Lampreys, the jawless vertebrates, contain three Pax6 genes with distinct expression in eye, brain and pancreas

10.1038/s41598-019-56085-8Scientific Reports911955

Perturbation of adhesion molecule-mediated chondrocyte-matrix interactions by 4-hydroxynonenal binding: implication in osteoarthritis pathogenesis

ABSTRACT: INTRODUCTION: Objectives were to investigate whether interactions between human osteoarthritic chondrocytes and 4-hydroxynonenal (HNE)-modified type II collagen (Col II) affect cell phenotype and functions and to determine the protective role of carnosine (CAR) treatment in preventing these effects. METHODS: Human Col II was treated with HNE at different molar ratios (MR) (1:20 to 1:200; Col II:HNE). Articular chondrocytes were seeded in HNE/Col II adduct-coated plates and incubated for 48 hours. Cell morphology was studied by phase-contrast and confocal microscopy. Adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and alpha1beta1 integrin at protein and mRNA levels were quantified by Western blotting, flow cytometry and real-time reverse transcription-polymerase chain reaction. Cell death, caspases activity, prostaglandin E2 (PGE2), metalloproteinase-13 (MMP-13), mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB) were assessed by commercial kits. Col II, cyclooxygenase-2 (COX-2), MAPK, NF-kappaB-p65 levels were analyzed by Western blotting. The formation of alpha1beta1 integrin-focal adhesion kinase (FAK) complex was revealed by immunoprecipitation. RESULTS: Col II modification by HNE at MR approximately 1:20, strongly induced ICAM-1, alpha1beta1 integrin and MMP-13 expression as well as extracellular signal-regulated kinases 1 and 2 (ERK1/2) and NF-kappaB-p65 phosphorylation without impacting cell adhesion and viability or Col II expression. However, Col II modification with HNE at MR approximately 1:200, altered chondrocyte adhesion by evoking cell death and caspase-3 activity. It inhibited alpha1beta1 integrin and Col II expression as well as ERK1/2 and NF-kappaB-p65 phosphorylation, but, in contrast, markedly elicited PGE2 release, COX-2 expression and p38 MAPK phosphorylation. Immunoprecipitation assay revealed the involvement of FAK in cell-matrix interactions through the formation of alpha1beta1 integrin-FAK complex. Moreover, the modification of Col II by HNE at a 1:20 or approximately 1:200 MR affects parameters of the cell shape. All these effects were prevented by CAR, an HNE-trapping drug. CONCLUSIONS: Our novel findings indicate that HNE-binding to Col II results in multiple abnormalities of chondrocyte phenotype and function, suggesting its contribution in osteoarthritis development. CAR was shown to be an efficient HNE-snaring agent capable of counteracting these outcomes

Selective deployment of transcription factor paralogs with submaximal strength facilitates gene regulation in the immune system

In multicellular organisms, duplicated genes can diverge through tissue-specific gene expression patterns, as exemplified by highly regulated expression of Runx transcription factor paralogs with apparent functional redundancy. Here we asked what cell type-specific biologies might be supported by the selective expression of Runx paralogs during Langerhans cell and inducible regulatory T cell differentiation. We uncovered functional non-equivalence between Runx paralogs. Selective expression of native paralogs allowed integration of transcription factor activity with extrinsic signals, while non-native paralogs enforced differentiation even in the absence of exogenous inducers. DNA-binding affinity was controlled by divergent amino acids within the otherwise highly conserved RUNT domain, and evolutionary reconstruction suggested convergence of RUNT domain residues towards sub-maximal strength. Hence, the selective expression of gene duplicates in specialized cell types can synergize with the acquisition of functional differences to enable appropriate gene expression, lineage choice and differentiation in the mammalian immune system

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Synthesis and Self-Assembly of Well-Defined Block Copolypeptides via Controlled NCA Polymerization

This article summarizes advances in the synthesis of well-defined polypeptides and block copolypeptides. Traditional methods used to polymerize α-amino acid-N-carboxyanhydrides (NCAs) are described, and limitations in the utility of these systems for the preparation of polypeptides are discussed. Improved initiators and methods that allow polypeptide synthesis with good control over chain length, chain length distribution, and chain-end functionality are also discussed. Using these methods, block and random copolypeptides of controlled dimensions (including molecular weight, sequence, composition, and molecular weight distribution) can now be prepared. The ability of well-defined block copolypeptides to assemble into supramolecular copolypeptide micelles, copolypeptide vesicles, and copolypeptide hydrogels is described. Many of these assemblies have been found to possess unique properties that are derived from the amino acid building blocks and ordered conformations of the polypeptide segments. © Springer-Verlag Berlin Heidelberg 2013

