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Inorganic materials are of increasing interest not only for bone repair but also for other applications in regenerative medicine. In this study, the combined effects of energy-providing, regeneratively active inorganic polyphosphate (polyP) and also morphogenetically active pearl powder on wound healing were investigated. Aragonite, the mineralic constituent of pearl nacre and thermodynamically unstable form of crystalline calcium carbonate, was found to be converted into a soluble state in the presence of a Ca2+-containing wound exudate, particularly upon addition of sodium polyP (Na-polyP), driven by the transfer of Ca2+ ions from aragonite to polyP, leading to liquid-liquid phase separation to form an aqueous Ca-polyP coacervate. This process is further enhanced in the presence of Ca-polyP nanoparticles (Ca-polyP-NP). Kinetic studies revealed that the coacervation of polyP and nacre aragonite in wound exudate is a very rapid process that results in the formation of a stronger gel with a porous structure compared to polyP alone. Coacervate formation, enabled by phase transition of crystalline aragonite in the presence of Na-polyP/Ca-polyP-NP and wound exudate, could also be demonstrated in a hydroxyethyl cellulose-based hydrogel used for wound treatment. Furthermore, it is shown that Na-polyP/Ca-polyP-NP together with nacre aragonite strongly enhances the proliferation of mesenchymal stem cells and promotes microtube formation in the in vitro angiogenesis assay with HUVEC endothelial cells. The latter effect was confirmed by gene expression studies, applying real-time polymerase chain reaction, using the biomarker genes VEGF (vascular endothelial growth factor) and hypoxia-inducible factor-1 α (HIF-1α). Division of Escherichia coli is suppressed when suspended in a matrix containing Na-polyP/Ca-polyP-NP and aragonite. The potential medical relevance of these findings is supported by an animal study on genetically engineered diabetic mice (db/db), which demonstrated a marked increase in granulation tissue and microvessel formation in regenerating experimental wounds treated with Ca-polyP-NP compared to controls. Co-administration of aragonite significantly accelerated the wound healing-promoting effect of polyP in db/db mice. Based on these results, we propose that the ability of polyP to form a mixed coacervate with aragonite, in addition to its energy (ATP)-generating function, can decisively contribute to the regenerative activity of this polymer in wound repair.
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Nubecularia bioherms represent unique bioconstructions that are restricted to the upper Serravallian of the Paratethys and have been reported since the 19th century. They occur in the Central Paratethys in the late Sarmatian and the Eastern Paratethys in the Bessarabian both regional stages of the respective Paratethyan areas. In this study, several locations in the Vienna and Styrian basins of the Central Paratethys were studied out of which four localities were documented in detail (Wolfsthal, Maustrenk, St. Margarethen-Zollhaus, Vienna-Ruzickagasse) to reconstruct their sedimentary setting, their internal composition, and their indications of environmental parameters. The detailed studies included logging of outcrop sections, petrographic, facies and biotic analyses of polished slabs and thin sections and also cathodoluminescence analyses. These concluded that these bioconstructions are not only composed of the foraminifer Nubecularia but represent a complex mixture and interrelationships of Nubecularia, serpulids and microbial carbonate. Four boundstone types can be differentiated: Nubecularia boundstone, Nubecularia-coralline algal boundstone, stromatolitic/thrombolitic boundstone and serpulid-nubeculariid-microbial boundstone. The first 3 types are characteristic of specific localities; the fourth type occurs in all studied locations and represents the terminal association on top of the three other types. The three basal boundstones are predominantly of columnar growth form irrespective of dominance of Nubecularia, coralline algae or microbial carbonate, and the terminal boundstone is widely irregularly organized. The general depositional environment is characterized by cross-bedded oolitic grainstones with abundant quartz grains, miliolid foraminifers and mollusks. Intercalated are microbial carbonates mostly stromatolites but also thrombolites. This indicates a general high water energy environment interrupted by more calm periods when the microbial carbonate was built. The 3 basal types of bioconstructions are interpreted to reflect decreasing food supply and/or oxygenation from Nubecularia over Nubecularia-coralline algal to stromatolitic/thrombolitic boundstone. The serpulid-nubeculariid-microbial boundstone reflects an internal succession with a decrease of the same parameters. Water depth is considered very shallow ranging from 0 to a few meters, and salinity was normal marine to hypersaline. The reconstructed paleoenvironment with dominating oolite shoals and seagrass meadows was not restricted to the Central Paratethys but extended over the entire Paratethys and represented the largest oolite facies area of the entire Cenozoic!
