Biocomposite macrospheres based on strontium-bioactive glass for application as bone fillers

Traditional bioactive glass powders are typically composed of irregular particles that can be packed into dense configurations presenting low interconnectivity, which can limit bone ingrowth. The use of novel biocomposite sphere formulations comprising bioactive factors as bone fillers are most advantageous, as it simultaneously allows for packing the particles in a 3-dimensional manner to achieve an adequate interconnected porosity, enhanced biological performance, and ultimately a superior new bone formation. In this work, we develop and characterize novel biocomposite macrospheres of Sr-bioactive glass using sodium alginate, polylactic acid (PLA), and chitosan (CH) as encapsulating materials for finding applications as bone fillers. The biocomposite macrospheres that were obtained using PLA have a larger size distribution and higher porosity and an interconnectivity of 99.7%. Loose apatite particles were observed on the surface of macrospheres prepared with alginate and CH by means of soaking into a simulated body fluid (SBF) for 7 days. A dense apatite layer was formed on the biocomposite macrospheresâ surface produced with PLA, which served to protect PLA from degradation. In vitro investigations demonstrated that biocomposite macrospheres had minimal cytotoxic effects on a human osteosarcoma cell line (SaOS-2 cells). However, the accelerated degradation of PLA due to the degradation of bioactive glass may account for the observed decrease in SaOS-2 cells viability. Among the biocomposite macrospheres, those composed of PLA exhibited the most promising characteristics for their potential use as fillers in bone tissue repair applications.This work was funded by grant #2019/15960-6, São Paulo Research Foundation in Brazil (FAPESP) and the Portuguese Foundation for Science and Technology (FCT), Reference UID/CTM/50025/2019 and FCT/Minister of Science, Technology and Higher Education in Portugal (MCTES) and by European Regional Development Fund (FEDER) funds through the COMPETE 2020 Program in the framework of ORAiDEA project (ref n° 39985 - AAC 31/SI/2017). The authors would also like to acknowledge Materials Research Center (CENIMAT) of the Associated Laboratory Institute of Nanostructures, Nanomodeling and Nanofabrication (i3N), NOVA University of LisbonCENIMAT|i3N and National Council for Scientific and Technological Development in Brazil CNPq (303149/2018-3). Ibrahim Fatih Cengiz acknowledges the FCT distinction attributed to him under the “Estímulo ao Emprego Científico” program (2021.01969.CEECIND). The authors thank the financial support provided under the projects: “HEALTH-UNORTE: Setting-up biobanks and regenerative medicine strategies to boost research in cardiovascular, musculoskeletal, neurological, oncological, immunological, and infectious diseases”, reference NORTE-01-0145-FEDER-000039, funded by the Norte Portugal Regional Coordination and Development Commission (CCDR-N), under the NORTE2020 Program; Projects LA/P/0037/2020, UIDP/50025/2020, and UIDB/50025/ 2020 of the Associate Laboratory i3N financed by national funds from FCT

Nucleon-nucleon interaction in the Skyrme model

We consider the interaction of two skyrmions in the framework of the sudden approximation. The widely used product ansatz is investigated. Its failure in reproducing an attractive central potential is associated with terms that violate G-parity. We discuss the construction of alternative ans\"atze and identify a plausible solution to the problem.Comment: 18 pages, 9 figure

A hybrid-capture approach to reconstruct the phylogeny of Scleractinia (Cnidaria: Hexacorallia)

