Influence of Si substitution on the reactivity of a-tricalcium phosphate

Silicon substituted calcium phosphates have been widely studied over the last ten years due to their enhanced osteogenic properties. Notwithstanding, the role of silicon on a-TCP reactivity is not clear yet. Therefore, the aim of this work was to evaluate the reactivity and the properties of Si-a-TCP in comparison to a-TCP. Precursor powders have similar properties regarding purity, particle size distribution and specific surface area, which allowed a better comparison of the Si effects on their reactivity and cements properties. Both Si-a-TCP and a-TCP hydrolyzed to a calcium-deficient hydroxyapatite when mixed with water but their conversion rates were different. Si-a-TCP exhibited a slower setting rate than a-TCP, i.e. kSSA for Si-TCP (0.021 g·m- 2·h- 1) was almost four times lower than for a-TCP (0.072 g·m- 2·h- 1). On the other hand, the compressive strength of the CPC resulting from fully reacted Si-a-TCP was significantly higher (12.80 ± 0.38 MPa) than that of a-TCP (11.44 ± 0.54 MPa), due to the smaller size of the entangled precipitated apatite crystals.Preprin

Plasma-Functionalized Isotactic Polypropylene Assembledwith Conducting Polymers for Bacterial Quantification byNADH Sensing

Rapid detection of bacterial presence on implantable medical devices isessential to prevent biofilm formation, which consists of densely packedbacteria colonies able to withstand antibiotic-mediated killing. In this work, asmart approach is presented to integrate electrochemical sensors fordetecting bacterial infections in biomedical implants made of isotacticpolypropylene (i-PP) using chemical assembly. The electrochemical detectionis based on the capacity of conducting polymers (CPs) to detect extracellularnicotinamide adenine dinucleotide (NADH) released from cellular respirationof bacteria, which allows distinguishing prokaryotic from eukaryotic cells.Oxygen plasma-functionalized free-standing i-PP, coated with a layer(≈1.1 μm in thickness) of CP nanoparticles obtained by oxidativepolymerization, is used as working electrode for the anodic polymerization ofa second CP layer (≈8.2 μm in thickness), which provides very highelectrochemical activity and stability. The resulting layered material, i-PPf/CP2,detects the electro-oxidation of NADH in physiological media with asensitivity 417 μA cm−2and a detection limit up to 0.14×10−3m, which isbelow the concentration of extracellular NADH found for bacterial cultures ofbiofilm-positive and biofilm-negative strains.Authors acknowledge MINECO/FEDER (RTI2018-098951-B-I00), the Agència de Gestió d’Ajuts Universitaris i de Recerca (2017SGR359), and B. Braun Surgical, S.A. for financial support. Support for the research of C.A. from ICREA Academia program for excellence in research is gratefully acknowledged

Novel CaLB-like Lipase Found Using ProspectBIO, a Software for Genome-Based Bioprospection

Enzymes have been highly demanded in diverse applications such as in the food, pharmaceutical, and industrial fuel sectors. Thus, in silico bioprospecting emerges as an efficient strategy for discovering new enzyme candidates. A new program called ProspectBIO was developed for this purpose as it can find non-annotated sequences by searching for homologs of a model enzyme directly in genomes. Here we describe the ProspectBIO software methodology and the experimental validation by prospecting for novel lipases by sequence homology to Candida antarctica lipase B (CaLB) and conserved motifs. As expected, we observed that the new bioprospecting software could find more sequences (1672) than a conventional similarity-based search in a protein database (733). Additionally, the absence of patent protection was introduced as a criterion resulting in the final selection of a putative lipase-encoding gene from Ustilago hordei (UhL). Expression of UhL in Pichia pastoris resulted in the production of an enzyme with activity towards a tributyrin substrate. The recombinant enzyme activity levels were 4-fold improved when lowering the temperature and increasing methanol concentrations during the induction phase in shake-flask cultures. Protein sequence alignment and structural modeling showed that the recombinant enzyme has high similarity and capability of adjustment to the structure of CaLB. However, amino acid substitutions identified in the active pocket entrance may be responsible for the differences in the substrate specificities of the two enzymes. Thus, the ProspectBIO software allowed the finding of a new promising lipase for biotechnological application without the need for laborious and expensive conventional bioprospecting experimental steps

Quantitative genetic analysis of floral traits shows current limits but potential evolution in the wild

The vast variation in floral traits across angiosperms is often interpreted as the result of adaptation to pollinators. However, studies in wild populations often find no evidence of pollinator-mediated selection on flowers. Evolutionary theory predicts this could be the outcome of periods of stasis under stable conditions, followed by shorter periods of pollinator change that provide selection for innovative phenotypes. We asked if periods of stasis are caused by stabilizing selection, absence of other forms of selection or by low trait ability to respond even if selection is present. We studied a plant predominantly pollinated by one bee species across its range. We measured heritability and evolvability of traits, using genome-wide relatedness in a large wild population, and combined this with estimates of selection on the same individuals. We found evidence for both stabilizing selection and low trait heritability as potential explanations for stasis in flowers. The area of the standard petal is under stabilizing selection, but the variability is not heritable. A separate trait, floral weight, presents high heritability, but is not currently under selection. We show how a simple pollination environment coincides with the absence of current prerequisites for adaptive evolutionary change, while heritable variation remains to respond to future selection pressures

NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas

In 2015 Weren et al. described a hereditary cancer syndrome caused by biallelic mutations in the DNA base excision repair gene NTHL1, characterized by attenuated adenomatous polyposis and increased colorectal cancer (CRC) risk, largely resembling the recessive syndrome caused by MUTYH mutations1. To date, 33 homozygous or compound heterozygous NTHL1 mutation carriers have been reported (21 families)1,2,3,4,5,6,7,8. More than 5 colonic adenomas (range: 6 to >50) were identified in 24 of the 28 (85%) mutation carriers who underwent colonoscopy screening, and CRC was diagnosed in 19 (68%) of them. Noteworthy, 17 carriers (57%) were diagnosed with multiple primary malignant tumors in extracolonic locations, being the most recurrently found breast and endometrial tumors, head neck squamous cell carcimomas, meningiomas, and bladder and basal cell carcinomas, suggesting that the NTHL1-associated syndrome is a multi-tumor disease rather than a solely CRC syndrome. On the other hand, the fact that at least ¼ (7/28) of the reported biallelic mutation carriers who underwent colonoscopy screening had ≤10 adenomas, and that ≥5 hyperplastic polyps were detected in five carriers (polyp number range: 5->30), lead us to suspect a possible association of NTHL1 mutations with nonpolyposis CRC and serrated/hyperplastic polyposis. Based on previous evidence and with the aim of refining the phenotypic characteristics of the NTHL1-associated syndrome, here we evaluated the implication of NTHL1 biallelic mutations in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated/hyperplastic polyposis

Analytical and clinical performance of the panbio COVID-19 antigen-detecting rapid diagnostic test

info:eu-repo/semantics/submittedVersio

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency < 0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency < 0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology

Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor

Essential tremor (ET) is a common movement disorder with an estimated prevalence of 5% of the population aged over 65 years. In spite of intensive efforts, the genetic architecture of ET remains unknown. We used a combination of whole-exome sequencing and targeted resequencing in three ET families. In vitro and in vivo experiments in oligodendrocyte precursor cells and zebrafish were performed to test our findings. Whole-exome sequencing revealed a missense mutation in TENM4 segregating in an autosomal-dominant fashion in an ET family. Subsequent targeted resequencing of TENM4 led to the discovery of two novel missense mutations. Not only did these two mutations segregate with ET in two additional families, but we also observed significant over transmission of pathogenic TENM4 alleles across the three families. Consistent with a dominant mode of inheritance, in vitro analysis in oligodendrocyte precursor cells showed that mutant proteins mislocalize. Finally, expression of human mRNA harboring any of three patient mutations in zebrafish embryos induced defects in axon guidance, confirming a dominant-negative mode of action for these mutations. Our genetic and functional data, which is corroborated by the existence of a Tenm4 knockout mouse displaying an ET phenotype, implicates TENM4 in ET. Together with previous studies of TENM4 in model organisms, our studies intimate that processes regulating myelination in the central nervous system and axon guidance might be significant contributors to the genetic burden of this disorde

Resisting and tolerating P. falciparum in pregnancy under different malaria transmission intensities.

BACKGROUND: Resistance and tolerance to Plasmodium falciparum can determine the progression of malaria disease. However, quantitative evidence of tolerance is still limited. We investigated variations in the adverse impact of P. falciparum infections among African pregnant women under different intensities of malaria transmission. METHODS: P. falciparum at delivery was assessed by microscopy, quantitative PCR (qPCR) and placental histology in 946 HIV-uninfected and 768 HIV-infected pregnant women from Benin, Gabon, Kenya and Mozambique. Resistance was defined by the proportion of submicroscopic infections and the levels of anti-parasite antibodies quantified by Luminex, and tolerance by the relationship of pregnancy outcomes with parasite densities at delivery. RESULTS: P. falciparum prevalence by qPCR in peripheral and/or placental blood of HIV-uninfected Mozambican, Gabonese and Beninese women at delivery was 6% (21/340), 11% (28/257) and 41% (143/349), respectively. The proportion of peripheral submicroscopic infections was higher in Benin (83%) than in Mozambique (60%) and Gabon (55%; P = 0.033). Past or chronic placental P. falciparum infection was associated with an increased risk of preterm birth in Mozambican newborns (OR = 7.05, 95% CI 1.79 to 27.82). Microscopic infections were associated with reductions in haemoglobin levels at delivery among Mozambican women (-1.17 g/dL, 95% CI -2.09 to -0.24) as well as with larger drops in haemoglobin levels from recruitment to delivery in Mozambican (-1.66 g/dL, 95% CI -2.68 to -0.64) and Gabonese (-0.91 g/dL, 95% CI -1.79 to -0.02) women. Doubling qPCR-peripheral parasite densities in Mozambican women were associated with decreases in haemoglobin levels at delivery (-0.16 g/dL, 95% CI -0.29 to -0.02) and increases in the drop of haemoglobin levels (-0.29 g/dL, 95% CI -0.44 to -0.14). Beninese women had higher anti-parasite IgGs than Mozambican women (P < 0.001). No difference was found in the proportion of submicroscopic infections nor in the adverse impact of P. falciparum infections in HIV-infected women from Kenya (P. falciparum prevalence by qPCR: 9%, 32/351) and Mozambique (4%, 15/417). CONCLUSIONS: The lowest levels of resistance and tolerance in pregnant women from areas of low malaria transmission were accompanied by the largest adverse impact of P. falciparum infections. Exposure-dependent mechanisms developed by pregnant women to resist the infection and minimise pathology can reduce malaria-related adverse outcomes. Distinguishing both types of defences is important to understand how reductions in transmission can affect malaria disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT00811421 . Registered 18 December 2008

Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis

Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance