we describe a case of a patient with windsock-like posterior mitral annulus perforation at the site of annular calcification caused by infective endocarditis. Three-dimensional transesophageal images of the perforation resembling an “alien’s mouth” are very striking for how 3-dimensional imaging can improve visualization of anatomy of the heart. (Level of Difficulty: Intermediate.)

EDTA Combined with C-Pilot Files and Microultrasound for Root Canal Calcification: Dredging Effect and Safety Analysis.

Objective This paper discussed the dredging effect and safety of ethylenediaminetetraacetic acid (EDTA) combined with C-pilot files and microultrasound (mUS) on root canal calcification. Methods From October 2021 to January 2022, 132 patients with calcified root canals treated in our hospital were selected as the research subjects. Among them, 64 cases who received EDTA combined with C-pilot Files and mUS plus ultrasonic instruments to dredge calcified root canals were regarded as the research group (RG), and another 68 cases given ultrasonic instruments plus C-pilot files were regarded as the control group (CG). The root canal dredging time was recorded, and the dredging success rate and total success rate of different tooth positions and calcification sites were compared between groups. The clinical efficacy was assessed 6 months after treatment. Pain severity was evaluated by the Pain Intensity Numerical Rating Scale (PI-NRS) before (T0), during (T1), and after treatment (T2). Finally, the incidence of adverse reactions within one week after treatment was counted. Results RG was observed with statistically higher success rates of root canal dredging in different tooth positions and calcified sites than CG (P < 0.05). Besides, the total effective rate of treatment was 92.19% in RG, which was also higher compared with CG, while the root canal dredging time in RG was shorter than that in CG (P < 0.05). Increased NRS scores were found in both groups at T1, and the score in RG was significantly lower compared with that in CG. At T2, both groups showed a lower PI-NRS score than T1 but higher than T0, and the score at T2 was also lower in RG as compared to CG (P < 0.05). Moreover, the reduced incidence of adverse reactions were observed in RG compared with CG (P < 0.05). Conclusions EDTA combined with C-pilot files and mUS can effectively improve the dredging success rate of root canals obstructed by calcification, shorten the dredging time, and improve patient comfort, which is an effective method for clinical dredging of calcification obstructed root canals.

Heterogeneous plaque geometry is associated with major adverse cardiovascular events

Abstract Objectives To determine whether coronary artery plaque-lumen geometry predicts major adverse cardiovascular events (MACE), and incorporating geometric measures enhances risk stratification from intravascular imaging. Background Prospective studies show that only a minority of plaques with higher-risk features result in future MACE, indicating the need for more predictive markers of plaque vulnerability. Plaques show heterogeneous structures and plaque-lumen geometry, both of which can promote high plaque structural stress (PSS); however, the relationships between geometric heterogeneity and MACE or PSS are unknown. Methods We examined plaque-lumen curvature, irregularity, lumen aspect ratio (LAR), roughness, PSS and their longitudinal heterogeneity (Figure 1A) in 35 non-culprit lesions (NCL) associated with MACE and 66 propensity-matched no-MACE NCL from the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study. Causes of heterogeneous geometry and PSS were examined using a separate group of co-registered virtual histology-intravascular ultrasound (VH-IVUS) and optical coherence tomography (OCT) images (n=53 plaques). Results Plaque geometry heterogeneity indices (HI) were increased in NCL MACE vs. no-MACE lesions across the whole plaque and peri-minimal luminal area (MLA) segments (HI curvature: p=0.002; HI irregularity: p&amp;lt;0.001; HI LAR: p=0.001; HI roughness: p=0.002). Peri-MLA HI roughness was an independent predictor of future MACE (hazard ratio: 3.69, p&amp;lt;0.001) (Figure 1B). Inclusion of HI roughness improved identification of NCLs leading to MACE in VH-defined thin-cap fibroatheromas (VH-TCFA, p=0.005), MLA ≤4mm2 (p=0.001), and plaque burden (PB) ≥70% (p&amp;lt;0.001) (Figure 1C–E), and further improved the ability of PSS to identify MACE NCLs in VH-TCFA (p=0.041), MLA ≤4mm2 (p=0.033), and PB ≥70% (p&amp;lt;0.001). HI roughness generally corresponded with HI PSS, but was also increased at sites of local calcification and multilayering. Conclusions Plaque-lumen geometric heterogeneity is increased across whole plaque and peri-MLA segments of NCLs causing MACE. Inclusion of geometric heterogeneity may improve the ability of intravascular imaging to predict MACE. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): British Heart Foundation