Atherosclerosis

Atherosclerosis is the multifactorial inflammatory disease of the vasculature that affects large- and medium-sized arterial vessels. It is the process in which lipid plaque builds up inside the lumen of arteries and restricts blood flow. It is responsible for the majority of heart attacks and strokes. The plaque is composed of a lipid-rich gruel, engorged inflammatory cells and free fats and cholesterol that become trapped in the sub-endothelial space, often with a thin overlaying vascular smooth muscle cell cap. While the first steps in the plaque development may take place in adolescence or earlier, it may be many decades for the plaque to reach full maturity and become rupture prone. Traditionally a destabilised plaque is characterised by a paucity of vascular smooth muscle cells that provide the structural support and mechanical strength, with an excess of inflammatory cells. These inflammatory cells initially attempt to resolve the lesions but later contribute to plaque expansion, such that the plaque grows in size overtime. Atheroma is also responsible for the decreased supply of oxygen to the heart that causes angina in stable patients but if the plaque ruptures is responsible for acute myocardial infarction and stroke. This chapter explores the development of the atherosclerosis and provides a historical perspective and the risk factors associated with the development of disease. The chapter investigates current research methods and clinical perspectives for the future

Soil and leaf fertilization of lettuce crop with cow urine Fertilização com urina de vaca em alface via solo e foliar

The use of cow urine can be considered an agricultural practice of low cost for farmers. Nevertheless, its efficiency on crop needs research information. The present research aimed to evaluate the effect of cow urine on the growth and yield of 'Regina 2000' lettuce, in an experiment carried out from January 13, 2006 to March 22, 2006. The experiment was set up with 12 treatments, in a split-plot design and four completely randomized blocks. The soil and leaf applications were installed in the plot. In the split-plot, cow urine was applied at different concentrations (0.00; 0.25; 0.50; 0.75; 1.00 and 1.25 %). The plot presented four rows with 1.75 m each, in 0.25 x 0.25 m spacing. The six central plants of the two central rows formed the sampled split-plot. At harvest, the following variables were evaluated: fresh (FLM) and dry (DLM) leaf mass, fresh (FSM) and dry (DSM) stem mass, stem length (SL), fresh (FRM) and dry (DRM) root mass, fresh (FHM) and dry (DHM) head mass and commercial yield (CY). The increase in cow urine concentrations increased the performance of all lettuce characteristics, except DRM, which presented reduction, and DSM and FRM, which were not affected. The highest yield was obtained with the concentration of 1.25% (17.00 t ha-1) applied to leaves and with 1.01% (14.92 t ha-1), applied to soil, corresponding, respectively to increases of 28.1% and 47.3%, in comparison to the control. Application to leaves, in comparison to application to soil, resulted in greater FLM (0.50 and 1.25%), SL (0.50; 0.75 and 1.25%), FSM and FRM (0.5%), FHM and CY (0.50 and 1.25%), but lower DSM and FRM (1.25%) and DRM (1.0 and 1.25%). The application of cow urine solution at 1.25% to leaves or 1.0% to soil is recommended for lettuce crops.<br>A utilização da urina de vaca pode ser considerada uma prática de custo baixo para os produtores rurais. Todavia, a sua eficiência sobre as culturas carece de informações da pesquisa. Assim, objetivou-se avaliar o efeito da urina de vaca sobre o crescimento e produção da alface em experimento conduzido de 13 de janeiro de 2006 a 22 de março de 2006, com a cv. Regina 2000. O experimento foi constituído de 12 tratamentos, em esquema de parcelas subdivididas, delineamento de blocos ao acaso, com quatro repetições. Nas parcelas foram alocadas as aplicações das soluções de urina (solo e foliar) e, nas subparcelas, as concentrações (0,00; 0,25; 0,50; 0,75; 1,00 e 1,25%). A subparcela foi constituída por quatro fileiras de 1,75 m, espaçamento de 0,25 x 0,25 m e consideraram-se, como úteis, as seis plantas centrais das duas fileiras centrais. Na colheita foram avaliados a massa da matéria fresca (MFF) e seca de folhas (MSF); massa da matéria fresca (MFC) e seca de caule (MSC); comprimento de caule (CC); massa da matéria fresca (MFR) e seca de raízes (MSR); massa da matéria fresca (MFCA) e seca da cabeça (MSCA) e produtividade comercial (PROD). Exceto a MSR, que diminuiu e MSC e MFR que não foram alteradas na aplicação via foliar, as demais características avaliadas apresentaram incremento às concentrações aplicadas. Maior produtividade de cabeça foi obtida com concentrações de 1,25% (17,0 t ha-1) aplicada via foliar e de 1,01% (14,9 t ha-1) aplicada via solo correspondendo, respectivamente, a aumentos em produtividade de 28,1% e de 47,3%, comparados à testemunha. A aplicação foliar, comparada via solo, proporcionou maior MFF (0,50 e 1,25%), CC (0,50; 0,75 e 1,25%), MFC e MFR (0,5%), MFCA e PROD (0,50 e 1,25%) e menores MSC e MFR (1,25%) e MSR (1,0 e 1,25%). Sugere-se, no cultivo da alface, a aplicação das doses de solução de urina às concentrações de 1,25% via foliar ou de 1,0%, via solos

Prediction of human active mobility in rural areas: development and validity tests of three different approaches.

Estimated and measured hours/week spent on active mobility had low correspondence, even the best predicting estimation method based on self-reported data, resulted in a R2 of 0.09 and Cohen's kappa of 0.07. A visual check indicated that, although predicted routes to work appeared to match GPS measured tracks, only a small proportion of active mobility was captured in this way, thus resulting in a low validity of overall predicted active mobility