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Carbonatos , Plantas , Fácies , ÁguaRESUMO
Nanoparticles of a particular, evolutionarily old inorganic polymer found across the biological kingdoms have attracted increasing interest in recent years not only because of their crucial role in metabolism but also their potential medical applicability: it is inorganic polyphosphate (polyP). This ubiquitous linear polymer is composed of 10-1000 phosphate residues linked by high-energy anhydride bonds. PolyP causes induction of gene activity, provides phosphate for bone mineralization, and serves as an energy supplier through enzymatic cleavage of its acid anhydride bonds and subsequent ATP formation. The biomedical breakthrough of polyP came with the development of a successful fabrication process, in depot form, as Ca- or Mg-polyP nanoparticles, or as the directly effective polymer, as soluble Na-polyP, for regenerative repair and healing processes, especially in tissue areas with insufficient blood supply. Physiologically, the platelets are the main vehicles for polyP nanoparticles in the circulating blood. To be biomedically active, these particles undergo coacervation. This review provides an overview of the properties of polyP and polyP nanoparticles for applications in the regeneration and repair of bone, cartilage, and skin. In addition to studies on animal models, the first successful proof-of-concept studies on humans for the healing of chronic wounds are outlined.
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Nanopartículas , Polifosfatos , Regeneração , Polifosfatos/química , Nanopartículas/química , Humanos , Animais , Regeneração/efeitos dos fármacos , Cicatrização/efeitos dos fármacosRESUMO
There is a need for novel nanomaterials with properties not yet exploited in regenerative nanomedicine. Based on lessons learned from the oldest metazoan phylum, sponges, it has been recognized that two previously ignored or insufficiently recognized principles play an essential role in tissue regeneration, including biomineral formation/repair and wound healing. Firstly, the dependence on enzymes as a driving force and secondly, the availability of metabolic energy. The discovery of enzymatic synthesis and regenerative activity of amorphous biosilica that builds the mineral skeleton of siliceous sponges formed the basis for the development of successful strategies for the treatment of osteochondral impairments in humans. In addition, the elucidation of the functional significance of a second regeneratively active inorganic material, namely inorganic polyphosphate (polyP) and its amorphous nanoparticles, present from sponges to humans, has pushed forward the development of innovative materials for both soft (skin, cartilage) and hard tissue (bone) repair. This energy-rich molecule exhibits a property not shown by any other biopolymer: the delivery of metabolic energy, even extracellularly, necessary for the ATP-dependent tissue regeneration. This review summarizes the latest developments in nanobiomaterials based on these two evolutionarily old, regeneratively active materials, amorphous silica and amorphous polyP, highlighting their specific, partly unique properties and mode of action, and discussing their possible applications in human therapy. The results of initial proof-of-concept studies on patients demonstrating complete healing of chronic wounds are outlined.
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Polímeros , Polifosfatos , Humanos , Animais , Nanomedicina , Materiais Biocompatíveis , Dióxido de SilícioRESUMO
Primary biliary cholangitis (PBC) is a rare cholestatic immune-mediated liver disease. The clinical course varies from mild to severe, with a substantial group of patients developing cirrhosis within a decade. These patients are at risk of hepatocellular carcinoma, decompensation and liver failure. First line Ursodeoxycholic acid (UDCA) treatment improves the cholestatic surrogate markers, and was recently associated with a favorable survival free of liver transplantation, even in case of an incomplete biochemical response. However, despite adequate UDCA therapy, patients remain at risk of liver disease progression. Therefore, on-treatment multifactor-based risk stratification is necessary to identify patients in need of additional therapy. This requires a personalized approach; especially as recent studies suggest that complete biochemical normalization as most stringent response criterion might be preferred in selected patients to optimize their outcome. Today, stricter biochemical goals might actually be reachable with the addition of farnesoid X receptor or peroxisome proliferator-activated receptor agonists, or, in highly-selected cases, use of corticosteroids. Randomized controlled trials showed improvements in the key biochemical surrogate markers with the addition of these drugs, which have also been associated with improved clinical outcome. Considering this evolving PBC landscape, with more versatile treatment options and treatment goals, this review recapitulates the recent insight in UDCA therapy, the selection of patients with a residual risk of liver disease progression and the results of the currently available second line treatment options.