Physiological Intracranial Calcifications in Children: A computed tomography-based study.

This study aimed to examined the frequency of physiological intracranial calcifications (PICs) in paediatric population using computed tomography (CT). The brain CT scans of consecutive patients (age range: 0-15 years) who had visited Sultan Qaboos University Hospital, Muscat, Oman, from January 2017 to December 2020 were retrospectively assessed for the presence of PICs. The presence of calcifications was identified using 3 mm-thick axial images and coronal and sagittal reformats. A total of 460 patients were examined, with a mean age of 6.54 ± 4.94 years. The frequency of PIC in boys and girls was 35.1% and 35.4%, respectively. PICs were most common in choroid plexus, observed in 35.2% (age range: 0.4-15 years, median: 12 years) of subjects, followed by the pineal gland in 21.1% (age range: 0.5-15 years, median: 12 years) and the habenular nucleus in 13.0% of subjects (age range: 2.9-15 years; median: 12 years). PICs were less common in falx cerebri, observed in 5.9% (age range: 2.8-15 years; median: 13 years) of subjects, and tentorium cerebelli, observed in 3.0% (age range: 7-15 years, median: 14 years) of subjects. PICs increased significantly with increase in age (P <0.001). Choroid plexus is the most frequent site of calcification. Choroid plexus and pineal gland calcifications may be present in infants younger than one year. Recognising PICs is clinically important for radiologists as they can be mistaken for haemorrhage or pathological entities such as neoplasms or metabolic diseases.

The Associations of Aortic Valve Sclerosis, Aortic Annular Increased Reflectivity, and Mitral Annular Calcification with Subsequent Aortic Stenosis in Older Individuals: Findings from the Cardiovascular Health Study

Although aortic valve sclerosis (AVS) is well described as preceding aortic stenosis (AS), the associations of AS with antecedent mitral annular calcification (MAC) and aortic annular increased reflectivity (AAIR) have not been characterized. In a population-based prospective study, the authors evaluated whether MAC, AAIR, and AVS are associated with the risk for incident AS. Among participants of the Cardiovascular Health Study free of AS at the 1994-1995 visit, the presence of MAC, AAIR, AVS, and the combination of all three was evaluated in 3,041 participants. Cox proportional-hazards regression was used to assess the association between the presence of calcification and the incidence of moderate or severe AS in three nested models adjusting for factors associated with atherosclerosis and inflammation both relevant to the pathogenesis of AS. Over a median follow-up period of 11.5years (interquartile range, 6.7-17.0years), 110 cases of incident moderate or severe AS were ascertained. Strong positive associations with incident moderate or severe AS were found for all calcification sites after adjustment for the main model covariates: AAIR (hazard ratio [HR], 2.90; 95% CI, 1.95-4.32; P<.0005), AVS (HR, 2.20; 95% CI, 1.44-3.37; P<.0005), MAC (HR, 1.67; 95% CI, 1.14-2.45; P=.008), and the combination of all three (HR, 2.50; 95% CI, 1.65-3.78; P<.0005). In a secondary analysis, the risk for AS increased with the number of sites at which calcification was present. In a large cohort of community-dwelling elderly individuals, there were strong associations between each of AAIR, AVS, MAC, and the combination of the three and incident moderate or severe AS. The novel finding that AAIR had a particularly strong association with incident AS, even after adjusting for other calcification sites, suggests its value in identifying individuals at risk for AS and potential inclusion in routine assessment by transthoracic echocardiography.

