The prevalence of aluminum (Al) intoxication has declined over the past 3 decades. However, different groups still report on the diagnosis of Al in bone. Prolonged and low-intensity exposures to Al ...may not be captured by serum Al measurements, preventing its proper diagnosis. We hypothesize that bone Al accumulation may be related to bone and cardiovascular events in the current Era.
To detect the diagnosis of bone Al accumulation; to explore bone and cardiovascular consequences of Al accumulation.
This is a sub-analysis of The Brazilian Registry of Bone Biopsy, a prospective, multicentre cohort, with a mean follow-up of 3.4 years, including patients with CKD undergoing bone biopsy; bone fracture and major cardiovascular events (MACE) were adjudicated; Al accumulation was identified by solochrome-azurine staining; history of previous Al accumulation was registered based on information provided by the nephrologist who performed the bone biopsy; bone histomorphometry parameters, clinical data, and general biochemistry were registered.
275 individuals were considered; 96 (35%) patients have diagnosed with bone Al accumulation and were younger 50 (41-56) vs. 55 (43-61) years; p = 0.026, had lower body mass index 23.5 (21.6-25.5) vs. 24.3 (22.1-27.8) kg/m2; p = 0.017, higher dialysis vintage 108 (48-183) vs. 71 (28-132) months; p = 0.002, presented pruritus 23 (24%) vs. 20 (11%); p = 0.005, tendon rupture 7 (7%) vs. 3 (2%); p = 0.03) and bone pain 2 (0-3) vs. 0 (0-3) units; p = 0.02. Logistic regression reveals that prior bone Al accumulation OR: 4.517 (CI: 1.176-17.353); p = 0.03 and dialysis vintage OR: 1.003 (CI: 1.000-1.007); p = 0.046 as independent determinants of bone Al accumulation; minor perturbations in dynamic bone parameters and no differences in bone fractures rate were noted; MACE was more prevalent in patients with bone Al accumulation 21 (34%) vs. 23 (18%) events; p = 0.016. Cox regression shows the actual/prior diagnosis of bone Al accumulation and diabetes mellitus as independent predictors for MACE: HR = 3.129 (CI: 1.439-6.804; p = 0.004) and HR = 2.785 (CI: 1.120-6.928; p = 0.028.
An elevated proportion of patients have bone Al accumulation, associated with a greater prevalence of bone pain, tendon rupture, and pruritus; bone Al accumulation was associated with minor perturbations in renal osteodystrophy; actual/prior diagnosis of bone Al accumulation and diabetes mellitus were independent predictors for MACE.
The Park Grass experiment (PGE) in the UK has been ongoing since 1856. Its purpose is to study the response of biological communities to the long-term treatments and associated changes in soil ...parameters, particularly soil pH. In this study, soil samples were collected across pH gradient (pH 3.6–7) and a range of fertilizers (nitrogen as ammonium sulfate, nitrogen as sodium nitrate, phosphorous) to evaluate the effects nutrients have on soil parameters and microbial community structure. Illumina 16S ribosomal RNA (rRNA) amplicon sequencing was used to determine the relative abundances and diversity of bacterial and archaeal taxa. Relationships between treatments, measured soil parameters, and microbial communities were evaluated. Clostridium, Bacteroides, Bradyrhizobium, Mycobacterium, Ruminococcus, Paenibacillus, and Rhodoplanes were the most abundant genera found at the PGE. The main soil parameter that determined microbial composition, diversity, and biomass in the PGE soil was pH. The most probable mechanism of the pH impact on microbial community may include mediation of nutrient availability in the soil. Addition of nitrogen to the PGE plots as ammonium sulfate decreases soil pH through increased nitrification, which causes buildup of soil carbon, and hence increases C/N ratio. Plant species richness and plant productivity did not reveal significant relationships with microbial diversity; however, plant species richness was positively correlated with soil microbial biomass. Plants responded to the nitrogen treatments with an increase in productivity and a decrease in the species richness.
Maternal immune activation (MIA) and poor maternal nutritional habits are risk factors for the occurrence of neurodevelopmental disorders (NDD). Human studies show the deleterious impact of prenatal ...inflammation and low n-3 polyunsaturated fatty acid (PUFA) intake on neurodevelopment with long-lasting consequences on behavior. However, the mechanisms linking maternal nutritional status to MIA are still unclear, despite their relevance to the etiology of NDD. We demonstrate here that low maternal n-3 PUFA intake worsens MIA-induced early gut dysfunction, including modification of gut microbiota composition and higher local inflammatory reactivity. These deficits correlate with alterations of microglia-neuron crosstalk pathways and have long-lasting effects, both at transcriptional and behavioral levels. This work highlights the perinatal period as a critical time window, especially regarding the role of the gut-brain axis in neurodevelopment, elucidating the link between MIA, poor nutritional habits, and NDD.
Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain ...barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg(-1) per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.
Neuronal primary cilia are signaling organelles with crucial roles in brain development and disease. Cilia structure is decisive for their signaling capacities but the mechanisms regulating it are ...poorly understood. We identify Fbxo41 as a novel Skp1/Cullin1/F-box (SCF) E3-ligase complex subunit that targets to neuronal centrioles where its accumulation promotes disassembly of primary cilia, and affects sonic hedgehog signaling, a canonical ciliary pathway. Fbxo41 targeting to centrioles requires its Coiled-coil and F-box domains. Levels of Fbxo41 at the centrioles inversely correlate with neuronal cilia length, and mutations that disrupt Fbxo41 targeting or assembly into SCF-complexes also disturb its function in cilia disassembly and signaling. Fbxo41 dependent cilia disassembly in mitotic and post-mitotic cells requires rearrangements of the actin-cytoskeleton, but requires Aurora A kinase activation only in mitotic cells, highlighting important mechanistical differences controlling cilia size between mitotic and post-mitotic cells. Phorbol esters induce recruitment of overexpressed Fbxo41 to centrioles and cilia disassembly in neurons, but disassembly can also occur in absence of Fbxo41. We propose that Fbxo41 targeting to centrosomes regulates neuronal cilia structure and signaling capacity in addition to Fbxo41-independent pathways controlling cilia size.
Proprioceptive neurons (PNs) are essential for the proper execution of all our movements by providing muscle sensory feedback to the central motor network. Here, using deep single cell RNAseq of ...adult PNs coupled with virus and genetic tracings, we molecularly identify three main types of PNs (Ia, Ib and II) and find that they segregate into eight distinct subgroups. Our data unveil a highly sophisticated organization of PNs into discrete sensory input channels with distinct spatial distribution, innervation patterns and molecular profiles. Altogether, these features contribute to finely regulate proprioception during complex motor behavior. Moreover, while Ib- and II-PN subtypes are specified around birth, Ia-PN subtypes diversify later in life along with increased motor activity. We also show Ia-PNs plasticity following exercise training, suggesting Ia-PNs are important players in adaptive proprioceptive function in adult mice.
Motor neuron degeneration, the defining feature of amyotrophic lateral sclerosis (ALS), is a primary example of cell-type specificity in neurodegenerative diseases. Using isogenic pairs of induced ...pluripotent stem cells (iPSCs) harboring different familial ALS mutations, we assess the capacity of iPSC-derived lower motor neurons, sensory neurons, astrocytes, and superficial cortical neurons to capture disease features including transcriptional and splicing dysregulation observed in human postmortem neurons. At early time points, differentially regulated genes in iPSC-derived lower motor neurons, but not other cell types, overlap with one-third of the differentially regulated genes in laser-dissected motor neurons from ALS compared with control postmortem spinal cords. For genes altered in both the iPSC model and bona fide human lower motor neurons, expression changes correlate between the two populations. In iPSC-derived lower motor neurons, but not other derived cell types, we detect the downregulation of genes affected by TDP-43-dependent splicing. This reduction takes place exclusively within genotypes known to involve TDP-43 pathology.
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•fALS iPSC LMNs capture one-third of gene expression changes in postmortem sALS LMNs•iPSC LMNs, but not other neurons, captured postmortem LMN gene expression changes•Dysregulated genes in fALS iPSC-LMNs include TDP-43 splicing targets•RNA clearance may be disrupted in postmortem LMNs but intact in iPSC LMNs
Amyotrophic lateral sclerosis causes motor neuron degeneration but leaves most other neurons intact. Held et al. find that familial ALS mutations cause distinct RNA profiles in iPSC-derived motor neurons compared with other cell types and that fALS iPSC motor neurons capture gene expression changes in postmortem sporadic ALS motor neurons.