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Colagogos e Coleréticos , Cirrose Hepática Biliar , Ácido Ursodesoxicólico , Humanos , Ácido Ursodesoxicólico/uso terapêutico , Cirrose Hepática Biliar/tratamento farmacológico , Colagogos e Coleréticos/uso terapêutico , Progressão da Doença , Receptores Citoplasmáticos e Nucleares/agonistas , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante de Fígado , Corticosteroides/uso terapêutico , Receptores Ativados por Proliferador de Peroxissomo/agonistasRESUMO
To combat infections, silver was used extensively in biomedical field but there was a need for a capping agent to eliminate its cytotoxic effects. In this study, polymeric calcium polyphosphate was doped by silver with three concentrations 1, 3 or 5 mol.% and were characterized by TEM, XRD, FTIR, TGA. Moreover, cytotoxicity, antibacterial, cell migration and DNA fragmentation assays were done to assure its safety. The results showed that the increase in silver percentage caused an increase in particle size. XRD showed the silver peaks, which indicated that it is present in its metallic form. The TGA showed that thermal stability was increased by increasing silver content. The antibacterial tests showed that the prepared nanoparticles have an antibacterial activity against tested pathogens. In addition, the cytotoxicity results showed that the samples exhibited non-cytotoxic behavior even with the highest doping concentration (5% Ag-CaPp). The cell migration assay showed that the increase in the silver concentration enhances cell migration up to 3% Ag-CaPp. The DNA fragmentation test revealed that all the prepared nanoparticles caused no fragmentation. From the results we can deduce that 3% Ag-CaPp was the optimum silver doped calcium polyphosphate concentration that could be used safely for medical applications.
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Nanopartículas Metálicas , Nanopartículas , Prata/farmacologia , Cálcio , Fragmentação do DNA , Extratos Vegetais , Antibacterianos/farmacologia , Cálcio da Dieta , Movimento Celular , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Biphasic calcium phosphates (BCP) may serve as off-the-shelf alternatives for iliac crest-derived autologous bone in alveolar cleft reconstructions. To add osteoinductivity to the osteoconductive BCPs to achieve similar regenerative capacity as autologous bone, a locally harvested buccal fat pad will be mechanically fractionated to generate microfragmented fat (MFAT), which has been shown to have high regenerative capacity due to high pericyte and mesenchymal stem cell content and a preserved perivascular niche. OBJECTIVE: Our primary objectives will be to assess the feasibility and safety of the BCP-MFAT combination. The secondary objective will be efficacy, which will be evaluated using radiographic imaging and histological and histomorphometric evaluation of biopsies taken 6 months postoperatively, concomitant with dental implant placement. METHODS: Eight patients with alveolar cleft (≥15 years) will be included in this prospective, nonblinded, first-in-human clinical study. MFAT will be prepared intraoperatively from the patient's own buccal fat pad. Regular blood tests and physical examinations will be conducted, and any adverse events (AEs) or serious EAs (SAEs) will be meticulously recorded. Radiographic imaging will be performed prior to surgery and at regular intervals after reconstruction of the alveolar cleft with the BCP-MFAT combination. Biopsies obtained after 6 months with a trephine drill used to prepare the implantation site will be assessed with histological and histomorphometric analyses after methylmethacrylate embedding and sectioning. RESULTS: The primary outcome parameter will be safety after 6 months' follow-up, as monitored closely using possible occurrences of SAEs based on radiographic imaging, blood tests, and physical examinations. For efficacy, radiographic imaging will be used for clinical grading of the bone construct using the Bergland scale. In addition, bone parameters such as bone volume, osteoid volume, graft volume, and number of osteoclasts will be histomorphometrically quantified. Recruitment started in November 2019, and the trial is currently in the follow-up stage. This protocol's current version is 1.0, dated September 15, 2019. CONCLUSIONS: In this first-in-human study, not only safety but also the histologically and radiographically assessed regenerative potential of the BCP-MFAT combination will be evaluated in an alveolar cleft model. When an SAE occurs, it will be concluded that the BCP-MFAT combination is not yet safe in the current setting. Regarding AEs, if they do not occur at a higher frequency than that in patients treated with standard care (autologous bone) or can be resolved by noninvasive conventional methods (eg, with analgesics or antibiotics), the BCP-MFAT combination will be considered safe. In all other cases, the BCP-MFAT combination will not yet be considered safe. TRIAL REGISTRATION: Indonesia Clinical Trial Registry INA-EW74C1N; https://tinyurl.com/28tnrr64. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42371.