Calcification response of reef corals to seasonal upwelling in the northern Arabian Sea (Masirah Island, Oman)

Abstract. Tropical shallow-water reefs are the most diverse ecosystems in the ocean. Their persistence rests upon adequate calcification rates of the reef building biota, such as reef corals. Coral calcification is favoured in oligotrophic environments with high seawater saturation states of aragonite (Ωsw), which leads to an increased vulnerability to anthropogenic ocean acidification and eutrophication. Here we present Porites calcification records from the northern Arabian Sea upwelling zone and investigate the coral calcification response to low Ωsw and high nutrient concentrations due to seasonal upwelling. The calcification rate was determined from the product of skeletal extension rate and bulk density. Skeletal Ba/Ca and Li/Mg proxy data were used to identify skeletal portions that calcified during upwelling and non-upwelling seasons, respectively, and to reconstruct growth temperatures. With regard to sub-annual calcification patterns, our results demonstrate compromised calcification rates during the upwelling season. This is due to declining extension rates, which we attribute to light dimming caused by high primary production. Interestingly, seasonal variations in skeletal density show no relationship with temporally low Ωsw during upwelling. This suggests relatively constant, year-round saturation states of aragonite at the site of calcification (Ωcf) independent of external variability in Ωsw. Although upwelling does not affect seasonal density variability, exceptionally low mean annual density implies permanent Ωcf adjustment to the lowest sub-annual Ωsw (e.g. upwelling). In the Arabian Sea upwelling zone, the mean annual calcification rate is similar to Porites from non-upwelling regions because low skeletal density is compensated by high extension growth. Variable responses of reef coral extension to nutrients, which either exacerbate or compensate negative effects of diminished skeletal density associated with ocean acidification, may therefore be critical to the maintenance of adequate carbonate accumulation rates in coral reefs under global change.

Stylasterid corals build aragonite skeletons in undersaturated water despite low pH at the site of calcification

Anthropogenic carbon emissions are causing seawater pH to decline, yet the impact on marine calcifiers is uncertain. Scleractinian corals and coralline algae strongly elevate the pH of their calcifying fluid (CF) to promote calcification. Other organisms adopt less energetically demanding calcification approaches but restrict their habitat. Stylasterid corals occur widely (extending well below the carbonate saturation horizon) and precipitate both aragonite and high-Mg calcite, however, their mode of biocalcification and resilience to ocean acidification are unknown. Here we measure skeletal boron isotopes (δ11B), B/Ca, and U/Ca to provide the first assessment of pH and rate of seawater flushing of stylasterid CF. Remarkably, both aragonitic and high-Mg calcitic stylasterids have low δ11B values implying little modification of internal pH. Collectively, our results suggest stylasterids have low seawater exchange rates into the calcifying space or rely on organic molecule templating to facilitate calcification. Thus, despite occupying similar niches to Scleractinia, Stylasteridae exhibit highly contrasting biocalcification, calling into question their resilience to ocean acidification.

Digital breast tomosynthesis-guided vacuum-assisted biopsy of suspicious calcifications at different sites within one breast: Is biopsy of more than one location needed?

ObjectiveTo investigate how often biopsy of two sites of morphologically similar or equally suspicious calcifications within the same breast yield differing histopathologic results, and how this may affect clinical management. Materials and methodsWe identified patients with two or more sites of calcifications categorized as Breast Imaging Reporting and Data System (BI-RADS) ≥ 4b within the same breast who underwent digital breast tomosynthesis-guided vacuum-assisted biopsy (DBT-guided VAB). We analyzed how often biopsy of two distinct sites yielded the same or differing histopathologic findings. The histopathologic findings were dichotomized into “actionable” and “non-actionable”, depending on the respective further management. We then analyzed how often the consecutive management would have been the same or different. ResultsOf 206 women undergoing DBT-guided VAB at our institution within 24 months, 21 consecutive patients (54 ± 10.2 years; range: 35–71) underwent DBT-guided VAB of two distinct sites of calcifications. Management of histologic findings was the same (both sites actionable or both sites non-actionable) in 12/21 (57 %), different in the remaining 9/21 patients (43 %). Of the nine patients whose differing histologic findings would have led to different clinical management, 4/9 had a high-risk lesion (atypical ductal hyperplasia n = 3, papilloma with epithelial atypia n = 1) vs benign changes (adenosis n = 4), 2/9 had high-grade DCIS vs benign changes (adenosis n = 1, fat necrosis n = 1), and 3/9 had invasive cancer (luminal A n = 2, luminal B n = 1) with high-grade DCIS vs pure high-grade DCIS. ConclusionsMultiple sites of calcifications within the same breast, even when morphologically similar or equally suspicious, may represent different histopathologic findings with different clinical management implications. Accordingly, in the presence of suspicious calcifications at multiple distinct sites within the same breast, biopsy of more than one site of calcification should be considered.

A GAN based approach for inferring progression trajectories of costal cartilage calcification from cross-sectional data at image level

BackgroundCostal cartilage calcification (CCC) increases with age and presents differently for men and women. In individuals, however, the cross-sectional studies that show such trends do not reveal the geometric trajectories through which calcification might accumulate across a lifetime. Generative adversarial networks have the potential to reveal such trajectories from cross-sectional data by learning population trends and synthesizing individualized images at progressive levels of calcification. MethodsChest wall mid-surface CT images with normalized cartilage morphologies were produced for 379 subjects aged 6 to 90, and labeled by sex and calcification severity. A conditional GAN with added loss terms to favor one-way accumulation of CCC was trained using organized image batches. GAN performance was assessed by comparing the distributions of images between the training and synthetic groups. ResultsSynthetic images generated from a common seed for a given sex and at successive calcification severity levels showed incremental and regional growth of calcification sites. CCC patterns for synthetic male and female images matched known sex-based differences, and individual CCC growth in synthetic images was consistent with previously observed population trends. These trends in the synthetic images were also quantified by structural similarity scores. Synthetic images generated from different input seeds further showed individual variance in specific regions and trajectories of CCC accumulation. ConclusionThis study inferred individual progression of CCC accumulation from uncalcified to severely calcified using cross-sectional image data. This information can inform computational models of the changing chest wall biomechanics with age, and the GAN-based technique shows potential for inferring longitudinal data from population trends in other clinical areas.

Role of Sclerostin in Cardiovascular Disease.

Sclerostin is most recognized for its role in controlling bone formation but is also expressed in the heart, aorta, coronary, and peripheral arteries. This review summarizes research on sclerostin's role in cardiovascular disease. Rodent studies have found sclerostin to be expressed at sites of arterial calcification. In contrast, aortic sclerostin was reported to be downregulated in a mouse model of abdominal aortic aneurysm, and transgenic upregulation or administration of sclerostin was found to prevent abdominal aortic aneurysm and atherosclerosis formation. Sclerostin deficiency was reported to stimulate cardiac rupture in one rodent model. In humans, 7 of 11 studies reported a significant association between high serum sclerostin and high carotid intima media thickness. Ten of 15 studies reported a significant association between high serum sclerostin and severe arterial calcification. Twelve of 14 studies reported a significant association between high serum sclerostin and high arterial stiffness or atherosclerosis severity. Four of 9 studies reported a significant association between high serum sclerostin and high risk of cardiovascular events. A meta-analysis of randomized controlled trials suggested that administration of the sclerostin blocking antibody romosozumab did not significantly increase the risk of major adverse cardiovascular events (risk ratio, 1.14 [95% CI, 0.83-1.57]; P=0.54) or cardiovascular death (risk ratio, 0.92 [95% CI, 0.53-1.59]; P=0.71). Human genetic studies reported variants predisposing to low arterial sclerostin expression were associated with a high risk of cardiovascular events. Overall, past research suggests a cardiovascular protective role of sclerostin but findings have been inconsistent, possibly due to variations in study design, the unique populations and models studied, and the heterogeneous methods used.