Bone graft infections are serious complications in orthopaedics and the growing resistance to antibiotics is increasing the need for antibacterial strategies. The use of magnesium oxide (MgO) is an ...interesting alternative since it possesses broad-spectrum antibacterial activity. Additionally, magnesium ions also play a role in bone regeneration, which makes MgO more appealing than other metal oxides. Therefore, a bone substitute composed of hydroxyapatite and MgO (HAp/MgO) spherical granules was developed using different sintering heat-treatment cycles to optimize its features. Depending on the sintering temperature, HAp/MgO spherical granules exhibited distinct surface topographies, mechanical strength and degradation profiles, that influenced the in vitro antibacterial activity and cytocompatibility. A proper balance between antibacterial activity and cytocompatibility was achieved with HAp/MgO spherical granules sintered at 1100 ºC. The presence of MgO in these granules was able to significantly reduce bacterial proliferation and simultaneously provide a suitable environment for osteoblasts growth. The angiogenic and inflammation potentials were also assessed using the in vivo chicken embryo chorioallantoic membrane (CAM) model and the spherical granules containing MgO stimulated angiogenesis without increasing inflammation. The outcomes of this study evidence a dual effect of MgO for bone regenerative applications making this material a promising antibacterial bone substitute.
We sought to determine whether high-dose folinic acid improves verbal communication in children with non-syndromic autism spectrum disorder (ASD) and language impairment in a double-blind placebo ...control setting. Forty-eight children (mean age 7 years 4 months; 82% male) with ASD and language impairment were randomized to receive 12 weeks of high-dose folinic acid (2 mg kg
per day, maximum 50 mg per day; n=23) or placebo (n=25). Children were subtyped by glutathione and folate receptor-α autoantibody (FRAA) status. Improvement in verbal communication, as measured by a ability-appropriate standardized instrument, was significantly greater in participants receiving folinic acid as compared with those receiving placebo, resulting in an effect of 5.7 (1.0,10.4) standardized points with a medium-to-large effect size (Cohen's d=0.70). FRAA status was predictive of response to treatment. For FRAA-positive participants, improvement in verbal communication was significantly greater in those receiving folinic acid as compared with those receiving placebo, resulting in an effect of 7.3 (1.4,13.2) standardized points with a large effect size (Cohen's d=0.91), indicating that folinic acid treatment may be more efficacious in children with ASD who are FRAA positive. Improvements in subscales of the Vineland Adaptive Behavior Scale, the Aberrant Behavior Checklist, the Autism Symptom Questionnaire and the Behavioral Assessment System for Children were significantly greater in the folinic acid group as compared with the placebo group. There was no significant difference in adverse effects between treatment groups. Thus, in this small trial of children with non-syndromic ASD and language impairment, treatment with high-dose folinic acid for 12 weeks resulted in improvement in verbal communication as compared with placebo, particularly in those participants who were positive for FRAAs.
•Accurate 1D model for Earth-air heat exchangers considering multi-layered soils.•Numerical comparisons among different models.•Parameter variation analysis increasing annual efficiency close to ...90%.•Achieving magnitude peaks of 5°C in thermal potential for South Brazil at low depths.
Earth-air heat exchangers (EAHE) represent a sustainable way to explore the soil to heat or cool buildings. Due to the Earth's thermal inertia, its superficial layers can be used as a heat source or sink, respectively, in the winter or summer. Hence, the EAHE employ buried ducts where the air is forced to flow and exchange heat with the soil. Such devices demand little energy, as they can use low powered fans or passive techniques for natural convection. Recurrent issues in the literature of EAHE explore how to improve their performances by analyzing their operational parameters; soil, climate, and global economic prospects; the development and validation of complete or simplified simulation models. This paper presents parameter analysis of EAHE to increase their thermal potentials (which is also related to the efficiency and the prospects for thermal comfort) and the heat exchanges (linked with the economy) considering a Brazilian city in a subtropical climate. The research uses simulations based on a validated 1D model. It is compared with three others, including 3D ones, giving more accurate results. Unlike most works covering 1D models, the methodology proposed here allows the study of multi-layered soils. After assessing the soil temperature variations, the results point out that most of the local thermal potential is attainable at relatively low depths, with magnitude peaks of 5°C. The parameter analyses are focused on this target potential, addressing changes in the airspeed, length, and diameter of the ducts. For all cases, the goal was achieved, allowing to obtain annual efficiencies close to 90%. However, only the tests increasing the length also increased the quantity of heat exchanged (in about 20%) and, consequently, proved to be economically affordable.
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