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Animal flesh foods are rich in bioavailable iron but infrequently consumed by young children. We aimed to determine whether flesh food intake was associated with iron and anaemia status among 585 Malawian infants enroled in a 6-month egg-feeding trial. The percentage of days of small fish, large fish and meat consumption were assessed through weekly 7-day animal-source food screeners. Grams of intake were assessed through 24-h recalls conducted at 6-9, 9-12 and 12-15 months of age. Plasma ferritin, soluble transferrin receptor (sTfR) and haemoglobin concentrations were measured at 6-9 and 12-15 months of age. Iron biomarkers were adjusted for inflammation during analysis. At enrolment, each flesh food category was consumed by <5% of children in the past 24 h. Over the next 6 months, small fish, large fish and meat were consumed on 25%, 8% and 6% of days, respectively, with mean usual intakes of <5 g/day. More frequent small fish consumption was associated with lower sTfR (geometric mean ratio [95% CI]: 0.98 mg/L [0.96, 1.00] per 10 percentage point difference) but not ferritin (1.03 µg/L [0.98, 1.07]) or haemoglobin (1.01 g/dL [1.00, 1.01]). Large fish consumption was associated with higher anaemia (prevalence ratio [95% CI]: 1.09 [1.01, 1.19]) and lower iron deficiency (0.96 [0.93, 1.00]) prevalence. Gram intakes of flesh food categories were not associated with any iron or anaemia indicators. Small fish were a primary contributor to flesh food intake in this cohort of Malawian children, although usual portions were small. Fish was associated with modest improvements to iron status, but meat was too infrequent to be associated with anaemia and iron deficiency.
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Anemia Ferropriva , Anemia , Deficiências de Ferro , Criança , Lactente , Animais , Humanos , Pré-Escolar , Ferro , Anemia Ferropriva/epidemiologia , Anemia/epidemiologia , Ferritinas , Hemoglobinas/metabolismo , Receptores da Transferrina , CarneRESUMO
The manaksite mineral KNaMnSi4O10 was synthesized and used to fabricate electrodes, which were investigated for electrochemical energy storage (EES) application using cyclic voltammetry (CV), galvanostatic charge and discharge (GCD), and electrochemical impedance spectroscopy (EIS). Optimum weight percentages (wt%) of electrode components were established as 10 wt% polytetrafluoroethylene (PTFE) binder, 15 wt% RuO2 and 5 wt% carbon black. RuO2 was added to improve electrical conductivity. A ratio of 13 : 3 for KNaMnSi4O10 : RuO2 was used in the fabrication of the electrode. A study of the suitable electrolyte and corresponding concentration to use was done using NaOH and KOH, both at concentrations of 1 M, 3 M and 6 M, with 3 M NaOH as the optimum electrolyte and concentration. The KNaMnSi4O10 yielded a specific capacity of 106 mA h g-1. An investigation into the energy storage mechanism from a plot of log I(ν) vs. log ν, where I is current and ν is the scan rate gave a b value parameter of 0.8; that is, in-between 0.5 obtained for a pure battery material and 1.0 for a pure capacitor material. Accordingly, KNaMnSi4O10 exhibited a battery-supercapacitor duality phenomenon consistent with supercapattery materials. The KNaMnSi4O10 electrochemical system involved both capacitive and diffusion-controlled processes and was found to have good cyclic stability. It is concluded that KNaMnSi4O10 is a potential electrochemical energy storage material.
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Gastroenterite , Rotavirus , Criança , Humanos , Lactente , Gastroenterite/diagnóstico , Testes Imunológicos , FezesRESUMO
Micronutrient deficiency is a common global health problem, and accurately assessing micronutrient biomarkers is crucial for planning and managing effective intervention programs. However, analyzing micronutrient data and applying appropriate cutoffs to define deficiencies can be challenging, particularly when considering the confounding effects of inflammation on certain micronutrient biomarkers. To address this challenge, we developed the Statistical Apparatus of Micronutrient Biomarker Analysis (SAMBA) R package, a new tool that increases ease and accessibility of population-based micronutrient biomarker analysis. The SAMBA package can analyze various micronutrient biomarkers to assess status of iron, vitamin A, zinc, and B vitamins; adjust for inflammation; account for complex survey design when appropriate; and produce reports of summary statistics and prevalence estimates of micronutrient deficiencies using recommended age-specific and sex-specific cutoffs. In this study, we aimed to provide a step-by-step procedure for how to use the SAMBA R package, including how to customize it for broader use, and made both the package and user manual publicly available on GitHub. SAMBA was validated by comparing results by analyzing 24 data sets on nonpregnant women of reproductive age from 23 countries and 30 data sets on preschool-aged children from 26 countries with those obtained by an independent analyst. SAMBA generated identical means, percentiles, and prevalence of micronutrient deficiencies to those calculated by the independent analyst. In conclusion, SAMBA simplifies and standardizes the process for deriving survey-weighted and inflammation-adjusted (when appropriate) estimates of the prevalence of micronutrient deficiencies, reducing the time from data cleaning to result generation. SAMBA is a valuable tool that facilitates the accurate and rapid analysis of population-based micronutrient biomarker data, which can inform public health research, programs, and policy across contexts.
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Desnutrição , Oligoelementos , Masculino , Criança , Pré-Escolar , Humanos , Feminino , Micronutrientes , Estado Nutricional , Desnutrição/epidemiologia , Biomarcadores , Inflamação , PrevalênciaRESUMO
Background: Vitamin A deficiency (VAD) is common in populations with limited dietary diversity and access to vitamin A-rich foods. Objectives: This analysis aimed to determine the impact of supplementing children's diets with 1 egg/d on the concentration of plasma retinol and RBP and the prevalence of VAD. Methods: Children age 6-9 mo living in the Mangochi district of Malawi were individually randomly assigned to receive 1 egg/d for 6 mo (n = 331) or continue their usual diet (n = 329) in the Mazira trial (clinicaltrials.gov; NCT03385252). This secondary analysis measured plasma retinol by HPLC and RBP, CRP, and α-1-acid glycoprotein (AGP) by ELISA techniques at enrollment and 6 mo follow-up. Retinol and RBP were adjusted for inflammation, and mean concentrations were compared between groups using linear regression models. In addition, prevalence ratios of VAD (retinol <0.7 µmol/L) were compared between groups using log-binomial or modified Poisson regression models. Results: After 6 mo of study participation, 489 were assessed for retinol (egg: n = 238; control: n = 251), and 575 (egg: n = 281; control: n = 294) were assessed for RBP. Prevalence of inflammation (CRP >5 mg/L or AGP >1 g/L: 62%) and inflammation-adjusted VAD (7%) at enrollment did not differ between groups. At follow-up, the egg intervention group did not differ from the control in inflammation-adjusted retinol [geometric mean (95% CI); egg: 1.10 µmol/L (1.07, 1.13); control: 1.08 (1.05, 1.12)], RBP [egg: 0.99 µmol/L (0.96, 1.02); control: 0.97 (0.94, 1.00)], or prevalence of VAD [egg: 6%; control: 3%; prevalence ratio: 1.87 (0.83, 4.24)]. Conclusions: Provision of 1 egg/d did not impact VAD, plasma retinol, or RBP among young children in rural Malawi, where the prevalence of VAD was low. Curr Dev Nutr 2023;x:xx.This trial was registered at [clinicaltrials.gov] as [NCT03385252].
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This study reports on a calcium copper tetrasilicate (CaCuSi4O10)/glassy carbon electrode (GCE) electrochemical sensor developed for rapid sensing and quantification of an antibacterial drug, norfloxacin, using both cyclic voltammetry and differential pulse voltammetry. The sensor was fabricated by modifying a glassy carbon electrode with the CaCuSi4O10. Electrochemical impedance spectroscopy was performed and the Nyquist plot showed that the CaCuSi4O10/GCE had a lower charge transfer resistance of 22.1 Ω cm2 compared to the GCE with a charge transfer resistance of 43.5 Ω cm2. Differential pulse voltammetry showed that the optimum pH for the electrochemical detection of norfloxacin in potassium phosphate buffer solution (PBS) electrolyte was pH 4.5 and an irreversible oxidative peak was found at 1.067 V. Two linear ranges were established at 0.01 to 0.55 µM and 0.55 µM to 82.1 µM, and the limit of detection was ca. 0.0046 µM. We further demonstrated that the electrochemical oxidation was controlled by both diffusion and adsorption processes. The sensor was investigated in the presence of interferents and was found to be selective toward norfloxacin. The pharmaceutical drug analysis was done to establish method reliability and a significantly low standard deviation of 2.3% was achieved. The results suggest that the sensor can be applied in the detection of norfloxacin.