An Unusual Case of Dense Mitral Annular Calcification in a Young with Plethora of Mitral Annular Premature Ventricular Complexes

We report a rare case of dense mitral annular calcification in a 26-year-old male presenting with recurrent palpitation for the last year with a plethora of mitral annular premature ventricular complexes (PVCs). PVCs had right bundle branch block morphology, were notched in inferior leads with negative QRS complexes in aVL suggestive of likely origin from the lateral mitral annulus. Patients with PVCs from mitral annulus are usually advised to undergo cardiac magnetic resonance imaging to localize the site of subtle mitral annular calcification and plan subsequent delivery of radiofrequency lesions at the same site during radiofrequency ablation. Dense calcification of the lateral mitral annulus is extremely rare to encounter in such a young age of below 30 years without the presence of any predisposing risk factors for calcification. Our case is the first illustration of dense mitral annular calcification secondary to the plethora of mitral annular PVCs in a symptomatic young person below the age of 30 years. PVCs-induced excessive local excursion with wear and tear phenomenon and secondary dystrophic calcification may be the plausible explanation behind this interesting presentation.

About some masked forms of chronic primary tuberculosis

Domestic authors pay considerable attention to the "masks" of tuberculosis, which is associated with the difficulties of their diagnosis [2, 3, 4, 5, 7]. Masked forms of tuberculosis are locally limited processes occurring with syndromes characteristic of non-tuberculosis diseases. Most often, these forms are observed in primary tuberculosis, especially in its chronic course. Chronic primary tuberculosis, first described by V. T. Shvaytsar, is a peculiar form of bronchoadenitis and is characterized by the presence of calcification sites and significant caseous changes in the affected lymph nodes, which serve as a source of prolonged intoxication and sensitization of the patient's body.

Magnetic resonance imaging evaluation of the correlation between calcific tendinitis and rotator cuff injury

BackgroundThis study aims to evaluate the incidence of calcific tendinitis (CaT) in rotator cuff tears (RCTs) and to assess the correlation between CaT and RCTs with magnetic resonance imaging (MRI).MethodsThe MRI of 108 patients with rotator cuff CaT admitted to our hospital from January 2019 to January 2021 were retrospectively analyzed. Another retrospective analysis was made of 108 patients with similar age, gender, occupation, and shoulder injury side to those in the first group. The incidence of RCTs and their correlation with CaT were assessed based on an MRI of shoulder joints.ResultsThere was a statistical difference (p < 0.05) in the incidence of RCTs between the CaT group (23.4%) and the control group (37.2%). No significant difference was observed in the size of the RCTs between the two groups (P = 0.422). In the CaT group, 17.4% of patients had complete tears, compared with 26.3% in the control group. There was no significant correlation between the calcification site and RCTs in the CaT group, and only 3.7% of patients suffered calcification and a tear in the exact location of the same tendon (P > 0.05, r = 0.03).ConclusionsCompared with patients with shoulder pain without CaT, patients with rotator cuff CaT suffered no increased risk of RCTs on MRI, so CaT and RCTs may have different pathological causes, and there is no significant correlation between the two.

Inhibition of the DNA Damage Response Attenuates Ectopic Calcification in Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum (PXE) is a heritable ectopic calcification disorder with multiorgan clinical manifestations. The gene at default, ABCC6, encodes an efflux transporter, ABCC6, which is a critical player regulating the homeostasis of inorganic pyrophosphate, a potent endogenous anticalcification factor. Previous studies suggested that systemic inorganic pyrophosphate deficiency is the major but not the exclusive cause of ectopic calcification in PXE. In this study, we show that the DNA damage response (DDR) and poly(ADP-ribose) (PAR) pathways are involved locally in PXE at sites of ectopic calcification. Genetic inhibition of PAR polymerase 1 gene PARP1, the predominant PAR-producing enzyme, showed a 54% reduction of calcification in the muzzle skin in Abcc6‒/‒Parp1‒/‒ mice, compared with that of age-matched Abcc6‒/‒Parp1+/+ littermates. Subsequently, oral administration of minocycline, an inhibitor of DDR/PAR signaling, resulted in an 86% reduction of calcification in the muzzle skin of Abcc6‒/‒ mice. Minocycline treatment also attenuated the DDR/PAR signaling and reduced the calcification of dermal fibroblasts derived from patients with PXE. The anticalcification effect of DDR/PAR inhibition was not accompanied by alterations in plasma inorganic pyrophosphate concentrations. These results suggest that local DDR/PAR signaling in calcification-prone tissues contributes to PXE pathogenesis and that its inhibition might provide a promising treatment strategy for ectopic calcification in PXE, a currently intractable disease.