A well-supported evolutionary tree representing most major lineages of scleractinian corals is in sight with the development and application of phylogenomic approaches. Specifically, hybrid-capture techniques are shedding light on the evolution and systematics of corals. Here, we reconstructed a broad phylogeny of Scleractinia to test previous phylogenetic hypotheses inferred from a few molecular markers, in particular, the relationships among major scleractinian families and genera, and to identify clades that require further research. We analysed 449 nuclear loci from 422 corals, comprising 266 species spanning 26 families, combining data across whole genomes, transcriptomes, hybrid capture and low-coverage sequencing to reconstruct the largest phylogenomic tree of scleractinians to date. Due to the large number of loci and data completeness (less than 38% missing data), node supports were high across shallow and deep nodes with incongruences observed in only a few shallow nodes. The “Robust” and “Complex” clades were recovered unequivocally, and our analyses confirmed that Micrabaciidae Vaughan, 1905 is sister to the “Robust” clade, transforming our understanding of the “Basal” clade. Several families remain polyphyletic in our phylogeny, including Deltocyathiidae Kitahara, Cairns, Stolarski & Miller, 2012, Caryophylliidae Dana, 1846, and Coscinaraeidae Benzoni, Arrigoni, Stefani & Stolarski, 2012, and we hereby formally proposed the family name Pachyseridae Benzoni & Hoeksema to accommodate Pachyseris Milne Edwards & Haime, 1849, which is phylogenetically distinct from Agariciidae Gray, 1847. Results also revealed species misidentifications and inconsistencies within morphologically complex clades, such as Acropora Oken, 1815 and Platygyra Ehrenberg, 1834, underscoring the need for reference skeletal material and topotypes, as well as the importance of detailed taxonomic work. The approach and findings here provide much promise for further stabilising the topology of the scleractinian tree of life and advancing our understanding of coral evolution

An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression

TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53–PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors. Significance: We analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy

Global, regional, and national burden of chronic kidney disease, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI

Comparing the Bacterial Diversity of Acute and Chronic Dental Root Canal Infections

This study performed barcoded multiplex pyrosequencing with a 454 FLX instrument to compare the microbiota of dental root canal infections associated with acute (symptomatic) or chronic (asymptomatic) apical periodontitis. Analysis of samples from 9 acute abscesses and 8 chronic infections yielded partial 16S rRNA gene sequences that were taxonomically classified into 916 bacterial species-level operational taxonomic units (OTUs) (at 3% divergence) belonging to 67 genera and 13 phyla. The most abundant phyla in acute infections were Firmicutes (52%), Fusobacteria (17%) and Bacteroidetes (13%), while in chronic infections the dominant were Firmicutes (59%), Bacteroidetes (14%) and Actinobacteria (10%). Members of Fusobacteria were much more prevalent in acute (89%) than in chronic cases (50%). The most abundant/prevalent genera in acute infections were Fusobacterium and Parvimonas. Twenty genera were exclusively detected in acute infections and 18 in chronic infections. Only 18% (n = 165) of the OTUs at 3% divergence were shared by acute and chronic infections. Diversity and richness estimators revealed that acute infections were significantly more diverse than chronic infections. Although a high interindividual variation in bacterial communities was observed, many samples tended to group together according to the type of infection (acute or chronic). This study is one of the most comprehensive in-deep comparisons of the microbiota associated with acute and chronic dental root canal infections and highlights the role of diverse polymicrobial communities as the unit of pathogenicity in acute infections. The overall diversity of endodontic infections as revealed by the pyrosequencing technique was much higher than previously reported for endodontic infections

Визуализация сетей покоя (resting state) фМРТ у пациентов с тяжелой черепно-мозговой травмой