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Mineral deficiencies are common in children living in low-resource areas. Eggs are a rich source of essential nutrients and have been shown to improve growth in young children, although little is known about their impact on mineral status. Children aged 6-9 months (n = 660) were randomized to receive either one egg/day for 6-months or no intervention. Anthropometric data, dietary recalls, and venous blood were collected at baseline and 6-months follow-up. Quantification of plasma minerals (n = 387) was done using inductively coupled plasma-mass spectroscopy. Difference-in-difference mean plasma mineral concentrations was determined from baseline and follow-up values and assessed between groups by intention-to-treat using ANCOVA regression models. Prevalence of zinc deficiency was 57.4% at baseline and 60.5% at follow-up. Mean difference (MD) of plasma magnesium, selenium, copper, and zinc levels were not different between groups. Plasma iron concentrations were significantly lower in the intervention compared to the control group (MD = - 9.29; 95% CI: - 15.95, - 2.64). Zinc deficiency was widely prevalent in this population. Mineral deficiencies were not addressed with the egg intervention. Further interventions are needed to improve the mineral status of young children.
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Desnutrição , Selênio , Humanos , Criança , Pré-Escolar , Cobre , Ferro , ZincoRESUMO
Bryozoan-serpulid-algal-thrombolite bioherms of up to 50 cm size are described from the Sarmatian (upper Middle Miocene) of the Central Paratethys. They occur on top of lower Sarmatian carbonate sediments of high-energy conditions and the individual bioherms settle on crests of ripples. The buildups are overlain and partly truncated by cross-bedded oolites of late Sarmatian age. Buildup growth starts with a Cryptosula/Hydroides (bryozoan/serpulid) pioneer community, followed by nodular Schizoporella (bryozoan) colonies overgrown by coralline algae/microbial mats and a thrombolite with calcareous algal filaments. All these constituents form a framestone fabric which is overall dominated by bryozoans labeling them as bryoherms. Inside the bioherms ecological successions of higher frequencies occur which are interpreted to reflect short-time environmental fluctuations such as nutrient availability, oxygenation (possible anoxia), salinity (possible brackish water), temperature and water level. The internal succession in individual bioherms is related to long-term environmental changes including general shallowing, increasing nutrient supply and decreasing water circulation and oxygenation. The described bioherms are most similar to modern bryostromatolites of the Coorong lagoon in S Australia and also similar to structures in the Netherlands. The widespread occurrence of bryoherms/bryostromatolites in the Central Paratethys suggests a phase of considerable eutrophication during the early Sarmatian.
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Amorphous calcium carbonate (ACC), precipitated in the presence of inorganic polyphosphate (polyP), has shown promise as a material for bone regeneration due to its morphogenetic and metabolic energy (ATP)-delivering properties. The latter activity of the polyP-stabilized ACC ("ACCâPP") particles is associated with the enzymatic degradation of polyP, resulting in the transformation of ACC into crystalline polymorphs. In a novel approach, stimulated by these results, it was examined whether "ACCâPP" also promotes the healing of skin injuries, especially chronic wounds. In in vitro experiments, "ACCâPP" significantly stimulated the migration of endothelial cells, both in tube formation and scratch assays (by 2- to 3-fold). Support came from ex vivo experiments showing increased cell outgrowth in human skin explants. The transformation of ACC into insoluble calcite was suppressed by protein/serum being present in wound fluid. The results were confirmed in vivo in studies on normal (C57BL/6) and diabetic (db/db) mice. Topical administration of "ACCâPP" significantly accelerated the rate of re-epithelialization, particularly in delayed healing wounds in diabetic mice (day 7: 1.5-fold; and day 13: 1.9-fold), in parallel with increased formation/maturation of granulation tissue. The results suggest that administration of "ACCâPP" opens a new strategy to improve ATP-dependent wound healing, particularly in chronic wounds.