Study on the characteristics of coronary calcification by Intravascular Ultrasound (IVUS)

Background: Percutaneous coronary angiography is considered the "gold standard" for the diagnosis of coronary artery disease and provides the necessary anatomical information to provide appropriate treatment. The limitation of coronary angiography is the accurate assessment of calcified coronary lesions. Intravascular ultrasonography has many advantages in the assessment of calcified coronary lesions.&#x0D; Methods: The descriptive clinical study. Evaluation of calcified coronary artery lesions by intravascular ultrasound&#x0D; Results: From January 2019 to December 2019, at the Hanoi Heart Institute, 64 patients had 64 coronary artery lesions surveyed by intravascular ultrasound. There were 42 (65,6%) calcified lesions assessed by IVUS and 25 (39,1%) calcified lesions were detected by coronary angiography. In addition, the location of calcified were revealed more in the LAD compared to other: LAD 60%, LCx 24%, RCA 12% and LM 4%.&#x0D; Conclusion: IVUS calcification detection rate is higher than coronary angiography. The most common site of calcification in the LAD.

New Insights on the Diurnal Mechanism of Calcification in the Stony Coral, Stylophora pistillata

Scleractinian corals are evolutionary-successful calcifying marine organisms, which utilize an endo-symbiotic relationship with photosynthetic dinoflagellate algae that supply energy products to their coral hosts. This energy further supports a higher calcification rate during the day in a process known as light enhanced calcification. Although this process has been studied for decades, the mechanisms behind it are still unknown. However, photosynthesis and respiration also cause daily fluctuations in oxygen and pH levels, resulting in the coral facing highly variable conditions. Here we correlated gene expression patterns with the physiological differences along the diel cycle to provide new insights on the daily dynamic processes, including circadian rhythm, calcification, symbiosis, cellular arrangement, metabolism, and energy budget. During daytime, when solar radiation levels are highest, we observed increased calcification rate combined with an extensive up-regulation of genes associated with reactive oxygen species, redox, metabolism, ion transporters, skeletal organic matrix, and mineral formation. During the night, we observed a vast shift toward up-regulation of genes associated with cilia movement, tissue development, cellular movement, antioxidants, protein synthesis, and skeletal organic matrix formation. Our results suggest that light enhanced calcification is related to several processes that occur across the diel cycle; during nighttime, tissue might elevate away from the skeleton, extending the calcifying space area to enable the formation of a new organic framework template. During daytime, the combination of synthesis of acid-rich proteins and a greater flux of ions to the sites of calcification facilitate the conditions for extensive mineral growth.

Abstract 12138: Cell Senescence Associated H3K9me3 Decline Sensitizes Aortic Valve Cell for Osteogenic Response