According to the literature, fMRI analysis at resting state (RS) is an informative methodological approach to the study of the basic level of a healthy and diseased brain’s functional activity. Averaging data over observation groups for various forms of cerebral pathology is often unacceptable. Previously, we mastered and applied the Independent Component Algorithm (ICA) in FSL software to visualize and analyze individual fMRI resting networks of healthy people.Objective: to analyze individual fMRI resting networks associated with the state of motor activity and consciousness in patients with severe traumatic brain injury (STBI).Materials and methods. Observation groups: 23 patients with SТBI (main) and 17 healthy volunteers (control). 3T fMRI recorded at rest. Individual (norm and STBI) and group (norm) analysis of RS networks was carried out by FSL software (ICA algorithm) and SPM8 in MATLAB.For the DMN and Sensorimotor networks, topography and total volume and intensity of their activation of their activation were determined.Results. The topography features reproduced in the group and individual analysis of fMRI of healthy people, as well as the averaged quantitative indicators of the rest networks were used as reference for pathology.In the context of motor activity, the RS Sensorimotor network was considered. Its topography is close to normal in most patients without or with mild hemiparesis. The growth of this defect is accompanied by a decrease in the integral quantitative indicators of the network, combined with asymmetric reduction (lack of activation in the contralateral motor cortex) in rough hemiparesis.In the context of consciousness, the expression and characteristics of the DMN network were compared in healthy people and in patients with STBI at its various levels: from clear to chronic vegetative state. It was revealed that a decrease in the level of consciousness is accompanied by a reduction in the cortical components of DMN, primarily the frontal (anterior DMN), not pronounced in the vegetative state. Activation of the caudal component of DMN (in particular, the posterior cingular cortex) persists in patients with depressed consciousness: distinct and even somewhat enhanced compared to the norm with its reversible form, less pronounced with chronicConclusion. The data obtained indicate the informative value of fMRI analysis of individual resting networks in the context of studying cerebral structural and functional foundations of consciousness and motor activity, as well as diagnosing the state of these functions in STBI.По данным литературы, анализ функциональной манитно-резонансной томографии (фМРТ) в состоянии покоя (RS) является информативным методическим подходом к исследованию базового уровня функциональной активности здорового и больного мозга. Усреднение данных по группам наблюдений при разных формах церебральной патологии зачастую неприемлемо. Ранее нами был освоен и применен алгоритм независимых компонент (ICA) в программном обеспечении FSL для визуализации и анализа индивидуальных сетей покоя фМРТ здоровых людей.Цель исследования: анализ индивидуальных сетей покоя фМРТ, сопряженных с состоянием двигательной активности и сознания, у пациентов с тяжелой черепно-мозговой травмой (ТЧМТ).Материал и методы. Группы наблюдений: 23 пациента с ТЧМТ, сопровождавшейся разной степенью угнетения сознания и двигательных нарушений в форме гемипареза (основная), и 17 здоровых испытуемых (контроль). У каждого записывали фМРТ 3 Тл в состоянии покоя с закрытыми глазами. Проводили групповой (в норме) и индивидуальный (в норме и при патологии) фМРТ-анализ RS с использованием программных средств FSL (алгоритм ICA) и SPM8 в среде MATLAB. Для сетей DMN и Sensorimotor определяли топографию активированных зон мозга, представленность сетей в группах наблюдений, общий объем и интенсивность их активации.Результаты. Воспроизводимые при групповом и индивидуальном анализе фМРТ здоровых людей особенности топографии, а также усредненные количественные показатели сетей покоя были использованы в качестве эталонных для патологии.В контексте двигательной активности рассматривали сенсомоторную сеть RS. Ее топография близка к норме у большинства пациентов без или с легким гемипарезом. Нарастание этого дефекта сопровождается  уменьшением интегральных количественных показателей сети, сочетающимся с асимметричной редукцией (отсутствием активации в контралатеральной моторной коре) при грубом гемипарезе.В контексте сознания анализировали особенности сети DMN у пациентов с ТЧМТ при разном его уровне: от ясного до хронического вегетативного состояния. Выявлено, что снижение уровня сознания сопровождается редукцией корковых составляющих DMN, в первую очередь лобных (anterior DMN), не выраженной при вегетативном состоянии. Активациия каудального компонента DMN (в частности, задней цингулярной коры) у пострадавших с угнетенным сознанием сохраняется: отчетливая и даже несколько усиленная по сравнению с нормой при обратимой его форме, менее выраженная – при хронической.Заключение. Полученные данные свидетельствуют об информативности фМРТ-анализа индивидуальных сетей покоя в контексте изучения церебральных структурно-функциональных основ сознания и двигательной активности, а также диагностики состояния этих функций при ТЧМТ

Pyrosequencing as a tool for better understanding of human microbiomes

Next-generation sequencing technologies have revolutionized the analysis of microbial communities in diverse environments, including the human body. This article reviews several aspects of one of these technologies, the pyrosequencing technique, including its principles, applications, and significant contribution to the study of the human microbiome, with especial emphasis on the oral microbiome. The results brought about by pyrosequencing studies have significantly contributed to refining and augmenting the knowledge of the community membership and structure in and on the human body in healthy and diseased conditions. Because most oral infectious diseases are currently regarded as biofilm-related polymicrobial infections, high-throughput sequencing technologies have the potential to disclose specific patterns related to health or disease. Further advances in technology hold the perspective to have important implications in terms of accurate diagnosis and more effective preventive and therapeutic measures for common oral diseases