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Understanding the optimal conditions required for bone healing can have a substantial impact to target the problem of non-unions and large bone defects. The combination of bioactive factors, regenerative progenitor cells and biomaterials to form a tissue engineered (TE) complex is a promising solution but translation to the clinic has been slow. We hypothesized the typical material testing algorithm used is insufficient and leads to materials being mischaracterized as promising. In the first part of this study, human bone marrow - derived mesenchymal stromal cells (hBM-MSCs) were embedded in three commonly used biomaterials (hyaluronic acid methacrylate, gelatin methacrylate and fibrin) and combined with relevant bioactive osteogenesis factors (dexamethasone microparticles and polyphosphate nanoparticles) to form a TE construct that underwent in vitro osteogenic differentiation for 28 days. Gene expression of relevant transcription factors and osteogenic markers, and von Kossa staining were performed. In the second and third part of this study, the same combination of TE constructs were implanted subcutaneously (cell containing) in T cell-deficient athymic Crl:NIH-Foxn1rnu rats for 8 weeks or cell free in an immunocompetent New Zealand white rabbit calvarial model for 6 weeks, respectively. Osteogenic performance was investigated via MicroCT imaging and histology staining. The in vitro study showed enhanced upregulation of relevant genes and significant mineral deposition within the three biomaterials, generally considered as a positive result. Subcutaneous implantation indicates none to minor ectopic bone formation. No enhanced calvarial bone healing was detected in implanted biomaterials compared to the empty defect. The reasons for the poor correlation of in vitro and in vivo outcomes are unclear and needs further investigation. This study highlights the discrepancy between in vitro and in vivo outcomes, demonstrating that in vitro data should be interpreted with extreme caution. In vitro models with higher complexity are necessary to increase value for translational studies. STATEMENT OF SIGNIFICANCE: Preclinical testing of newly developed biomaterials is a crucial element of the development cycle. Despite this, there is still significant discrepancy between in vitro and in vivo test results. Within this study we investigate multiple combinations of materials and osteogenic stimulants and demonstrate a poor correlation between the in vitro and in vivo data. We propose rationale for why this may be the case and suggest a modified testing algorithm.
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Substitutos Ósseos , Células-Tronco Mesenquimais , Ratos , Humanos , Animais , Coelhos , Osteogênese/fisiologia , Substitutos Ósseos/farmacologia , Substitutos Ósseos/metabolismo , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/metabolismo , Engenharia Tecidual , Diferenciação Celular/fisiologia , Alicerces TeciduaisRESUMO
Two new caryophyllene-type sesquiterpenes pestalotiopsins U and V (1 and 2) and three known compounds pestalotiopsin B (7), pestaloporinate B (8), and pestalotiopsin C (9) were isolated by the cultivation of the endophytic fungus Pestalotiopsis lespedezae on solid rice medium, while four additional new caryophyllene pestalotiopsins W-Z (3-6) were obtained when 3.5% NaI was added to the fungal culture medium. The structures of the new compounds were determined by HRESIMS and 1D/2D nuclear magnetic resonance data. Compounds 1-9 were tested for cytotoxicity against the mouse lymphoma cell line L5178Y, but only 6 displayed significant activity with an IC50 value of 2.4 µM.
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The Mariana forearc system, in the northwestern Pacific, is known as the only convergent margin setting with currently active serpentine mud volcanism. The Fantangisña serpentinite mud volcano lies 62 km west of the Mariana trench, within the influence of the North Equatorial Current (NEC). Cores recovered by International Ocean Discovery Program (IODP) Expedition 366 contain pelagic sediments overlying layered serpentinite mud deposits. At the bottom of the sequence, nannofossil-rich forearc deposits were recovered from under the seamount edifice. In this study, we investigated 47 samples from Site U1498A on the southern flank of the seamount for benthic and planktonic foraminifera assemblages. Statistical analyses on planktonic assemblages differentiated two sample groups related to the ratio between thermocline/mixed layer taxa, which indicate fluctuations in the depth of the thermocline (DOT) during the Pleistocene. Variations in the DOT reflect changes in the intensity of the NEC associated with El Niño/La Niña conditions. Mudflows do not influence the ecology of planktonic foraminifera but possibly enhance their preservation against dissolution, which was instead detected in the pelagic deposit as suggested by common Globigerinoides conglobatus. Benthic foraminifers were rare in serpentinite mud deposits as they are severely affected by mudflows. Conversely, they showed high diversity pre-/post-mud-volcanism, and indicate oligotrophic bottom-water conditions.