Introduction: Cell senescence has been identified as an impact etiological factor in cardiovascular diseases, as well as calcific aortic valve disease (CAVD) . In our previous experiment results, We found that a large number of senescent aortic valve interstitial cells (AVIC) accumulated in the calcific aortic valve tissues, especially around the calcification sites. But the role and mechanism of cellular senescence in the development of calcified aortic stenosis have not been clarified. We hypothesized valvular interstitial cell senescence sensitize interstitial cell for osteogenic response through enhancing cell senescence associated epigenetic modification. Methods and Results: Representative immunofluorescence results of the clinical samples show that p16INK4A positive cells in the calcific aortic valve expressed more osteogenic associated factors, such as Runx2 and BMP2. And RAS system hyperactivation seemed to be an impact association with aortic valve calcification. Then we found Angiotensin II (1μM, 72h) chronic irritation induces valve interstitial cell senescence associated secretion phenotype (SASP) and activates osteogenic response through ERK1/2 and NF-κB pathway. ChIP-qPCR results demonstrated H3K9Me3 modifications on the promoters of Runx2, ACTA2(also known as α-SMA), IL-6, IL-8, MCP-1 were significantly decreased in angiotensin II pretreated AVIC. Blockage of angiotensin II and ABT-263 pretreatment inhibited valvular interstitial cell to convert into osteoblast-like phenotype induced by Angiotensin II, as well as attenuating senescence associated secretion phenotype factors yield. Blockage of angiotensin II receptor and p16 INK4A knockdown contributed to recover H3K9me3 modification on the promoters of those gene in angiotensin II pretreated AVIC through attenuating angiotensin II-induced ubiquitination degradation of SUV39H1. Conclusion: p16 INK4A mediated H3K9me3 decline sensitizes aortic valvular interstitial cell for osteogenic response, which impacts on aortic valve homeostasis and aortic valve calcification. Taken together, p16 INK4A positive senescent cells would be the potential target on prevention and treatment of calcific aortic valve disease.

Engineered osteoclasts as living treatment materials for heterotopic ossification therapy

Osteoclasts (OCs), the only cells capable of remodeling bone, can demineralize calcium minerals biologically. Naive OCs have limitations for the removal of ectopic calcification, such as in heterotopic ossification (HO), due to their restricted activity, migration and poor adhesion to sites of ectopic calcification. HO is the formation of pathological mature bone within extraskeletal soft tissues, and there are currently no reliable methods for removing these unexpected calcified plaques. In the present study, we develop a chemical approach to modify OCs with tetracycline (TC) to produce engineered OCs (TC-OCs) with an enhanced capacity for targeting and adhering to ectopic calcified tissue due to a broad affinity for calcium minerals. Unlike naive OCs, TC-OCs are able to effectively remove HO both in vitro and in vivo. This achievement indicates that HO can be reversed using modified OCs and holds promise for engineering cells as “living treatment agents” for cell therapy.

Understanding coralline algal responses to ocean acidification: Meta-analysis and synthesis.

Ocean acidification (OA) is a major threat to the persistence of biogenic reefs throughout the world's ocean. Coralline algae are comprised of high magnesium calcite and have long been considered one of the most susceptible taxa to the negative impacts of OA. We summarize these impacts and explore the causes of variability in coralline algal responses using a review/qualitative assessment of all relevant literature, meta-analysis, quantitative assessment of critical responses, and a discussion of physiological mechanisms and directions for future research. We find that most coralline algae experienced reduced abundance, calcification rates, recruitment rates, and declines in pH within the site of calcification in laboratory experiments simulating OA or at naturally elevated CO2 sites. There were no other consistent physiological responses of coralline algae to simulated OA (e.g., photo-physiology, mineralogy, and survival). Calcification/growth was the most frequently measured parameters in coralline algal OA research, and our meta-analyses revealed greater declines in seawater pH were associated with significant decreases in calcification in adults and similar but nonsignificant trends for juveniles. Adults from the family Mesophyllumaceae also tended to be more robust to OA, though there was insufficient data to test similar trends for juveniles. OA was the dominant driver in the majority of laboratory experiments where other local or global drivers were assessed. The interaction between OA and any other single driver was often additive, though factors that changed pH at the surface of coralline algae (light, water motion, epiphytes) acted antagonistically or synergistically with OA more than any other drivers. With advances in experimental design and methodological techniques, we now understand that the physiology of coralline algal calcification largely dictates their responses to OA. However, significant challenges still remain, including improving the geographic and life-history spread of research effort and a need for holistic assessments of physiology.